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Epidermolysis bullosa simplex, autosomal recessive K14 (EBS-AR KRT14) is a basal subtype of epidermolysis bullosa simplex (EBS) characterized by generalized or, less frequently, localized acral blistering.
## Epidemiology
Prevalence is unknown but 19 cases have been reported to date.
## Clinical description
Onset of the disease is usually at birth. Milia are rare but atrophic scarring and dystrophic nails usually occur, along with focal keratoderma (palms and soles) and, rarely, ichthyotic plaques. Extracutaneous involvement is common, including anemia, growth retardation, oral cavity abnormalities (blisters and erosions, and caries) and constipation.
## Etiology
EBS-AR KRT14 is due to mutations in the KRT14 gene (17q12-q21), encoding keratin 14.
## Genetic counseling
Transmission is autosomal recessive.
## Prognosis
The disease is frequently associated with significant morbidity, but life-expectancy is normal.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Epidermolysis bullosa simplex, autosomal recessive K14 | c3715082 | 4,900 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=89838 | 2021-01-23T19:02:40 | {"omim": ["601001"], "icd-10": ["Q81.0"], "synonyms": ["EBS, autosomal recessive K14", "EBS-AR KRT14", "KRT14-related autosomal recessive EBS", "KRT14-related autosomal recessive epidermolysis bullosa simplex"]} |
Sever's disease
Other namesApophysitis of the Calcaneus
X-ray of the foot of an 11-year-old child,showing sclerosis and fragmentation of the calcaneal apophysis. This is a sign of low sensitivity and specificity of Sever's disease, because those with Sever's disease may not have it, and it is commonly present in feet without any symptoms.[1]
SpecialtyRheumatology
SymptomsPain in the heel
Diagnostic methodclinical, imaging (xray)
Sever's Disease, otherwise known as apophysitis of the calcaneus, is an inflammation of the growth plate in the heel of growing children. The condition presents as pain in the heel and is caused by repetitive stress to the heel and is thus particularly common in active children. It usually resolves when the bone has completed growth or activity is lessened. The pain can be eased through stretching.
## Contents
* 1 Symptoms
* 2 Cause
* 3 Prevention
* 4 Treatment
* 5 Recovery
* 6 Eponym
* 7 See also
* 8 References
* 8.1 Further reading
* 9 External links
## Symptoms[edit]
The most prominent symptom of Sever's disease is heel pain which is usually aggravated by physical activity such as walking, running or jumping. The pain is localised to the posterior and plantar side of the heel over the calcaneal apophysis. Sometimes, the pain may be so severe that it may cause limping and interfere with physical performance in sports. External appearance of the heel is almost always normal, and signs of local disease such as edema, erythema (redness) are absent. The main diagnostic tool is pain on medial-lateral compression of the calcaneus in the area of growth plate, the so-called “squeeze test.” Foot radiographs are usually normal. Therefore, the diagnosis of Sever's disease is primarily clinical.[2]
## Cause[edit]
Sever's disease is directly related to overuse of the bone and tendons in the heel. This can come from playing sports or anything that involves a lot of heel movement. It can be associated with starting a new sport, or the start of a new season. Children who are going through adolescence are also at risk of getting it because the heel bone grows quicker than the leg.[3][4] Bearing too much weight on the heel can also cause it, as can excessive traction since the bones and tendons are still developing. It occurs more commonly in children who over-pronate, and involves both heels in more than half of patients. It is the equivalent of Osgood Schlatter disease of the knee.
## Prevention[edit]
* Maintain good flexibility through stretching exercises
* Avoid excessive running on hard surfaces
* Use quality, well-fitting shoes with firm support and a shock-absorbent sole
## Treatment[edit]
Treatment may consist of one or more of the following:
* Elevating the heel
* Stretching hamstring and calf muscles 2–3 times daily
* Using R.I.C.E. (Rest, Ice, Compression, Elevation)[5]
* Foot orthotics
* Medication
* Physical therapy
* Icing daily (morning)
* Heating therapy
* Avoiding high-heeled shoes
## Recovery[edit]
Sever's disease is self-recovering, meaning that it will go away on its own when the foot is used less or when the bone is through growing. The condition is not expected to create any long-term disability, and expected to subside in 2 or more weeks.[5] Some orthopedic surgeons will put the affected foot in a cast to immobilize it.
While symptoms can resolve quickly, they can recur. Sever's disease is more common in boys than girls; the average age of symptom onset is nine to eleven years.
## Eponym[edit]
It is named for James Warren Sever (1878–1964), an American orthopedic doctor, who described it in 1912.[6] Sever had "The Principles of Orthopaedic Surgery" published in 1940 through the Macmillan Company.
## See also[edit]
* List of childhood diseases
## References[edit]
1. ^ Mark A Noffsinger (2016-09-07). "Calcaneal Apophysitis (Sever Disease) Workup". Medscape. Retrieved 2017-01-19.
2. ^ Kose, Ozkan (2010). "Do we really need radiographic assessment for the diagnosis of non-specific heel pain (calcaneal apophysitis) in children?". Skeletal Radiology. 39 (4): 359–361. doi:10.1007/s00256-009-0774-y. PMID 19672591. S2CID 19889365.
3. ^ "Sever's Disease". Kidshealth.org. Retrieved 2014-04-29.
4. ^ Hendrix CL (2005). "Calcaneal apophysitis (Sever disease)". Clinics in Podiatric Medicine and Surgery. 22 (1): 55–62, vi. doi:10.1016/j.cpm.2004.08.011. PMID 15555843.
5. ^ a b Madden CC, Mellion MB (1996). "Sever's disease and other causes of heel pain in adolescents". American Family Physician. 54 (6): 1995–2000. PMID 8900359.
6. ^ "Sever disease - definition of Sever disease in the medical dictionary - by the Free Online Medical Dictionary, Thesaurus and Encyclopedia". Medical-dictionary.thefreedictionary.com. Retrieved 2014-04-29.
### Further reading[edit]
* Micheli LJ, Ireland ML (1987). "Prevention and management of calcaneal apophysitis in children: an overuse syndrome". J Pediatr Orthop. 7 (1): 34–8. doi:10.1097/01241398-198701000-00007. PMID 3793908. S2CID 762007.
* Bailey, Christopher; Cannon, Mary (May 2014). "Sever Disease (Calcaneal Apophysitis)". The Journal of the American Osteopathic Association. 114 (5): 411. doi:10.7556/jaoa.2014.081. PMID 24778005.
* Foot Physicians - Pediatric Heel Pain
## External links[edit]
Classification
D
* ICD-10: M92.6
* ICD-9-CM: 732.5
* v
* t
* e
Bone and joint disease
Bone
Inflammation
endocrine:
* Osteitis fibrosa cystica
* Brown tumor
infection:
* Osteomyelitis
* Sequestrum
* Involucrum
* Sesamoiditis
* Brodie abscess
* Periostitis
* Vertebral osteomyelitis
Metabolic
* Bone density
* Osteoporosis
* Juvenile
* Osteopenia
* Osteomalacia
* Paget's disease of bone
* Hypophosphatasia
Bone resorption
* Osteolysis
* Hajdu–Cheney syndrome
* Ainhum
* Gorham's disease
Other
* Ischaemia
* Avascular necrosis
* Osteonecrosis of the jaw
* Complex regional pain syndrome
* Hypertrophic pulmonary osteoarthropathy
* Nonossifying fibroma
* Pseudarthrosis
* Stress fracture
* Fibrous dysplasia
* Monostotic
* Polyostotic
* Skeletal fluorosis
* bone cyst
* Aneurysmal bone cyst
* Hyperostosis
* Infantile cortical hyperostosis
* Osteosclerosis
* Melorheostosis
* Pycnodysostosis
Joint
Chondritis
* Relapsing polychondritis
Other
* Tietze's syndrome
Combined
Osteochondritis
* Osteochondritis dissecans
Child
leg:
* hip
* Legg–Calvé–Perthes syndrome
* tibia
* Osgood–Schlatter disease
* Blount's disease
* foot
* Köhler disease
* Sever's disease
spine
* * Scheuermann's_disease
arm:
* wrist
* Kienböck's disease
* elbow
* Panner disease
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Sever's disease | c0264097 | 4,901 | wikipedia | https://en.wikipedia.org/wiki/Sever%27s_disease | 2021-01-18T18:55:40 | {"icd-10": ["M92.6"], "wikidata": ["Q1415326"]} |
An autosomal dominant cerebellar ataxia type 1 that is characterized by the adult-onset of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor of hands, hyperreflexia and spasmodic torticollis.
## Epidemiology
Spinocerebellar ataxia type 35 (SCA35) has been reported worldwide in less than 30 cases to date.
## Clinical description
Disease onset occurs in adulthood with manifestations of progressive gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses (Babinski sign), reduced proprioception, and hyperreflexia. Cognitive impairment is rare. Patients are usually wheelchair bound 10 years or more after the onset of symptoms. Head MRI shows diffuse cerebellar atrophy without involvement of the brainstem.
## Etiology
SCA35 is caused by a mutation in the TGM6 gene (20p13) encoding transglutaminase 6 (TG6), a member of the transglutaminase family of enzymes. TG6 is expressed in the kidney, skin, eyes and neurons but the exact process that leads to SCA35 is unknown.
## Diagnostic methods
Diagnosis is based on the characteristic clinical findings and molecular genetic testing. As the manifestations of SCA35 are not specific, diagnosis is only confirmed with the finding of a mutation in the TGM6 gene.
## Differential diagnosis
Differential diagnosis includes other types of ADCA.
## Antenatal diagnosis
Antenatal diagnosis is possible in families with a known mutation.
## Genetic counseling
SCA35 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
## Management and treatment
There is no cure for SCA35 and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.
## Prognosis
SCA35 is slowly progressive disease, and most of reported patients are usually wheelchair bound 10 years or more after the onset of symptoms.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Spinocerebellar ataxia type 35 | c3888031 | 4,902 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=276193 | 2021-01-23T17:28:45 | {"gard": ["12366"], "omim": ["613908"], "icd-10": ["G11.8"], "synonyms": ["SCA35"]} |
This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.
## Epidemiology
It has been described in two males.
## Clinical description
Additional features included bilateral inguinal hernias, undescended testes, and impaired vision with cataracts and colobomata.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome | c1863878 | 4,903 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2250 | 2021-01-23T18:40:42 | {"mesh": ["C537429"], "omim": ["603457"], "icd-10": ["Q87.0"], "synonyms": ["Bosma arhinia-microphthalmia syndrome", "Bosma-Henkin-Christiansen syndrome"]} |
A rare genetic endocrine disease characterized by intrauterine growth restriction, failure of an adolescent growth spurt with proportional adult short stature, insulin resistance, and early adulthood-onset diabetes. Minimal subluxation of the fifth metacarpal-phalangeal joint has been reported, while metaphyseal dysplasia is absent. Testicular volume is low, but fertility is normal. There is no evidence of primary adrenal insufficiency.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Intrauterine growth restriction-short stature-early adult-onset diabetes syndrome | None | 4,904 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=436144 | 2021-01-23T17:33:50 | {"icd-10": ["Q87.1"]} |
Bare lymphocyte syndrome
SpecialtyHematology
Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency.[1]
## Contents
* 1 Presentation
* 2 Symptoms
* 3 Genetics
* 3.1 BLS II
* 3.2 BLS I
* 4 Diagnosis
* 4.1 Classification
* 5 Treatment
* 6 References
* 7 External links
## Presentation[edit]
The bare lymphocyte syndrome, type II (BLS II) is a rare recessive genetic condition in which a group of genes called major histocompatibility complex class II (MHC class II) are not expressed.
The result is that the immune system is severely compromised and cannot effectively fight infection. Clinically, this is similar to severe combined immunodeficiency (SCID), in which lymphocyte precursor cells are improperly formed. As a notable contrast, however, bare lymphocyte syndrome does not result in decreased B- and T-cell counts, as the development of these cells is not impaired.
## Symptoms[edit]
TAP deficiency syndrome is the best characterized of BLS I.[2] Symptoms can include recurrent bacterial infections of the respiratory tract and chronic skin lesions. Bronchiectasis and respiratory failure and complete destruction of the nose and cerebral abscess are severe complications.[2]
Diarrhea can be among the associated conditions.[3]
## Genetics[edit]
### BLS II[edit]
The genetic basis for BLSII is not due to defects in the MHC II genes themselves. The genetic basis is the result of mutations in genes that code for proteins (transcription factors) that normally regulate the expression (gene transcription) of the MHC II genes. That is, one of the several proteins that are required to switch on MHC II genes in various cells types (primarily those in the immune system) is absent. The genes responsible were cloned by the laboratories of Bernard Mach[4] in Switzerland and Jeremy Boss[5] at Emory University in Atlanta, Georgia.
Mutation in any one of four genes can lead to BLS II. The genes' names are:
* class II trans-activator (CIITA)
* regulatory factor of the Xbox 5 (RFX5)
* RFX-associated protein (RFXAP)
* RFX ankyrin repeats (RFXANK; also known as RFXB)
### BLS I[edit]
BLS I, also called "HLA class I deficiency", which is much more rare, is associated with TAP2, TAP1, or TAPBP deficiencies.[6] The TAP proteins are involved in pumping degraded cytosolic peptides across the endoplasmic reticulum membrane so they can bind HLA class I. Once the peptide:HLA class I complex forms, it is transported to the membrane of the cell. However, a defect in the TAP proteins prevents pumping of peptides into the endoplasmic reticulum so no peptide:HLA class I complexes form, and therefore, no HLA class I is expressed on the membrane. Just like BLS II, the defect isn't in the MHC protein, but rather another accessory protein.
## Diagnosis[edit]
### Classification[edit]
* Type 1: MHC class I
* Type 2: MHC class II
## Treatment[edit]
Though BLSII is an attractive candidate for gene therapy, bone marrow transplant is currently the only treatment.
## References[edit]
1. ^ DeSandro AM, Nagarajan UM, Boss JM (September 2000). "Associations and interactions between bare lymphocyte syndrome factors". Mol. Cell. Biol. 20 (17): 6587–99. doi:10.1128/MCB.20.17.6587-6599.2000. PMC 86141. PMID 10938133.
2. ^ a b Gadola, S. D.; Moins-Teisserenc, H. T.; Trowsdale, J.; Gross, W. L.; Cerundolo, V. (August 2000). "TAP deficiency syndrome. IMMUNODEFICIENCY REVIEW". Clinical and Experimental Immunology. 121 (2): 173–178. doi:10.1046/j.1365-2249.2000.01264.x. ISSN 0009-9104. PMC 1905688. PMID 10931128.
3. ^ "Immunologic Disease and Disorders". Archived from the original on 2007-02-17.
4. ^ Reith W, Mach B (2001). "The bare lymphocyte syndrome and the regulation of MHC expression". Annu. Rev. Immunol. 19: 331–73. doi:10.1146/annurev.immunol.19.1.331. PMID 11244040.
5. ^ DeSandro A, Nagarajan UM, Boss JM (1999). "The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes". Am. J. Hum. Genet. 65 (2): 279–86. doi:10.1086/302519. PMC 1377925. PMID 10417269.
6. ^ Online Mendelian Inheritance in Man (OMIM): 604571
## External links[edit]
Classification
D
* ICD-10: D81.6
* OMIM: 604571 209920
* MeSH: D016511
* DiseasesDB: 29570
* v
* t
* e
Lymphoid and complement disorders causing immunodeficiency
Primary
Antibody/humoral
(B)
Hypogammaglobulinemia
* X-linked agammaglobulinemia
* Transient hypogammaglobulinemia of infancy
Dysgammaglobulinemia
* IgA deficiency
* IgG deficiency
* IgM deficiency
* Hyper IgM syndrome (1
* 2
* 3
* 4
* 5)
* Wiskott–Aldrich syndrome
* Hyper-IgE syndrome
Other
* Common variable immunodeficiency
* ICF syndrome
T cell deficiency
(T)
* thymic hypoplasia: hypoparathyroid (Di George's syndrome)
* euparathyroid (Nezelof syndrome
* Ataxia–telangiectasia)
peripheral: Purine nucleoside phosphorylase deficiency
* Hyper IgM syndrome (1)
Severe combined
(B+T)
* x-linked: X-SCID
autosomal: Adenosine deaminase deficiency
* Omenn syndrome
* ZAP70 deficiency
* Bare lymphocyte syndrome
Acquired
* HIV/AIDS
Leukopenia:
Lymphocytopenia
* Idiopathic CD4+ lymphocytopenia
Complement
deficiency
* C1-inhibitor (Angioedema/Hereditary angioedema)
* Complement 2 deficiency/Complement 4 deficiency
* MBL deficiency
* Properdin deficiency
* Complement 3 deficiency
* Terminal complement pathway deficiency
* Paroxysmal nocturnal hemoglobinuria
* Complement receptor deficiency
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Bare lymphocyte syndrome | c0242583 | 4,905 | wikipedia | https://en.wikipedia.org/wiki/Bare_lymphocyte_syndrome | 2021-01-18T18:44:29 | {"gard": ["8427"], "mesh": ["D016511"], "icd-10": ["D81.6"], "wikidata": ["Q3508735"]} |
Non-amyloid fibrillary glomerulopathy (non-amyloid FGP) is a rare cause of glomerulonephritis (GN) characterized by glomerular accumulation of non-amyloid fibrils in the mesangium and the glomerular (and rarely tubular) basement membrane, that mainly presents with renal insufficiency, micro-hematuria and nephrotic range proteinuria. Non-amyloid FGP and immunotactoid glomerulopathy (ITG, see this term) are often grouped together as pathogenetically related diseases.
## Epidemiology
Non-amyloid FGP is encountered in approximately 0.5 to 1.0% of native kidney biopsies. A peak of occurrence between the fifth and sixth decades of life is observed. Females are slightly more affected than men, and the disease mainly affects the Caucasian population.
## Clinical description
The disease is characterized by subnephrotic or nephrotic range proteinuria, frequently associated with macro- or microscopic hematuria, hypertension and renal insufficiency. Patients present with edema, ascites, pleural effusion and an elevated risk of blood clots and infection.
## Etiology
Non-amyloid FGP etiology is unknown. The disease is generally considered idiopathic but it may be associated with secondary causes such as a monoclonal (mainly immunoglobulin G4; IgG4) or oligoclonal (containing both IgG1 and IgG4) gammopathy, hepatitis B and C infections, autoimmune diseases and malignancies.
## Diagnostic methods
The diagnosis of non-amyloid FGP is based on the biopsy specimen's absence of reactivity with Congo red and other agents typically used for the histochemical demonstration of amyloid tissues (i.e. Thioflavin T), as well as observation on light, fluorescence and electron microscopy. Crescents may be present, sometimes associated with crescentic fibrillary GN (FGN). Common histological patterns include those of a membranoproliferative GN, mesangial proliferative GN, diffuse proliferative GN with endocapillary exudation, sclerosing GN or membranous thickening of the capillary tufts. At the ultrastructural level, glomerular structures are infiltrated by amorphous acellular material composed of randomly arranged, non-branching fibrils, around twice the size of amyloid fibrils, and with no apparent lumen. Fibrillary deposits usually consist of polyclonal IgG and complement component 3. Granular electron-dense deposits may also be present and admixed among the accumulations of fibrils. Other laboratory features may include low serum albumin and an increase in creatinine and blood cholesterol.
## Differential diagnosis
Differential diagnosis includes amyloidosis, ITG (see these terms) and the immune deposits seen in lupus nephritis (lupus membranous GN).
## Management and treatment
Different therapeutic strategies have been reported for the disease, but treatment options are still not defined. The treatment of nephrotic syndrome is based on prednisone, alone in patients with preserved renal function, or associated with cyclophosphamide in cases with crescentic FGN. Clinical trial data demonstrated the association of rituximab with a decrease of proteinuria and a possible role of rituximab in preventing or slowing the progression of renal disease in patients with preserved renal function has been hypothesized.
## Prognosis
Despite treatment, non-amyloid FGP prognosis remains poor, with progression to end-stage renal failure occurring within a few months to a few years in about half of patients. Fibril deposition may recur in transplanted allografts but the recurrent disease has a relatively benign course.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Non-amyloid fibrillary glomerulopathy | c4273674 | 4,906 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97566 | 2021-01-23T17:48:57 | {"gard": ["12740"], "icd-10": ["N03.6"], "synonyms": ["Congo red-negative amyloidosis-like glomerulopathy", "Non-amyloid fibrillary glomerulonephritis"]} |
Hemicrania continua
SpecialtyNeurology
Hemicrania continua (HC) is a persistent unilateral headache that responds to indomethacin. It is usually unremitting, but rare cases of remission have been documented.[1] Hemicrania continua is considered a primary headache disorder, meaning that it is not caused by another condition.
## Contents
* 1 Symptoms
* 2 Cause
* 3 Diagnosis
* 3.1 Differential diagnosis
* 3.2 Classification
* 4 Treatment
* 5 Epidemiology
* 6 References
* 7 External links
## Symptoms[edit]
In addition to persistent daily headache of HC, which is usually mild to moderate (and frequently severe), HC can present other symptoms.[2] These additional symptoms of HC can be divided into three main categories:
1. Autonomic symptoms:
* conjunctival injection
* tearing
* rhinorrhea
* nasal stuffiness
* eyelid edema
* forehead sweating
2. Stabbing headaches:
* Short, "jabbing" headaches superimposed over the persistent daily headache.
* Usually lasting less than one minute.
3. Migrainous features:
* throbbing pain
* nausea and/or vomiting
* phonophobia
* photophobia
## Cause[edit]
The cause of hemicrania continua is unknown.[citation needed]
## Diagnosis[edit]
The following diagnostic criteria are given for hemicrania continua:[3]
1. Headache for more than 3 months fulfilling other 3 criteria:
2. All of the following characteristics:
* Unilateral pain without side-shift
* Daily and continuous, without pain-free periods
* Moderate intensity, but with exacerbations of severe pain
3. At least one of the following autonomic features occurs during exacerbations and ipsilateral to the side of pain:
* Conjunctival injection and/or lacrimation
* Nasal congestion and/or rhinorrhea
* Ptosis and/or miosis
4. Complete response to therapeutic doses of indomethacin, although cases of hemicrania continua that do not resolve with indomethacin treatment have been documented.[4]
A variant on hemicrania continua has also been described, in which the attacks may shift sides, although meeting the above criteria in all other respects.[5][6][7][8]
There is no definitive diagnostic test for hemicrania continua. Diagnostic tests such as imaging studies may be ordered to rule out other causes for the headache. When the symptoms of hemicrania continua are present, it's considered "diagnostic" if they respond completely to indomethacin. The efficacy of indomethacin may not be long term for all patients, as can eventually become ineffective.[citation needed]
### Differential diagnosis[edit]
The factor that allows hemicrania continua and its exacerbations to be differentiated from migraine and cluster headache is that hemicrania continua is completely responsive to indomethacin. Triptans and other abortive medications do not affect hemicrania continua.[citation needed]
### Classification[edit]
The International Headache Society's International Classification of Headache Disorders classifies hemicrania continua as a primary headache disorder.[3]
## Treatment[edit]
Hemicrania continua generally responds only to indomethacin 25–300 mg daily, which must be continued long term. Unfortunately, gastrointestinal side effects are a common problem with indomethacin, which may require additional acid-suppression therapy to control.[9]
In patients who are unable to tolerate indomethacin, the use of celecoxib 400–800 mg per day (Celebrex) and rofecoxib 50 mg per day (Vioxx - no longer available) have both been shown to be effective and are likely to be associated with fewer GI side effects.[10] There have also been reports of two patients who were successfully managed with topiramate 100–200 mg per day (Topamax) although side effects with this treatment can also prove problematic.[8][11]
Greater occipital nerve (GON) block comprising 40 mg Depomedrone and 10 mls of 1% Lignocaine injected into the affected nerve is effective, up to a period of approximately three months. Changing the 'cocktail' to include (for example) 10 mls of .5% Marcaine and changing to 2% Lignocaine, whilst in theory should increase the longevity, renders the injection completely ineffective. See 4.2 Posology and method of administration (flocculation).[12][13]
Occipital nerve stimulation may be highly effective when other treatments fail to relieve the intractable pain.[14]
## Epidemiology[edit]
Hemicrania was mentioned in 1881 in The Therapeutic Gazette Vol. 2, by G.S.Davis,[15] and the incident has been cited in King's American Dispensatory (1898 and later editions)[16] in the description of the strong analgesic Jamaican Dogwood, a relatively low dose of which reportedly produced convulsions and prolonged respiratory depression over six hours in an elderly woman with this condition.[citation needed]
In newer times, Hemicrania continua was described in 1981;[17] at that time around 130 cases were described in the literature.[17] However, rising awareness of the condition has led to increasingly frequent diagnosis in headache clinics, and it seems that it is not as rare as these figures would imply. The condition occurs more often in women than men and tends to present first in adulthood, although it has also been reported in children as young as 5 years old.[18]
## References[edit]
1. ^ Mark Thompson, "Hemicrania Continua"
2. ^ Goadsby P, Silberstein S, Dodick D (205). Chronic Daily Headache for clinicians. B C Decker Inc. p. 220. ISBN 978-1-55009-265-3.
3. ^ a b "The International Classification of Headache Disorders 2nd Edition (ICHD-2)" (PDF). the Headache Classification Subcommittee of the International Headache Society. Retrieved 2012-09-22.
4. ^ Prakash, S; Shah, N. D.; Bhanvadia, R. J. (2009). "Hemicrania continua unresponsive or partially responsive to indomethacin: Does it exist? A diagnostic and therapeutic dilemma". The Journal of Headache and Pain. 10 (1): 59–63. doi:10.1007/s10194-008-0088-9. PMC 3451756. PMID 19096758.
5. ^ Newman LC, Lipton RB, Russell M, Solomon S (1992). "Hemicrania continua: attacks may alternate sides". Headache. 32 (5): 237–8. doi:10.1111/j.1526-4610.1992.hed3205237.x. PMID 1628961.
6. ^ Marano E, Giampiero V, Gennaro DR, di Stasio E, Bonusa S, Sorge F (1994). ""Hemicrania continua": a possible case with alternating sides". Cephalalgia. 14 (4): 307–8. doi:10.1046/j.1468-2982.1994.1404305-4.x. PMID 7954766.
7. ^ Newman LC, Spears RC, Lay CL (2004). "Hemicrania continua: a third case in which attacks alternate sides". Headache. 44 (8): 821–3. doi:10.1111/j.1526-4610.2004.04153.x. PMID 15330832.
8. ^ a b Matharu MS, Bradbury P, Swash M (2006). "Hemicrania continua: side alternation and response to topiramate". Cephalalgia. 26 (3): 341–4. doi:10.1111/j.1468-2982.2005.01034.x. PMID 16472344.
9. ^ Pareja JA, Caminero AB, Franco E, Casado JL, Pascual J, Sánchez del Río M (2001). "Dose, efficacy and tolerability of long-term indomethacin treatment of chronic paroxysmal hemicrania and hemicrania continua". Cephalalgia: An International Journal of Headache. 21 (9): 906–10. doi:10.1046/j.1468-2982.2001.00287.x. PMID 11903285.
10. ^ Peres MF, Silberstein SD (2002). "Hemicrania continua responds to cyclooxygenase-2 inhibitors". Headache. 42 (6): 530–1. doi:10.1046/j.1526-4610.2002.02131.x. PMID 12167145.
11. ^ Brighina F, Palermo A, Cosentino G, Fierro B (2007). "Prophylaxis of hemicrania continua: two new cases effectively treated with topiramate". Headache. 47 (3): 441–3. doi:10.1111/j.1526-4610.2007.00733.x. PMID 17371364.
12. ^ DEPO-MEDRONE WITH LIDOCAINE INJECTION
13. ^ Blumenfeld, Andrew; Ashkenazi, Avi; Napchan, Uri; Bender, Steven D.; Klein, Brad C.; Berliner, Randall; Ailani, Jessica; Schim, Jack; Friedman, Deborah I.; Charleston, Larry; Young, William B.; Robertson, Carrie E.; Dodick, David W.; Silberstein, Stephen D.; Robbins, Matthew S. (1 March 2013). "Expert Consensus Recommendations for the Performance of Peripheral Nerve Blocks for Headaches – A Narrative Review". Headache: The Journal of Head and Face Pain. 53 (3): 437–446. doi:10.1111/head.12053. PMID 23406160.
14. ^ "- MDedge - Neurology Reviews". www.neurologyreviews.com.
15. ^ Davis, G.S. (1881). The Therapeutic Gazette, Volume 2. p. 54.
16. ^ King; Felter; Lloyd, John; Harvey Wickes; John Uri (1898). King's American Dispensatory. Cincinnati: Ohio Valley Co. p. 1511.CS1 maint: multiple names: authors list (link)
17. ^ a b Medina JL, Diamond S (1981). "Cluster headache variant. Spectrum of a new headache syndrome". Arch. Neurol. 38 (11): 705–9. doi:10.1001/archneur.1981.00510110065010. PMID 7305699.
18. ^ Peres MF, Silberstein SD, Nahmias S, et al. (2001). "Hemicrania continua is not that rare". Neurology. 57 (6): 948–51. doi:10.1212/wnl.57.6.948. PMID 11577748.
## External links[edit]
Classification
D
* ICD-10: G44.8
* ICD-9-CM: 339.41
* v
* t
* e
Headache
Primary
ICHD 1
* Migraine
* Familial hemiplegic
* Retinal migraine
ICHD 2
* Tension
* Mixed tension migraine
ICHD 3
* Cluster
* Chronic paroxysmal hemicrania
* SUNCT
ICHD 4
* Hemicrania continua
* Thunderclap headache
* Sexual headache
* New daily persistent headache
* Hypnic headache
Secondary
ICHD 5
* Migralepsy
ICHD 7
* Ictal headache
* Post-dural-puncture headache
ICHD 8
* Hangover
* Medication overuse headache
ICHD 13
* Trigeminal neuralgia
* Occipital neuralgia
* External compression headache
* Cold-stimulus headache
* Optic neuritis
* Postherpetic neuralgia
* Tolosa–Hunt syndrome
Other
* Vascular
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Hemicrania continua | c2349425 | 4,907 | wikipedia | https://en.wikipedia.org/wiki/Hemicrania_continua | 2021-01-18T18:57:04 | {"gard": ["10795"], "icd-9": ["339.41"], "icd-10": ["G44.80"], "orphanet": ["443070"], "synonyms": [], "wikidata": ["Q973425"]} |
## Summary
### Clinical characteristics.
SLC39A14 deficiency is characterized by evidence between ages six months and three years of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance). Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have succumbed in their first decade due to secondary complications such as respiratory infections.
### Diagnosis/testing.
The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia-parkinsonism (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and biallelic pathogenic variants in SLC39A14 on molecular genetic testing.
### Management.
Treatment of manifestations: Symptomatic treatment includes physiotherapy and orthopedic management to prevent contractures and maintain ambulation; use of adaptive aids (walker or wheelchair) for gait abnormalities; and use of assistive communication devices. Support by a speech and language/feeding specialist and nutritionist to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Antispasticity medications (baclofen and botulinum toxin) and L-dopa have had limited success. While chelation therapy with intravenous administration of disodium calcium edetate early in the disease course shows promise, additional studies are warranted.
Prevention of primary manifestations: Unknown, but disodium calcium edetate chelation therapy shows promise; additional studies are warranted.
Surveillance: Routine monitoring of:
* Height and weight using age- and gender-appropriate growth charts;
* Swallowing and diet to assure adequate nutrition;
* Ambulation and speech;
* Whole-blood manganese levels and brain MRI to assess treatment response and disease progression.
Agents/circumstances to avoid:
* Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
* High manganese content of total parenteral nutrition
* Foods very high in manganese, including: cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds
Evaluation of relatives at risk: Molecular genetic testing for the familial SLC39A14 pathogenic variants of apparently asymptomatic younger sibs of an affected individual allows early identification of sibs who would benefit from prompt initiation of treatment and preventive measures.
### Genetic counseling.
SLC39A14 deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC39A14 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
## Diagnosis
### Suggestive Findings
SLC39A14 deficiency should be suspected in individuals with typical clinical, neuroimaging, and laboratory findings [Tuschl et al 2016]:
* Clinical findings. Infantile or early-childhood onset of:
* Delay in acquisition of developmental motor milestones or loss of developmental motor milestones;
* Progressive pharmaco-resistant dystonia;
* Parkinsonism signs (tremor, bradykinesia, hypomimia);
* Bulbar dysfunction;
* Dysarthria.
* Neuroimaging. Brain MRI findings characteristic of manganese deposition (Figure 1) including T1-weighted hyperintensity of the following:
* Globus pallidus and striatum, with thalamic sparing;
Note: Basal ganglia changes on T1-weighted imaging are accompanied by T2-weighted hypointensity.
* White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons;
* Anterior pituitary gland.
* Laboratory findings. Hypermanganesemia. Whole-blood manganese levels are markedly elevated, usually above 1,000 nmol/L (normal reference range <320 nmol/L).
#### Figure 1
A. Axial T1-weighted image showing the hyperintensity of the globus pallidus (white arrows), and the cerebral white matter (dashed arrows) B. Axial T2-weighted image showing the hypointensity of the globus pallidus (white arrows)
### Establishing the Diagnosis
The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and identification of biallelic pathogenic variants in SLC39A14 on molecular genetic testing [Tuschl et al 2016] (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SLC39A14 deficiency is likely to be broad, children with the suggestive clinical, laboratory, and neuroimaging findings could be diagnosed using gene-targeted testing (see Option 1), whereas those with early-onset dystonia-parkinsonism indistinguishable from other inherited disorders with parkinsonism-dystonia are more likely to be diagnosed using genomic testing (see Option 2).
#### Option 1
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of SLC39A14 deficiency, molecular genetic testing approaches can include single-gene testing and use of a multigene panel.
* Single-gene testing. Sequence analysis of SLC39A14 is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no exon or whole-gene deletions have been reported.
* A multigene panel that includes SLC39A14 and other genes of interest (see Differential Diagnosis) may also be considered.
Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
#### Option 2
When the phenotype is indistinguishable from other movement disorders, molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic sequencing; recommended) or gene-targeted testing (multigene panel; to consider).
* Recommended testing. Comprehensive genomic testing (when available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
* Testing to consider. A multigene panel that includes SLC39A14 and other genes of interest (see Differential Diagnosis) may be considered; however, given the rarity of SLC39A14 deficiency, many panels for inherited dystonia-parkinsonism and/or this complex neurologic phenotype may not include this gene. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
### Table 1.
Molecular Genetic Testing Used in SLC39A14 Deficiency
View in own window
Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
SLC39A14Sequence analysis 37/7 6
Gene-targeted deletion/duplication analysis 4None reported
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
6\.
Five reported consanguineous families [Tuschl et al 2016] and two other families, one consanguineous and one nonconsanguineous [Author, personal observation]
## Clinical Characteristics
### Clinical Description
SLC39A14 deficiency has only recently been identified in 11 individuals from seven families [Tuschl et al 2016; Author, personal observation]; therefore, information on the phenotypic spectrum and disease progression is limited.
Onset occurs between ages six months and three years. Affected children present with delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance).
Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor.
By the end of the first decade, they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, scoliosis, and loss of independent ambulation.
Although there appears to be relative cognitive sparing (psychometric testing has not been possible), a degree of learning disability is present in all children.
Some affected children succumb in their first decade due to secondary complications such as respiratory infections.
Neuropathology. The neuropathologic findings in one individual with SLC39A14 deficiency [Tuschl et al 2016] included:
* Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
* Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
* A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
### Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
### Prevalence
The disease prevalence is not established. To date only 11 individuals with SLC39A14 deficiency from seven families have been identified. These seven families are from different ethnic backgrounds and six are consanguineous [Tuschl et al 2016; Author, personal observation].
## Differential Diagnosis
### Table 2.
Disorders to Consider in the Differential Diagnosis of SLC39A14 Deficiency
View in own window
DisorderGene(s)MOIClinical Features of This Disorder
Overlapping w/SLC39A14 DeficiencyDistinguishing from SLC39A14 Deficiency
Disorders of manganese homeostasisDystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease (SLC30A10 deficiency)SLC30A10AR
* Dystonia-parkinsonism
* Hypermanganesemia
* Brain MRI features consistent w/manganese deposition
* Presents with polycythemia, abnormal iron indices, & liver disease in addition to the neurologic phenotype
* Absence of Mn deposition in the liver w/T1 hyperintensity on liver MRI
Acquired hypermanganesemia 1N/AN/A
* Often presents w/psychiatric symptoms
* History of Mn exposure from environmental sources, parenteral nutrition, or contaminated ephedrone preparations
Acquired hepatocerebral degeneration 2N/AN/A
* Liver disease is the predominant feature; it precedes development of neurologic symptoms.
Early-onset NBIA disorders (see NBIA Overview)PKANPANK2AR
* Parkinsonism-dystonia
* T2-weighted hypointensity of the globus pallidus on brain MRI
* Usually presents w/additional clinical features (e.g., pigmentary retinopathy, optic atrophy, oculomotor abnormalities, axonal neuropathy, cognitive decline, seizures)
* Lacks the T1-weighted hyperintensity of the globus pallidus on brain MRI due to Mn deposition
PLANPLA2G6AR
MPANC19orf12AR
BPANWDR45XL
FAHNFA2HAR
Kufor-Rakeb syndromeATP13A2AR
CoPANCOASYAR
Disorders of copper metabolismWilson diseaseATP7BAR
* Parkinsonism-dystonia
* Liver disease, psychiatric symptoms, low serum ceruloplasmin & high non-ceruloplasmin-bound serum copper
* No Mn deposition on brain MRI
Inherited forms of dystonia (see Dystonia Overview)DYT1 early-onset isolated dystoniaTOR1AAD
* Early-onset generalized dystonia
* No features consistent w/Mn deposition on brain MRI
* Absent hypermanganesemia
KMT2B-related early-onset dystoniaKMT2BAD
MECR-related childhood-onset dystonia and optic atrophy 3MECRAR
* Additional optic atrophy
* No features consistent w/Mn deposition on brain MRI
SLC6A3-related dopamine transporter deficiency syndromeSLC6A3AR
* Parkinsonism-dystonia
* No features consistent w/Mn deposition on brain MRI
Tyrosine hydroxylase-deficient dopa-responsive dystoniaTHAR
GTP cyclohydrolase 1-deficient dopa-responsive dystoniaGCH1AD
Sepiapterin reductase deficiency dopa-responsive dystoniaSPRAR
Inherited Forms of Parkinson Disease (see Parkinson Disease Overview)
Inherited neurodegenerative/metabolic disorders
(see Dystonia Overview, Table 4 for hereditary neurodegenerative or metabolic
disorders characterized by complex dystonia)
* Complex dystonia
* No features consistent w/Mn deposition on brain MRI
AD = autosomal dominant; AR = autosomal recessive; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; FAHN = fatty acid hydroxylase-associated neurodegeneration. Mn = manganese; MOI = mode of inheritance; MPAN = mitochondrial membrane protein-associated neurodegeneration; NBIA = neurodegeneration with brain iron accumulation; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = PLA2G6-associated neurodegeneration; XL = X-linked
1\.
Mortimer et al [2012], Santos et al [2014], Janocha-Litwin et al [2015]
2\.
Miletić et al [2014]
3\.
Heimer et al [2016]
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SLC39A14 deficiency, the following evaluations are recommended:
* Neurologic examination for dystonia, parkinsonism, and spasticity, including evaluation of ambulation and speech
* Assessment for physiotherapy, occupational therapy, and/or speech therapy
* Evaluation of swallowing and nutritional status
* Brain MRI, if not performed as part of the diagnostic evaluation
* Assessment of whole-blood manganese levels, if not performed as part of the diagnostic evaluation
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Symptomatic treatment. Early initiation of physiotherapy and orthopedic management aims to prevent contractures and maintain ambulation. As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.
Support by a speech and language/feeding specialist and nutritionist is indicated to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Gastric feeding tube and/or tracheostomy may be required to prevent aspiration pneumonia.
Note that symptomatic treatment with L-dopa and antispasticity medications including benzodiazepines, baclofen, and botulinum toxin has been attempted with limited success. There has been partial but poorly sustained response to trihexyphenidyl at high doses of 20 mg/day and intrathecal baclofen of 1,500-2,000 µg/day in two older sibs reported by Tuschl et al [2016].
Chelation therapy. Disodium calcium edetate, which primarily promotes the urinary excretion of manganese, was given intravenously (20 mg/kg/dose) twice daily for five days each month to a female age five years with SLC39A14 deficiency [Tuschl et al 2016]. After six months of treatment, neurologic manifestations improved and the child regained the ability to walk.
In contrast, treatment of a female age 17 years with advanced disease (severe generalized dystonia with prominent oromandibular involvement, contractures, and scoliosis) did not affect disease progression as she continued to deteriorate with worsening tremor and stiffness. Hence, it is likely necessary to initiate chelation treatment early in the disease course.
It is anticipated that chelation therapy will need to be lifelong.
Potential adverse effects of disodium calcium edetate chelation therapy include thrombocytopenia and leukopenia, nephrotoxicity, hepatoxicity, hypocalcemia, and trace metal and vitamin deficiencies [Lamas et al 2012]. Monitoring includes the following:
* Complete blood count
* Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
* Assessment of liver function
* Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
* Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
* Assessment of iron status
Treatment may need to be discontinued if:
* White blood count is <3.5x109/L
* Neutrophil count is <2.0x109/L
* Platelet count is <150x109/L
* >2+ proteinuria is detected on more than one occasion (with no evidence of infection)
The above cut-off values are based on guidelines for D-penicillamine treatment [Chakravarty et al 2008]. Because chelation treatment with disodium calcium edetate may prevent early death and reduce morbidity in SLC39A14 deficiency, lower cut-off values may be acceptable. For each affected individual, the benefits of clinical treatment need to be carefully weighed against the risk of adverse effects.
### Prevention of Primary Manifestations
Chelation therapy with disodium calcium edetate may prevent primary disease manifestations in affected sibs who are asymptomatic (see Treatment of Manifestations).
### Surveillance
Routine monitoring of:
* Height and weight using age and gender appropriate growth charts;
* Swallowing and diet to assure adequate nutrition;
* Ambulation and speech;
* Whole-blood manganese levels and brain MRI to assess treatment response and disease progression.
### Agents/Circumstances to Avoid
The following should be avoided:
* Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
* High manganese content of total parenteral nutrition
* Foods very high in manganese, including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
### Evaluation of Relatives at Risk
Molecular genetic testing of apparently asymptomatic younger sibs of an affected individual for the familial SLC39A14 pathogenic variants allows early identification of sibs who would benefit from prompt initiation of treatment and preventive measures (see Agents/Circumstances to Avoid).
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
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*[ND]: No data
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*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
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*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
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*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
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*[ITA]: Italy
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*[KAZ]: Kazakhstan
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*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
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*[GBR]: Great Britain
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*[BEL]: Belgium
*[CAN]: Canada
| SLC39A14 Deficiency | None | 4,908 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK431123/ | 2021-01-18T20:58:41 | {"synonyms": ["SLC39A14-Related Early-Onset Dystonia-Parkinsonism"]} |
Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of serious health problems, infants with achondrogenesis usually die before birth, are stillborn, or die soon after birth from respiratory failure. However, some infants have lived for a short time with intensive medical support.
Researchers have described at least three forms of achondrogenesis, designated as type 1A, type 1B, and type 2. The types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause. However, types 1A and 1B are often hard to tell apart without genetic testing.
Achondrogenesis type 1A, which is also called the Houston-Harris type, is the least well understood of the three forms. Affected infants have extremely short limbs, a narrow chest, short ribs that fracture easily, and a lack of normal bone formation (ossification) in the skull, spine, and pelvis.
Achondrogenesis type 1B, also known as the Parenti-Fraccaro type, is characterized by extremely short limbs, a narrow chest, and a prominent, rounded abdomen. The fingers and toes are short and the feet may turn inward and upward (clubfeet). Affected infants frequently have a soft out-pouching around the belly-button (an umbilical hernia) or near the groin (an inguinal hernia).
Infants with achondrogenesis type 2, which is sometimes called the Langer-Saldino type, have short arms and legs, a narrow chest with short ribs, and underdeveloped lungs. This condition is also associated with a lack of ossification in the spine and pelvis. Distinctive facial features include a prominent forehead, a small chin, and, in some cases, an opening in the roof of the mouth (a cleft palate). The abdomen is enlarged, and affected infants often have a condition called hydrops fetalis, in which excess fluid builds up in the body before birth.
## Frequency
Achondrogenesis types 1A and 1B are rare genetic disorders; their incidence is unknown. Combined, achondrogenesis type 2 and hypochondrogenesis (a similar skeletal disorder) occur in 1 in 40,000 to 60,000 newborns.
## Causes
Mutations in the TRIP11, SLC26A2, and COL2A1 genes cause achondrogenesis type 1A, type 1B, and type 2, respectively.
The genetic cause of achondrogenesis type 1A was unknown until recently, when researchers discovered that the condition can result from mutations in the TRIP11 gene. This gene provides instructions for making a protein called GMAP-210. This protein plays a critical role in the Golgi apparatus, a cell structure in which newly produced proteins are modified so they can carry out their functions. Mutations in the TRIP11 gene prevent the production of functional GMAP-210, which alters the structure and function of the Golgi apparatus. Researchers suspect that cells called chondrocytes in the developing skeleton may be most sensitive to these changes. Chondrocytes give rise to cartilage, a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears. Malfunction of the Golgi apparatus in chondrocytes likely underlies the problems with bone formation in achondrogenesis type 1A.
Achondrogenesis type 1B is the most severe of a spectrum of skeletal disorders caused by mutations in the SLC26A2 gene. This gene provides instructions for making a protein that is essential for the normal development of cartilage and for its conversion to bone. Mutations in the SLC26A2 gene cause the skeletal problems characteristic of achondrogenesis type 1B by disrupting the structure of developing cartilage, which prevents bones from forming properly.
Achondrogenesis type 2 is one of several skeletal disorders that result from mutations in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen. This type of collagen is found mostly in cartilage and in the clear gel that fills the eyeball (the vitreous). It is essential for the normal development of bones and other connective tissues that form the body's supportive framework. Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, which prevents bones and other connective tissues from developing properly.
### Learn more about the genes associated with Achondrogenesis
* COL2A1
* SLC26A2
* TRIP11
## Inheritance Pattern
Achondrogenesis type 1A and type 1B both have an autosomal recessive pattern of inheritance, which means both copies of the TRIP11 or SLC26A2 gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but do not show signs and symptoms of the condition.
Achondrogenesis type 2 is considered an autosomal dominant disorder because one copy of the altered gene in each cell is sufficient to cause the condition. It is almost always caused by new mutations in the COL2A1 gene and typically occurs in people with no history of the disorder in their family.
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
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*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
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| Achondrogenesis | c0265273 | 4,909 | medlineplus | https://medlineplus.gov/genetics/condition/achondrogenesis/ | 2021-01-27T08:24:47 | {"gard": ["2882"], "mesh": ["C536015"], "omim": ["200600", "600972", "200610"], "synonyms": []} |
A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-3 (DKCA3) is caused by heterozygous mutation in the TINF2 gene (604319) on chromosome 14q12.
Description
Dyskeratosis congenita is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals have an increased risk of aplastic anemia and malignancy. Less common features include epiphora, premature gray hair, microcephaly, developmental delay, and pulmonary fibrosis, among others. The phenotype is highly variable. All affected individuals have shortened telomeres due to a defect in telomere maintenance (summary by Savage et al., 2008).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DCKA1 (127550).
Clinical Features
Savage et al. (2008) reported a family with autosomal dominant DKC affecting 6 individuals, including 2 monozygotic male twins. Age at onset ranged from 10 to 31 years, and common clinical features included leukoplakia, nail dystrophy, and lacey reticular skin pigmentation. Three patients had severe aplastic anemia, and most had epiphora. One of the twins died at age 37 years from aplastic anemia and pulmonary hemorrhage, and the other died at age 43 of aplastic anemia, non-Hodgkin lymphoma, and pulmonary failure. Both of these individuals developed bilateral avascular necrosis of the hip.
Tsangaris et al. (2008) reported an 18-month-old girl with DKC who presented with pancytopenia and ataxia. Brain imaging showed cerebellar hypoplasia. She later developed a small area of leukoplakia but had no nail dystrophy or skin hyperpigmentation. Laboratory studies showed shortened telomeres and decreased telomerase activity (92.5% reduction compared to control values). The authors emphasized that DKC is a pleomorphic disorder and that ataxia can be an additional feature found in up to 6.8% of patients (Kirwan and Dokal, 2008). Tsangaris et al. (2008) noted that the combination of ataxia and pancytopenia without other typical features of DKC has been considered a distinct disorder (159550), but concluded that ataxia-pancytopenia is part of the phenotypic spectrum of DKC.
Walne et al. (2008) identified heterozygous mutations in the TINF2 gene in 33 (18.9%) of 175 cases of uncharacterized DKC. Most of the mutations were de novo. All the DKC patients with a TINF2 mutation had severe disease, with variable features of aplastic anemia, developmental delay, short stature, retinopathy, microcephaly, osteoporosis, cerebellar hypoplasia, alopecia, intracranial calcification, and dental loss.
Sasa et al. (2012) reported 2 unrelated patients with DKCA3 confirmed by genetic analysis (Q269X; 604319.0005 and Q271X; 604319.0007, respectively). One was a 4-year-old Hispanic boy who presented with pancytopenia and was found to have nail dystrophy, oral leukoplakia, and lacy hyperpigmentation of the neck and genital regions. He also had undescended testis and phimosis. Telomere flow-FISH analysis showed telomere lengths below the first percentile in all white blood cell subsets tested. He underwent hematopoietic stem cell transplantation. The second child was a Caucasian girl who presented at age 21 months with severe aplastic anemia and underwent hematopoietic stem cell transplantation. Subsequently, she developed skin hyperpigmentation, nail dystrophy, and oral leukoplakia, as well as epiphora, esophageal stricture, and osteopenia-related fractures. At age 10 years, she had progressive interstitial lung disease with fibrosis, gastrointestinal bleeding secondary to enteropathy, and noncirrhotic portal hypertension. She died at age 12 years from multiorgan failure.
Vulliamy et al. (2012) identified 16 new families with mutations in exon 6 of the TINF2 gene ascertained from 224 consecutive patients with different forms of bone marrow failure, including 46 with criteria meeting dyskeratosis congenita, 122 with aplastic anemia, and 57 with some features of DKC. Seven of the 46 patients with DKC carried TINF2 mutations, 5 of whom had the R252H mutation (604319.0002). Two of the DKC patients with the R252H mutation had a severe from of the disorder, with additional features including growth retardation, retinopathy, ataxia, developmental delay, and cerebellar hypoplasia, consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome. Nine of 57 patients with bone marrow failure and some features of DKC were found to carry mutations, including 2 with R282H, and 4 with nonsense or frameshift mutations (see, e.g., 604319.0005 and 604319.0008). Telomere length was only available for 7 of the mutation carriers, 6 of whom had shortened telomeres. The seventh patient had a missense variant that was also found in an asymptomatic individual, and both had normal telomere lengths, suggesting that this variant was not disease causing. Vulliamy et al. (2012) concluded that TINF2 mutations can cause a spectrum of clinical features and that telomere length should be able to distinguish pathogenic mutations from polymorphic variants in the absence of functional data. Most of the mutations appeared to occur de novo.
Molecular Genetics
Using a candidate gene approach with evidence for linkage to chromosome 14q11.2, Savage et al. (2008) identified a heterozygous missense mutation in the TINF2 gene (K280Q; 604319.0001) as the cause of dyskeratosis congenita in a family with autosomal dominant inheritance. The mutation was present only in individuals with telomere lengths below the first percentile for age. Subsequent screening of TINF2 in 8 molecularly uncharacterized probands with very short telomeres revealed mutations in 4. Three of these 4 probands carried the same mutation; all mutations were in extremely close proximity and near the end of the TRF1 (600951)-binding domain of the TIN2 protein.
Tsangaris et al. (2008) identified a de novo heterozygous mutation in the TINF2 gene (R282H; 604319.0002) in an 18-month-old girl with DKC who presented with pancytopenia and ataxia.
Walne et al. (2008) identified heterozygous mutations in the TINF2 gene in 33 (18.9%) of 175 cases of uncharacterized DKC. Of these 33 samples, 21 were found to have a mutation in arg282 in exon 6 (see, e.g., R282H, 604319.0002 and R282C, 604319.0004). The remaining 12 mutations were all in a tight cluster between residues 280 and 298. No additional mutations were found elsewhere in the gene. Most of the mutations were de novo. Clinically, all the DKC patients with a TINF2 mutation had severe disease associated with shorter telomeres compared to patients with DKC1 mutations (300126).
The 2 truncating mutations identified by Sasa et al. (2012) in 2 unrelated children with severe DKC (Q269X; 604319.0005 and Q271X; 604319.0007, respectively) both occurred in exon 6, but affected the more N-terminal region compared to earlier reported mutations and thus extended the affected segment of the gene to amino acid 269. In vitro functional expression studies in HEK293 cells showed that the Q269X mutant protein was markedly impaired in its ability to interact with TERF1 (600951). This was in contrast to R282H (604319.0002), which retained substantial ability to interact with TERF1. These findings indicated that disrupted TERF1 binding is not the main factor driving disease pathogenesis, but may contribute to a more severe phenotype.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Intrauterine growth retardation \- Poor growth HEAD & NECK Head \- Microcephaly Ears \- Deafness Eyes \- Blockage of the lacrimal ducts \- Epiphora \- Retinopathy Mouth \- Oral leukoplakia Teeth \- Tooth loss RESPIRATORY Lung \- Pulmonary fibrosis \- Pulmonary failure GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Osteoporosis Limbs \- Avascular necrosis of the hip (2 patients) SKIN, NAILS, & HAIR Skin \- Reticular pigmentation pattern \- Leukoplakia \- Dry skin Nails \- Dysplastic nails Hair \- Premature greying \- Short, fine hair \- Alopecia NEUROLOGIC Central Nervous System \- Speech delay \- Learning difficulties \- Intracranial calcifications \- Cerebellar hypoplasia \- Cerebellar ataxia HEMATOLOGY \- Bone marrow failure \- Pancytopenia \- Aplastic anemia \- Thrombocytopenia \- Leukopenia \- Increased fetal hemoglobin NEOPLASIA \- Increased risk of malignancy LABORATORY ABNORMALITIES \- Shortened telomeres \- Decreased telomerase activity MISCELLANEOUS \- Highly variable phenotype and severity, even within families \- Age at onset ranges from childhood to adulthood \- Phenotypic overlap with Revesz syndrome ( 268130 ) MOLECULAR BASIS \- Caused by mutation in the TRF1-interacting nuclear factor 2 gene (TINF2, 604319.0001 ) ▲ Close
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT 3 | c1846142 | 4,910 | omim | https://www.omim.org/entry/613990 | 2019-09-22T15:56:47 | {"doid": ["0070018"], "mesh": ["C536068"], "omim": ["613990"], "orphanet": ["3322", "1775"], "genereviews": ["NBK22301"]} |
Buchheit et al. (1969) described 2 sisters with idiopathic intracranial hypertension with papilledema (pseudotumor cerebri). Traviesa et al. (1976) described 3 affected sisters. The patients are typically young females who are obese and may be pregnant or suffering from chronic dysfunctional uterine bleeding. Johnston and Morgan (1991) described a mother and 2 of 4 daughters who had a diagnosis of pseudotumor cerebri and 1 son who developed communicating hydrocephalus.
Warner et al. (2002) quantified vitamin A in the cerebrospinal fluid of patients with idiopathic intracranial hypertension, elevated intracranial pressure of other causes, and normal intracranial pressure. Vitamin A could be detected by high-pressure liquid chromatography in most of the specimens. There was a significantly higher level of vitamin A in the cerebrospinal fluid of some patients with idiopathic intracranial hypertension. The authors concluded that vitamin A toxicity might play a role in the pathogenesis of idiopathic intracranial hypertension.
Katz et al. (2002) demonstrated the presence of both somatostatin receptor types 1 (182451) and 2 (182452) in all samples of normal human choroid plexus and arachnoid granulations. The authors proposed that these receptors might be involved in the processes of cerebrospinal fluid production and absorption and, thus, might play a role in the increased intracranial pressure of idiopathic intracranial hypertension.
HEENT \- Idiopathic intracranial hypertension \- Papilledema \- Pseudotumor cerebri Inheritance \- Autosomal recessive ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
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*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| INTRACRANIAL HYPERTENSION, IDIOPATHIC | c0033845 | 4,911 | omim | https://www.omim.org/entry/243200 | 2019-09-22T16:26:17 | {"doid": ["11459"], "mesh": ["D011559"], "omim": ["243200"], "icd-9": ["348.2"], "icd-10": ["G93.2"], "orphanet": ["238624"], "synonyms": ["Alternative titles", "PSEUDOTUMOR CEREBRI"]} |
This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (June 2009) (Learn how and when to remove this template message)
Conorenal syndrome
Other namesMainzer-Saldino syndrome or Saldino-Mainzer disease
SpecialtyMedical genetics
Conorenal syndrome, is a collection of medical conditions that seem to have a common genetic cause.
## Contents
* 1 Genetics
* 2 Mechanism
* 3 Outcomes
* 4 History
* 5 References
* 6 External links
## Genetics[edit]
The exact gene loci has not been characterized.
* NPHP3: Olbrich, et al.,[1] found mutations in the NPHP3 gene that cause nepnroonophthisis and a version of Retinitis Pigmentosa called Lebers Congenital Amaurosis (Senior Loken Syndrome) and hepatic syndrome. Their research leads them to conclude "Our findings suggest that the NPHP genes (NPHP1, NPHP3, NPHP4) involved in the pathogenesis of recessive cystic kidney disease also belong to a common pathway in the primary cilium of kidney cells."
* NPHP5: Otto, et al. found through positional cloning that NPHP5 (IQCB1) is the most frequent cause of a disease very similar to Conorenal Syndrome (renal-retinal Senior-Loken Syndrome).
## Mechanism[edit]
While it is not fully characterized as such, yet, conorenal syndrome seems to be an uncharacterized form of ciliopathy. A ciliopathy is a disease that affects the cilia (sensing cells within the body).
The link to ciliar problems as a cause for Nephronopthisis and similar Kidney diseases is relatively new. Watnick and Germino[2] note that NPHP1 and NPHP4 encode for the proteins nephrocystin and nephrocystin-4 (nephroretinin). These have been shown to interact in a series of cell-cell and cell-matrix signaling proteins. NPHP2 has been also shown to have possible links to the function of the primary renal cilium and to control of the cell cycle (Otto).[3] Otto further found that nephrocystin, inversin (INVS) and nephroretinin colocalize in the primary cilia of cultured renal epithelia cells.[3] One interesting connection is that primary cilia in renal cells may perform a sensing function which maintains the renal tubules. The loss of cystoproteins may lead to dysregulated growth.
The link to a ciliar dysfunction in the Retinal degenerative diseases also comes from Otto. Like the described Kidney diseases, Retinitis Pigmentosa is a disease where the ciliar cells (Rods and Cones) fail to thrive. In a study of patients with a disease similar to Conorenal (renal-retinal Senior-Loken) the authors state "We show that nephrocystin-5, RPGR and calmodulin can be coimmniprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of renal-retinal Senior Loken Syndrome." In other words, there is a common link between certain kidney diseases and some forms of RP and it is through the something related to a problem in the cilia cells. This may be a problem in the cells themselves, or with something that keeps them alive and healthy.
## Outcomes[edit]
When originally characterized by Giedion, there was a relatively high mortality rate due to untreated kidney failure (end stage kidney disease - ESKD). The remarkable improvements in kidney transplantation have reduced the mortality of Conorenal Syndrome substantially if not eliminated it entirely. Most diagnosis of the disease occurs when children present with kidney failure – usually between the ages of 10 and 14. There is no known cure for the syndrome and management of the syndrome is supportive.
## History[edit]
The syndrome was originally characterized during 1970 by Mainzer,[4] et al., in a paper published in the American Journal of Medicine. In 1979, Giedion [5] named the syndrome "conorenal syndrome" after a study of eight children. The children had chronic kidney failure and the epiphyses of their fingers were cone-shaped and protruded into the metaphysis; some also had retinitis pigmentosa (also called RP, a progressive degeneration of the retina which affects night vision and peripheral vision) or ataxia (an inability to coordinate muscular movements). In 1995, a group led by Mendley studied two siblings and determined that renal histopathologic (features that can be identified in the laboratory) and clinical features of a primarily glomerular disorder (a kidney disorder involving the glomeruli, or clusters of blood vessels that act as filters in the kidney) were features of the syndrome.[6] A recent article by Beals and Weleber (2007) also noted that a majority of patients also have small capital femoral epiphyses (the very tops of the femur where it hits the hip socket ) and/or mild abnormalities of the promixal femoral metaphysis.[7]
## References[edit]
1. ^ Olbrich H, Fliegauf M, Hoefele J, et al. (August 2003). "Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis". Nat. Genet. 34 (4): 455–9. doi:10.1038/ng1216. PMID 12872122.
2. ^ Watnick T, Germino G (August 2003). "From cilia to cyst". Nat. Genet. 34 (4): 355–6. doi:10.1038/ng0803-355. PMID 12923538.
3. ^ a b Otto EA, Loeys B, Khanna H, et al. (March 2005). "Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin". Nat. Genet. 37 (3): 282–8. doi:10.1038/ng1520. PMID 15723066.
4. ^ Mainzer F, Saldino RM, Ozonoff MB, Minagi H (October 1970). "Familial nephropathy associatdd with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities". Am. J. Med. 49 (4): 556–62. doi:10.1016/S0002-9343(70)80051-1. PMID 4991086.
5. ^ Giedion A (February 1979). "Phalangeal cone shaped epiphysis of the hands (PhCSEH) and chronic renal disease--the conorenal syndromes". Pediatr Radiol. 8 (1): 32–8. doi:10.1007/BF00973675. PMID 431989.
6. ^ Mendley SR, Poznanski AK, Spargo BH, Langman CB (May 1995). "Hereditary sclerosing glomerulopathy in the conorenal syndrome". Am. J. Kidney Dis. 25 (5): 792–7. doi:10.1016/0272-6386(95)90556-1. PMID 7747734.
7. ^ Beals RK, Weleber RG (October 2007). "Conorenal dysplasia: a syndrome of cone-shaped epiphysis, renal disease in childhood, retinitis pigmentosa and abnormality of the proximal femur". Am. J. Med. Genet. A. 143A (20): 2444–7. doi:10.1002/ajmg.a.31948. PMID 17853467.
## External links[edit]
Classification
D
* OMIM: 266920
* MeSH: C535463
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Conorenal syndrome | c1849437 | 4,912 | wikipedia | https://en.wikipedia.org/wiki/Conorenal_syndrome | 2021-01-18T18:44:17 | {"gard": ["8600"], "mesh": ["C535463"], "umls": ["C1849437"], "orphanet": ["140969"], "wikidata": ["Q5162309"]} |
A rare idiopathic interstitial pneumonia characterized by temporally uniform alveolar and interstitial mononuclear cell inflammation (cellular type) and/or fibrosis of the alveolar walls (fibrotic type) with preserved alveolar architecture. Other types of interstitial lung disease must be excluded. Symptoms are non-specific and include dyspnea, cough, and often constitutional symptoms such as fever and fatigue. Pulmonary function test reveals a restrictive pattern. Computed tomography shows predominantly lower lobe subpleural reticular changes, traction bronchiectasis, and ground-glass opacities. The cellular type of the disease is less common but carries a better prognosis.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Non-specific interstitial pneumonia | c1290344 | 4,913 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=91364 | 2021-01-23T17:40:25 | {"umls": ["C1290344"], "icd-10": ["J84.8"], "synonyms": ["NSIP", "Non-specific idiopathic interstitial pneumonia"]} |
Experience one may have when moving to a cultural environment which is different from one's own
For other uses, see Culture shock (disambiguation).
The encounter with the conquerors with steel and horses shocked the Aztecs, so they confused the Europeans with prophets from the east.
Traveler from Australia visiting a small farm in Sierra Leone.
Culture shock is an experience a person may have when one moves to a cultural environment which is different from one's own; it is also the personal disorientation a person may feel when experiencing an unfamiliar way of life due to immigration or a visit to a new country, a move between social environments, or simply transition to another type of life.[1] One of the most common causes of culture shock involves individuals in a foreign environment. Culture shock can be described as consisting of at least one of four distinct phases: honeymoon, negotiation, adjustment, and adaptation.
Common problems include: information overload, language barrier, generation gap, technology gap, skill interdependence, formulation dependency, homesickness (cultural), boredom (job dependency), response ability (cultural skill set).[2] There is no true way to entirely prevent culture shock, as individuals in any society are personally affected by cultural contrasts differently.[3]
## Contents
* 1 Oberg's four phases model
* 1.1 Honeymoon
* 1.2 Negotiation
* 1.3 Adjustment
* 1.4 Adaptation
* 2 Development
* 3 Reverse culture shock
* 4 Outcomes
* 5 Transition shock
* 6 See also
* 7 References
## Oberg's four phases model[edit]
According to acculturation model, people will initially have (1) honeymoon period, and then there will be (2) transition period, that is, cultural shock. This period may be marked by rejection of the new culture, as well as romanticizing one's home culture. But then, with some time and perhaps help from local people or other culture brokers, people will start to (3) adapt (the dotted line depicted some people hated by new cultures instead). And (4) refers to some people returning to their own places and re-adapting to the old culture.
Kalervo Oberg first proposed his model of cultural adjustment in a talk to the Women's Club of Rio de Janeiro in 1954.[4][5][6]
### Honeymoon[edit]
During this period, the differences between the old and new culture are seen in a romantic light. For example, in moving to a new country, an individual might love the new food, the pace of life, and the locals' habits. During the first few weeks, most people are fascinated by the new culture. They associate with nationals who speak their language, and who are polite to the foreigners. Like most honeymoon periods, this stage eventually ends.[7]
### Negotiation[edit]
After some time (usually around three months, depending on the individual), differences between the old and new culture become apparent and may create anxiety. Excitement may eventually give way to unpleasant feelings of frustration and anger as one continues to experience unfavorable events that may be perceived as strange and offensive to one's cultural attitude. Language barriers, stark differences in public hygiene, traffic safety, food accessibility and quality may heighten the sense of disconnection from the surroundings.[8]
While being transferred into a different environment puts special pressure on communication skills, there are practical difficulties to overcome, such as circadian rhythm disruption that often leads to insomnia and daylight drowsiness; adaptation of gut flora to different bacteria levels and concentrations in food and water; difficulty in seeking treatment for illness, as medicines may have different names from the native country's and the same active ingredients might be hard to recognize.
Still, the most important change in the period is communication: People adjusting to a new culture often feel lonely and homesick because they are not yet used to the new environment and meet people with whom they are not familiar every day. The language barrier may become a major obstacle in creating new relationships: special attention must be paid to one's and others' culture-specific body language signs, linguistic faux pas, conversation tone, linguistic nuances and customs, and false friends.
In the case of students studying abroad, some develop additional symptoms of loneliness that ultimately affect their lifestyles as a whole. Due to the strain of living in a different country without parental support, international students often feel anxious and feel more pressure while adjusting to new cultures—even more so when the cultural distances are wide, as patterns of logic and speech are different and a special emphasis is put on rhetoric.
### Adjustment[edit]
Again, after some time (usually 6 to 12 months), one grows accustomed to the new culture and develops routines. One knows what to expect in most situations and the host country no longer feels all that new. One becomes concerned with basic living again, and things become more "normal". One starts to develop problem-solving skills for dealing with the culture and begins to accept the culture's ways with a positive attitude. The culture begins to make sense, and negative reactions and responses to the culture are reduced.[9]
### Adaptation[edit]
In the mastery stage individuals are able to participate fully and comfortably in the host culture. Mastery does not mean total conversion; people often keep many traits from their earlier culture, such as accents and languages. It is often referred to as the bicultural stage.
## Development[edit]
Gary R. Weaver wrote that culture shock has "three basic causal explanations": loss of familiar cues, the breakdown of interpersonal communications, and an identity crisis.[10] Peter S. Adler emphasized the psychological causes.[11] Tema Milstein wrote that it can have positive effects.[12]
## Reverse culture shock[edit]
Reverse culture shock (also known as "re-entry shock" or "own culture shock"[13]) may take place—returning to one's home culture after growing accustomed to a new one can produce the same effects as described above.[14][15] These are results from the psychosomatic and psychological consequences of the readjustment process to the primary culture.[16] The affected person often finds this more surprising and difficult to deal with than the original culture shock. This phenomenon, the reactions that members of the re-entered culture exhibit toward the re-entrant, and the inevitability of the two are encapsulated in the following saying, also the title of a book by Thomas Wolfe: You Can't Go Home Again.
Reverse culture shock is generally made up of two parts: idealization and expectations. When an extended period of time is spent abroad we focus on the good from our past, cut out the bad, and create an idealized version of the past. Secondly, once removed from our familiar setting and placed in a foreign one we incorrectly assume that our previous world has not changed. We expect things to remain exactly the same as when we left them. The realization that life back home is now different, that the world has continued without us, and the process of readjusting to these new conditions as well as actualizing our new perceptions about the world with our old way of living causes discomfort and psychological anguish.[17]
## Outcomes[edit]
There are three basic outcomes of the adjustment phase:[18]
* Some people find it impossible to accept the foreign culture and to integrate. They isolate themselves from the host country's environment, which they come to perceive as hostile, withdraw into an (often mental) "ghetto" and see return to their own culture as the only way out. This group is sometimes known as "Rejectors" and describes approximately 60% of expatriates.[19] These "Rejectors" also have the greatest problems re-integrating back home after return.[20]
* Some people integrate fully and take on all parts of the host culture while losing their original identity. This is called cultural assimilation. They normally remain in the host country forever. This group is sometimes known as "Adopters" and describes approximately 10% of expatriates.[19]
* Some people manage to adapt to the aspects of the host culture they see as positive, while keeping some of their own and creating their unique blend. They have no major problems returning home or relocating elsewhere. This group can be thought to be cosmopolitan. Approximately 30% of expats belong to this group.[19]
Culture shock has many different effects, time spans, and degrees of severity.[21] Many people are handicapped by its presence and do not recognize what is bothering them.[citation needed]
## Transition shock[edit]
Culture shock is a subcategory of a more universal construct called transition shock. Transition shock is a state of loss and disorientation predicated by a change in one's familiar environment that requires adjustment. There are many symptoms of transition shock, including:[22]
* Anger
* Boredom
* Compulsive eating/drinking/weight gain
* Desire for home and old friends
* Excessive concern over cleanliness
* Excessive sleep
* Feelings of helplessness and withdrawal
* Getting "stuck" on one thing
* Glazed stare
* Homesickness
* Hostility towards host nationals
* Impulsivity
* Irritability
* Mood swings
* Physiological stress reactions
* Stereotyping host nationals
* Suicidal or fatalistic thoughts
* Withdrawal
## See also[edit]
Wikivoyage has a travel guide for Culture shock.
* Cultural conflict
* Cultural cringe
* Cultural intelligence
* Cultural schema theory
* Expatriate
* Fresh off the boat
* Future Shock
* Intercultural communication
* Jetlag
* Neophobia
* Outsourced (film)
* Student exchange program
## References[edit]
1. ^ Macionis, John, and Linda Gerber. "Chapter 3 - Culture." Sociology. 7th edition ed. Toronto, ON: Pearson Canada Inc., 2010. 54. Print.
2. ^ Pedersen, Paul. The Five Stages of Culture Shock: Critical Incidents Around the World. Contributions in psychology, no. 25. Westport, Conn: Greenwood Press, 1995.
3. ^ Barna, LaRay M. "HOW CULTURE SHOCK AFFECTS COMMUNICATION." Communication 5.1 (n.d.): 1-18. SocINDEX with Full Text. EBSCO.29 Sept.2009.web.
4. ^ https://www.princeton.edu/oip/practical-matters/Cultural-Adjustment.pdf
5. ^ http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.461.5459&rep=rep1&type=pdf
6. ^ Oberg, Kalervo: "Cultural shock: Adjustment to new cultural environments, Practical Anthropology 7 (1960), pp. 177–182
7. ^ Oberg, Kalervo. "Culture Shock and the problem of Adjustment to the new cultural environments". World Wide Classroom Consortium for International Education & Multicultural studies. 29 Sept 2009.
8. ^ Mavrides, Gregory PhD “Culture Shock and Clinical Depression.” Foreign Teachers Guide to Living and Working in China. Middle Kingdom Life, 2009. Web. 29 Sept. 2009.
9. ^ Sarah (25 May 2016). "Adjust To New Cultures Like A Pro". thewanderlanders.com. Archived from the original on 4 October 2017. Retrieved 19 March 2018.
10. ^ G.R. Weaver, Understanding and coping with cross-cultural adjustment stress. In: G.R. Weaver, Editor, Culture, communication, and conflict: Readings in intercultural relations, Ginn Press, Needham Heights, MA (1994), pp. 169–189.
11. ^ Adler, P.S. 1975. The transitional experience: An alternative view of culture shock. Journal of Humanistic Psychology 15 4, pp. 13–23
12. ^ Milstein, T. 2005 Transformation abroad: Sojourning and the perceived enhancement of self-efficacy. International Journal of Intercultural Relations, 29(2): 217-238
13. ^ Martin Woesler, A new model of intercultural communication – critically reviewing, combining and further developing the basic models of Permutter, Yoshikawa, Hall, Geert Hofstede, Thomas, Hallpike, and the social-constructivism, Bochum/Berlin 2009, book series Comparative Cultural Sciences vol. 1
14. ^ Clarke, Laura (6 November 2016). "How expats cope with losing their identity". BBC Capital. British Broadcasting Corporation. Retrieved 5 December 2017.
15. ^ Garone, Elizabeth (3 November 2014). "Expat culture shock boomerangs in the office". BBC Capital. British Broadcasting Corporation. Retrieved 5 December 2017.
16. ^ Huff, Jennifer L. (2001). "Parental attachment, reverse culture shock, perceived social support, and college adjustment of missionary children". Journal of Psychology & Theology. 9 (3): 246–264. doi:10.1177/009164710102900307. S2CID 142635674.
17. ^ Martin, Hank "Dealing with Reverse Culture Shock." Breaking Trail Online. http://brktrail.com/rshock/ Archived 2016-02-24 at the Wayback Machine
18. ^ Winkelman, Michael (1994). "Cultural Shock and Adaptation". Journal of Counseling & Development. 73 (2): 121–126. doi:10.1002/j.1556-6676.1994.tb01723.x.
19. ^ a b c "Culture Shock". Archived from the original on 2019-08-08. Retrieved 2019-08-08.
20. ^ Winant, Howard (2001). The World Is A Ghetto. New York, NY: Basic Books. p. 258. ISBN 0-465-04341-0.
21. ^ Christofi, Victoria, and Charles L. Thompson "You Cannot Go Home Again: A Phenomenological Investigation of Returning to the Sojourn Country After Studying Abroad." Journal of Counselling & Development 85.1 (2007): 53-63. SocINDEX with Full Text. EBSCO. Web. 15 Oct. 2009.
22. ^ CESA. "Dealing with culture shock". Management Entity: Office of International Research, Education, and Development. Archived from the original on 28 August 2009. Retrieved 29 September 2009.
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* GND: 4226366-9
* LCCN: sh85034763
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Culture shock | c0221521 | 4,914 | wikipedia | https://en.wikipedia.org/wiki/Culture_shock | 2021-01-18T18:31:41 | {"wikidata": ["Q268586"]} |
Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy, a neurodegenerative disorder. Signs and symptoms typically begin during childhood or adolescence and worsen over time. Early symptoms include involuntary muscle jerking or twitching (stimulus-sensitive myoclonus) and tonic-clonic seizures. Episodes of myoclonus may be brought on by exercise, stress, light, or other stimuli (triggers). Over time, people with ULD develop ataxia, lack of coordination, intention tremor, and difficulty speaking (dysarthria). People with ULD may also develop emotional sensitivity, depression, and a mild impairment of intellectual performance over time.
ULD is caused by mutations in the CSTB gene and inheritance is autosomal recessive. The diagnosis can be confirmed with genetic testing. Treatment aims to control symptoms and increase quality of life. Treatment typically includes medications to lessen the severity of myoclonus and the frequency of seizures, as well as psychosocial support. Myoclonus may be resistant to medications, while seizures can often be controlled. In the past, the life span of people with ULD was significantly shortened, but with advances in treatment and support, life expectancy now appears to be near normal.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Unverricht-Lundborg disease | c0751785 | 4,915 | gard | https://rarediseases.info.nih.gov/diseases/3876/unverricht-lundborg-disease | 2021-01-18T17:57:14 | {"mesh": ["D020194"], "omim": ["254800"], "umls": ["C0751785"], "orphanet": ["308"], "synonyms": ["Myoclonus progressive epilepsy of Unverricht and Lundborg", "EPM1", "Epilepsy, progressive myoclonus 1", "Progressive myoclonus epilepsy baltic myoclonic epilepsy", "Myoclonic epilepsy of Unverricht and Lundborg", "Epilepsy, progressive myoclonic type 1"]} |
A rare neurologic disease characterized by lethargy, hypotonia, poor feeding, opisthotonus, and a typical high-pitched cry due to bilirubin accumulation in the globus pallidus, sub-thalamic nuclei, and other brain regions, resulting from severe neonatal unconjugated hyperbilirubinemia. Onset of symptoms is typically within the first three to five days of life. Additional features include fever, apnea, seizures, and coma. Especially respiratory failure or refractory seizures may lead to a fatal outcome.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Acute bilirubin encephalopathy | c0155685 | 4,916 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=529799 | 2021-01-23T19:00:08 | {"synonyms": ["ABE", "Acute kernicterus"]} |
## Clinical Features
Figuera et al. (2002) described a 4-generation Mexican family with camptodactyly, distinctive facial features, spinal defects, thin hands and feet, and mild mental retardation. Facial features included flat facies, telecanthus, simplified ears, retrognathia, and symblepharon pterygium. Other clinical features included short neck with pterygium colli, multiple nevi of the face and torso, and external rotation of the fourth and fifth toes. Radiographs revealed spina bifida occulta at the cervicodorsal and dorsolumbar levels, widened femoral necks, cortical thickening, and delayed bone age.
Inheritance
Figuera et al. (2002) suggested autosomal dominant inheritance, but no male-to-male transmission was demonstrated.
Nomenclature
Figuera et al. (2002) proposed that this syndrome be designated Guadalajara camptodactyly syndrome type III.
INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Flat face \- Retrognathia \- Widened columella Ears \- Simple ears Eyes \- Hypertelorism \- Telecanthus \- Symblepharon (adhesion of the eyelid to the eyeball) Nose \- Widened nasal tip Neck \- Short neck \- Torticollis \- Short sternocleidomastoid \- Pterygium colli GENITOURINARY External Genitalia (Male) \- Small penis SKELETAL \- Delayed bone age Spine \- Spina bifida occulta Pelvis \- Widened femoral neck Limbs \- Cortical thickening Hands \- Thin hands \- Camptodactyly \- Thenar hypoplasia \- Hypothenar hypoplasia \- Poorly defined palmar creases \- Absent interphalangeal creases Feet \- Thin feet \- External rotation 4th and 5th toes SKIN, NAILS, & HAIR Skin \- Multiple nevi (face and torso) \- Poorly defined palmar creases \- Absent interphalangeal creases NEUROLOGIC Central Nervous System \- Hypotonia \- Developmental delay \- Mental retardation, mild ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| CAMPTODACTYLY SYNDROME, GUADALAJARA, TYPE III | c2677809 | 4,917 | omim | https://www.omim.org/entry/611929 | 2019-09-22T16:02:36 | {"mesh": ["C567455"], "omim": ["611929"], "orphanet": ["488434"], "synonyms": []} |
Anemia that is characterized by a deficiency of red blood cells, white blood cells and platelets produced by bone marrow
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Aplastic anaemia
Other namesAplastic anaemia
SpecialtyOncology, hematology
Aplastic anemia[1] is a disease in which the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there.[2] Aplastic anaemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.[3][4]
It is more frequent in people in their teens and twenties but is also common among the elderly. It can be caused by heredity, immune disease, or exposure to chemicals, drugs, or radiation. However, in about one-half of cases, the cause is unknown.[3][4]
The definitive diagnosis is by bone marrow biopsy; normal bone marrow has 30–70% blood stem cells, but in aplastic anemia, these cells are mostly gone and replaced by fat.[3][4]
First-line treatment for aplastic anaemia consists of immunosuppressive drugs, typically either anti-lymphocyte globulin or anti-thymocyte globulin, combined with corticosteroids, chemotherapy and ciclosporin. Hematopoietic stem cell transplantation is also used, especially for patients under 30 years of age with a related matched marrow donor.[3][4]
The disease is also known as the cause of death of Eleanor Roosevelt and Marie Curie.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 4 Treatment
* 4.1 Follow-up
* 5 Prognosis
* 6 Etymology
* 7 Epidemiology
* 8 Notable cases
* 9 See also
* 10 References
* 11 External links
## Signs and symptoms[edit]
Anemia may lead to feeling tired, pale skin and a fast heart rate.[5]
Low platelets are associated with an increased risk of bleeding, bruising and petechiae. Low white blood cells increase the risk of infections.[5]
## Causes[edit]
Aplastic anemia can be caused by exposure to certain chemicals, drugs, radiation, infection, immune disease; in about half the cases, a definitive cause is unknown. It is not a familial line hereditary condition, nor is it contagious. It can be acquired due to exposure to other conditions but if a person develops the condition, their offspring would not develop it by virtue of their genetic relationship.[3][4]
Aplastic anemia is also sometimes associated with exposure to toxins such as benzene, or with the use of certain drugs, including chloramphenicol, carbamazepine, felbamate, phenytoin, quinine, and phenylbutazone. Many drugs are associated with aplasia mainly according to case reports, but at a very low probability. As an example, chloramphenicol treatment associated with aplasia in less than one in 40,000 treatment courses, and carbamazepine aplasia is even rarer.[6]
Exposure to ionizing radiation from radioactive materials or radiation-producing devices is also associated with the development of aplastic anemia. Marie Curie, famous for her pioneering work in the field of radioactivity, died of aplastic anemia after working unprotected with radioactive materials for a long period of time; the damaging effects of ionizing radiation were not then known.[7]
Aplastic anemia is present in up to 2% of patients with acute viral hepatitis.[8]
One known cause is an autoimmune disorder in which white blood cells attack the bone marrow.[1] Acquired aplastic anemia is a T-cell mediated autoimmune disease, in which regulatory T cells are decreased in patients, and T-bet, a transcription factor and key regulator of Th1 development and function, is upregulated in affected T-cells. As a result of active transcription of the IFN-gamma gene by T-bet, IFN-gamma levels are increased, which reduces colony formation of hematopoietic progenitor cells in vitro by inducing apoptosis of CD34+ cells of bone marrow.[9]
Short-lived aplastic anemia can also be a result of parvovirus infection.[10] In humans, the P antigen (also known as globoside), one of the many cellular receptors that contribute to a person's blood type, is the cellular receptor for parvovirus B19 virus that causes erythema infectiosum (fifth disease) in children. Because it infects red blood cells as a result of the affinity for the P antigen, parvovirus causes complete cessation of red blood cell production. In most cases, this goes unnoticed, as red blood cells live on average 120 days, and the drop in production does not significantly affect the total number of circulating red blood cells. In people with conditions where the cells die early (such as sickle cell disease), however, parvovirus infection can lead to severe anemia.[citation needed]
More frequently parvovirus B19 is associated with aplastic crisis which involves only the red blood cells (despite the name). Aplastic anemia involves all different cell lines.
Viruses that have been linked to the development of aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, parvovirus B19, and HIV.
In some animals, aplastic anemia may have other causes. For example, in the ferret (Mustela putorius furo), it is caused by estrogen toxicity, because female ferrets are induced ovulators, so mating is required to bring the female out of heat. Intact females, if not mated, will remain in heat, and after some time the high levels of estrogen will cause the bone marrow to stop producing red blood cells.[citation needed]
## Diagnosis[edit]
The condition needs to be differentiated from pure red cell aplasia. In aplastic anemia, the patient has pancytopenia (i.e., leukopenia and thrombocytopenia) resulting in decrease of all formed elements. In contrast, pure red cell aplasia is characterized by reduction in red cells only. The diagnosis can only be confirmed on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a complete blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.[citation needed]
The following tests aid in determining differential diagnosis for aplastic anemia:
1. Bone marrow aspirate and biopsy: to rule out other causes of pancytopenia (i.e. neoplastic infiltration or significant myelofibrosis).
2. History of iatrogenic exposure to cytotoxic chemotherapy: can cause transient bone marrow suppression
3. X-rays, computed tomography (CT) scans, or ultrasound imaging tests: enlarged lymph nodes (sign of lymphoma), kidneys and bones in arms and hands (abnormal in Fanconi anemia)
4. Chest X-ray: infections
5. Liver tests: liver diseases
6. Viral studies: viral infections
7. Vitamin B12 and folate levels: vitamin deficiency
8. Blood tests for paroxysmal nocturnal hemoglobinuria
9. Test for antibodies: immune competency
## Treatment[edit]
Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine intake, or, in more severe cases, a bone marrow transplant, a potential cure.[11] The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease"). In young patients with an HLA matched sibling donor, bone marrow transplant can be considered as first-line treatment, patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched unrelated donor transplants are considered a second-line therapy.
Medical therapy of aplastic anemia often includes a course of antithymocyte globulin (ATG) and several months of treatment with cyclosporine to modulate the immune system. Chemotherapy with agents such as cyclophosphamide may also be effective but has more toxicity than ATG. Antibody therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Corticosteroids are generally ineffective,[12] though they are used to ameliorate serum sickness caused by ATG. Normally, success is judged by bone marrow biopsy 6 months after initial treatment with ATG.[13]
One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality, due to severe infections as a result of prolonged neutropenia.[13]
In the past, before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infections), as in the case of Ted DeVita.[14]
### Follow-up[edit]
Full blood counts are required on a regular basis to determine whether the patient is still in a state of remission.
Many patients with aplastic anemia also have clones of cells characteristic of the rare disease paroxysmal nocturnal hemoglobinuria (PNH, anemia with thrombopenia and/or thrombosis), sometimes referred to as AA/PNH. Occasionally PNH dominates over time, with the major manifestation intravascular hemolysis. The overlap of AA and PNH has been speculated to be an escape mechanism by the bone marrow against destruction by the immune system. Flow cytometry testing is performed regularly in people with previous aplastic anemia to monitor for the development of PNH.[citation needed]
## Prognosis[edit]
Untreated, severe aplastic anemia has a high risk of death.[15] Modern treatment, by drugs or stem cell transplant, has a five-year survival rate that exceeds 45%, with younger age associated with higher survival.[16]
Survival rates for stem cell transplant vary depending on age and availability of a well-matched donor. Five-year survival rates for patients who receive transplants have been shown to be 42% for patients under age 20, 32% for those 20–40 years old, and closer to 10% for patients over age 40. Success rates are better for patients who have donors that are matched siblings and worse for patients who receive their marrow from unrelated donors.[17]
Older people (who are generally too frail to undergo bone marrow transplants), and people who are unable to find a good bone marrow match, undergoing immune suppression have five-year survival rates of up to 35%.[citation needed]
Relapses are common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10–15% of severe aplastic anemia cases evolve into myelodysplastic syndrome and leukemia.[citation needed] According to a study, for children who underwent immunosuppressive therapy, about 15.9% of children who responded to immunosuppressive therapy encountered relapse.[18]
Milder disease can resolve on its own.[citation needed]
## Etymology[edit]
Aplastic is a combination of two ancient Greek elements: a- meaning "not", and -plasis "forming into a shape." [19] Anemia is a combination of the ancient Greek element an- meaning "not", and -emia from new Latin from Greek -(h)aimia "blood."[20]
## Epidemiology[edit]
Aplastic anemia is a rare, non cancerous disorder where the blood marrow is unable to adequately produce blood cells required for survival.[21][22] It is estimated that the incidence of aplastic anemia is 0.7-4.1 cases per million people worldwide with the prevalence between men and women being approximately equal.[23] The incidence rate of aplastic anemia in Asia is 2-3 times higher than it is in the West, with the incidence of the disease in the United States is 300-900 cases per year.[22][23] The disease most commonly affects adults aged 15–25 and over the age of 60, but the disease can be observed in all age groups.[22] The majority of instances of this disease are acquired during life and not inherited.[21] These acquired cases are often linked to environmental exposures such as chemicals, drugs, and infectious agents that damage the blood marrow and compromise the ability of the marrow to generate new blood cells.[23] However, in many instances the underlying cause for the disease is not found. This is referred to as idiopathic aplastic anemia and accounts for 75% of cases.[22] This compromises the effectiveness of treatment since treatment of the disease is often aimed at the underlying cause.[24] Those with a higher risk for aplastic anemia include individuals that are exposed to high-dose radiation, exposed to toxic chemicals, take certain prescription drugs, have pre-existing autoimmune disorders or blood disease, or are pregnant.[25] The five-year survival rate is higher than 75% among recipients of blood marrow transplantation.[24] Other treatment strategies include medications and blood transfusions.[25] Patients that are untreated will often die within a year as a result of the disease due to related complications, which are most commonly bleeding and infection due to deficiency of platelets and white blood cells, respectively.[24] There is not a screening test that currently exists for early detection and diagnosis of aplastic anemia.[22]
## Notable cases[edit]
* Marie Curie[26]
* Eleanor Roosevelt[27]
* Donny Schmit[28]
* Ted DeVita[29]
* Demetrio Stratos[30]
* John Dill (British Field Marshal)[31]
## See also[edit]
* Fanconi anemia
* Acquired pure red cell aplasia
## References[edit]
1. ^ a b Young, Neal S. (2018-10-25). "Aplastic Anemia". The New England Journal of Medicine. 379 (17): 1643–1656. doi:10.1056/NEJMra1413485. ISSN 1533-4406. PMC 6467577. PMID 30354958.
2. ^ Acton, Ashton (22 July 2013). Aplastic Anemia. ScholarlyEditions. p. 36. ISBN 978-1-4816-5068-7. "Aplastic anaemia (AA) is a rare bone marrow failure disorder with high mortality rate, which is characterized by pancytopenia and an associated increase in the risk of hemorrhage, infection, organ dysfunction and death."
3. ^ a b c d e Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005). Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill. ISBN 978-0-07-140235-4.
4. ^ a b c d e Merck Manual, Professional Edition, Aplastic Anemia (Hypoplastic Anemia)
5. ^ a b Peinemann, F; Bartel, C; Grouven, U (23 July 2013). "First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia". The Cochrane Database of Systematic Reviews. 7 (7): CD006407. doi:10.1002/14651858.CD006407.pub2. PMC 6718216. PMID 23881658.
6. ^ Adias; Erhabor (2013-02-11). Haematology Made Easy. AuthorHouse. pp. 229–. ISBN 978-1-4772-4651-1.
7. ^ "Marie Curie - The Radium Institute (1919-1934): Part 3". American Institute of Physics.
8. ^ Clark, Michael; Kumar, Parveen, eds. (July 2011). Kumar & Clark's clinical medicine (7th ed.). Edinburgh: Saunders Elsevier. ISBN 978-0-7020-2992-9.
9. ^ Zeng, Y; Katsanis, E (June 2015). "The complex pathophysiology of acquired aplastic anaemia". Clinical and Experimental Immunology. 180 (3): 361–370. doi:10.1111/cei.12605. ISSN 0009-9104. PMC 4449765. PMID 25683099.
10. ^ Aplastic Anemia: New Insights for the Healthcare Professional. ScholarlyEditions. 22 July 2013. p. 39. ISBN 9781481663182.
11. ^ Locasciulli A, Oneto R, Bacigalupo A, et al. (2007). "Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT)". Haematologica. 92 (1): 11–8. doi:10.3324/haematol.10075. PMID 17229630.
12. ^ Gale, Robert Peter (1981-10-01). "Aplastic Anemia: Biology and Treatment". Annals of Internal Medicine. 95 (4): 477–94. doi:10.7326/0003-4819-95-4-477. ISSN 0003-4819. PMID 6116472.
13. ^ a b Tisdale JF, Maciejewski JP, Nunez O, et al. (2002). "Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial". Blood. 100 (13): 4668–4670. doi:10.1182/blood-2002-02-0494. PMID 12393567.
14. ^ "NIH Clinical Center: Clinical Center News, NIH Clinical Center". Retrieved 2007-12-04.
15. ^ Gamper CJ (Nov 2016). "High-Dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia". Journal of Pediatric Hematology/Oncology. Journal of Pediatric Hematology Oncology. 38 (8): 627–635. doi:10.1097/MPH.0000000000000647. PMC 5074865. PMID 27467367.
16. ^ DeZern, Amy E; Brodsky, Robert A (10 January 2014). "Clinical management of aplastic anemia". Expert Review of Hematology. 4 (2): 221–230. doi:10.1586/ehm.11.11. PMC 3138728. PMID 21495931.
17. ^ Scheinberg, Phillip; Young, Neal S. (April 19, 2012). "How I treat acquired aplastic anemia". Blood. 120 (6): 1185–96. doi:10.1182/blood-2011-12-274019. PMC 3418715. PMID 22517900. Free Text
18. ^ Kamio, T.; Ito, E.; Ohara, A.; Kosaka, Y.; Tsuchida, M.; Yagasaki, H.; Mugishima, H.; Yabe, H.; Morimoto, A.; Ohga, S.; Muramatsu, H.; Hama, A.; Kaneko, T.; Nagasawa, M.; Kikuta, A.; Osugi, Y.; Bessho, F.; Nakahata, T.; Tsukimoto, I.; Kojima, S. (21 March 2011). "Relapse of aplastic anemia in children after immunosuppressive therapy: a report from the Japan Childhood Aplastic Anemia Study Group". Haematologica. 96 (6): 814–819. doi:10.3324/haematol.2010.035600. PMC 3105642. PMID 21422115. "In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia."
19. ^ Flexner, Stuart; Hauck, Leonore, eds. (1993). Random House Unabridged Dictionary (2nd ed.). New York City: Random House. p. 98. ISBN 0-679-42917-4.
20. ^ Flexner, Stuart; Hauck, Leonore, eds. (1993). Random House Unabridged Dictionary (2nd ed.). New York City: Random House. p. 78. ISBN 0-679-42917-4.
21. ^ a b "What is aplastic anaemia?".
22. ^ a b c d e "December Is National Aplastic Anemia Awareness Month" (PDF).
23. ^ a b c Issaragrisil, Surapol; Kaufman, David W.; Anderson, Theresa; Chansung, Kanchana; Leaverton, Paul E.; Shapiro, Samuel; Young, Neal S. (2006-02-15). "The epidemiology of aplastic anemia in Thailand". Blood. 107 (4): 1299–1307. doi:10.1182/blood-2005-01-0161. ISSN 0006-4971. PMC 1895423. PMID 16254144.
24. ^ a b c Moore, Christine A.; Krishnan, Koyamangalath (2019), "Aplastic Anemia", StatPearls, StatPearls Publishing, PMID 30480951, retrieved 2019-12-05
25. ^ a b "Aplastic Anemia".
26. ^ Rollyson, Carl (2004). Marie Curie: Honesty In Science. iUniverse. p. x. ISBN 978-0-595-34059-0.
27. ^ "Health". in Beasley, Maurine Hoffman; Holly Cowan Shulman; Henry R. Beasley (2001). The Eleanor Roosevelt Encyclopedia. Greenwood Publishing Group. pp. 230–32. ISBN 978-0-313-30181-0. Retrieved December 10, 2012.
28. ^ "AMA Motorcycle Museum Hall of Fame | Donny Schmit". www.motorcyclemuseum.org.
29. ^ "Oncologist Discusses Advancements In Treatment And The Ongoing War On Cancer". NPR.org. October 28, 2015.
30. ^ Pavese, Antonella (22 October 2006). "The life and times of Demetrio Stratos". AntonellaPavese.com. Retrieved 19 August 2019.
31. ^ Danchev, Alex (1991). "The Strange Case of Field Marshal Sir John Dill" (PDF). cambridge.org.com. Retrieved 15 October 2019.
## External links[edit]
* Mayo Clinic
* MedlinePlus Encyclopedia: 000554—Idiopathic aplastic anemia
Classification
D
* ICD-10: D60-D61
* ICD-9-CM: 284
* OMIM: 609135
* MeSH: D000741
* DiseasesDB: 866
External resources
* MedlinePlus: 000554
* eMedicine: med/162
* v
* t
* e
Diseases of red blood cells
↑
Polycythemia
* Polycythemia vera
↓
Anemia
Nutritional
* Micro-: Iron-deficiency anemia
* Plummer–Vinson syndrome
* Macro-: Megaloblastic anemia
* Pernicious anemia
Hemolytic
(mostly normo-)
Hereditary
* enzymopathy: Glucose-6-phosphate dehydrogenase deficiency
* glycolysis
* pyruvate kinase deficiency
* triosephosphate isomerase deficiency
* hexokinase deficiency
* hemoglobinopathy: Thalassemia
* alpha
* beta
* delta
* Sickle cell disease/trait
* Hereditary persistence of fetal hemoglobin
* membrane: Hereditary spherocytosis
* Minkowski–Chauffard syndrome
* Hereditary elliptocytosis
* Southeast Asian ovalocytosis
* Hereditary stomatocytosis
Acquired
AIHA
* Warm antibody autoimmune hemolytic anemia
* Cold agglutinin disease
* Donath–Landsteiner hemolytic anemia
* Paroxysmal cold hemoglobinuria
* Mixed autoimmune hemolytic anemia
* membrane
* paroxysmal nocturnal hemoglobinuria
* Microangiopathic hemolytic anemia
* Thrombotic microangiopathy
* Hemolytic–uremic syndrome
* Drug-induced autoimmune
* Drug-induced nonautoimmune
* Hemolytic disease of the newborn
Aplastic
(mostly normo-)
* Hereditary: Fanconi anemia
* Diamond–Blackfan anemia
* Acquired: Pure red cell aplasia
* Sideroblastic anemia
* Myelophthisic
Blood tests
* Mean corpuscular volume
* normocytic
* microcytic
* macrocytic
* Mean corpuscular hemoglobin concentration
* normochromic
* hypochromic
Other
* Methemoglobinemia
* Sulfhemoglobinemia
* Reticulocytopenia
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Aplastic anemia | c0002874 | 4,918 | wikipedia | https://en.wikipedia.org/wiki/Aplastic_anemia | 2021-01-18T19:05:59 | {"gard": ["5836"], "mesh": ["D000741"], "umls": ["C0178416", "C0002874"], "orphanet": ["182040"], "wikidata": ["Q846316"]} |
In psychology and psychiatry, clanging refers to a mode of speech characterized by association of words based upon sound rather than concepts. For example, this may include compulsive rhyming or alliteration without apparent logical connection between words. This is associated with the irregular thinking apparent in psychotic mental illnesses (e.g. mania and schizophrenia).[1] Gustav Aschaffenburg found that manic individuals generated these "clang-associations" roughly 10–50 times more than non-manic individuals.[2] Aschaffenburg also found that the frequency of these associations increased for all individuals as they became more fatigued.[3]
Clanging refers specifically to behavior that is situationally inappropriate. While a poet rhyming is not evidence of mental illness, disorganized speech that impedes the patient's ability to communicate is a disorder in itself, often seen in schizophrenia.[4]
## See also[edit]
* Thought disorder
* Word salad
## References[edit]
1. ^ Peralta, Victor; Cuesta, Manuel J.; de Leon, Jose (March 1992). "Formal thought disorder in schizophrenia: A factor analytic study". Comprehensive Psychiatry. 33 (2): 105–110. doi:10.1016/0010-440X(92)90005-B. PMID 1544294.
2. ^ Kraepelin, Emil (1921). Manic-depressive insanity and paranoia. Edinburgh: E. & S. Livingstone. p. 32.
3. ^ Spitzer, Manfred (1999). The mind within the net: Models of learning, thinking, and acting. Cambridge: MIT. p. 219.
4. ^ Covington MA, He C, Brown C, Naçi L, McClain JT, Fjordbak BS, Semple J, Brown J (Sep 2005). "Schizophrenia and the structure of language: the linguist's view" (PDF). Schizophr. Res. 77 (1): 85–98. CiteSeerX 10.1.1.532.2190. doi:10.1016/j.schres.2005.01.016. PMID 16005388. S2CID 7206375.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Clanging | c0233658 | 4,919 | wikipedia | https://en.wikipedia.org/wiki/Clanging | 2021-01-18T18:29:44 | {"umls": ["C0233658"], "wikidata": ["Q5125787"]} |
## Clinical Features
Neuhauser et al. (1983) described 2 unrelated families in which a total of 5 members had recurrent encephalopathy affecting cerebellar and extrapyramidal structures. Affected individuals had onset in infancy or early childhood of acute encephalopathic episodes following presumably viral infections. The episodes were characterized by lethargy, poor coordination, tremor, involuntary movements, and loss of coordination and voluntary motor skills. All psychomotor abilities were fully regained after these initial episodes; however, the attacks were recurrent during childhood, and all patients later developed residual neurologic impairment, including hypotonia, areflexia, extensor plantar responses, choreoathetoid movements, ataxia, intention tremor, and variable dysarthria.
Inheritance
The transmission pattern in the families reported by Neuhauser et al. (1983) was consistent with autosomal dominant inheritance.
INHERITANCE \- Autosomal dominant MUSCLE, SOFT TISSUES \- Hypotonia, mild NEUROLOGIC Central Nervous System \- Encephalopathic attacks, episodic, associated with infection \- Attacks characterized by lethargy, incoordination, loss of motor skills \- Residual ataxia \- Areflexia \- Intention tremor \- Incoordination \- Choreoathetoid movements \- Dysarthria \- Extensor plantar responses (variable) MISCELLANEOUS \- Onset in infancy or early childhood \- Onset usually after viral-like infection \- Initial recovery, but residual neurologic impairment occurs after repeated encephalopathic episodes ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| ENCEPHALOPATHY, RECURRENT, OF CHILDHOOD | c1851708 | 4,920 | omim | https://www.omim.org/entry/130950 | 2019-09-22T16:41:41 | {"mesh": ["C536407"], "omim": ["130950"], "orphanet": ["2672"]} |
Not to be confused with Hoarding (animal behavior).
Animal hoarding of rabbits
Animal hoarding is keeping a higher-than-usual number of animals as domestic pets without ability to properly house or care for them, while at the same time denying this inability. Compulsive hoarding can be characterized as a symptom of mental disorder rather than deliberate cruelty towards animals. Hoarders are deeply attached to their pets and find it extremely difficult to let the pets go. They typically cannot comprehend that they are harming their pets by failing to provide them with proper care. Hoarders tend to believe that they provide the right amount of care for them.[1] The American Society for the Prevention of Cruelty to Animals provides a "Hoarding Prevention Team", which works with hoarders to help them attain a manageable and healthy number of pets.[2]
## Contents
* 1 Characteristics of a hoarder
* 2 Legal solutions
* 2.1 United States
* 2.1.1 Animal cruelty statutes
* 2.1.2 Penalties under state animal cruelty statutes
* 2.1.3 Criticism of applying animal cruelty laws to hoarding
* 2.1.4 Hoarding-specific laws
* 2.1.5 Hoarding-specific municipal ordinances
* 2.1.6 Problems with prosecuting hoarders
* 2.2 United Kingdom
* 3 Dangers
* 3.1 Health effects on animals
* 3.1.1 Malnourishment
* 3.1.2 Overcrowding
* 3.1.3 Owner neglect
* 3.1.4 Lasting consequences
* 3.2 Health effects on humans
* 3.2.1 Sanitation concerns
* 3.2.2 Zoonotic diseases
* 3.2.3 Self-neglect and child/elder abuse
* 4 Mental health issues
* 4.1 Delusional disorder
* 4.2 Attachment disorder
* 4.3 Obsessive–compulsive disorder
* 5 Popular culture and fiction
* 6 See also
* 7 References
* 8 External links
## Characteristics of a hoarder[edit]
An animal hoarder keeps an unusually large number of pets for their premises, and fails to care for them properly. A hoarder is distinguished from an animal breeder, who would have numerous animals as the central component of their business; this distinction can be problematic, however, as some hoarders are former breeders who have ceased selling and caring for their animals, while others will claim to be breeders as a psychological defense mechanism, or in hopes of forestalling intervention. Gary Patronek, director of the Center for Animals and Public Policy at Tufts University, defines hoarding as the "pathological human behavior that involves a compulsive need to obtain and control animals, coupled with a failure to recognize their suffering".[3] According to another study, the distinguishing feature is that a hoarder "fails to provide the animals with adequate food, water, sanitation, and veterinary care, and... is in denial about this inability to provide adequate care."[4] Along with other compulsive hoarding behaviors, it is linked in the DSM-IV to obsessive compulsive disorder and obsessive compulsive personality disorder.[5] The DSM-5 includes a diagnosis of hoarding disorder.[6]
Alternatively, animal hoarding could be related to addiction, dementia, or even focal delusion.[4]
The number of animals involved alone is not a determinative factor in identifying hoarding. Instead, the issue is the owner's inability to provide care for the animals and the owner's refusal to acknowledge that both the animals and the household are deteriorating.[7] For instance, in one animal hoarding case, 11 cats were seized from a trailer.[8] The deputy police officer testified that the trailer smelled so strongly of feline waste that despite suffering from severe congestion at the time of the investigation, she had a hard time staying in there for more than a few minutes.[8] The deputy further testified that she could not step anywhere in the trailer without stepping on fresh, old, or smeared fecal matter, and that even the stove and sink were filled with bio-hazardous waste.[8] Yet, a Canadian woman, who died leaving 100 properly fed, spayed/neutered, vaccinated, and groomed cats, was not considered an animal hoarder because her animals were properly cared for.[9]
The Hoarding of Animals Research Consortium (HARC) identifies the following characteristics as common to all hoarders:
* Accumulation of numerous animals, which has overwhelmed that person's ability to provide even minimal standards of nutrition, sanitation, and veterinary care;
* Failure to acknowledge the deteriorating condition of the animals (including disease, starvation, and even death) and the household environment (severe overcrowding, very unsanitary conditions); and−
* Failure to recognize the negative effect of the collection on their own health and well-being, and on that of other household members.[7]
Compulsive hoarding can be characterized as a symptom of mental disorder rather than deliberate cruelty towards animals. Hoarders are deeply attached to their pets and find it extremely difficult to let the pets go. They typically cannot comprehend that they are harming their pets by failing to provide them with proper care. Hoarders tend to believe that they provide the right amount of care for their pets.[1] The American Society for the Prevention of Cruelty to Animals provides a "Hoarding Prevention Team", which works with hoarders to help them attain a manageable and healthy number of pets.[2]
## Legal solutions[edit]
### United States[edit]
#### Animal cruelty statutes[edit]
In the United States, animal hoarders can be prosecuted under state animal cruelty laws for failing to provide a certain level of care to their animals.[10] The following provides some examples of the standards currently in effect. In Alaska, the cruelty statute defines a minimum standard of care for animals that includes (1) food and water sufficient to maintain each animal in good health; (2) an environment compatible with protecting and maintaining the good health and safety of the animal; and (3) reasonable medical care at times and to the extent available and necessary to maintain the animal in good health.[11] Likewise, in Colorado, a person commits cruelty to animals if he or she knowingly, recklessly, or with criminal negligence deprives an animal of necessary sustenance, neglects any animal, allows the animal to be housed in a manner that results in chronic or repeated serious physical harm, or fails to provide the animal with proper food, drink, or protection from the weather consistent with the species, breed, and type of animal involved.[12] In Colorado's animal cruelty statute, “neglect” means failure to provide food, water, protection from the elements, or other care generally considered to be normal, usual, and accepted for an animal's health and well-being consistent with the species, breed, and type of animal.[13]
Since failure to provide proper care for animals is an act of omission or neglect rather than an affirmative act, the failure to care for an animal is considered a misdemeanor offense in most states.[10] For instance, in Alaska, if an animal owner fails to provide the aforementioned standards of care, the state has prima facie evidence of a failure to care for an animal.[14] If the prosecutor can prove the owner's failure to care for an animal was done with criminal negligence and the failure to care for the animal caused its death or severe physical pain or prolonged suffering, then the owner may be guilty of a Class A misdemeanor.[15] In Colorado, failure to provide an animal with the proper standard of care is a Class 1 misdemeanor.[16] In Virginia, each owner must provide for each of his companion animals: adequate feed; adequate water; adequate shelter that is properly cleaned; adequate space in the primary enclosure for the particular type of animal depending upon its age, size, species, and weight; adequate exercise; adequate care, treatment, and transportation; and veterinary care when needed to prevent suffering or disease transmission.[17] Violation of these standards is a Class 4 misdemeanor.[17] A second or subsequent violation may result in a higher grade misdemeanor.[17] Likewise, under Virginia's animal cruelty statute, any person who deprives any animal of necessary food, drink, shelter or emergency veterinary treatment is guilty of a Class 1 misdemeanor.[18]
However, some states, like California and New Hampshire, may provide felony provisions for depriving an animal of necessary sustenance, drink, and shelter.[19][20] In Colorado, it is a class 6 felony upon a second or subsequent conviction of animal cruelty.[12] In Maine, a person who is guilty of cruelty to animals may face criminal or civil charges at the discretion of the state's attorney.[21]
#### Penalties under state animal cruelty statutes[edit]
Penalties for failing to provide proper care or medical care to animals under state animal cruelty statutes can include fines, animal forfeiture, the cost of care for the seized animals, and jail time.[10] Since animal hoarding is sometimes associated with mental illness, a situation may arise when an alleged animal neglecter is found incompetent to stand trial due to a mental disability and thus remains the rightful owner of the animals he or she has neglected (i.e. the animals were not forfeited). In the Matter of a Protective Order for Jean Marie Primrose, for example, after a tip from a veterinarian, police confiscated 11 cats from a woman's feces and urine covered, rat infested trailer in Oregon; the cats were then placed in the care of a rescue organization. The woman was charged with criminal second degree animal neglect. After being diagnosed with a mild case of mental retardation, however, the judge found the woman unable to aid and assist in her own defense. The second degree charge was thereby dismissed. Since the woman was not convicted of a crime, her rights to the 11 cats were not forfeited. Yet, from the time the cats were seized to the time of the dismissal, the rescue organization accrued more than $30,000 in cat care fees. The rescue organization therefore placed a lien on the cats, meaning the woman could not get her cats back until she paid off her debt. After the dismissal of the case, however, the woman never made any attempt to contact the rescue organization about returning her cats. The fate of the cats therefore remained in limbo. The rescue organization could have either kept the cats and kept accruing care fees because not being rightful owners, they could not place the cats into homes, or forgiven the debt and returned the cats to the woman. Since the rescue organization felt the woman was incapable of adequately caring for the cats and since the organization did not want to invest more money that would likely remain uncompensated, the organization filed a petition for a limited protective order as a fiduciary for the care and placement of the cats. The probate court ruled against organization, but the appeals court overturned the lower court's order and held that the probate court did indeed have authority to enter a limited protective order under ORS 125.650 as a "fiduciary necessary to implement a protective order." The probate court, then, granted the limited protective order and the organization was allowed to place the cats into new homes.[22] This case was considered a landmark by the Animal Legal Defense Fund.[23]
In addition to jail time, animal forfeiture, and fines, a state, such as California, may allow courts to order psychological counseling at the court's discretion or may require the defendant to undergo anger management, such as the case in Colorado.[10] Prosecutors may also be able to request bans on future pet ownership or request limits on the number of animals a convicted hoarder may keep.[10] For instance, in ALDF v. Conyers, over one hundred dogs and nine birds were confiscated from the defendants’ home.[24] About 70 of those dogs had severe oral disease, disintegrating jaws, and scarred corneas. One dog, who was caged in the basement, could barely stand up and kept soiling himself, which lead to his skin being scalded from the urine and feces.[24] An officer also noticed the dog's tongue hanging out of his mouth, but later learned that his tongue was sticking out because his jaw had disintegrated.[24] The Animal Legal Defense Fund moved for a permanent injunction to enjoin defendants from owning animals from the date of the court's final judgment to 10 years.[24]
#### Criticism of applying animal cruelty laws to hoarding[edit]
Although animal hoarders can be prosecuted under state animal cruelty laws, many scholars maintain that basic animal cruelty laws are inefficient in prosecuting hoarders.[10] As Stephan Otto, director of legislative affairs for the Animal Legal Defense Fund explains: “Only a handful of states allow felony charges for the worst kinds of animal neglect . . . They also need stronger laws that take into account when multiple numbers of animals were in involved in a case.”[10] HARC's research on 56 animal hoarding cases illustrates Otto's point:
> In sixteen cases, individuals were charged with one count of animal cruelty for their entire group of animals rather than one count of cruelty for each animal involved. In several other cases, hoarders were only charged with one count of failure to license or provide a rabies vaccination when there were dozens of animals involved.[10]
Prosecutors and judges, however, discourage multiple charges, believing that they “clog” the system. The difficulty of proving each charge also accounts for this discouragement.[10] In order to bring one charge of cruelty for each animal, prosecutors and animal agencies must provide proof of cruelty to each animal, matching each animal with its count number.[10] Charging the hoarder with only one count reduces the burdens on the system, the prosecutors, and the animal agencies, but undermines the severity of the charges.[10]
#### Hoarding-specific laws[edit]
Only two states have laws regarding the hoarding of animals: Illinois and Hawaii.
Passed in 2001, the Illinois Humane Care for Animals Act was amended to include a definition a companion animal hoarder and mandated psychological counseling for animal hoarders who violate Section 3.[10] A person convicted of violating section 3 of the Act (which requires the provision of food and water, adequate shelter and protection from the weather, veterinary care, and humane care and treatment) is guilty of a misdemeanor with a second or subsequent violation raising the offense to a Class 4 felony.[10] One commentator, Victoria Hayes, JD, believed that although Illinois’ legal definition of a “companion animal hoarder” is a step in the right direction, the definition does not provide any extra tools to a prosecutor.[10] Animal hoarding itself is not prohibited by the statute, she said, and the prosecutor must still show a violation of Section 3 of the Humane Care for Animals Act. It is important to note that animal hoarding itself is not prohibited by the Illinois statute.[10]
Hawaii, on the other hand, specifically outlaws animal hoarding. In 2008, animal hoarding became a misdemeanor offense. Hawaii's Penal Code now provides:
(1) A person commits the offense of animal hoarding if the person intentionally, knowingly, or recklessly;
> * (a) Possesses more than fifteen dogs, cats, or a combination of dogs and cats;
> * (b) Fails to provide necessary sustenance for each dog or cat; and
> * (c) Fails to correct the conditions under which the dogs or cats are living, where conditions injurious to the dogs’, cats’, or owner’s health and well-being result from the person’s failure to provide necessary sustenance.
>
(2) Animal hoarding is a misdemeanor.[25]
Hawaii's law specifically criminalizes hoarding, while depriving an animal of necessary sustenance can also constitute a separate offense of animal cruelty. The hoarding law differs from ordinances that limit the number of pets a person can have because it only prohibits keeping more than fifteen dogs and cats if the owner fails to provide necessary care for the animals and that failure causes injury to the animals or the owner.[10]
An important aspect of the law is that prosecutors may be able to charge hoarders with one count of animal hoarding that covers all of the animals.[10] When hoarding is prosecuted under state animal cruelty laws, prosecutors must charge hoarders with multiple counts of animal cruelty—one for each animal on the premises.[10] By creating the offense of “hoarding”, Hawaii's law seems to allow prosecutors to charge hoarders with one count of animal hoarding that covers every animal the person has hoarded, easing the prosecution's burden of providing documentation of each individual animal's injury.[10] This will also decrease the cumbersome burden multiple charges can place on courts.[10] Prosecutors will also be able to bring separate charges of animal cruelty for individual animals whose injuries are easiest to document.[10]
Hawaii's statute does not mandate psychological counseling for convicted hoarders or restrict future animal ownership.[10]
Anti-hoarding legislation has been proposed, but not passed, in several other states.[26]
#### Hoarding-specific municipal ordinances[edit]
While a state may not have an animal hoarding specific statute, its municipalities may have animal hoarding specific ordinances. For instance, the city of Alto, Georgia's ordinance specifically prohibits hoarders.[27] The ordinance defines a hoarder as a person or entity that:
> (a) Collects animals and fails to provide them with humane/adequate care;
>
> (b) Collects dead animals that are not properly disposed of as required by this article; or
>
> (c) Collects, houses, or harbors animals in filthy, unsanitary conditions that constitute a health hazard to the animals being kept, and/or to the animals or residents of adjacent property.
[27]
If a person is convicted of being a hoarder under this ordinance, that person may not own, possess, or have on his premises in Alto any animal for one year from the date of conviction. The person may also be punished by a fine not to exceed $1,000.00 and/or by imprisonment in the common jail of the town not to exceed six months. [27]
The Animal Law Coalition has a Model Animal Hoarding Specific Ordinance (available under “Resources” at its website) that can be adapted by various communities.[28]
More controversially, a municipality may limit the number of pets a person is allowed to keep in his or her home in hopes of preventing animal hoarding. These are called pet limitation ordinances. Gary J. Patronek, in The Problem of Animal Hoarding, Municipal Lawyer 6 (2001), stated that pet limitation ordinances are “wildly unpopular, difficult to enforce, and likely to be opposed by a broad coalition of pet fanciers, breeders, rescue groups, and animal protection organizations.” While a hoarding specific ordinance, like Alto, prohibits keeping numerous animals in conditions that are harmful to the animals’ health, pet limitation ordinances simply prohibit keeping more than a certain number of animals regardless of the level of care provided to the animals.[10] As mentioned previously in this article, the number of animals involved alone is not a determinative factor in identifying hoarding and it is possible for a person to successfully care for a large number of animals. Examples of pet limitation ordinances include: Aurora, Colorado and Banks County, Georgia.[29][30] In Banks County, Georgia, the number of dogs a person can own differs based on the zone in which the person's property is located.
Some pet limitation ordinances, however, provide exemptions to the pet restrictions. For instance, in Great Falls, Montana, a person who owns or harbors any more than the number of dogs and cats permitted by the ordinance for a period of more than thirty (30) days must obtain a multiple animal permit. Additionally, a breeder can be exempt from the ordinance by obtaining a Multiple Animal Hobby Breeder Permit. These exemptions are, no doubt, provided to lessen the opposition and problems of pet limitation ordinances.[31]
#### Problems with prosecuting hoarders[edit]
Prosecuting animal hoarding cases is “complex, time consuming, and costly; as made evident in the Primrose case, the high cost of caring for animals rescued from hoarders, who often must be cared for at the rescuer’s expense, is a huge disincentive for prosecuting these types of cases. Especially since the animal rescue operation may never be compensated for its expenses. Further, as Dr. Gary Patronek explains, “[p]rosecutors don't really have the tools they need to fully go after these cases . . . and they often don't have the support of other agencies that they need.” [10] This lack of communication among various governmental agencies, such as code enforcement, the health department, and animal control, impedes the detection of animal hoarders and thereby the prosecution of hoarders.[10] Further, since animal hoarding cases do not get widespread attention, they do not garner community support, which is also a disincentive for prosecution.[10] Additionally, officials may opt to forgo charges or enter into lenient plea-bargains in exchange for custody of the animals because they fear that the animals will languish in shelters while prosecution is pending.[10] These attempts to “strike a balance between helping both the hoarder and the animals involved” are generally ineffective because of high recidivism rates among hoarders.[10] When hoarders are prosecuted, there is broad inconsistency in the number and severity of charges brought.[10] These inconsistencies may arise because some prosecutors and judges discourage multiple charges, believing that they “clog” the system.[10] The difficulty of proving each charge also accounts for these inconsistencies. In order to bring one charge of cruelty for each animal, prosecutors and animal agencies must provide proof of cruelty to each animal, matching each animal with its count number.[10] Adversely, charging the hoarder with only one count reduces the burdens on the system, the prosecutors, and the animal agencies, but undermines the severity of the charges.[10] Laws that create a separate offense of animal hoarding may solve this problem by allowing one count of hoarding to be brought in every case that encompasses the hoarding aspect of the charge rather than focusing on each individual count of cruelty.[10]
### United Kingdom[edit]
In the United Kingdom, an RSPCA spokeswoman said the society was campaigning for legislation to monitor people who take in large numbers of animals.[32]
## Dangers[edit]
The health issues in animal hoarding encompass a variety of concerns related to both individual and public health. Animal hoarding is the cause of many severe health risks that threaten the hoarded animals, individuals living in hoarding residences, and surrounding neighbors.
### Health effects on animals[edit]
Due to the harmful effects on the health of the animals involved, animal hoarding is considered a form of cruelty to animals.[3] Hoarders often fail to provide basic care for their animals, thus resulting in disease and often death. The primary animal health issues involved are malnourishment and problems related to overcrowding and neglect. Consequences of hoarding are long-lasting and continue to affect the animals even after they have been rescued and provided with better care.[33]
#### Malnourishment[edit]
Lack of sufficient food and water is a common feature of hoarding situations. The immediate consequence of this is starvation and death.[3] One study found at least one dead animal present in over half of examined cases, the leading cause of death being an insufficient food and water supply.[34] Malnourishment also leads to increased susceptibility to disease, and the hoarded animals are often in advanced stages of sickness.[34] Furthermore, when there is a limited food supply, animals may resort to aggressive behavior in competing for available food, killing and sometimes even eating other animals.[35]
#### Overcrowding[edit]
Overcrowding also leads to acute animal health problems in hoarding situations. The number of animals found in hoarding cases range from dozens to several hundreds, with extreme cases involving over a thousand animals. Animals are confined to houses, apartments, or trailer-homes.[34] In one case, 306 cats were removed from a home, 87 of which were dead. Corpses were found embedded in the chimney and living room furniture.[3] In addition to lack of living space, overcrowding facilitates the spread of diseases among animals.[35] Furthermore, in cases where more than one species is confined to the same living space, animals can pose a danger to one other due to inter-species aggression.[36]
#### Owner neglect[edit]
Various other health problems arise from hoarders' neglect of the animals and inability to provide basic care for them. Lack of veterinary attention is notable among these. Hoarders, refusing to acknowledge the deteriorating health conditions of their animals and scared they will be forced to give up custody, often refuse to take their animals to veterinarians.[33] As a result, diseases are left untreated and allowed to become more severe. Another problem tied to neglect is poor sanitary conditions for the animals. Basic animal waste management is absent in virtually all animal-hoarding situations, and animals are filthy and often infected with parasites as a result.[35] Furthermore, animals suffer behaviorally from a lack of socialization caused by an absence of normal interaction with other animals.[33]
#### Lasting consequences[edit]
Many of these health problems continue to cause suffering even after the animals are rescued. Strained animal shelters or humane societies, forced to prioritize when dealing with numerous rescued animals, may be unable to provide immediate treatment to many animals.[36] Furthermore, many of the rescued animals, due to health or behavioral problems, may not be suitable for adoption.[33] Euthanasia, even in cases where the animals are not beyond rehabilitation, is often the only option for rescued animals.[36] The effects of hoarding on the health and socialization of the animals involved are severe and lasting, taking heavy tolls on both their physical and psychological well-being.
### Health effects on humans[edit]
Animal hoarding also causes many health problems for the people involved. Hoarders, by definition, fail to correct the deteriorating sanitary conditions of their living spaces, and this gives rise to several health risks for those living in and around hoarding residences.[3] Animal hoarding is at the root of a string of human health problems including poor sanitation, fire hazards, zoonotic diseases, envenomation, and neglect of oneself and one's dependents.
#### Sanitation concerns[edit]
Poor sanitation practices, a general characteristic of hoarding households, pose health risks to both animals and humans. In typical hoarding residences, animal waste is found coating interior surfaces, including beds, countertops, and cupboards.[37] In one case, floors and other surfaces were found to be covered in a six-inch layer of feces and garbage.[3]
In addition to severe odors which may pose a nuisance to neighbors, animal waste poses serious health risks through both the spread of parasites and the presence of noxious ammonia levels.[35] OSHA, the United States agency regulating air quality standards in work-related environments, has identified an ammonia level of 300 parts per million as life-threatening for humans;[33] in many hoarding cases the atmospheric ammonia level in the housing space approaches this number,[36] requiring the use of protective clothing and breathing apparati during inspections or interventions.[37] In an extreme case, the ammonia level in the hoarder's house was 152 parts per million even after ventilation.[33]
The presence of animal waste also prevents sanitary storage and preparation of food, which puts residents at risk of contracting food-related illnesses and parasites.[37] Insect and rodent infestation can both follow and worsen hoarding conditions, and can potentially spread to the surrounding environment including to nearby buildings.[36] In one case, an elementary school had to be shut down due to a flea infestation that had spread from a nearby dog hoarder residence.[37]
Hoarders are frequently found to collect large numbers of inanimate objects in addition to animals,[34] giving rise to clutter as well. Hoarded objects can include newspapers, trash, clothing, and food; the clutter inhibits normal movement around the house, hampering household maintenance and sanitary food preparation, heightening the risk of accidents, and contributing to the overall level of squalor.[34] A lack of functioning toilets, sinks, electricity, or proper heating (often due to hoarders not paying bills, though poor maintenance may also be a cause) further exacerbates the problem.[37] Fire hazards comprise yet another health issue tied to poor sanitation;[37] the clutter found in many hoarding households prevents workable fire escape plans and serves as possible fuel when located close to heat sources. The risk is amplified when hoarders, due to inoperative heating systems, seek alternate heating methods such as fireplaces, stoves, or kerosene heaters.[37][38]
#### Zoonotic diseases[edit]
Another human health issue caused by animal hoarding is the risk of zoonotic diseases. Defined as "human diseases acquired from or transmitted to any other vertebrate animal",[39] zoonotic diseases can often be lethal and in all cases constitute a serious public health concern. Examples of well-known zoonotic diseases include bubonic plague, influenza, and rabies.[40] Common domesticated animals constitute a large portion of animals carrying zoonoses,[39] and as a result, humans involved in animal hoarding situations are at particular risk of contracting disease.[34] Zoonoses that may arise in hoarding situations—through vectors such as dog, cat, or rat bites—include rabies, salmonellosis, catscratch fever, hookworm, and ringworm.[41] One zoonosis of special concern is toxoplasmosis, which can be transmitted to humans through cat feces or badly-prepared meat, and is known to cause severe birth defects or stillbirth in the case of infected pregnant women.[42] The risk of zoonotic diseases is amplified by the possibility of community epidemics.
#### Self-neglect and child/elder abuse[edit]
Main article: Diogenes syndrome
The problems of self-neglect and elder and child abuse are also health problems associated with animal hoarding. Self-neglect can be defined as "the inability to provide for oneself the goods or services to meet basic needs", and has been shown to be an "independent risk factor for death".[43] While self-neglect is a condition generally associated with the elderly, animal hoarders of any age can and do suffer from it.[37] This is demonstrated by the fact that hoarders' lifestyles often match the degenerate sanitary conditions that surround them. Child and elder abuse arise when dependents are living with the hoarder. According to one study, dependents lived with hoarders in over half of the cases.[33] As with his or her animals, the hoarder often fails to provide adequate care for dependents both young and old, who suffer from a lack of basic necessities as well as the health problems caused by unsanitary conditions.[34] In one case, two children of a couple hoarding 58 cats and other animals were forced to repeat kindergarten and first grade because of excessive absence due to respiratory infections.[37] Self-neglect and neglect of dependents make up a major human health concern of animal hoarding.
## Mental health issues[edit]
Evidence suggests that there is "a strong mental health component" in animal hoarding, though it has not been firmly linked to any specific psychological disorder.[38] Models that have been projected to explain animal hoarding include delusional disorder, attachment disorder, obsessive–compulsive disorder, zoophilia, dementia, and addiction.[44] Direct evidence for most is lacking, however.[37]
### Delusional disorder[edit]
Animal hoarders display symptoms of delusional disorder in that they have a "belief system out of touch with reality".[38] Virtually all hoarders lack insight into the extent of deterioration in their habitations and on the health of their animals, refusing to acknowledge that anything is wrong.[37] Furthermore, hoarders may believe they have "a special ability to communicate and/or empathize with animals",[44] rejecting any offers of assistance. Delusional disorder is an effective model in that it offers an explanation of hoarders' apparent blindness to the realities of their situations.
### Attachment disorder[edit]
Another model that has been suggested to explain animal hoarding is attachment disorder, which is primarily caused by poor parent-child relationships during childhood. It is characterized by an inability to form "close relationships [with other humans] in adulthood".[44] As a result, those suffering from attachment disorder may turn to animals for companionship. Interviews with animal hoarders have revealed that hoarders have often experienced domestic trauma in childhood, which is the basis of the evidence for this model.[44]
### Obsessive–compulsive disorder[edit]
Perhaps the strongest psychological model put forward to explain animal hoarding is obsessive–compulsive disorder (OCD). An overwhelming sense of responsibility for something is characteristic of people with OCD, who then take unrealistic measures to fulfill their perceived duty. Animal hoarders often feel a strong sense of responsibility to take care of and protect animals, and their solution—that of acquiring as many animals as they possibly can—is unrealistic.[44] Further, the hoarding of inanimate objects, practiced by a majority of animal hoarders,[37] is a fairly common occurrence in people with OCD.[44] These connections between animal hoarding and obsessive–compulsive disorder suggest that OCD may be a useful model in explaining animal hoarding behavior.[44] However, this theory has also been refuted by some; Dr. Akimitsu Yokoyama theorizes that animal hoarding could be explained using Asperger syndrome.[45]
## Popular culture and fiction[edit]
* On the Animal Planet TV series Confessions: Animal Hoarding, friends and family of animal hoarders intervene to offer them support to make a change in the form of psychological help and veterinary care or placement for their pets.
* In the animated series The Simpsons, animal hoarding is represented by the semi-recurring character Crazy Cat Lady Eleanor Abernathy. She is a mentally ill old woman covered by cats, who is often seen speaking in gibberish and throwing cats at people.
* In Ann Bannon's novel Journey to a Woman, Vega's mother and grandfather own an excessive number of cats and could be considered to be animal hoarders.
* In webtoon Lookism, an arc featuring an animal hoarder nabbed both Daniel Park and Johan Song's dogs. But she was later released after posting bail and restarted her hoarding.
## See also[edit]
* Cat lady
* Compulsive hoarding
* Geriatric medicine
* Monomania
## References[edit]
1. ^ a b Davis, Susan; Flaherty (illus), Jake (2002). "Prosecuting Animal Hoarders is like Herding Cats" (PDF). California Lawyer (September): 26, 28, 29, 67. Archived from the original (PDF) on July 3, 2004.
2. ^ a b Hoarding of Animals Research Consortium (HARC) (2004). "Commonly asked questions about hoarding". Archived from the original on 2010-01-12.
3. ^ a b c d e f Patronek, Gary J. "Animal hoarding: its roots and recognition." Veterinary Medicine 101.8 (2006): 520.
4. ^ a b Berry, Colin, M.S., Gary Patronek, V.M.D., Ph.D., and Randall Lockwood, Ph.D. "Long-Term Outcomes in Animal Hoarding Cases" (PDF). Archived from the original (PDF) on March 3, 2006.CS1 maint: uses authors parameter (link)
5. ^ "Mental health issues and animal hoarding". Archived from the original on 2014-06-13.
6. ^ American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). Arlington, VA: American Psychiatric Publishing. ISBN 978-0-89042-555-8.
7. ^ a b Hayes, Victoria (May 2010). "Detailed Discussion of Animal Hoarding". The Animal Legal and Historical Center. Michigan State University College of Law. Retrieved 2014-04-08.
8. ^ a b c Leek Leiberan, Margaret H. (March 2006). "In the Matter of a Protective Order for Jean Marie Primrose" (PDF). pleading. Retrieved 2014-04-08.
9. ^ Avery, Lisa (2005). "From Helping to Hoarding to Hurting: When the Acts of "Good Samaritans" Become Felony Animal Cruelty". Val. U. L. Rev. 39: 826. Retrieved 8 April 2014.
10. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag Hayes, Victoria (2010). "Detailed Discussion of Animal Hoarding". The Animal Legal and Historical Society. Michigan State University College of Law. Retrieved 2014-04-12.
11. ^ "3". Act No. 03.55.100 of 2004. Retrieved 2014-04-12.
12. ^ a b "18". Act No. 18-9-202 of 2012. Retrieved 2014-04-12.
13. ^ "18". Act No. 18-9-201(4) of 2012. Retrieved 2014-04-12.
14. ^ "11". Act No. 11.61.140(d) of 2010. Retrieved 2014-04-12.
15. ^ "11". Act No. 11.61.140(a)(2) of 2010. Retrieved 2014-04-12.
16. ^ "18". Act No. 18-9-202(2)(a) of 2012. Retrieved 2014-04-12.
17. ^ a b c "3.2". Article 2, Act No. 3.2-6503 of 2003. Retrieved 2014-04-12.
18. ^ "3.2". Article 9, Act No. 3.2-6570 of 2013. Retrieved 2014-04-12.
19. ^ "14". Act No. 597 of 2011. Retrieved 2014-04-12.
20. ^ "LXII". Act No. 644:8 of 2008. Retrieved 2014-04-12.
21. ^ "7". Act No. 4016 of 2007. Retrieved 2014-04-12.
22. ^ "In the Matter of a Protective Order for Jean Marie Primrose". The Animal Legal and Historical Center. Michigan State University College of Law. 2005. Retrieved 2014-04-12.
23. ^ "Once Neglected, Now Protected – ALDF Wins Historic Ruling for Abused Animals". Animal Legal Defense Fund. Animal Legal Defense Fund. 2007. Archived from the original on 2014-04-13. Retrieved 2014-04-12.
24. ^ a b c d "ALDF v. Conyers". The Animal Legal and Historical Center. 2007. Retrieved 2014-04-12.
25. ^ "37". Act No. 711-1109.6 of 2009. Retrieved 2014-04-12.
26. ^ ASPCA (2010). "Frequently Asked Questions About Animal Hoarding". ASPCA. ASPCA. Archived from the original on 2014-04-16. Retrieved 2014-04-12.
27. ^ a b c "Alto, Georgia Ordinance". Retrieved 30 April 2014.
28. ^ "Animal Law Coalition".
29. ^ "Aurora, Colorado Ordinance". Retrieved 30 April 2014.
30. ^ "Banks County, Georgia Ordinance". Retrieved 30 April 2014.
31. ^ "Great Falls, MontanaOrdinance". Retrieved 30 April 2014.
32. ^ "Health: Pet hoarders may need help". BBC News. 1999-06-22. Retrieved 2010-01-01.
33. ^ a b c d e f g Berry, Colin, Gary Patronek, and Randy Lockwood. "Long-term outcomes in animal hoarding cases." Animal Law 11 (2005): 167-194.
34. ^ a b c d e f g Patronek, Gary. "Hoarding of animals: an under-recognized problem in a difficult to study population." Public Health Reports (Hyattsville) 114.1 (1999-02): 81-88.[dead link]
35. ^ a b c d "The Hoarding of Animals Research Consortium (HARC)". Tufts University. Archived from the original on 2011-01-17. Retrieved 2007-12-07.
36. ^ a b c d e Patronek, Gary (18 November 2007). "Large scale removal and rescue of animals" (PDF). Hoarding of Animals Research Consortium. Tufts University. Archived from the original (pdf) on October 13, 2006.
37. ^ a b c d e f g h i j k l Arluke, Arnie; et al. (May 2002). "Health Implications of Animal Hoarding". Health & Social Work. 27 (2): 125. doi:10.1093/hsw/27.2.125.
38. ^ a b c Patronek, Gary. "The Problem of Animal Hoarding." Animal Law May/June 2001: 6-9, 19.
39. ^ a b "animal disease." Encyclopædia Britannica. 2007. Encyclopædia Britannica Online. 8 Dec. 2007 <http://search.eb.com/eb/article-63292>.
40. ^ Last, Ed. John M. (2007). "zoonosis". A Dictionary of Public Health: Oxford Reference Online. Oxford University Press.
41. ^ John M. Last "animals as carriers of disease" The Oxford Companion to Medicine. Stephen Lock, John M. Last, and George Dunea. Oxford University Press 2001. Oxford Reference Online. Oxford University Press. Brigham Young University (BYU). 8 December 2007.
42. ^ "toxoplasmosis" A Dictionary of Public Health. Ed. John M. Last, Oxford University Press, 2007. Oxford Reference Online. Brigham Young University. 8 December 2007.
43. ^ Dyer, Carmel Bitondo, et al. "Self-Neglect Among the Elderly: A Model Based on More Than 500 Patients Seen by a Geriatric Medicine Team." American Journal of Public Health. 97 (2007-09): 1671.
44. ^ a b c d e f g Frost, Randy (2000). "People Who Hoard Animals". Psychiatric Times. 17 (4).
45. ^ Philips, Allie (2011). Defending the Defenseless: A Guide to Protecting and Advocating for Pets. Rowman & Littlefield Publishers. p. 125. ISBN 9781442202146.
## External links[edit]
* Confessions: Animal Hoarding on Animal Planet
* Animal Hoarding documentary project
* Inside Animal Hoarding (with video)
* People Who Hoard Animals, Psychiatric Times
* Hoarding, Humane Society of the United States
* The Hoarding of Animals Research Consortium, Tufts University
* Animal Hoarding, American Society for the Prevention of Cruelty to Animals
* Animal Legal Defense Fund
* Animal Hoarding: Alone in a Crowded Room
* News and information on animal hoarding and large scale animal cruelty
* Mary Chantrell, a Notorious 19th Century Cat Hoarder
* v
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*[c.]: circa
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*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Animal hoarding | None | 4,921 | wikipedia | https://en.wikipedia.org/wiki/Animal_hoarding | 2021-01-18T19:08:02 | {"wikidata": ["Q489499"]} |
Placentitis
Gross pathology of severe intervillositis, with dark red and soggy tissue.
SpecialtyOB/GYN
Histopathology of acute subchorionic intervillositis, with neutrophils in Langhan’s layer of fibrinoid (by the fetal surface, at the base of a chorionic villus, seen at top right).
Placentitis is an inflammation of the placenta. The main forms of placentitis are:
* Villitis, inflammation of chorionic villi.
* Intervillositis, inflammation of the intervillous space.[1]
It may be caused by vertically transmitted infections.
Because of the close proximity, placentitis often occurs simultaneously as funisitis (inflammation of the umbilical cord) and chorioamnionitis (inflammation of the fetal membranes).
Chronic lymphocytic placental inflammation occurs in 5% to 15% of pregnancies, and are generally not associated with documented infection.[2]
## Contents
* 1 Villitis of unknown etiology
* 2 Chronic histiocytic intervillositis
* 3 See also
* 4 References
* 5 External links
## Villitis of unknown etiology[edit]
Main article: Villitis of unknown etiology
Villitis of unknown etiology (VUE), also known as chronic villitis, is a placental injury. VUE is an inflammatory condition involving the chorionic villi (placental villi). VUE is a recurrent condition and can be associated with intrauterine growth restriction (IUGR). IUGR involves the poor growth of the foetus, stillbirth, miscarriage, and premature delivery.[3][4] VUE recurs in about 1/3 of subsequent pregnancies.[5]
VUE is a common lesion characterised by inflammation in the placental chorionic villi. VUE is also characterised by the transfer of maternal lymphocytes across the placenta.[4]
VUE is diagnosed in 7–10% placentas in pregnancies. Roughly 80% of the VUE cases are in term placentas (greater than 37 weeks of pregnancy). A case of VUE in a placenta less than 32 weeks old should be screened for infectious villitis.[3]
## Chronic histiocytic intervillositis[edit]
Chronic Histiocytic Intervillositis (CHI or CHIV) also known as Chronic Intervillositis of Unknown (A)etiology (CIUE) and Massive Chronic Intervillositis (MCI) is defined as a diffuse infiltration of mononuclear cells (histiocytes, lymphocytes, monocytes) of maternal origin into the intervillous space within the placenta. It often results in severe intrauterine growth restriction which can lead to miscarriage or stillbirth. Overall perinatal mortality rate is high: 41%[6] to 77%.[7] Recurrence rate is also high: 67%[7] to 100%.[6]
## See also[edit]
* Chorioamnionitis
## References[edit]
1. ^ Schubert, Pawel T; Mason, Deidre; Martines, Roosacelis; Deleon-Carnes, Marlene; Zaki, Sherif R; Roberts, Drucilla J (2018). "Spectrum of Changes Seen With Placental Intravascular Organisms". Pediatric and Developmental Pathology. 22 (3): 229–235. doi:10.1177/1093526618801616. ISSN 1093-5266.
2. ^ Redline, Raymond W. (2007). "Placental Inflammation": 90–101. doi:10.1007/978-1-84628-743-5_4. Cite journal requires `|journal=` (help)
3. ^ a b Redline, RW. (Oct 2007). "Villitis of unknown etiology: noninfectious chronic villitis in the placenta". Hum Pathol. 38 (10): 1439–46. doi:10.1016/j.humpath.2007.05.025. PMID 17889674.
4. ^ a b Tamblyn J, Lissauer D, Powell R, Cox P, Kilby M (2013). "The immunological basis of villitis of unknown etiology – Review". Placenta. 34 (10): 846–55. doi:10.1016/j.placenta.2013.07.002. PMID 23891153.
5. ^ Feeley L, Mooney EE (2010). "Villitis of unknown aetiology: correlation of recurrence with clinical outcome". J Obstet Gynaecol. 30 (5): 476–9. doi:10.3109/01443611003802339. PMID 20604650.
6. ^ a b Parant O, Capdet J, Kessler S, Aziza J, Berrebi A. "Chronic intervillositis of unknown etiology (CIUE): relation between placental lesions and perinatal outcome". European Journal of Obstetrics, Gynecology, and Reproductive Biology. 143: 9–13. doi:10.1016/j.ejogrb.2008.06.012. PMID 19121887.
7. ^ a b Boyd TK, Redline RW. "Chronic histiocytic intervillositis: A placental lesion associated with recurrent reproductive loss". Human Pathology. 31: 1389–96. doi:10.1016/s0046-8177(00)80009-x. PMID 11112214.
## External links[edit]
* CHI Support
* CHI Facebook Support Group
This article has not been added to any content categories. Please help out by adding categories to it so that it can be listed with similar articles. (January 2021)
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Placentitis | c0032059 | 4,922 | wikipedia | https://en.wikipedia.org/wiki/Placentitis | 2021-01-18T19:05:41 | {"umls": ["C0032059"], "wikidata": ["Q2099131"]} |
Bacterial infection of the prostate gland
Chronic Bacterial Prostatitis
SpecialtyUrology
Chronic bacterial prostatitis is a bacterial infection of the prostate gland. It should be distinguished from other forms of prostatitis such as acute bacterial prostatitis and chronic pelvic pain syndrome (CPPS).[1]
## Contents
* 1 Signs and symptoms
* 2 Diagnosis
* 3 Treatment
* 4 Prognosis
* 5 Additional images
* 6 References
* 7 External links
## Signs and symptoms[edit]
Chronic bacterial prostatitis is a relatively rare condition that usually presents with an intermittent UTI-type picture. It is defined as recurrent urinary tract infections in men originating from a chronic infection in the prostate. Symptoms may be completely absent until there is also bladder infection, and the most troublesome problem is usually recurrent cystitis.[2]
Chronic bacterial prostatitis occurs in less than 5% of patients with prostate-related non-BPH lower urinary tract symptoms (LUTS).
Dr. Weidner, Professor of Medicine, Department of Urology, University of Gießen, has stated: "In studies of 656 men, we seldom found chronic bacterial prostatitis. It is truly a rare disease. Most of those were E-coli."[3]
## Diagnosis[edit]
In chronic bacterial prostatitis, there are bacteria in the prostate, but there may be no symptoms or milder symptoms than occur with acute prostatitis.[4] The prostate infection is diagnosed by culturing urine as well as prostate fluid (expressed prostatic secretions or EPS) which are obtained by the doctor performing a rectal exam and putting pressure on the prostate. If no fluid is recovered after this prostatic massage, a post massage urine should also contain any prostatic bacteria.[citation needed]
Prostate specific antigen levels may be elevated, although there is no malignancy. Semen analysis is a useful diagnostic tool.[5] Semen cultures are also performed. Antibiotic sensitivity testing is also done to select the appropriate antibiotic. Other useful markers of infection are seminal elastase and seminal cytokines.
## Treatment[edit]
Antibiotic therapy has to overcome the blood/prostate barrier that prevents many antibiotics from reaching levels that are higher than minimum inhibitory concentration.[6] A blood-prostate barrier restricts cell and molecular movement across the rat ventral prostate epithelium.[7] Treatment requires prolonged courses (4–8 weeks) of antibiotics that penetrate the prostate well.[8] The fluoroquinolones, tetracyclines and macrolides have the best penetration. There have been contradictory findings regarding the penetrability of nitrofurantoin[contradictory], quinolones (ciprofloxacin, levofloxacin), sulfas (Bactrim, Septra), doxycycline and macrolides (erythromycin, clarithromycin). This is particularly true for gram-positive infections.[citation needed]
In a review of multiple studies, levofloxacin was found to reach prostatic fluid concentrations 5.5 times higher than ciprofloxacin, indicating a greater ability to penetrate the prostate.[9]
Clinical success rates with oral antibiotics can reach 70% to 90% at 6 months, although trials comparing them with placebo or no treatment do not exist.[10]
Persistent infections may be helped in 80% of patients by the use of alpha blockers (tamsulosin, alfuzosin), or long term low dose antibiotic therapy.[11] Recurrent infections may be caused by inefficient urination (benign prostatic hypertrophy, neurogenic bladder), prostatic stones or a structural abnormality that acts as a reservoir for infection.
In theory, the ability of some strains of bacteria to form biofilms might be one of the factors that facilitate development of chronic bacterial prostatitis.[12]
Bacteriophages hold promise as another potential treatment for chronic bacterial prostatatis.[13]
The addition of prostate massage to courses of antibiotics was previously proposed as being beneficial and prostate massage may mechanically break up the biofilm and enhance the drainage of the prostate gland.[14][15] However, in more recent trials, this was not shown to improve outcome compared to antibiotics alone.[16]
## Prognosis[edit]
Over time, the relapse rate is high, exceeding 50%. However, recent research indicates that combination therapies offer a better prognosis than antibiotics alone.
A 2007 study showed that repeated combination pharmacological therapy with antibacterial agents (ciprofloxacin/azithromycin), alpha-blockers (alfuzosin) and Serenoa repens extracts may eradicate infection in 83.9% of patients with clinical remission extending throughout a follow-up period of 30 months for 94% of these patients.[17]
A 2014 study of 210 patients randomized into two treatment groups found that recurrence occurred within 2 months in 27.6% of the group using antibiotics alone (prulifloxacin 600 mg), but in only 7.8% of the group taking prulifloxacin in combination with Serenoa repens extract, Lactobacillus Sporogens and Arbutin.[18]
Large prostatic stones was shown to be related with the presence of bacteria,[19] a higher urinary symptoms and pain score, a higher IL-1β and IL-8 concentration in seminal plasma, a greater prostatic inflammation and a lower response to antibiotic treatment.[20]
## Additional images[edit]
* Prostate, urethra, and seminal vesicles.
* The arteries of the pelvis.
* Male pelvic organs seen from right side.
## References[edit]
1. ^ Holt JD, Garrett WA, McCurry TK, Teichman JM (February 2016). "Common Questions About Chronic Prostatitis". American Family Physician. 93 (4): 290–6. PMID 26926816.
2. ^ Habermacher GM, Chason JT, Schaeffer AJ (2006). "Prostatitis/chronic pelvic pain syndrome". Annual Review of Medicine. 57 (1): 195–206. doi:10.1146/annurev.med.57.011205.135654. PMID 16409145.
3. ^ Schneider H, Ludwig M, Hossain HM, Diemer T, Weidner W (October 2003). "The 2001 Giessen Cohort Study on patients with prostatitis syndrome--an evaluation of inflammatory status and search for microorganisms 10 years after a first analysis". Andrologia. 35 (5): 258–62. doi:10.1046/j.1439-0272.2003.00586.x. PMID 14535851. S2CID 21022117.
4. ^ "Prostatitis - Symptoms". NHS Choices. 2017-10-19.
5. ^ Magri V, Wagenlehner FM, Montanari E, Marras E, Orlandi V, Restelli A, et al. (July 2009). "Semen analysis in chronic bacterial prostatitis: diagnostic and therapeutic implications". Asian Journal of Andrology. 11 (4): 461–77. doi:10.1038/aja.2009.5. PMC 3735310. PMID 19377490.
6. ^ Fulmer BR, Turner TT (May 2000). "A blood-prostate barrier restricts cell and molecular movement across the rat ventral prostate epithelium". The Journal of Urology. 163 (5): 1591–4. doi:10.1016/S0022-5347(05)67685-9. PMID 10751894.
7. ^ Barza M (January 1993). "Anatomical barriers for antimicrobial agents". European Journal of Clinical Microbiology & Infectious Diseases. 12 Suppl 1 (Suppl 1): S31-5. doi:10.1007/BF02389875. PMID 8477760. S2CID 23753756.
8. ^ Charalabopoulos K, Karachalios G, Baltogiannis D, Charalabopoulos A, Giannakopoulos X, Sofikitis N (December 2003). "Penetration of antimicrobial agents into the prostate" (PDF). Chemotherapy. 49 (6): 269–79. doi:10.1159/000074526. PMID 14671426. S2CID 14731590.
9. ^ "Levofloxacin and Its Effective Use in the Review Management of Bacterial Prostatitis" (PDF). Archived from the original (PDF) on 2017-08-09. Retrieved 2016-02-08.
10. ^ Bowen DK, Dielubanza E, Schaeffer AJ (August 2015). "Chronic bacterial prostatitis and chronic pelvic pain syndrome". BMJ Clinical Evidence. 2015: 1802–1831. PMC 4551133. PMID 26313612.
11. ^ Shoskes DA, Hakim L, Ghoniem G, Jackson CL (April 2003). "Long-term results of multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome". The Journal of Urology. 169 (4): 1406–10. doi:10.1097/01.ju.0000055549.95490.3c. PMID 12629373.
12. ^ Wagenlehner FM, Pilatz A, Bschleipfer T, Diemer T, Linn T, Meinhardt A, et al. (August 2013). "Bacterial prostatitis". World Journal of Urology. 31 (4): 711–6. doi:10.1007/s00345-013-1055-x. PMID 23519458. S2CID 1925596.
13. ^ Letkiewicz S, Międzybrodzki R, Kłak M, Jończyk E, Weber-Dąbrowska B, Górski A (November 2010). "The perspectives of the application of phage therapy in chronic bacterial prostatitis". FEMS Immunology and Medical Microbiology. 60 (2): 99–112. doi:10.1111/j.1574-695X.2010.00723.x. PMID 20698884.
14. ^ Nickel JC, Downey J, Feliciano AE, Hennenfent B (September 1999). "Repetitive prostatic massage therapy for chronic refractory prostatitis: the Philippine experience". Techniques in Urology. 5 (3): 146–51. PMID 10527258.
15. ^ Shoskes DA, Zeitlin SI (May 1999). "Use of prostatic massage in combination with antibiotics in the treatment of chronic prostatitis". Prostate Cancer and Prostatic Diseases. 2 (3): 159–162. doi:10.1038/sj.pcan.4500308. PMID 12496826.
16. ^ Ateya A, Fayez A, Hani R, Zohdy W, Gabbar MA, Shamloul R (April 2006). "Evaluation of prostatic massage in treatment of chronic prostatitis". Urology. 67 (4): 674–8. doi:10.1016/j.urology.2005.10.021. PMID 16566972.
17. ^ Magri V, Trinchieri A, Pozzi G, Restelli A, Garlaschi MC, Torresani E, et al. (May 2007). "Efficacy of repeated cycles of combination therapy for the eradication of infecting organisms in chronic bacterial prostatitis". International Journal of Antimicrobial Agents. 29 (5): 549–56. doi:10.1016/j.ijantimicag.2006.09.027. PMID 17336504.
18. ^ Busetto GM, Giovannone R, Ferro M, Tricarico S, Del Giudice F, Matei DV, et al. (July 2014). "Chronic bacterial prostatitis: efficacy of short-lasting antibiotic therapy with prulifloxacin (Unidrox®) in association with saw palmetto extract, lactobacillus sporogens and arbutin (Lactorepens®)". BMC Urology. 14 (1): 53. doi:10.1186/1471-2490-14-53. PMC 4108969. PMID 25038794.
19. ^ Mazzoli, Sandra (August 2010). "Biofilms in chronic bacterial prostatitis (NIH-II) and in prostatic calcifications". FEMS Immunology and Medical Microbiology. 59 (3): 337–344. doi:10.1111/j.1574-695X.2010.00659.x. ISSN 1574-695X. PMID 20298500.
20. ^ Soric, Tomislav; Selimovic, Mirnes; Bakovic, Lada; Šimurina, Tatjana; Selthofer, Robert; Dumic, Jerka (2017). "Clinical and Biochemical Influence of Prostatic Stones". Urologia Internationalis. 98 (4): 449–455. doi:10.1159/000455161. ISSN 1423-0399. PMID 28052296. S2CID 4927272.
## External links[edit]
Classification
D
* ICD-10: N41.1
* ICD-9-CM: 601.1
* DiseasesDB: 10801
External resources
* MedlinePlus: 000523
* eMedicine: med/1920
* Prostatitis at Curlie
* NHS Choices (prostatitis)
* v
* t
* e
Male diseases of the pelvis and genitals
Internal
Testicular
* Orchitis
* Hydrocele testis
* Testicular cancer
* Testicular torsion
* Male infertility
* Aspermia
* Asthenozoospermia
* Azoospermia
* Hyperspermia
* Hypospermia
* Oligospermia
* Necrospermia
* Teratospermia
Epididymis
* Epididymitis
* Spermatocele
* Hematocele
Prostate
* Prostatitis
* Acute prostatitis
* Chronic bacterial prostatitis
* Chronic prostatitis/chronic pelvic pain syndrome
* Asymptomatic inflammatory prostatitis
* Benign prostatic hyperplasia
* Prostate cancer
Seminal vesicle
* Seminal vesiculitis
External
Penis
* Balanoposthitis / Balanitis
* Balanitis plasmacellularis
* Pseudoepitheliomatous keratotic and micaceous balanitis
* Phimosis
* Paraphimosis
* Priapism
* Sexual dysfunction
* Erectile dysfunction
* Peyronie's disease
* Penile cancer
* Penile fracture
* Balanitis xerotica obliterans
Other
* Hematospermia
* Retrograde ejaculation
* Postorgasmic illness syndrome
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Chronic bacterial prostatitis | c1720797 | 4,923 | wikipedia | https://en.wikipedia.org/wiki/Chronic_bacterial_prostatitis | 2021-01-18T18:53:48 | {"mesh": ["D011472"], "icd-9": ["601.1"], "icd-10": ["N41.1"], "wikidata": ["Q5248740"]} |
Warfarin sensitivity is a condition in which individuals have a low tolerance for the drug warfarin. Warfarin is an anticoagulant, which means that it thins the blood, preventing blood clots from forming. Warfarin is often prescribed to prevent blood clots in people with heart valve disease who have replacement heart valves, people with an irregular heart beat (atrial fibrillation), or those with a history of heart attack, stroke, or a prior blood clot in the deep veins of the arms or legs (deep vein thrombosis).
Many people with warfarin sensitivity take longer than normal to break down (metabolize) warfarin. The medication remains active in their body longer than usual, so they require lower doses. These individuals are classified as "slow metabolizers" of warfarin. Other people with warfarin sensitivity do not need as much drug to prevent clots because their clot-forming process is naturally slower than average and can be stopped by low warfarin doses. If people with warfarin sensitivity take the average dose (or more) of warfarin, they are at risk of an overdose, which can cause abnormal bleeding in the brain, gastrointestinal tract, or other tissues, and may lead to serious health problems or death.
Warfarin sensitivity does not appear to cause any health problems other than those associated with warfarin drug treatment.
## Frequency
The prevalence of warfarin sensitivity is unknown. However, it appears to be more common in people who are older and those with lower body weights.
Of the approximately 2 million people in the U.S. who are prescribed warfarin annually, 35,000 to 45,000 individuals go to hospital emergency rooms with warfarin-related adverse drug events. While it is unclear how many of these events are due to warfarin sensitivity, the most common sign is excessive internal bleeding, which often occurs when individuals with warfarin sensitivity are given too much of the medication.
## Causes
Many genes are involved in the metabolism of warfarin and in determining the drug's effects in the body. Certain common changes (polymorphisms) in the CYP2C9 and VKORC1 genes account for most of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism. The polymorphisms associated with warfarin sensitivity often differ by population and ethnic background.
The CYP2C9 gene provides instructions for making an enzyme that breaks down various substances in the body. The CYP2C9 enzyme breaks down steroids, fatty acids, and certain drugs, including warfarin. Several CYP2C9 gene polymorphisms decrease the activity of the CYP2C9 enzyme and slow the body's metabolism of warfarin. As a result, the drug remains active in the body for a longer period of time, leading to warfarin sensitivity.
The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Warfarin prevents (inhibits) the action of the VKORC1 enzyme and slows the activation of clotting proteins and clot formation. Certain VKORC1 gene polymorphisms decrease the amount of functional VKORC1 enzyme available to help activate clotting proteins. Individuals develop warfarin sensitivity because a lower warfarin dose is needed to inhibit the VKORC1 enzyme, as there is less functional enzyme that needs to be suppressed.
While changes in specific genes, particularly CYP2C9 and VKORC1, affect how the body reacts to warfarin, many other factors, including sex, age, weight, diet, and other medications, also play a role in the body's interaction with this drug.
### Learn more about the genes associated with Warfarin sensitivity
* CYP2C9
* F9
* VKORC1
Additional Information from NCBI Gene:
* CYP4F2
* GGCX
## Inheritance Pattern
The polymorphisms associated with this condition are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to result in warfarin sensitivity. However, different polymorphisms affect the activity of warfarin to varying degrees. Additionally, people who have more than one polymorphism in a gene or polymorphisms in multiple genes associated with warfarin sensitivity have a lower tolerance for the drug's effect or take even longer to clear the drug from their body.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Warfarin sensitivity | c0750384 | 4,924 | medlineplus | https://medlineplus.gov/genetics/condition/warfarin-sensitivity/ | 2021-01-27T08:24:40 | {"gard": ["12639"], "mesh": ["C563039"], "omim": ["122700"], "synonyms": []} |
## Clinical Features
Sconyers et al. (1983) described male and female offspring of nonconsanguineous parents who died in the neonatal period with a severe skeletal dysplasia that radiologically and histologically resembled Kniest syndrome but differed in clinical course and inheritance. Kniest syndrome (156550) is usually not lethal in the neonatal period and is inherited as an autosomal dominant. In the cases of Sconyers et al. (1983), x-rays showed dumbbell-shaped long bones superficially like those of Kniest dysplasia but with markedly shortened diaphyses and metaphyseal irregularities. Histologically, a 'Swiss cheese' appearance superficially like that of Kniest dysplasia was seen, but in addition distinctive changes were present in the growth plate and resting cartilage. By electron microscopy, the chondrocyte endoplasmic reticulum was found to have an appearance different from that observed in either normal or Kniest cartilage. Both pregnancies were complicated by polyhydramnios and both neonates were severely hydropic. Reference was made to another autosomal recessive Kniest-like dysplasia, the Rolland-Desbuquois syndrome (see 224400). For discussion of another Kniest-like dysplasia, see 245160.
INHERITANCE \- Autosomal recessive GROWTH Height \- Dwarfism, short-limbed HEAD & NECK Head \- Macrocephaly, relative \- Large anterior fontanelle Face \- Flat face Ears \- Low-set ears Mouth \- Cleft palate Neck \- Short neck CARDIOVASCULAR Heart \- Atrial septal defect CHEST External Features \- Narrow chest Ribs Sternum Clavicles & Scapulae \- Wide anterior ribs \- Short ribs ABDOMEN External Features \- Protuberant abdomen SKELETAL \- 'Swiss-cheese" appearance of cartilage \- Enlarged chondrocytes \- Matrix degeneration with large aggregated collagen fibers Spine \- Platyspondyly \- Coronal clefts \- Hypoplastic vertebral bodies Pelvis \- Hypoplastic ilia \- Vertical ischia Limbs \- Rhizomelic limb shortening \- Dumbbell-shaped long bones \- Metaphyseal flaring \- Irregular metaphyses Hands \- Brachydactyly Feet \- Talipes equinovarus \- Brachydactyly MUSCLE, SOFT TISSUES \- Edema PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios Delivery \- Preterm delivery \- Breech presentation ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| KNIEST-LIKE DYSPLASIA, LETHAL | c1855605 | 4,925 | omim | https://www.omim.org/entry/245190 | 2019-09-22T16:26:04 | {"mesh": ["C537208"], "omim": ["245190"], "orphanet": ["2347"]} |
Goodpasture syndrome is an autoimmune disease that affects the lungs and kidneys and is characterized by pulmonary alveolar hemorrhage (bleeding in the lungs) and a kidney disease known as glomerulonephritis. Some use the term "Goodpasture syndrome" for the findings of glomerulonephritis and pulmonary hemorrhage and the term "Goodpasture disease" for those patients with glomerulonephritis, pulmonary hemorrhage, and anti-GBM antibodies. Currently, the preferred term for both conditions is “anti-GBM antibody disease”. Circulating antibodies are directed against the collagen of the part of the kidney known as the glomerular basement membrane (GBM), resulting in acute or rapidly progressive glomerulonephritis. Antibodies also attack the collagen of the air sacs of the lung (alveoli) resulting in bleeding of the lung (pulmonary hemorrhage). Symptoms may include general body discomfort or pain, bleeding from the nose and/or blood in the urine, respiratory problems, anemia, chest pain, and kidney failure. Anti-GBM disease is thought to result from an environmental insult (smoking, infections, exposure to certain drugs) in a person with genetic susceptibility, such as a specific human leukocyte antigen (HLA) type. Diagnosis is confirmed with the presence of anti-GBM antibody in the blood or in the kidney. The treatment of choice is plasmapheresis in conjunction with prednisone and cyclophosphamide.
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Goodpasture syndrome | c0403529 | 4,926 | gard | https://rarediseases.info.nih.gov/diseases/2551/goodpasture-syndrome | 2021-01-18T18:00:14 | {"mesh": ["D019867"], "omim": ["233450"], "orphanet": ["375"], "synonyms": ["Rapidly progressive glomerulonephritis with pulmonary hemorrhage", "Anti-glomerular basement membrane antibody disease", "Glomerulonephritis - pulmonary hemorrhage", "Pulmonary renal syndrome"]} |
This article relies largely or entirely on a single source. Relevant discussion may be found on the talk page. Please help improve this article by introducing citations to additional sources.
Find sources: "Lattice degeneration" – news · newspapers · books · scholar · JSTOR (July 2020)
Lattice degeneration
This condition is inherited in an autosomal dominant manner
SpecialtyOphthalmology
SymptomsLattice degeneration itself does not cause symptoms
Diagnostic methodThe only way to diagnose the condition is with a dilated fundus examination by an eye care provider. A dilated fundus examination is done by administering dilating eye drops in your eyes to expand the pupil so that the retina can be carefully evaluated. Dilating drops will cause your vision to be blurry for several hours before returning to normal.
Lattice degeneration is a disease of the human eye wherein the peripheral retina becomes atrophic in a lattice pattern and may develop tears, breaks, or holes, which may further progress to retinal detachment. It is an important cause of retinal detachment in young myopic individuals. The cause is unknown, but pathology reveals inadequate blood flow resulting in ischemia and fibrosis.[citation needed]
Lattice degeneration occurs in approximately 6–8% of the general population and in approximately 30% of phakic retinal detachments.[1] Similar lesions are seen in patients with Ehlers-Danlos syndrome, Marfan syndrome, and Stickler syndrome, all of which are associated with an increased risk of retinal detachment. Risk of developing lattice degeneration in one eye is also increased if lattice degeneration is already present in the other eye.[1]
## Treatment[edit]
Barrage laser is at times done prophylactically around a hole or tear associated with lattice degeneration in an eye at risk of developing a retinal detachment. It is not known if surgical interventions such as laser photocoagulation or cryotherapy is effective in preventing retinal detachment in patients with lattice degeneration or asymptomatic retinal detachment.[1] Laser photocoagulation has been shown to reduce risks of retinal detachment in symptomatic lattice degeneration.[citation needed] There are documented cases wherein retina detached from areas which were otherwise healthy despite being treated previously with laser.[citation needed]
## References[edit]
1. ^ a b c Wilkinson, Charles P. (2014-09-05). "Interventions for asymptomatic retinal breaks and lattice degeneration for preventing retinal detachment". The Cochrane Database of Systematic Reviews (9): CD003170. doi:10.1002/14651858.CD003170.pub4. ISSN 1469-493X. PMC 4423540. PMID 25191970.
## External links[edit]
Classification
D
* OMIM: 150500
External resources
* eMedicine: oph/397
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Lattice degeneration | c0154856 | 4,927 | wikipedia | https://en.wikipedia.org/wiki/Lattice_degeneration | 2021-01-18T19:00:11 | {"umls": ["C0154856"], "wikidata": ["Q17139523"]} |
11q22.2q22.3 microdeletion syndrome is a rare chromosomal anomaly characterized by mild intellectual disability, developmental delay, short stature, hypotonia and dysmorphic facial features. Anxiety and short attention span have also been reported.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| 11q22.2q22.3 microdeletion syndrome | None | 4,928 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=444002 | 2021-01-23T16:52:32 | {"icd-10": ["Q93.5"], "synonyms": ["Del(11)(q22.2q22.3)", "Monosomy 11q22.2q22.3"]} |
For the joint inflammation condition, see Synovitis.
Inflammation of the mucous membrane that lines the sinuses resulting in symptoms
Sinusitis
Other namesSinus infection, rhinosinusitis
A CT scan showing sinusitis of the ethmoid sinus
SpecialtyOtorhinolaryngology
SymptomsThick nasal mucus, plugged nose, pain in the face, fever[1][2]
CausesInfection (bacterial, fungal, viral), allergies, air pollution, structural problems in the nose[2]
Risk factorsAsthma, cystic fibrosis, poor immune function[1]
Diagnostic methodUsually based on symptoms[1]
Differential diagnosisMigraine[3]
PreventionHandwashing, avoiding smoking
TreatmentPain medications, nasal steroids, nasal irrigation, antibiotic[1][4]
Frequency10–30% each year (developed world)[1][5]
Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain.[1][6] Other signs and symptoms may include fever, headaches, a poor sense of smell, sore throat, and a cough.[2] It is defined as acute sinusitis if it lasts less than 4 weeks, and as chronic sinusitis if it lasts for more than 12 weeks.[1]
Sinusitis can be caused by infection, allergies, air pollution, or structural problems in the nose.[2] Most cases are caused by a viral infection.[2] Recurrent episodes are more likely in persons with asthma, cystic fibrosis, and poor immune function.[1] X-rays are not usually needed unless complications are suspected.[1] In chronic cases, confirmatory testing is recommended by either direct visualization or computed tomography.[1]
Some cases may be prevented by hand washing, avoiding smoking, and immunization.[2] Pain killers such as naproxen, nasal steroids, and nasal irrigation may be used to help with symptoms.[1][4] Recommended initial treatment for acute sinusitis is watchful waiting.[1] If symptoms do not improve in 7–10 days or get worse, then an antibiotic may be used or changed.[1] In those in whom antibiotics are used, either amoxicillin or amoxicillin/clavulanate is recommended first line.[1] Surgery may occasionally be used in people with chronic disease.[7]
Sinusitis is a common condition.[1] It affects between about 10 and 30 percent of people each year in the United States and Europe.[1][5] Chronic sinusitis affects about 12.5% of people.[8] Treatment of sinusitis in the United States results in more than US$11 billion in costs.[1] The unnecessary and ineffective treatment of viral sinusitis with antibiotics is common.[1]
## Contents
* 1 Signs and symptoms
* 1.1 Chronic
* 1.2 By location
* 1.3 Complications
* 2 Causes
* 2.1 Acute
* 2.2 Chronic
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Classification
* 4.2 Acute
* 4.3 Chronic
* 5 Treatment
* 5.1 Antibiotics
* 5.2 Corticosteroids
* 5.3 Surgery
* 5.4 Treatments directed to rhinovirus infection
* 6 Prognosis
* 7 Epidemiology
* 8 Research
* 9 See also
* 10 References
* 11 External links
## Signs and symptoms[edit]
Headache or facial pain or pressure of a dull, constant, or aching sort over the affected sinuses is common with both acute and chronic stages of sinusitis. This pain is usually localized to the involved sinus and may worsen when the affected person bends over or when lying down. Pain often starts on one side of the head and progresses to both sides.[9] Acute sinusitis may be accompanied by thick nasal discharge that is usually green in color and may contain pus or blood.[10] Often, a localized headache or toothache is present, and these symptoms distinguish a sinus-related headache from other types of headaches, such as tension and migraine headaches. Another way to distinguish between toothache and sinusitis is that the pain in sinusitis is usually worsened by tilting the head forward and with the Valsalva maneuver.[11]
Other symptoms associated with acute rhinosinusitis include cough, fatigue, hyposmia, anosmia and ear fullness or pressure.[12]
Sinus infections can also cause middle-ear problems due to the congestion of the nasal passages. This can be demonstrated by dizziness, "a pressurized or heavy head", or vibrating sensations in the head. Postnasal drip is also a symptom of chronic rhinosinusitis.
Halitosis (bad breath) is often stated to be a symptom of chronic rhinosinusitis; however, gold-standard breath analysis techniques[clarification needed] have not been applied. Theoretically, several possible mechanisms of both objective and subjective halitosis may be involved.[11]
A 2005 review suggested that most "sinus headaches" are migraines.[13] The confusion occurs in part because migraine involves activation of the trigeminal nerves, which innervate both the sinus region and the meninges surrounding the brain. As a result, accurately determining the site from which the pain originates is difficult. People with migraines do not typically have the thick nasal discharge that is a common symptom of a sinus infection.[14]
### Chronic[edit]
Symptoms may include any combination of: nasal congestion, facial pain, headache, night-time coughing, an increase in previously minor or controlled asthma symptoms, general malaise, thick green or yellow discharge, feeling of facial fullness or tightness that may worsen when bending over, dizziness, aching teeth, and/or bad breath.[15] Often, chronic sinusitis can lead to anosmia, the inability to smell objects.[15]
### By location[edit]
The four paired paranasal sinuses are the frontal, ethmoidal, maxillary, and sphenoidal sinuses. The ethmoidal sinuses are further subdivided into anterior and posterior ethmoid sinuses, the division of which is defined as the basal lamella of the middle nasal concha. In addition to the severity of disease, discussed below, sinusitis can be classified by the sinus cavity it affects:
* Maxillary – can cause pain or pressure in the maxillary (cheek) area (e.g., toothache,[11] or headache) (J01.0/J32.0)
* Frontal – can cause pain or pressure in the frontal sinus cavity (located above the eyes), headache, particularly in the forehead (J01.1/J32.1)
* Ethmoidal – can cause pain or pressure pain between/behind the eyes, the sides of the upper part of the nose (the medial canthi), and headaches (J01.2/J32.2)[16]
* Sphenoidal – can cause pain or pressure behind the eyes, but is often felt in the top of the head, over the mastoid processes, or the back of the head.[16]
### Complications[edit]
Stage Description
I Preseptal cellulitis
II Orbital cellulitis
III Subperiosteal abscess
IV Orbital abscess
V Cavernous sinus septic thrombosis
Complications are thought to be rare (1 case per 10000).[17]
The proximity of the brain to the sinuses makes the most dangerous complication of sinusitis, particularly involving the frontal and sphenoid sinuses, infection of the brain by the invasion of anaerobic bacteria through the bones or blood vessels. Abscesses, meningitis, and other life-threatening conditions may result. In extreme cases, the patient may experience mild personality changes, headache, altered consciousness, visual problems, seizures, coma, and possibly death.[9]
Sinus infection can spread through anastomosing veins or by direct extension to close structures. Orbital complications were categorized by Chandler et al. into five stages according to their severity (see table).[18] Contiguous spread to the orbit may result in periorbital cellulitis, subperiosteal abscess, orbital cellulitis, and abscess. Orbital cellulitis can complicate acute ethmoiditis if anterior and posterior ethmoidal veins thrombophlebitis enables the spread of the infection to the lateral or orbital side of the ethmoid labyrinth. Sinusitis may extend to the central nervous system, where it may cause cavernous sinus thrombosis, retrograde meningitis, and epidural, subdural, and brain abscesses.[19] Orbital symptoms frequently precede intracranial spread of the infection . Other complications include sinobronchitis, maxillary osteomyelitis, and frontal bone osteomyelitis.[20][21][22][23] Osteomyelitis of the frontal bone often originates from a spreading thrombophlebitis. A periostitis of the frontal sinus causes an osteitis and a periostitis of the outer membrane, which produces a tender, puffy swelling of the forehead.[citation needed]
The diagnosis of these complications can be assisted by noting local tenderness and dull pain, and can be confirmed by CT and nuclear isotope scanning. The most common microbial causes are anaerobic bacteria and S. aureus. Treatment includes performing surgical drainage and administration of antimicrobial therapy. Surgical debridement is rarely required after an extended course of parenteral antimicrobial therapy.[24] Chronic sinus infections may lead to mouth breathing, which can result in mouth dryness and an increased risk of gingivitis. Decongestants may also cause mouth dryness.[25]
Once an odontogenic infection involves the maxillary sinus, it may then spread to the orbit or to the ethmoid sinus, the nasal cavity, and frontal sinuses, and in unusual instances can spread from the maxillary sinus causing orbital cellulitis, blindness, meningitis, subdural empyema, brain abscess and life-threatening cavernous sinus thrombosis.[26][27]
Infection of the eye socket is a rare complication of ethmoid sinusitis, which may result in the loss of sight and is accompanied by fever and severe illness. Another possible complication is the infection of the bones (osteomyelitis) of the forehead and other facial bones – Pott's puffy tumor.[9]
## Causes[edit]
Maxillary sinusitis may also develop from problems with the teeth, and these cases were calculated to be about 40% in one study and 50% in another.[27] The cause of this situation is usually a periapical or periodontal infection of a maxillary posterior tooth, where the inflammatory exudate has eroded through the bone superiorly to drain into the maxillary sinus.[27]
An estimated 0.5 to 2.0% of viral rhinosinusitis (VRS) will develop into bacterial infections in adults and 5 to 10% in children.[12]
### Acute[edit]
Acute sinusitis is usually precipitated by an earlier upper respiratory tract infection, generally of viral origin, mostly caused by rhinoviruses (with RVA and RVC giving more severe infection than RVB), coronaviruses, and influenza viruses, others caused by adenoviruses, human parainfluenza viruses, human respiratory syncytial virus, enteroviruses other than rhinoviruses, and metapneumovirus. If the infection is of bacterial origin, the most common three causative agents are Streptococcus pneumoniae(38%), Haemophilus influenzae(36%), and Moraxella catarrhalis(16%).[12][28] Until recently, H. influenzae was the most common bacterial agent to cause sinus infections. However, introduction of the H. influenzae type B (Hib) vaccine has dramatically decreased these infections and now non-typable H. influenzae (NTHI) is predominantly seen in clinics. Other sinusitis-causing bacterial pathogens include S. aureus and other streptococci species, anaerobic bacteria and, less commonly, Gram-negative bacteria. Viral sinusitis typically lasts for 7 to 10 days.[17]
Acute episodes of sinusitis can also result from fungal invasion. These infections are typically seen in people with diabetes or other immune deficiencies (such as AIDS or transplant on immunosuppressive antirejection medications) and can be life-threatening. In type I diabetics, ketoacidosis can be associated with sinusitis due to mucormycosis.[29]
### Chronic[edit]
By definition, chronic sinusitis lasts longer than 12 weeks and can be caused by many different diseases that share chronic inflammation of the sinuses as a common symptom. It is subdivided into cases with and without polyps. When polyps are present, the condition is called chronic hyperplastic sinusitis; however, the causes are poorly understood.[17] It may develop with anatomic derangements, including deviation of the nasal septum and the presence of concha bullosa (pneumatization of the middle concha) that inhibit the outflow of mucus, or with allergic rhinitis, asthma, cystic fibrosis, and dental infections.[30]
Chronic rhinosinusitis represents a multifactorial inflammatory disorder, rather than simply a persistent bacterial infection.[17] The medical management of chronic rhinosinusitis is now focused upon controlling the inflammation that predisposes people to obstruction, reducing the incidence of infections.[31] Surgery may be needed if medications are not working.[31]
Attempts have been made to provide a more consistent nomenclature for subtypes of chronic sinusitis. The presence of eosinophils in the mucous lining of the nose and paranasal sinuses has been demonstrated for many people, and this has been termed eosinophilic mucin rhinosinusitis (EMRS). Cases of EMRS may be related to an allergic response, but allergy is not often documented, resulting in further subcategorization into allergic and nonallergic EMRS.[32]
A more recent, and still debated, development in chronic sinusitis is the role that fungi play in this disease.[33] Whether fungi are a definite factor in the development of chronic sinusitis remains unclear, and if they are, what is the difference between those who develop the disease and those who remain free of symptoms. Trials of antifungal treatments have had mixed results.[34]
Recent theories of sinusitis indicate that it often occurs as part of a spectrum of diseases that affect the respiratory tract (i.e., the "one airway" theory) and is often linked to asthma.[35][36]
Both smoking and secondhand smoke are associated with chronic rhinosinusitis.[8]
Other diseases such as cystic fibrosis and granulomatosis with polyangiitis can also cause chronic sinusitis.[37]
## Pathophysiology[edit]
Biofilm bacterial infections may account for many cases of antibiotic-refractory chronic sinusitis.[38][39][40] Biofilms are complex aggregates of extracellular matrix and interdependent microorganisms from multiple species, many of which may be difficult or impossible to isolate using standard clinical laboratory techniques.[41] Bacteria found in biofilms have their antibiotic resistance increased up to 1000 times when compared to free-living bacteria of the same species. A recent study found that biofilms were present on the mucosa of 75% of people undergoing surgery for chronic sinusitis.[42]
## Diagnosis[edit]
### Classification[edit]
Illustration depicting sinusitis
Sinusitis (or rhinosinusitis) is defined as an inflammation of the mucous membrane that lines the paranasal sinuses and is classified chronologically into several categories:[15]
* Acute sinusitis – A new infection that may last up to four weeks and can be subdivided symptomatically into severe and nonsevere. Some use definitions up to 12 weeks.[1]
* Recurrent acute sinusitis – Four or more full episodes of acute sinusitis that occur within one year
* Subacute sinusitis – An infection that lasts between four and 12 weeks, and represents a transition between acute and chronic infection
* Chronic sinusitis – When the signs and symptoms last for more than 12 weeks.[1]
* Acute exacerbation of chronic sinusitis – When the signs and symptoms of chronic sinusitis exacerbate, but return to baseline after treatment
Roughly 90% of adults have had sinusitis at some point in their lives.[43]
### Acute[edit]
Health care providers distinguish bacterial and viral sinusitis by watchful waiting.[1] If a person has had sinusitis for fewer than 10 days without the symptoms becoming worse, then the infection is presumed to be viral.[1] When symptoms last more than 10 days or get worse in that time, then the infection is considered bacterial sinusitis.[44] Pain in the teeth and bad breath are also more indicative of bacterial disease.[45]
Imaging by either X-ray, CT or MRI is generally not recommended unless complications develop.[44] Pain caused by sinusitis is sometimes confused for pain caused by pulpitis (toothache) of the maxillary teeth, and vice versa. Classically, the increased pain when tilting the head forwards separates sinusitis from pulpitis.[citation needed]
For cases of maxillary sinusitis, limited field CBCT imaging, as compared to periapical radiographs, improves the ability to detect the teeth as the sources for sinusitis. A coronal CT picture may also be useful.[27]
### Chronic[edit]
For sinusitis lasting more than 12 weeks, a CT scan is recommended.[44] On a CT scan, acute sinus secretions have a radiodensity of 10 to 25 Hounsfield units (HU), but in a more chronic state they become more viscous, with a radiodensity of 30 to 60 HU.[46]
Nasal endoscopy and clinical symptoms are also used to make a positive diagnosis.[17] A tissue sample for histology and cultures can also be collected and tested.[47] Nasal endoscopy involves inserting a flexible fiber-optic tube with a light and camera at its tip into the nose to examine the nasal passages and sinuses.
Sinus infections, if they result in tooth pain, usually present with pain involving more than one of the upper teeth, whereas a toothache usually involves a single tooth. Dental examination and appropriate radiography aid in ruling out pain arise from a tooth.[25]
* CT of chronic sinusitis
* CT scan of chronic sinusitis, showing a filled right maxillary sinus with sclerotic thickened bone.
* MRI image showing sinusitis. Edema and mucosal thickening appears in both maxillary sinuses.
* Maxillary sinusitis caused by a dental infection associated with periorbital cellulitis
* Frontal sinusitis
* X-ray of left-sided maxillary sinusitis marked by an arrow. There is lack of the air transparency indicating fluid in contrast to the other side.
## Treatment[edit]
Treatments[48][49]
Treatment Indication Rationale
Time Viral and some bacterial sinusitis Sinusitis is usually caused by a virus which is not affected by antibiotics.[48]
Antibiotics Bacterial sinusitis Cases accompanied by extreme pain, skin infection, or which last a long time may be caused by bacteria.[48]
Nasal irrigation Nasal congestion Can provide relief by helping decongest.[48]
Drink liquids Thick phlegm Remaining hydrated loosens mucus.[48]
Antihistamines Concern with allergies Antihistamines do not relieve typical sinusitis or cold symptoms much; this treatment is not needed in most cases.[48]
Nasal spray Desire for temporary relief Tentative evidence that it helps symptoms.[4] Does not treat cause. Not recommended for more than three days' use.[48]
Recommended treatments for most cases of sinusitis include rest and drinking enough water to thin the mucus.[50] Antibiotics are not recommended for most cases.[50][51]
Breathing low-temperature steam such as from a hot shower or gargling can relieve symptoms.[50][52] There is tentative evidence for nasal irrigation in acute sinusitis, for example during upper respiratory infections.[4] Decongestant nasal sprays containing oxymetazoline may provide relief, but these medications should not be used for more than the recommended period. Longer use may cause rebound sinusitis.[53] It is unclear if nasal irrigation, antihistamines, or decongestants work in children with acute sinusitis.[54] There is no clear evidence that plant extracts such as Cyclamen europaeum are effective as an intranasal wash to treat acute sinusitis.[55] Evidence is inconclusive on whether anti-fungal treatments improve symptoms or quality of life.[56]
### Antibiotics[edit]
Most sinusitis cases are caused by viruses and resolve without antibiotics.[17] However, if symptoms do not resolve within 10 days, amoxicillin/clavulanate is a reasonable antibiotic association for first treatment.[17] A 2018 Cochrane review, however, found no evidence that people with symptoms lasting seven days or more before consulting their physician are more likely to have bacterial sinusitis as one study found that about 80% of patients have symptoms lasting more than 7 days and another about 70%.[57] Antibiotics are specifically not recommended in those with mild / moderate disease during the first week of infection due to risk of adverse effects, antibiotic resistance, and cost.[58]
Fluoroquinolones, and a newer macrolide antibiotic such as clarithromycin or a tetracycline like doxycycline, are used in those who have severe allergies to penicillins.[59] Because of increasing resistance to amoxicillin the 2012 guideline of the Infectious Diseases Society of America recommends amoxicillin-clavulanate as the initial treatment of choice for bacterial sinusitis.[60] The guidelines also recommend against other commonly used antibiotics, including azithromycin, clarithromycin, and trimethoprim/sulfamethoxazole, because of growing antibiotic resistance. The FDA recommends against the use of fluoroquinolones when other options are available due to higher risks of serious side effects.[61]
A short-course (3–7 days) of antibiotics seems to be just as effective as the typical longer-course (10–14 days) of antibiotics for those with clinically diagnosed acute bacterial sinusitis without any other severe disease or complicating factors.[62] The IDSA guideline suggest five to seven days of antibiotics is long enough to treat a bacterial infection without encouraging resistance. The guidelines still recommend children receive antibiotic treatment for ten days to two weeks.[60]
### Corticosteroids[edit]
For unconfirmed acute sinusitis, nasal sprays using corticosteroids have not been found to be better than a placebo either alone or in combination with antibiotics.[63] For cases confirmed by radiology or nasal endoscopy, treatment with intranasal corticosteroids alone or in combination with antibiotics is supported.[64] The benefit, however, is small.[65]
For confirmed chronic rhinosinusitis, there is limited evidence that intranasal steroids improve symptoms and insufficient evidence that one type of steroid is more effective.[66][67]
There is only limited evidence to support short treatment with corticosteroids by mouth for chronic rhinosinusitis with nasal polyps.[68][69][70] There is limited evidence to support corticosteroids by mouth in combination with antibiotics for acute sinusitis; it has only short-term effect improving the symptoms.[71][72]
### Surgery[edit]
For sinusitis of dental origin, treatment focuses on removing the infection and preventing reinfection, by removal of the microorganisms, their byproducts, and pulpal debris from the infected root canal.[27] Systemic antibiotics are ineffective as a definitive solution, but may afford temporary relief of symptoms by improving sinus clearing, and may be appropriate for rapidly spreading infections, but debridement and disinfection of the root canal system at the same time is necessary. Treatment options include non-surgical root canal treatment, periradicular surgery, tooth replantation, or extraction of the infected tooth. [27]
For chronic or recurring sinusitis, referral to an otolaryngologist may be indicated, and treatment options may include nasal surgery. Surgery should only be considered for those people who do not benefit with medication.[69][73] It is unclear how benefits of surgery compare to medical treatments in those with nasal polyps as this has been poorly studied.[74][75]
A number of surgical approaches can be used to access the sinuses and these have generally shifted from external/extranasal approaches to intranasal endoscopic ones. The benefit of functional endoscopic sinus surgery (FESS) is its ability to allow for a more targeted approach to the affected sinuses, reducing tissue disruption, and minimizing post-operative complications.[76] The use of drug eluting stents such as propel mometasone furoate implant may help in recovery after surgery.[77]
Another recently developed treatment is balloon sinuplasty. This method, similar to balloon angioplasty used to "unclog" arteries of the heart, utilizes balloons in an attempt to expand the openings of the sinuses in a less invasive manner.[31] The effectiveness of the functional endoscopic balloon dilation approach compared to conventional FESS is not known.[31]
### Treatments directed to rhinovirus infection[edit]
A study has shown that patients given spray formulation of 0.73 mg of Tremacamra (a soluble intercellular adhesion molecule 1 [ICAM-1] receptor) reduced the severity of illness.[28]
## Prognosis[edit]
A 2018 review has found that without the use of antibiotics, about 46% were cured after one week and 64% after two weeks.[57]
## Epidemiology[edit]
Sinusitis is a common condition, with between 24 and 31 million cases occurring in the United States annually.[78][79] Chronic sinusitis affects approximately 12.5% of people.[8]
## Research[edit]
Based on recent theories on the role that fungus may play in the development of chronic sinusitis, antifungal treatments have been used, on a trial basis. These trials have had mixed results.[17]
## See also[edit]
* Fungal sinusitis
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76. ^ Stammberger H (February 1986). "Endoscopic endonasal surgery--concepts in treatment of recurring rhinosinusitis. Part I. Anatomic and pathophysiologic considerations". Otolaryngology–Head and Neck Surgery. 94 (2): 143–7. doi:10.1177/019459988609400202. PMID 3083326. S2CID 34575985.
77. ^ Liang J, Lane AP (March 2013). "Topical Drug Delivery for Chronic Rhinosinusitis". Current Otorhinolaryngology Reports. 1 (1): 51–60. doi:10.1007/s40136-012-0003-4. PMC 3603706. PMID 23525506.
78. ^ Anon JB (April 2010). "Upper respiratory infections". The American Journal of Medicine. 123 (4 Suppl): S16-25. doi:10.1016/j.amjmed.2010.02.003. PMID 20350632.
79. ^ Dykewicz MS, Hamilos DL (February 2010). "Rhinitis and sinusitis". The Journal of Allergy and Clinical Immunology. 125 (2 Suppl 2): S103-15. doi:10.1016/j.jaci.2009.12.989. PMID 20176255.
## External links[edit]
Classification
D
* ICD-10: J01, J32
* ICD-9-CM: 461, 473
* MeSH: D012852
* DiseasesDB: 12136
* SNOMED CT: 36971009
External resources
* MedlinePlus: 000647
* eMedicine: article/232670
* Patient UK: Sinusitis
* Sinusitis at Curlie
* "Sinusitis". MedlinePlus. U.S. National Library of Medicine.
* v
* t
* e
Diseases of the respiratory system
Upper RT
(including URTIs,
common cold)
Head
sinuses
Sinusitis
nose
Rhinitis
Vasomotor rhinitis
Atrophic rhinitis
Hay fever
Nasal polyp
Rhinorrhea
nasal septum
Nasal septum deviation
Nasal septum perforation
Nasal septal hematoma
tonsil
Tonsillitis
Adenoid hypertrophy
Peritonsillar abscess
Neck
pharynx
Pharyngitis
Strep throat
Laryngopharyngeal reflux (LPR)
Retropharyngeal abscess
larynx
Croup
Laryngomalacia
Laryngeal cyst
Laryngitis
Laryngopharyngeal reflux (LPR)
Laryngospasm
vocal cords
Laryngopharyngeal reflux (LPR)
Vocal fold nodule
Vocal fold paresis
Vocal cord dysfunction
epiglottis
Epiglottitis
trachea
Tracheitis
Laryngotracheal stenosis
Lower RT/lung disease
(including LRTIs)
Bronchial/
obstructive
acute
Acute bronchitis
chronic
COPD
Chronic bronchitis
Acute exacerbation of COPD)
Asthma (Status asthmaticus
Aspirin-induced
Exercise-induced
Bronchiectasis
Cystic fibrosis
unspecified
Bronchitis
Bronchiolitis
Bronchiolitis obliterans
Diffuse panbronchiolitis
Interstitial/
restrictive
(fibrosis)
External agents/
occupational
lung disease
Pneumoconiosis
Aluminosis
Asbestosis
Baritosis
Bauxite fibrosis
Berylliosis
Caplan's syndrome
Chalicosis
Coalworker's pneumoconiosis
Siderosis
Silicosis
Talcosis
Byssinosis
Hypersensitivity pneumonitis
Bagassosis
Bird fancier's lung
Farmer's lung
Lycoperdonosis
Other
* ARDS
* Combined pulmonary fibrosis and emphysema
* Pulmonary edema
* Löffler's syndrome/Eosinophilic pneumonia
* Respiratory hypersensitivity
* Allergic bronchopulmonary aspergillosis
* Hamman-Rich syndrome
* Idiopathic pulmonary fibrosis
* Sarcoidosis
* Vaping-associated pulmonary injury
Obstructive / Restrictive
Pneumonia/
pneumonitis
By pathogen
* Viral
* Bacterial
* Pneumococcal
* Klebsiella
* Atypical bacterial
* Mycoplasma
* Legionnaires' disease
* Chlamydiae
* Fungal
* Pneumocystis
* Parasitic
* noninfectious
* Chemical/Mendelson's syndrome
* Aspiration/Lipid
By vector/route
* Community-acquired
* Healthcare-associated
* Hospital-acquired
By distribution
* Broncho-
* Lobar
IIP
* UIP
* DIP
* BOOP-COP
* NSIP
* RB
Other
* Atelectasis
* circulatory
* Pulmonary hypertension
* Pulmonary embolism
* Lung abscess
Pleural cavity/
mediastinum
Pleural disease
* Pleuritis/pleurisy
* Pneumothorax/Hemopneumothorax
Pleural effusion
Hemothorax
Hydrothorax
Chylothorax
Empyema/pyothorax
Malignant
Fibrothorax
Mediastinal disease
* Mediastinitis
* Mediastinal emphysema
Other/general
* Respiratory failure
* Influenza
* Common cold
* SARS
* Coronavirus disease 2019
* Idiopathic pulmonary haemosiderosis
* Pulmonary alveolar proteinosis
* v
* t
* e
Common cold
Viruses
* Adenovirus
* Coronavirus
* Enterovirus
* Rhinovirus
Symptoms
* Cough
* Fatigue
* Fever
* Headache
* Loss of appetite
* Malaise
* Muscle aches
* Nasal congestion
* Rhinorrhea
* Sneezing
* Sore throat
* Weakness
Complications
* Acute bronchitis
* Bronchiolitis
* Croup
* Otitis media
* Pharyngitis
* Pneumonia
* Sinusitis
* Strep throat
Drugs
* Antiviral drugs
* Pleconaril (experimental)
Authority control
* NDL: 00576408
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Sinusitis | c0037199 | 4,929 | wikipedia | https://en.wikipedia.org/wiki/Sinusitis | 2021-01-18T19:03:07 | {"mesh": ["D012852"], "umls": ["C0037199"], "wikidata": ["Q183344"]} |
Free-living amebae belonging to the genera Acanthamoeba, Balamuthia, Naegleria and Sappinia are important causes of disease in humans and animals. Naegleria fowleri produces an acute, and usually lethal, central nervous system (CNS) disease called primary amebic meningoencephalitis (PAM). Acanthamoeba spp. and Balamuthia mandrillaris are opportunistic free-living amebae capable of causing granulomatous amebic encephalitis (GAE) in individuals with compromised immune systems. Sappinia pedata has been implicated in a case of amebic encephalitis. Naegleria fowleri and Acanthamoeba spp., are commonly found in lakes, swimming pools, tap water, and heating and air conditioning units.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Amoebiasis due to free-living amoebae | None | 4,930 | gard | https://rarediseases.info.nih.gov/diseases/12650/amoebiasis-due-to-free-living-amoebae | 2021-01-18T18:02:09 | {"synonyms": []} |
A number sign (#) is used with this entry because variation in the IRAKM gene (604459) has been associated with susceptibility to asthma-related traits linked to the chromosome 12q13-q24 region.
Description
Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al., 2001; Illig and Wjst, 2002; Pillai et al., 2006).
For a general phenotypic description and a discussion of genetic heterogeneity of asthma, see 600807.
Mapping
Raby et al. (2003) genotyped 55 nuclear families with at least 2 asthmatic sibs (212 individuals) using 32 microsatellite markers on chromosome 12. Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P value = 0.05), airways responsiveness (PC20) at 147 cM (P = 0.01), and indices of pulmonary function (FEV1 and BDPR) at 134 cM (P = 0.05 and P less than 0.01, respectively). No linkage was observed for the atopy-related phenotypes.
To identify genetic components of asthma in the candidate region 12q13-q24, Balaci et al. (2007) performed linkage and association analyses by transmission disequilibrium tests and case-control analysis using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions is thought to facilitate the study of multifactorial traits. Analysis using a cut-off age of 13 years at asthma onset detected significant linkage to a portion of 12q13-q24. Linkage analysis revealed that the 12q13-q24 region was significantly linked to asthma in a subgroup of 60 families (66 sibs) with exclusively early-onset cases, yielding a multipoint lod score of 3.56, P = 5.2 x 10(-5), between markers D12S75 and D12S335.
In a genomewide linkage analysis of 423 nonsmokers from 8 large Costa Rican asthma pedigrees, Celedon et al. (2007) found evidence for linkage to airway responsiveness on chromosome 12q24.31 (maximum multipoint lod score of 3.79 at 144 cM), with a relatively narrow 1.5-lod unit support interval for the observed linkage peak (142 to 147 cM).
Molecular Genetics
In the Sardinian founder population, Balaci et al. (2007) identified IRAKM (604459) as the gene contributing to the linkage they found to chromosome 12q13-q24, and they showed that it is associated with early-onset persistent asthma. They defined both protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Three tag SNPS within IRAKM (rs11465955, rs1624395, rs1370128) were sufficient to identify protective and predisposing SNP haplotypes. The risk haplotype (TAT) was associated with early-onset persistent asthma (46.0% cases vs 35.6% controls), whereas the wildtype haplotype (CGC) was less frequent in cases than in controls (46.4% vs 56.8%). Furthermore, estimation of sex- and age-adjusted haplotype effects achieved an odds ratio of the risk haplotype of 1.73 (95% CI 1.24-2.40), with a multiplicative effect on disease. Sequence analysis in patients found mutations, including inactivating lesions (604459.0001, 604459.0002), in the IRAKM coding region. Both inactivating mutations were coinherited with the predisposing risk haplotype and were associated with early-onset asthma. Immunohistochemistry of lung biopsies showed that IRAKM is highly expressed in epithelial cells. Thus, IRAKM is involved in the pathogenesis of early-onset persistent asthma. As a negative regulator of the Toll-like receptor (see 601194)/IL1R (147810) pathways, IRAKM is a master regulator of NF-kappa-B (see 164011) and inflammation. The data suggested a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicated IRAKM as a potential target for therapeutic intervention against asthma.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 5 | c1970224 | 4,931 | omim | https://www.omim.org/entry/611064 | 2019-09-22T16:03:42 | {"omim": ["611064"], "synonyms": ["Alternative titles", "ASRT5"]} |
This article is missing information about causes of condition. Please expand the article to include this information. Further details may exist on the talk page. (April 2020)
Penoscrotal transposition (PST) is a group of congenital defects involving an abnormal spatial arrangement of penis and scrotum.
## Contents
* 1 Types
* 2 Causes
* 3 Treatment
* 4 References
## Types[edit]
There are two types of penoscrotal transposition.[1]
* Complete penoscrotal transposition
* Incomplete penoscrotal transposition
In incomplete penoscrotal transposition, penis is located in the middle of the scrotum, but in complete transposition, penis is located in the perineum. [2]
## Causes[edit]
This section is empty. You can help by adding to it. (April 2020)
## Treatment[edit]
Gold standard of PST treatment is surgical repair.[2] Repair technique of penoscrotal transposition included a Glenn–Anderson technique, which is developed by F. Glenn and E. Everett Anderson.[3][4]
## References[edit]
1. ^ Manjunath K, Venkatesh M (July 2014). "M-plasty for correction of incomplete penoscrotal transposition". World Journal of Plastic Surgery. 3 (2): 138–41. PMC 4236992. PMID 25489538.
2. ^ a b Beyazıt F, Pek E, Aylanç H (March 2017). "A rare case of complete penoscrotal transposition with hypospadias in a newborn". Turkish Journal of Obstetrics and Gynecology. 14 (1): 74–75. doi:10.4274/tjod.88262. PMC 5558323. PMID 28913140.
3. ^ Glenn JF, Anderson EE (November 1973). "Surgical correction of incomplete penoscrotal transposition". The Journal of Urology. 110 (5): 603–5. doi:10.1016/s0022-5347(17)60293-3. PMID 4750909.
4. ^ Pinke LA, Rathbun SR, Husmann DA, Kramer SA (November 2001). "Penoscrotal transposition: review of 53 patients". The Journal of Urology. 166 (5): 1865–8. doi:10.1016/s0022-5347(05)65708-4. PMID 11586250.
* v
* t
* e
Congenital malformations and deformations of urinary system
Abdominal
Kidney
* Renal agenesis/Potter sequence, Papillorenal syndrome
* cystic
* Polycystic kidney disease
* Meckel syndrome
* Multicystic dysplastic kidney
* Medullary sponge kidney
* Horseshoe kidney
* Renal ectopia
* Nephronophthisis
* Supernumerary kidney
* Pelvic kidney
* Dent's disease
* Alport syndrome
Ureter
* Ectopic ureter
* Megaureter
* Duplicated ureter
Pelvic
Bladder
* Bladder exstrophy
Urethra
* Epispadias
* Hypospadias
* Posterior urethral valves
* Penoscrotal transposition
Vestigial
Urachus
* Urachal cyst
* Urachal fistula
* Urachal sinus
* v
* t
* e
Male congenital anomalies of the genitalia, including Intersex and DSD
Internal
Testicle
* Cryptorchidism
* Polyorchidism
* Monorchism
* Anorchia
* Sertoli cell-only syndrome
* True hermaphroditism
* Mixed gonadal dysgenesis
* Swyer syndrome
Vas deferens
* Congenital absence of the vas deferens
Other
* Persistent Müllerian duct syndrome
External
Penis
* Hypospadias
* Epispadias
* Chordee
* Micropenis
* Penile agenesis
* Diphallia
* Penoscrotal transposition
Other
* Pseudohermaphroditism
This medical article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Penoscrotal transposition | c1868854 | 4,932 | wikipedia | https://en.wikipedia.org/wiki/Penoscrotal_transposition | 2021-01-18T18:36:12 | {"gard": ["4273"], "mesh": ["C536650"], "umls": ["C1868854"], "orphanet": ["2842"], "wikidata": ["Q55786963"]} |
Myelophthisic anemia
SpecialtyHematology
Myelophthisic anemia (or myelophthisis) is a severe type of anemia found in some people with diseases that affect the bone marrow. Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue[1] by fibrosis, tumors, or granulomas. The word comes from the roots myelo-, which refers to bone marrow, and phthysis, shrinkage or atrophy.
## Contents
* 1 Causes
* 2 Pathophysiology
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 External links
## Causes[edit]
Myelophthisis can occur in the setting of chronic myeloproliferative disease (e.g. myelofibrosis), leukemia, lymphoma, and metastatic carcinoma or myeloma. It is common in people who have chronic idiopathic myelofibrosis. It has been linked to small-cell lung cancer, breast cancer or prostate cancer that metastasizes to the bone marrow.[2]
Currently, the most common cause is displacement of bone marrow by metastatic cancer (extramedullary hematopoiesis tends to be modest). Other causes include myeloproliferative disorders (especially late-stage or spent polycythemia vera), granulomatous diseases, and (lipid) storage diseases. Myelofibrosis can occur in all of these. Factors that may contribute to decreased RBC production include a decreased quantity of functioning hematopoietic tissue, disordered metabolism related to the underlying disorder, and, in some cases, erythrophagocytosis.
## Pathophysiology[edit]
Some cases of myelophthisis are thought to be related to the release of cytokines that simulate fibroblastic proliferation and fibrosis in the marrow.[2]
## Diagnosis[edit]
The first test for diagnosis myelophthisis involves looking at a small sample of blood under a microscope. Myelophthisis is suggested by the presence of red blood cells that contain nuclei or are teardrop-shaped (dacryocytes), or immature granulocyte precursor cells which indicates leukoerythroblastosis is occurring because the displaced hematopoietic cells begin to undergo extramedullary hematopoiesis. These immature granulocytes are seen in peripheral blood smears. Diagnosis is confirmed when a bone marrow biopsy demonstrates significant replacement of the normal bone marrow compartment by fibrosis, malignancy or other infiltrative process. The presence of immature blood cell precursors helps distinguish another cause of pancytopenia, aplastic anemia, from myelophthisic anemia because in aplastic anemia the hematopoietic cells are damaged and immature blood cells are not seen in the peripheral blood.
There may be evidence of extramedullary hematopoiesis[3] (marrow elements can be found in the spleen, liver).
## Treatment[edit]
Treatment of this disorder involves treatment of the underlying cancer.[2][4]
## See also[edit]
* List of circulatory system conditions
* List of hematologic conditions
## References[edit]
1. ^ "Hematopathology".
2. ^ a b c American Society of hematology self-assessment program, second edition, 2005, page 82.
3. ^ Makoni SN, Laber DA (May 2004). "Clinical spectrum of myelophthisis in cancer patients". Am. J. Hematol. 76 (1): 92–3. doi:10.1002/ajh.20046. PMID 15114608.
4. ^ "Myelophthisic Anemia: Anemias Caused by Deficient Erythropoiesis: Merck Manual Professional". Retrieved 2008-03-08.
## External links[edit]
Classification
D
* ICD-10: D61.9
* ICD-9-CM: 284.2
* MeSH: D000750
External resources
* eMedicine: med/1562
* Myelophthisic Anemia at eMedicine
* v
* t
* e
Diseases of red blood cells
↑
Polycythemia
* Polycythemia vera
↓
Anemia
Nutritional
* Micro-: Iron-deficiency anemia
* Plummer–Vinson syndrome
* Macro-: Megaloblastic anemia
* Pernicious anemia
Hemolytic
(mostly normo-)
Hereditary
* enzymopathy: Glucose-6-phosphate dehydrogenase deficiency
* glycolysis
* pyruvate kinase deficiency
* triosephosphate isomerase deficiency
* hexokinase deficiency
* hemoglobinopathy: Thalassemia
* alpha
* beta
* delta
* Sickle cell disease/trait
* Hereditary persistence of fetal hemoglobin
* membrane: Hereditary spherocytosis
* Minkowski–Chauffard syndrome
* Hereditary elliptocytosis
* Southeast Asian ovalocytosis
* Hereditary stomatocytosis
Acquired
AIHA
* Warm antibody autoimmune hemolytic anemia
* Cold agglutinin disease
* Donath–Landsteiner hemolytic anemia
* Paroxysmal cold hemoglobinuria
* Mixed autoimmune hemolytic anemia
* membrane
* paroxysmal nocturnal hemoglobinuria
* Microangiopathic hemolytic anemia
* Thrombotic microangiopathy
* Hemolytic–uremic syndrome
* Drug-induced autoimmune
* Drug-induced nonautoimmune
* Hemolytic disease of the newborn
Aplastic
(mostly normo-)
* Hereditary: Fanconi anemia
* Diamond–Blackfan anemia
* Acquired: Pure red cell aplasia
* Sideroblastic anemia
* Myelophthisic
Blood tests
* Mean corpuscular volume
* normocytic
* microcytic
* macrocytic
* Mean corpuscular hemoglobin concentration
* normochromic
* hypochromic
Other
* Methemoglobinemia
* Sulfhemoglobinemia
* Reticulocytopenia
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Myelophthisic anemia | c0002890 | 4,933 | wikipedia | https://en.wikipedia.org/wiki/Myelophthisic_anemia | 2021-01-18T18:46:27 | {"mesh": ["D000750"], "umls": ["C0002890"], "icd-9": ["284.2"], "wikidata": ["Q3331923"]} |
Mitochondrial myopathy-lactic acidosis-deafness is a type of metabolic myopathy described only in two sisters to date, presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Mitochondrial myopathy-lactic acidosis-deafness syndrome | c1855033 | 4,934 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2597 | 2021-01-23T17:18:49 | {"gard": ["3682"], "mesh": ["C537476"], "omim": ["251950"], "umls": ["C1855033"], "icd-10": ["G71.3"], "synonyms": ["Mitochondrial myopathy-lactic acidosis-hearing loss syndrome"]} |
A rare syndromic intestinal malformation characterized by ulcer formation in the umbilical cord associated with congenital upper-intestinal atresia, typically presenting with intra-uterine hemorrhaging from the ulcer site and subsequent fetal bradycardia.
## Epidemiology
Whilst about 66 cases have been described to date in the medical and scientific literature, the entity is probably grossly under-reported due to lack of awareness.
## Clinical description
Umbilical cord ulceration (UCU) occurs in the context of duodenal or jejunal intestinal atresia, developing in 6.5-13.6% of infants with a prenatal diagnosis of congenital upper intestinal atresia (CUIA). Onset of the UCU typically occurs from gestational week 30 onwards. Symptoms of UCU usually begin with the onset of premature labor or rupture of membranes, where the increased intra-uterine pressure causes rupture of the umbilical vessel into the amniotic cavity, triggering massive fetal hemorrhage and subsequent bradycardia. Severe anemia is typically present at birth. The degree of ulceration ranges from only desquamation of the epithelium to exposure of the umbilical artery or vein. Cases that do not significantly hemorrhage, especially lower grade lesions, may go undiagnosed.
## Etiology
Whilst the exact mechanism of pathogenesis is unclear, it is suspected that UCU is closely related to in-utero regurgitation of bile. Other mechanisms proposed include vascular hyper-reactivity and secondary ischemia, causing simultaneous occurrence of both UCU and CUIA, due to an epithelial abnormality (similar to the association of epidermolysis bullosa with intestinal atresia).
## Diagnostic methods
Prenatal ultrasound findings of CUIA with polyhydramnios should raise suspicion of associated UCU. However, in these cases, confirmation of diagnosis is most often done postnatally upon examination of umbilical cord.
## Differential diagnosis
Differential diagnoses include absence of Wharton's jelly, omphalomesenteric duct with gastric mucosa, umbilical cord hemangioma, and umbilical hematoma.
## Antenatal diagnosis
Suggestive ultrasound (US) findings include signs of CUIA and polyhydramnios. Whilst there is an increased risk of UCU in cases of CUIA, prenatal detection of UCU is challenging. In high-risk cases, increased frequency of ultrasound monitoring with a meticulous evaluation of the umbilical cord, especially at the fetal end, is advisable but technically difficult. Findings suspicious of blood in amniotic fluid include observations of bleeding from the umbilical cord by color Doppler or changes in the luminosity of the amniotic fluid indicating the presence of blood. Measurement of bile acid concentration in amniotic fluid can further help in segregation of high-risk cases.
## Management and treatment
It is currently difficult to present a method by which sudden fetal death can be prevented. The risk of UCU must be explained elaborately to the parents of fetuses with CUIA. Daily monitoring of high risk cases with fetal kick chart and non‐stress test (NST) is advisable for early detection of UCU. Termination of pregnancy may be considered when hemorrhage is confirmed via amniocentesis or ultrasound findings are suggestive of blood in amniotic fluid. In cases of polyhydramnios with CUIA, continuous fetal heart monitoring at the onset of premature labor or premature rupture of membranes has been found to improve outcome. Awareness of this association and immediate delivery of fetus at first signs of hemorrhage or hypoxia will help prevent stillbirths and poor neonatal outcomes.
## Prognosis
Prognosis of Umbilical cord ulceration-intestinal atresia syndrome is poor, with intra-uterine fetal or neonatal death occurring in the majority of cases. Prompt intervention, initiated with immediate delivery at the first signs of fetal hemorrhage/hypoxia, may improve the outcome.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Umbilical cord ulceration-intestinal atresia syndrome | c2931371 | 4,935 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3405 | 2021-01-23T17:46:37 | {"gard": ["5403"], "mesh": ["C536938"], "umls": ["C2931371"]} |
Familial Partial Lipodystrophy, Dunnigan Type
Autosomal dominant is the manner of inheritance of this condition
Dunnigan-type familial partial lipodystrophy, also known as FPLD Type II and abbreviated as (FPLD2), is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region. FPLD recapitulates the main metabolic attributes of the insulin resistance syndrome, including central obesity, hyperinsulinemia, glucose intolerance and diabetes[1] usually type 2,[2] dyslipidemia, hypertension,[1] and early endpoints of atherosclerosis.[2] It can also result in hepatic steatosis.[3] FPLD results from mutations in LMNA gene, which is the gene that encodes nuclear lamins A and C.[1] The condition is named after Scottish doctor Matthew Dunnigan, who pioneered early study into the disorder. [4]
## See also[edit]
* Familial partial lipodystrophy
## References[edit]
1. ^ a b c Hegele, RA (December 2000). "Familial partial lipodystrophy: A monogenic form of the insulin resistance syndrome". Molecular Genetics and Metabolism. 71 (4): 539–44. doi:10.1006/mgme.2000.3092. PMID 11136544.
2. ^ a b Hegele, RA (September 2000). "Insulin resistance in human partial lipodystrophy". Current Atherosclerosis Reports. 2 (5): 397–404. doi:10.1007/s11883-000-0078-0. PMID 11122771.
3. ^ Ludtke, A; Genschel, J; Brabant, G; Bauditz, J; et al. (October 2005). "Hepatic steatosis in Dunnigan-type familial partial lipodystrophy". The American Journal of Gastroenterology. 100 (10): 2218–24. PMID 16181372.
4. ^ Köbberling, J; Dunnigan, M (1986). "Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state". Journal of Medical Genetics. 23 (2): 120–127. doi:10.1136/jmg.23.2.120. PMC 1049565. PMID 3712389.
## External links[edit]
Classification
D
* ICD-10: E88.1
* OMIM: 151660
* v
* t
* e
Cytoskeletal defects
Microfilaments
Myofilament
Actin
* Hypertrophic cardiomyopathy 11
* Dilated cardiomyopathy 1AA
* DFNA20
* Nemaline myopathy 3
Myosin
* Elejalde syndrome
* Hypertrophic cardiomyopathy 1, 8, 10
* Usher syndrome 1B
* Freeman–Sheldon syndrome
* DFN A3, 4, 11, 17, 22; B2, 30, 37, 48
* May–Hegglin anomaly
Troponin
* Hypertrophic cardiomyopathy 7, 2
* Nemaline myopathy 4, 5
Tropomyosin
* Hypertrophic cardiomyopathy 3
* Nemaline myopathy 1
Titin
* Hypertrophic cardiomyopathy 9
Other
* Fibrillin
* Marfan syndrome
* Weill–Marchesani syndrome
* Filamin
* FG syndrome 2
* Boomerang dysplasia
* Larsen syndrome
* Terminal osseous dysplasia with pigmentary defects
IF
1/2
* Keratinopathy (keratosis, keratoderma, hyperkeratosis): KRT1
* Striate palmoplantar keratoderma 3
* Epidermolytic hyperkeratosis
* IHCM
* KRT2E (Ichthyosis bullosa of Siemens)
* KRT3 (Meesmann juvenile epithelial corneal dystrophy)
* KRT4 (White sponge nevus)
* KRT5 (Epidermolysis bullosa simplex)
* KRT8 (Familial cirrhosis)
* KRT10 (Epidermolytic hyperkeratosis)
* KRT12 (Meesmann juvenile epithelial corneal dystrophy)
* KRT13 (White sponge nevus)
* KRT14 (Epidermolysis bullosa simplex)
* KRT17 (Steatocystoma multiplex)
* KRT18 (Familial cirrhosis)
* KRT81/KRT83/KRT86 (Monilethrix)
* Naegeli–Franceschetti–Jadassohn syndrome
* Reticular pigmented anomaly of the flexures
3
* Desmin: Desmin-related myofibrillar myopathy
* Dilated cardiomyopathy 1I
* GFAP: Alexander disease
* Peripherin: Amyotrophic lateral sclerosis
4
* Neurofilament: Parkinson's disease
* Charcot–Marie–Tooth disease 1F, 2E
* Amyotrophic lateral sclerosis
5
* Laminopathy: LMNA
* Mandibuloacral dysplasia
* Dunnigan Familial partial lipodystrophy
* Emery–Dreifuss muscular dystrophy 2
* Limb-girdle muscular dystrophy 1B
* Charcot–Marie–Tooth disease 2B1
* LMNB
* Barraquer–Simons syndrome
* LEMD3
* Buschke–Ollendorff syndrome
* Osteopoikilosis
* LBR
* Pelger–Huet anomaly
* Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
Microtubules
Kinesin
* Charcot–Marie–Tooth disease 2A
* Hereditary spastic paraplegia 10
Dynein
* Primary ciliary dyskinesia
* Short rib-polydactyly syndrome 3
* Asphyxiating thoracic dysplasia 3
Other
* Tauopathy
* Cavernous venous malformation
Membrane
* Spectrin: Spinocerebellar ataxia 5
* Hereditary spherocytosis 2, 3
* Hereditary elliptocytosis 2, 3
Ankyrin: Long QT syndrome 4
* Hereditary spherocytosis 1
Catenin
* APC
* Gardner's syndrome
* Familial adenomatous polyposis
* plakoglobin (Naxos syndrome)
* GAN (Giant axonal neuropathy)
Other
* desmoplakin: Striate palmoplantar keratoderma 2
* Carvajal syndrome
* Arrhythmogenic right ventricular dysplasia 8
* plectin: Epidermolysis bullosa simplex with muscular dystrophy
* Epidermolysis bullosa simplex of Ogna
* plakophilin: Skin fragility syndrome
* Arrhythmogenic right ventricular dysplasia 9
* centrosome: PCNT (Microcephalic osteodysplastic primordial dwarfism type II)
Related topics: Cytoskeletal proteins
This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Dunnigan familial partial lipodystrophy | c1720860 | 4,936 | wikipedia | https://en.wikipedia.org/wiki/Dunnigan_familial_partial_lipodystrophy | 2021-01-18T18:50:51 | {"mesh": ["D052496"], "orphanet": ["2348"], "wikidata": ["Q5315596"]} |
Continued use of cannabis despite clinically significant impairment
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed.
Find sources: "Cannabis use disorder" – news · newspapers · books · scholar · JSTOR (December 2013)
Cannabis use disorder
Other namesCannabis addictions, marijuana addiction
SpecialtyPsychiatry
Cannabis use disorder (CUD), also known as cannabis addiction or marijuana addiction, is defined in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and ICD-10 as the continued use of cannabis despite clinically significant impairment.[1][2]
## Contents
* 1 Signs and symptoms
* 1.1 Dependency
* 1.2 Withdrawal
* 2 Cause
* 2.1 Risk factors
* 2.2 High risk groups
* 2.2.1 Adolescents
* 3 Diagnosis
* 4 Treatment
* 4.1 Psychological
* 4.2 Medication
* 4.3 Barriers to treatment
* 5 Epidemiology
* 6 Research
* 7 See also
* 8 References
* 9 External links
## Signs and symptoms[edit]
Cannabis use is associated with comorbid mental health problems, such as mood and anxiety disorders, and discontinuing cannabis use is difficult for some users.[3] Psychiatric comorbidities are often present in dependent cannabis users including a range of personality disorders.[4]
Based on annual survey data, some high school seniors who report smoking daily (nearly 7%, according to one study) may function at a lower rate in school than students that do not.[5] The sedating and anxiolytic properties of tetrahydrocannabinol (THC) in some users might make the use of cannabis an attempt to self-medicate personality or psychiatric disorders.[6]
### Dependency[edit]
Prolonged cannabis use produces both pharmacokinetic changes (how the drug is absorbed, distributed, metabolized, and excreted) and pharmacodynamic changes (how the drug interacts with target cells) to the body. These changes require the user to consume higher doses of the drug to achieve a common desirable effect (known as a higher tolerance), reinforcing the body's metabolic systems for eliminating the drug more efficiently and further down-regulating cannabinoid receptors in the brain.[7]
Cannabis users have shown decreased reactivity to dopamine, suggesting a possible link to a dampening of the reward system of the brain and an increase in negative emotion and addiction severity.[8]
Cannabis users can develop tolerance to the effects of THC. Tolerance to the behavioral and psychological effects of THC has been demonstrated in adolescent humans and animals.[9][10] The mechanisms that create this tolerance to THC are thought to involve changes in cannabinoid receptor function.[9]
One study has shown that between 2001–2002 and 2012–2013, the use of marijuana in the US doubled.[11]
Cannabis dependence develops in about 9% of users, significantly less than that of heroin, cocaine, alcohol, and prescribed anxiolytics,[12] but slightly higher than that for psilocybin, mescaline, or LSD.[13] Of those who use cannabis daily, 10–20% develop dependence.[14]
### Withdrawal[edit]
Cannabis withdrawal symptoms occurs in one-half of people in treatment for cannabis use disorders.[15] Symptoms may include dysphoria (anxiety, irritability, depression, restlessness), disturbed sleep, gastrointestinal symptoms, and decreased appetite. It is often paired with Rhythmic movement disorder. Most symptoms begin during the first week of abstinence and resolve after a few weeks.[3] About 12% of heavy cannabis users showed cannabis withdrawal as defined by the DSM-5, and this was associated with significant disability as well as mood, anxiety and personality disorders.[16]
## Cause[edit]
Cannabis addiction is often due to prolonged and increasing use of the drug. Increasing the strength of the cannabis taken and an increasing use of more effective methods of delivery often increase the progression of cannabis dependency. It can also be caused by being prone to becoming addicted to substances, which can either be genetically or environmentally acquired.[17]
### Risk factors[edit]
Certain factors are considered to heighten the risk of developing cannabis dependence and longitudinal studies over a number of years have enabled researchers to track aspects of social and psychological development concurrently with cannabis use. Increasing evidence is being shown for the elevation of associated problems by the frequency and age at which cannabis is used, with young and frequent users being at most risk.[18]
The main factors in Australia, for example, related to a heightened risk for developing problems with cannabis use include frequent use at a young age; personal maladjustment; emotional distress; poor parenting; school drop-out; affiliation with drug-using peers; moving away from home at an early age; daily cigarette smoking; and ready access to cannabis. The researchers concluded there is emerging evidence that positive experiences to early cannabis use are a significant predictor of late dependence and that genetic predisposition plays a role in the development of problematic use.[19]
### High risk groups[edit]
A number of groups have been identified as being at greater risk of developing cannabis dependence and, in Australia, for example, have been found to include adolescent populations, Aboriginal and Torres Strait Islanders and people suffering from mental health conditions.[20]
#### Adolescents[edit]
The endocannabinoid system is directly involved in adolescent brain development.[21] Adolescent cannabis users are therefore particularly vulnerable to the potential adverse effects of cannabis use.[21] Adolescent cannabis use is associated with increased cannabis misuse as an adult, issues with memory and concentration, long-term cognitive complications, and poor psychiatric outcomes including social anxiety, suicidality and addiction.[22][23][24]
There are a lot of reasons why adolescents start a smoking habit. According to a study completed by Bill Sanders, friends influence, difficult household problems, and experimentation are some of the reasons why this population starts to smoke marijuana. [25] This segment of population seems to be one of the most influenceable group there is. [26] They want to follow the group and look "cool", "hip" and accepted by their friends.[27] This fear of rejection plays a big role in their decision to smoke pot. However it does not seem to be the most important factor. According to a study from Canada, the lack of knowledge about cannabis seems to be the main reason why adolescents start to smoke.[28] The authors observed a high correlation between adolescents that knew about the mental and physical harms of cannabis and their consumption.[29] It goes without saying that from the 1045 young participants, the ones who could name the less amount of negative effects about this drug were usually the ones who were consuming it.[30] They were not isolated cases either. Actually, the study showed that the proportion of teenagers who saw cannabis as a high-risk drug and the ones who thought the contrary was about the same.[31]
Pregnancy
There is an association between smoking cannabis during pregnancy and low birth weight.[32] Smoking cannabis during pregnancy can lower the amount of oxygen delivered to the developing fetus, which can restrict fetal growth.[32] The active ingredient in cannabis (D9-tetrahydrocannabinol, THC) is fat soluble and can enter into breastmilk during lactation.[32] THC in breastmilk can then subsequently be taken up by a breastfeeding infant, as shown by the presence of THC in the infant's feces. However, the evidence for long-term effects of exposure to THC through breastmilk is unclear.[33][34][35]
## Diagnosis[edit]
Cannabis use disorder is recognized in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5),[36] which also added cannabis withdrawal as a new condition.[37]
In the 2013 revision for the DSM-5, DSM-IV abuse and dependence were combined into cannabis use disorder. The legal problems criterion (from cannabis abuse) has been removed, and the craving criterion was newly added, resulting in a total of 11 criteria. These are: hazardous use, social/interpersonal problems, neglected major roles, withdrawal, tolerance, used larger amounts/longer, repeated attempts to quit/control use, much time spent using, physical/psychological problems related to use, activities given up and craving. For a diagnosis of DSM-5 cannabis use disorder, at least 2 of these criteria need to be present in the last 12-month period. Additionally, three severity levels have been defined: mild (2-3 criteria), moderate (4-5 criteria) and severe (six or more criteria) cannabis use disorder.[38]
Cannabis use disorder is also recognized in the 11th revision of the International Classification of Diseases (ICD-11),[39] adding more subdivisions including time intervals of pattern of use (episodic, continuous, or unspecified) and dependence (current, early full remission, sustained partial remission, sustained full remission, or unspecified) compared to the 10th revision.[40]
A 2019 meta-analysis found that 34% of people with cannabis-induced psychosis transitioned to schizophrenia. This was found to be comparatively higher than hallucinogens (26%) and amphetamines (22%).[41]
To screen for cannabis-related problems, several methods are used. Scales specific to cannabis, which provides the benefit of being cost efficient compared to extensive diagnostic interviews, include the Cannabis Abuse Screening Test (CAST), Cannabis Use Identification Test (CUDIT), and Cannabis Use Problems Identification Test (CUPIT).[42] Scales for general drug use disorders are also used, including the Severity Dependence Scale (SDS), Drug Use Disorder Identification Test (DUDIT), and Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST).[43] However, there are no gold standard and both older and newer scales are still in use.[43] To quantify cannabis use, methods such as Timeline Follow-Back (TLFB) and Cannabis Use Daily (CUD) are used.[43] These methods measure general consumption and not grams of psychoactive substance as the concentration of THC may vary among drug users.[43]
## Treatment[edit]
Clinicians differentiate between casual users who have difficulty with drug screens, and daily heavy users, to a chronic user who uses multiple times a day.[6] In the US, as of 2013[update], cannabis is the most commonly identified illicit substance used by people admitted to treatment facilities.[14] Demand for treatment for cannabis use disorder increased internationally between 1995 and 2002.[44] In the United States, the average adult who seeks treatment has consumed cannabis for over 10 years almost daily and has attempted to quit six or more times.[13]
Treatment options for cannabis dependence are far fewer than for opiate or alcohol dependence. Most treatment falls into the categories of psychological or psychotherapeutic, intervention, pharmacological intervention or treatment through peer support and environmental approaches.[19] No medications have been found effective for cannabis dependence,[45] but psychotherapeutic models hold promise.[3] Screening and brief intervention sessions can be given in a variety of settings, particularly at doctor's offices, which is of importance as most cannabis users seeking help will do so from their general practitioner rather than a drug treatment service agency.[46]
The most commonly accessed forms of treatment in Australia are 12-step programmes, physicians, rehabilitation programmes, and detox services, with inpatient and outpatient services equally accessed.[47] In the EU approximately 20% of all primary admissions and 29% of all new drug clients in 2005, had primary cannabis problems. And in all countries that reported data between 1999 and 2005 the number of people seeking treatment for cannabis use increased.[48]
### Psychological[edit]
Psychological intervention includes cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), contingency management (CM), supportive-expressive psychotherapy (SEP), family and systems interventions, and twelve-step programs.[3][49]
Evaluations of Marijuana Anonymous programs, modelled on the 12-step lines of Alcoholics Anonymous and Narcotics Anonymous, have shown small beneficial effects for general drug use reduction.[medical citation needed] In 2006, the Wisconsin Initiative to Promote Healthy Lifestyles implemented a program that helps primary care physicians identify and address marijuana use problems in patients.[50]
### Medication[edit]
As of 2020, there is no single medication that has been proven effective for treating cannabis use disorder; research is focused on three treatment approaches: agonist substitution, antagonist, and modulation of other neurotransmitter systems.[3][45] More broadly, the goal of medication therapy for cannabis use disorder centers around targeting the stages of the addiction: acute intoxication/binge, withdrawal/negative affect, and preoccupation/anticipation.[51]
For the treatment of the withdrawal/negative affect symptom domain of cannabis use disorder, medications may work by alleviating restlessness, irritable or depressed mood, anxiety, and insomnia.[52] Bupropion, which is a norepinephrine–dopamine reuptake inhibitor, has been studied for the treatment of withdrawal with largely poor results.[52] Atomoxetine has also shown poor results, and is as a norepinephrine reuptake inhibitor, though it does increase the release of dopamine through downstream effects in the prefrontal cortex (an area of the brain responsible for planning complex tasks and behavior).[52] Venlafaxine, a serotonin–norepinephrine reuptake inhibitor, has also been studied for cannabis use disorder, with the thought that the serotonergic component may be useful for the depressed mood or anxious dimensions of the withdrawal symptom domain.[52] While venlafaxine has been shown to improve mood for people with cannabis use disorder, a clinical trial in this population actually found worse cannabis abstinence rates compared to placebo.[52] It is worth noting that venlafaxine is sometimes poorly tolerated, and infrequent use or abrupt discontinuation of its use can lead to withdrawal symptoms from the medication itself, including irritability, dysphoria, and insomnia.[53] It is possible that venlafaxine use actually exacerbated cannabis withdrawal symptoms, leading people to use more cannabis than placebo to alleviate their discomfort.[52] Mirtazapine, which increases serotonin and norepinephrine, has also failed to improve abstinence rates in people with cannabis use disorder.[52]
People sometimes use cannabis to cope with their anxiety, and cannabis withdrawal can lead to symptoms of anxiety.[52] Buspirone, a serotonin 1A receptor (5-HT1A) agonist, has shown limited efficacy for treating anxiety in people with cannabis use disorder, though there may be better efficacy in males than in females.[52] Fluoxetine, a selective serotonin reuptake inhibitor, has failed to show efficacy in adolescents with both cannabis use disorder and depression.[52] SSRIs are a class of antidepressant drugs that are also used for the treatment of anxiety disorders, such as generalized anxiety disorder.[54] Vilazodone, which has both SSRI and 5-HT1A agonism properties, also failed to increase abstinence rates in people with cannabis use disorder.[52]
Studies of divalproex have found no significant benefit, though some studies have found mixed results.[52] Baclofen, a GABA-B receptor agonist and antispasmodic medication, has been found to reduce cravings but without a significant benefit towards preventing relapse or improving sleep.[52] Zolpidem, a GABA-A receptor agonist and "Z-hypnotic" medication, has shown some efficacy in treating insomnia due to cannabis withdrawal, though there is a potential for misuse.[52] Entacapone was well tolerated and decreased cannabis cravings in a trial on a small number of patients.[3] Topiramate, an antiepileptic drug, has shown mixed results in adolescents, reducing the volume of cannabis consumption without significantly increasing abstinence, with somewhat poor tolerability.[52] Gabapentin, an indirect GABA modulator, has shown some preliminary benefit for reducing cravings and cannabis use.[52]
The agonist substitution approach is one that draws upon the analogy of the success of nicotine replacement therapy for nicotine addiction. Dronabinol, which is synthetic THC, has shown benefit in reducing cravings and other symptoms of withdrawal, though without preventing relapse or promoting abstinence.[52] Combination therapy with dronabinol and the alpha 2 adrenergic receptor agonist lofexidine have shown mixed results, with possible benefits towards reducing withdrawal symptoms.[52] However, overall, the combination of dronabinol and lofexidine is likely not effective for the treatment of cannabis use disorder.[52] Nabilone, a synthetic THC analogue, has shown benefits in reducing symptoms of withdrawal such as difficulty sleeping, and decreased overall cannabis use.[52] Despite its psychoactive effects, the slower onset of action and longer duration of action of nabilone make it less likely to be abused than cannabis itself, which makes nabilone a promising harm reduction strategy for the treatment of cannabis use disorder.[52] The combination of nabilone and zolpidem has been shown to decrease sleep-related and mood-related symptoms of cannabis withdrawal, in addition to decreasing cannabis use.[52] Nabiximols, a combined THC and cannabidiol (CBD) product that is formulated as an oral (buccal) spray, has been shown to improve withdrawal symptoms without improving abstinence rates.[52] Oral CBD has not shown efficacy in reducing the signs or symptoms of cannabis use, and likely has no benefit in cannabis use withdrawal symptoms.[52] The CB-1 receptor antagonist rimonabant has shown efficacy in reducing the effects of cannabis in users, but with a risk for serious psychiatric side effects.[52]
Naltrexone, a mu opioid receptor antagonist, has shown mixed results for cannabis use disorder—both increasing the subjective effects of cannabis when given acutely, but potentially decreasing the overall use of cannabis with chronic administration.[52] N-acetylcysteine (NAC) has shown some limited benefit in decreasing cannabis use in adolescents, though not with adults.[52] Lithium, a mood stabilizer, has shown mixed results for treating symptoms of cannabis withdrawal, but is likely ineffective.[52] Quetiapine, a second-generation antipsychotic, has been shown to treat cannabis withdrawal related insomnia and decreased appetite at the expense of exacerbating cravings.[52] Oxytocin, a neuropeptide that the body produces, has shown some benefit in reducing the use of cannabis when administered intranasally in combination with motivational enhancement therapy sessions, though the treatment effect did not persist between sessions.[52]
Over-the-counter sedating Antihistamines such as Doxylamine have sedating and anti-emetic effects and may provide short term relief but should only be used within advised dosages.
### Barriers to treatment[edit]
Research that looks at barriers to cannabis treatment frequently cites a lack of interest in treatment, lack of motivation and knowledge of treatment facilities, an overall lack of facilities, costs associated with treatment, difficulty meeting program eligibility criteria and transport difficulties.[dubious – discuss][55][56][57]
## Epidemiology[edit]
Cannabis is one of the most widely used drugs in the world. In the United States, between 42%[2] and 49%[58] of people have used cannabis, an estimated 9% of those who use cannabis develop dependence.[13][59][needs update] Of Australians aged 14 years and over 34.8% have used cannabis one or more times in their life.[60] In the U.S., cannabis is the most commonly identified illicit substance used by people admitted to treatment facilities.[3] Most of these people were referred there by the criminal justice system. Of admittees 16% either went on their own, or were referred by family or friends.[61]
In the European Union (data as available in 2018, information for individual countries was collected between 2012 and 2017), 26.3% of adults aged 15–64 used cannabis at least once in their lives, and 7.2% used cannabis in the last year. The highest prevalence of cannabis use among 15 to 64 years old in the EU was reported in France, with 41.4% having used cannabis at least once in their life, and 2.17% used cannabis daily or almost daily. Among young adults (15–34 years old), 14.1% used cannabis in the last year.[62]
Among adolescents (15–16 years old) in a European school based study (ESPAD), 16% of students have used cannabis at least once in their life, and 7% (boys: 8%, girls: 5%) of students had used cannabis in the last 30 days.[63]
Globally, 22.1 million people (0.3% of the worlds population) were estimated to suffer from cannabis dependence.[64]
## Research[edit]
Medications such as SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine may not be helpful to treat cannabis use disorder, but the evidence is very weak and further research is required.[45] THC preparations, gabapentin, oxytocin, and N-acetylcysteine also require more research to determine if they are effective as the evidence base is weak.[45]
Heavy cannabis use has been associated with impaired cognitive functioning, however, its specific details are difficult to elucidate due to the potential use of additional substances of users, and lack of longitudinal studies.[65]
## See also[edit]
* La Guardia Committee, the first in-depth study into the effects of cannabis.
* Medical cannabis
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Cannabis use disorder | c0006870 | 4,937 | wikipedia | https://en.wikipedia.org/wiki/Cannabis_use_disorder | 2021-01-18T18:46:45 | {"mesh": ["D002189"], "umls": ["C0006870"], "wikidata": ["Q3743620"]} |
A number sign (#) is used with this entry because of evidence that recurrent infections associated with encephalopathy, hepatic dysfunction, and cardiovascular malformations is caused by homozygous mutation in the FADD gene (602457) on chromosome 11q13.3.
Clinical Features
Bolze et al. (2010) studied a large consanguineous Pakistani pedigree in which a brother and 2 sisters and a female cousin suffered from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction involving modestly elevated transaminases without cholestasis, metabolic derangement, or synthetic defects, sometimes accompanied by generalized seizures that were difficult to control. Episodes lasted several days, sometimes requiring intensive care. Cranial imaging in 3 patients suggested cerebral atrophy, despite recovery in 2 of them. For some of the episodes, it was possible to identify a viral trigger, including varicella zoster virus, measles-mumps-rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV). One of the sisters died at 4 years of age during such an episode, and the other sister and brother died of fatal invasive pneumococcal disease at ages 4 months and 14 months, respectively. Their affected cousin was alive at 2.75 years of age. Howell-Jolly bodies were detected in 2 patients despite the presence of a spleen, indicating functional hyposplenism. Two of the 4 patients had congenital cardiovascular malformations: pulmonary atresia and a ventricular septal defect in 1 sister, and a left-sided superior vena cava that drained into the left atrium in the cousin. In the previous generation, another 5 family members had died in childhood, 2 with 'epilepsy' and 2 from infection (pneumonia and measles, respectively), suggesting that there may have been up to 9 family members with this disorder over 2 generations. Laboratory findings in affected individuals were similar to those seen in autoimmune lymphoproliferative syndrome (ALPS; 601859), including high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6; 134638) levels, but the Pakistani patients did not exhibit the clinical features of ALPS.
Mapping
In a large consanguineous Pakistani kindred with recurrent infections accompanied by encephalopathy and hepatic dysfunction, Bolze et al. (2010) combined homozygosity mapping with whole-exome sequencing and identified 2 homozygous regions in patients that were heterozygous in unaffected relatives: an 8-Mb interval on chromosome 11 and a 9-Mb interval on chromosome 18. Sequencing identified only 1 nonsynonymous variant within the candidate intervals that had not been previously reported, on chromosome 11.
Molecular Genetics
In 2 sisters and their cousin from a large consanguineous Pakistani pedigree, who had recurrent infections associated with encephalopathy, hepatic dysfunction, and cardiovascular malformations, Bolze et al. (2010) identified homozygosity for a missense mutation in the the FADD gene (602457.0001). The mutation segregated with disease in the kindred and was not found in 282 Pakistani controls. Based on the patients' laboratory findings as well as in vitro and in vivo studies of FADD deficiency, Bolze et al. (2010) concluded that the observed bacterial infections result partly from functional hyposplenism, and the viral infections from impaired interferon immunity.
INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Ventricular septal defect Vascular \- Superior vena cava left-sided, draining into left atrium \- Pulmonary atresia ABDOMEN Liver \- Liver dysfunction, mild \- Transaminases mildly elevated Spleen \- Functional hyposplenism \- Howell-Jolly bodies present NEUROLOGIC Central Nervous System \- Encephalopathy \- Cerebral atrophy \- Seizures IMMUNOLOGY \- Recurrent infections \- Increased number of CD4(-)CD8(-)TCR-alpha-beta(+) T cells LABORATORY ABNORMALITIES \- Increased Fas ligand \- Increased interleukin 10 MOLECULAR BASIS \- Caused by mutation in the Fas-associated via death domain gene (FADD, 602457.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| INFECTIONS, RECURRENT, WITH ENCEPHALOPATHY, HEPATIC DYSFUNCTION, AND CARDIOVASCULAR MALFORMATIONS | c3151062 | 4,938 | omim | https://www.omim.org/entry/613759 | 2019-09-22T15:57:34 | {"omim": ["613759"], "orphanet": ["306550"], "synonyms": ["FADD DEFICIENCY", "Alternative titles"]} |
A number sign (#) is used with this entry because of evidence that cavitary optic disc anomalies (CODA) is caused by heterozygous mutation in the MMP19 gene (601807) on chromosome 12q13.
Clinical Features
Honkanen et al. (2007) reported a 4-generation family, descended from a Russian immigrant who settled in the midwestern United States in the late 1800s, with autosomal dominant inheritance of cavitary optic nerve head (ONH) anomalies and abnormal ONH vasculature. Seventeen clinically affected individuals, one of whom had previously been reported (Moore et al., 2000), and 2 obligate carriers were identified. Most (64.7%) had bilateral involvement. Visual acuity in affected eyes ranged from 20/20 to no light perception. Although the appearance of affected nerves varied greatly, most lacked a well-formed central retinal artery and instead had multiple radial cilioretinal arteries. Prominent cupping was seen in most affected nerves. Four individuals for whom information was available were treated for glaucoma but none had documented elevated intraocular pressure (IOP). Two patients, one of whom had been followed for 13 years, demonstrated bilateral progressive ONH cupping at normal IOP. Nine (56.3%) of the 16 individuals examined had evidence of serous macular detachments; 5 of these had bilateral macular disease. The authors noted that although some of the observed ONH abnormalities could be described as colobomatous, others displayed characteristics more typical of ONH pits, megalopapilla, or morning glory discs. Honkanen et al. (2007) stated that their pedigree was similar to the pedigrees described by Savell and Cook (1976) (see 120430) and Slusher et al. (1989).
Mapping
In the affected members of the 4-generation family with autosomal dominant inheritance of cavitary optic disc anomalies described by Honkanen et al. (2007), Fingert et al. (2007) found linkage of the disorder to chromosome 12q with a maximum 2-point lod score of 4.06 (theta = 0) for marker D12S1700. They found no mutations in the coding sequences of 3 candidate genes: GDF11 (603936), NEUROD4 (611635), or WIF1 (605186).
Molecular Genetics
In a 4-generation family with cavitary disc anomalies mapping to chromosome 12q, Hazlewood et al. (2015) performed whole-exome sequencing of genes located in this region but did not detect any plausible disease-causing variants. Genotyping for copy number variation (CNV) in this region revealed heterozygous triplication of a 6-kb DNA segment located 2.1-kb upstream of the MMP19 gene (601807.0001) that was present in all 17 affected individuals and absent from unaffected family members. By quantitative PCR in 24 additional unrelated patients with a clinical diagnosis of CODA or its component features, including optic pit, optic nerve coloboma, or morning glory disc anomaly, Hazlewood et al. (2015) identified 1 CODA patient with the same DNA triplication upstream of MMP19. The mutation was also present in the proband's affected mother; DNA was unavailable from his affected maternal grandmother. There were no obvious differences in optic nerve appearance between CODA patients carrying the MMP19 CNV and those without the CNV. Noting that the excavated optic nerve head of CODA resembles damage caused by glaucoma, Hazlewood et al. (2015) performed quantitative PCR analysis of DNA from 172 patients with glaucoma, including 84 with normal intraocular pressures and 88 with elevated intraocular pressures, but detected no chromosome 12 CNVs.
### Exclusion Studies
In a 4-generation family with CODA mapping to chromosome 12q, Fingert et al. (2007) analyzed the coding sequences of 3 candidate genes, GDF11 (603936), NEUROD4 (611635), and WIF1 (605186), but found no mutations.
Using DNA from 2 members of the same family with CODA studied by Fingert et al. (2007), Hazlewood et al. (2015) tested for mutations in 7 additional candidate genes but detected no plausible mutations.
INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity \- Night blindness (rare) \- Visual field defects \- Colobomatous optic nerve head (in some patients) \- Optic nerve head pit (in some patients) \- Enlarged optic nerve head (in some patients) \- Morning glory disc appearance (in some patients) \- Progressive optic nerve head cupping (in some patients) \- Multiple cilioretinal arteries radiating from disk margin \- Central retinal artery and/or vein undetectable \- Serous macular detachments (in some patients) \- Peripapillary pigmentary changes (in some patients) \- Peripapillary atrophy (in some patients) \- Scleral ring around optic nerve (in some patients) \- Macular holes (rare) MISCELLANEOUS \- Onset of symptoms in adolescence or early adulthood \- Broad spectrum of optic nerve head anomalies, with significant inter-eye differences in some patients \- More than half of patients develop retinal detachments and/or retinoschisis later in life \- Some patients are asymptomatic and diagnosed incidentally MOLECULAR BASIS \- Caused by mutation in a regulatory element upstream of the matrix metalloproteinase-19 gene (MMP19, 601807.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| CAVITARY OPTIC DISC ANOMALIES | c1969063 | 4,939 | omim | https://www.omim.org/entry/611543 | 2019-09-22T16:03:09 | {"mesh": ["C566924"], "omim": ["611543"], "orphanet": ["464760"], "synonyms": ["Familial CODA"]} |
Melanistic black eastern grey squirrel
Melanistic guinea pigs are rare, and are used in rituals by Andean curanderos.[1]
The term melanism refers to black pigment and is derived from the Greek: μελανός.[2] Melanism is the increased development of the dark-colored pigment melanin in the skin or hair.
Pseudomelanism, also called abundism, is another variant of pigmentation, identifiable by dark spots or enlarged stripes, which cover a large part of the body of the animal, making it appear melanistic.[3]
The morbid deposition of black matter, often of a malignant character causing pigmented tumors, is called melanosis.[4]
## Contents
* 1 Adaptation
* 1.1 Industrial melanism
* 2 In cats
* 3 In birds
* 4 In humans
* 4.1 Peutz–Jeghers syndrome
* 5 Socio-politics
* 6 See also
* 7 References
* 8 Bibliography
## Adaptation[edit]
A melanistic European adder (Vipera berus) compared to a normal-colored adder
Melanism related to the process of adaptation is called adaptive. Most commonly, dark individuals become fitter to survive and reproduce in their environment as they are better camouflaged. This makes some species less conspicuous to predators, while others, such as black panthers, use it as a foraging advantage during night hunting.[5] Typically, adaptive melanism is heritable: A dominant allele, which is entirely or nearly entirely expressed in the phenotype, is responsible for the excessive amount of melanin.
Adaptive melanism has been shown to occur in a variety of animals, including mammals such as squirrels, many cats and canids, and coral snakes. Adaptive melanism can lead to the creation of morphs, the most notable example being the peppered moth, whose evolutionary history in the United Kingdom is offered as a classic instructional tool for teaching the principles of natural selection.[6]
### Industrial melanism[edit]
Main article: Industrial melanism
Industrial melanism is an evolutionary effect in insects such as the peppered moth, Biston betularia in areas subject to industrial pollution. Darker pigmented individuals are favored by natural selection, apparently because they are better camouflaged against polluted backgrounds. When pollution was later reduced, lighter forms regained the advantage and melanism became less frequent.[7][8][9][10][11][12] Other explanations have been proposed, such as that the melanin pigment enhances function of immune defences,[13] or a thermal advantage from the darker coloration.[14][15][16]
## In cats[edit]
See also: Black cat
Melanistic and normally coloured jaguars
Melanistic coat coloration occurs as a common polymorphism in 11 of 37 felid species and reaches high population frequency in some cases but never achieves complete fixation. The black panther, a melanistic leopard, is common in the equatorial rainforest of Malaya and the tropical rainforest on the slopes of some African mountains, such as Mount Kenya. The serval also has melanistic forms in certain areas of East Africa. In the jaguarundi, coloration varies from dark brown and gray to light reddish. Melanic forms of jaguar are common in certain parts of South America.[17] In 1938 and 1940, two melanistic bobcats were trapped alive in sub-tropical Florida.[18]
Pseudomelanism on a cheetah
In 2003, the dominant mode of inheritance of melanism in jaguars was confirmed by performing phenotype-transmission analysis in a 116-individual captive pedigree. Melanistic animals were found to carry at least one copy of a mutant MC1R sequence allele, bearing a 15-base pair inframe deletion. Ten unrelated melanistic jaguars were either homozygous or heterozygous for this allele. A 24-base pair deletion causes the incompletely dominant allele for melanism in the jaguarundi. Sequencing of the agouti signalling peptide in the agouti gene coding region revealed a 2-base pair deletion in black domestic cats. These variants were absent in melanistic individuals of Geoffroy's cat, oncilla, pampas cat and Asian golden cat, suggesting that melanism arose independently at least four times in the cat family.[19]
Melanism in leopards is inherited as a Mendelian, monogenic recessive trait relative to the spotted form. Pairings of black animals have a significantly smaller litter size than other possible pairings.[20] Between January 1996 and March 2009, Indochinese leopards were photographed at 16 sites in the Malay Peninsula in a sampling effort of more than 1000 trap nights. Of 445 photographs of melanistic leopards, 410 were taken south of the Kra Isthmus, where the non-melanistic morph was never photographed. These data suggest the near fixation of the dark allele in the region. The expected time to fixation of this recessive allele due to genetic drift alone ranged from about 1,100 years to about 100,000 years.[21] Melanism in leopards has been hypothesized to be causally associated with a selective advantage for ambush.[22] Other theories are that genes for melanism in felines may provide resistance to viral infections, or a high-altitude adaptation, since black fur absorbs more light for warmth.[23]
## In birds[edit]
White Silkie rooster
Black Silkie rooster
The Silkie chicken commonly exhibits this trait. In April 2015, an extremely rare black flamingo was spotted on the Mediterranean island of Cyprus.[24]
Ayam Cemani is an uncommon and relatively modern breed of chicken from Indonesia. They have a dominant gene that causes hyperpigmentation (Fibromelanosis), making the chicken entirely black; including feathers, beak, and internal organs.
## In humans[edit]
Melanism, meaning a mutation that results in completely dark skin, does not exist in humans[citation needed]. Melanin is the primary determinant of the degree of skin pigmentation and protects the body from harmful ultraviolet radiation. The same ultraviolet radiation is essential for the synthesis of vitamin D in skin, so lighter colored skin - less melanin - is an adaptation related to the prehistoric movement of humans away from equatorial regions, as there is less exposure to sunlight at higher latitudes. People from parts of Africa, South Asia, Southeast Asia, and Australia may have very dark skin, but this is not melanism.
### Peutz–Jeghers syndrome[edit]
This rare genetic disorder is characterized by the development of macules with Hyperpigmentation on the lips and oral mucosa (melanosis), as well as benign polyps in the gastrointestinal tract.[25]
## Socio-politics[edit]
Further information: Melanin theory
The term melanism has been used on Usenet, internet forums and blogs to mean an African-American social movement holding that dark-skinned humans are the original people from which those of other skin color originate. The term melanism has been used in this context as early as the mid-1990s[26] and was promoted by some Afrocentrists, such as Frances Cress Welsing.
## See also[edit]
* Albinism
* Albino and white squirrels
* Amelanism
* Black squirrel
* Erythrism
* Heterochromia iridum
* Leucism
* Piebaldism
* Vitiligo
* Xanthochromism
* Peutz–Jeghers syndrome
* Ocular melanosis
* Melanosis
## References[edit]
1. ^ Morales, E. (1995). The Guinea Pig : Healing, Food, and Ritual in the Andes. University of Arizona Press. ISBN 0-8165-1558-1.
2. ^ Liddell, H. G.; Scott, R. (1940). "μελα^νός". A Greek-English Lexicon, revised and augmented throughout by Sir Henry Stuart Jones, with the assistance of Roderick McKenzie. Oxford: Clarendon Press.
3. ^ Osinga, N.; Hart, P.; van VoorstVaader, P. C. (2010). "Albinistic common seals (Phoca vitulina) and melanistic grey seals (Halichoerus grypus) rehabilitated in the Netherlands". Animal Biology. 60 (3): 273−281. doi:10.1163/157075610x516493. S2CID 84554567.
4. ^ Webster's Revised Unabridged Dictionary (1913). Melanosis Archived 2013-07-29 at the Wayback Machine. C. & G. Merriam Co. Springfield, Massachusetts. Page 910
5. ^ King, R.C., Stansfield, W.D., Mulligan, P.K. (2006). A Dictionary of Genetics, 7th ed., Oxford University Press
6. ^ Begon, M.; Townsend, C. R. & Harper, J. L. (2006). Ecology: From individuals to ecosystems (Fourth ed.). Malden, Oxford: Wiley Publishing. ISBN 9781405151986.
7. ^ Majerus, M. E. (2009). Industrial melanism in the peppered moth, Biston betularia: an excellent teaching example of Darwinian evolution in action. Evolution: Education and Outreach, 2(1), 63-74.
8. ^ McIntyre, N. E. (2000). Ecology of urban arthropods: a review and a call to action. Annals of the Entomological Society of America, 93(4), 825-835.
9. ^ Cook, L. M., Saccheri, I. J., 2013. The peppered moth and industrial melanism: evolution of a natural selection case study. Journal of Heredity 110:207-12
10. ^ Grant, B. S., Wiseman L. L., 2002. Recent history of melanism in American peppered moths. Journal of Heredity 93:86-90.
11. ^ Brakefield, P. M., Liebert, T. G., 2000. Evolutionary dynamics of declining melanism in the peppered moth in the Netherlands. Proceedings of the Royal Society of London Biology 267:1953-1957.
12. ^ Grant, B. S., Cook, A. D., Clarke, C. A., & Owen, D. F. (1998). Geographic and temporal variation in the incidence of melanism in peppered moth populations in America and Britain. Journal of Heredity, 89(5), 465-471.
13. ^ Mikkola, K., & Rantala, M. J. (2010). Immune defence, a possible nonvisual selective factor behind the industrial melanism of moths (Lepidoptera). Biological Journal of the Linnean Society, 99(4), 831-838.
14. ^ Mikkola, K., Albrecht, A., 1988. The melanism of Adalia-bipunctata around the Gulf of Finland as an industrial phenomenon (Coleoptera, Coccinellidae). Annales Zoologici Fennici 25:177-85.
15. ^ Muggleton, J., Lonsdale, D., Benham, B. R., 1975. Melanism in Adalia-bipunctata L (ColCoccinellidae) and its relationship to atmospheric pollution. Journal of Applied Ecology 2:451-464.
16. ^ De Jong, P. W., Verhoog, M. D., Brakefield, P. M., 1992. Sperm competition and melanic polymorphism in the 2-spot ladybird, Adalla bipunctata (Coleoptera, Coccinellidae). Journal of Heredity 70:172-178.
17. ^ Searle, A. G. (1968) Comparative Genetics of Coat Colour in Mammals. Logos Press, London
18. ^ Ulmer, F. A. (1941) Melanism in the Felidae, with special reference to the Genus Lynx. Journal of Mammalogy 22 (3): 285–288.
19. ^ Eizirik, E.; Yuhki, N.; Johnson, W. E.; Menotti-Raymond, M.; Hannah, S. S.; O'Brien, S. J. (2003). "Molecular Genetics and Evolution of Melanism in the Cat Family". Current Biology. 13 (5): 448–453. doi:10.1016/S0960-9822(03)00128-3. PMID 12620197. S2CID 19021807.
20. ^ Robinson, R. (1970). "Inheritance of black form of the leopard Panthera pardus". Genetica. 41 (1): 190–197. doi:10.1007/BF00958904. PMID 5480762. S2CID 5446868.
21. ^ Kawanishi, K.; Sunquist, M. E.; Eizirik, E.; Lynam, A. J.; Ngoprasert, D.; Wan Shahruddin, W. N.; Rayan, D. M.; Sharma, D. S. K.; Steinmetz, R. (2010). "Near fixation of melanism in leopards of the Malay Peninsula". Journal of Zoology. 282 (3): 201–206. doi:10.1111/j.1469-7998.2010.00731.x.
22. ^ Majerus, M. E. N. (1998). Melanism: evolution in action. Oxford University Press, New York
23. ^ Seidensticker, J., Lumpkin, S. (2006). Smithsonian Q & A: the ultimate question and answer book. Cats. Collins, New York
24. ^ Krol, Charlotte (2015-04-09). "Rare black flamingo spotted in Cyprus". The Telegraph. Archived from the original on 2015-04-25. Retrieved 2015-05-16.
25. ^ Broomfield, Denis (2018). "Mystery behind labial and oral melanotic macules: Clinical, dermoscopic and pathological aspects of Laugier-Hunziker syndrome". World Journal of Clinical Cases. 6 (10): 322–334. PMC 6163135. PMID 30283795.
26. ^ "Sundiata, AFROCENTRISM: THE ARGUMENT WE'RE REALLY HAVING". Retrieved 2007-06-23.
## Bibliography[edit]
Wikimedia Commons has media related to Melanism.
* David Attenborough (2002). The Life of Mammals (TV-Series and book). United Kingdom: BBC.
* Kettlewell, Bernard (1973). The Evolution of Melanism. Clarendon Press. ISBN 0-19-857370-7.
* Majerus, Michael (1998). Melanism: Evolution in Action. Oxford University Press. ISBN 0-19-854982-2.
* Melanism and disease resistance in insects
* Fryer, G. 2013. How should the history of industrial melanism in moths be interpreted? The Linnean. 29 (2): 15 - 22.
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Pigmentation disorders/Dyschromia
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*[AA]: Adrenergic agonist
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*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
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| Melanism | c0025209 | 4,940 | wikipedia | https://en.wikipedia.org/wiki/Melanism | 2021-01-18T19:01:37 | {"mesh": ["D008548"], "wikidata": ["Q725450"]} |
Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.
The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.
A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.
Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.
Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.
## Frequency
GEFS+ is a rare condition. Its prevalence is unknown.
## Causes
Mutations in several genes, including some that have not been identified, can cause GEFS+. The most commonly associated gene is SCN1A. More than 80 percent of Dravet syndrome cases and about 10 percent of other GEFS+ cases are caused by changes in this gene. Mutations in other genes have been found in only a small number of affected individuals or families.
The SCN1A gene and others associated with GEFS+ provide instructions for making pieces (subunits) of channels that transport positively charged sodium atoms (sodium ions) into cells. The transport of these ions helps generate and transmit electrical signals between nerve cells (neurons). Proteins produced from other genes involved in GEFS+ are subunits of another type of ion channel called the GABAA receptor. GABAA receptor channels block (inhibit) signaling between neurons. Still other GEFS+-associated genes are also involved in nerve signaling.
Mutations in the SCN1A gene have a variety of effects on sodium channels. Many mutations that cause Dravet syndrome reduce the number of functional channels in each cell. Mutations that cause the milder GEFS+ disorders likely alter the channel's structure. All of these genetic changes affect the ability of the channels to transport sodium ions into neurons. Some mutations are thought to reduce channel activity while others may increase it. It is unclear, however, how these changes underlie the development of seizures. Some studies show that certain SCN1A gene mutations cause signaling between neurons to be constantly turned on (stimulated). Researchers believe that overstimulation of certain neurons in the brain triggers the abnormal brain activity associated with seizures. It is not known if all SCN1A gene mutations have the same effect.
Changes in GABAA receptor subunit genes impair the channel's function, causing uncontrolled signaling between neurons, which likely leads to seizures.
Researchers do not understand how changes in any one of the genes associated with GEFS+ can lead to a range of seizure disorders. Because the disorders are so varied, even among family members, researchers believe that other genes and environmental factors help determine the severity of the condition.
### Learn more about the genes associated with Genetic epilepsy with febrile seizures plus
* SCN1A
* SCN9A
Additional Information from NCBI Gene:
* GABRD
* GABRG2
* SCN1B
* SCN2A
* STX1B
## Inheritance Pattern
GEFS+ is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new (de novo) mutations in the gene and occur in people with no history of the disorder in their family.
Dravet syndrome is almost always caused by de novo mutations, although it can be inherited from a parent who has a milder form of GEFS+. Other forms of GEFS+ are usually inherited from an affected parent. Rarely, Dravet syndrome or other forms of GEFS+ are inherited from a parent with somatic mosaicism. Somatic mosaicism means that some of the body's cells have the gene mutation, and others do not. A parent with mosaicism may be less severely affected or not show any signs or symptoms of GEFS+.
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*[AA]: Adrenergic agonist
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
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*[LIT]: Lithuania
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*[AUS]: Australia
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*[LUX]: Luxembourg
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| Genetic epilepsy with febrile seizures plus | c2751604 | 4,941 | medlineplus | https://medlineplus.gov/genetics/condition/genetic-epilepsy-with-febrile-seizures-plus/ | 2021-01-27T08:25:44 | {"gard": ["10430", "2169"], "omim": ["613060", "607681", "604233", "604403", "613863", "616172"], "synonyms": []} |
A coronary occlusion is the partial or complete obstruction of blood flow in a coronary artery. This condition may cause a heart attack.
In some patients coronary occlusion causes only mild pain, tightness or vague discomfort which may be ignored; however, the myocardium, the muscle tissue of the heart, may be damaged.
According to Robert K. Massie's Nicholas and Alexandra: The Fall of the Romanov Dynasty, Tsar Nicholas II may have suffered a coronary occlusion right before he was toppled from his throne during the Russian Revolution in 1917.[1]
## See also[edit]
* Arterial embolism
## Citations[edit]
1. ^ Massie, Robert K. (2012), Nicholas and Alexandra: The Fall of the Romanov Dynasty. New York, The Modern Library, p. 433. ISBN 0679645616. Accessed 2016-11-19. Originally published in 1967 by Artheneum (United States) as Nicholas and Alexandra: An Intimate Account of the Last of the Romanovs and the Fall of Imperial Russia. ISBN 978-0-679-64561-0.
This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it.
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*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
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*[BMI]: body mass index
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*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
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| Coronary occlusion | c0151814 | 4,942 | wikipedia | https://en.wikipedia.org/wiki/Coronary_occlusion | 2021-01-18T18:41:25 | {"mesh": ["D054059"], "wikidata": ["Q5172192"]} |
Personality disorder
Haltlose personality disorder
Other names\- Willenlosen Psychopath[1][2][3]
\- Unstable psychopath[4]
\- Unstable drifter[5][6][7]
\- Disinhibited Personality[8]
SpecialtyPsychiatry
Usual onsetEarly adulthood[9]
DurationLong term
Causes\- Maternal indolence (proposed)[10]
\- Childhood institutionalization (proposed)[10]
\- Parental rejection (proposed)[11]
\- Hereditary predisposition through the mother (proposed)[12][13]
Risk factorsParental neglect[10]
Maternal alcoholism[14]
Diagnostic methodBased on reported symptoms
Symptoms can be tested using TCI and ZKPQ[15]
Differential diagnosis\- ADHD[16]
\- Asthenic PD[17]
\- Delayed maturity[18]
\- Simplex or Disorganized schizophrenia[18][19]
\- Epilepsy (When Haltlose is combined with alcoholism)[20][21]
-Dependant PD[22]
Prognosis\- "Particularly unfavorable" regarding relapse[23] and long-term decline[24]
\- Can be controlled by external influence[25][26][18]
\- Although ideation and threats are common, typically lack the courage to commit suicide.[27]
\- Normal intelligence[28]
FrequencyEqual representation between males and females[13]
Haltlose personality disorder is an ICD-10 personality disorder[29] in which affected individuals possess psychopathic traits built upon short-sighted selfishness[21] and irresponsible hedonism, combined with an inability to anchor one's identity to a future or past.[30][31] The symptoms of Haltlose share similarities with frontal lobe syndrome, sociopathic and histrionic personality traits,[30][32] and are characterized by a lack of inhibition[33] and "the immaturity of moral and volitional qualities...and the absence of positive ethical attitudes."[34][unreliable source?]
Described by Emil Kraepelin and Gustav Aschaffenburg in the early twentieth century,[35][36][37] and further distinguished by Karl Jaspers, Eugen and Manfred Bleuler, it has been colloquially dubbed psychopathy with an "absence of intent or lack of will".[3]
With other hyperthymics, Haltlose personalities were considered to make up "the main component of serious crime",[23] and are studied as one of the strains of psychopathy relevant to criminology[38][39][40] as they are "very easily involved in the criminal history"[41] and may become aggressors[4][42] or homicidal.[43] Their psychopathy is difficult to identify as a shallow sense of conformity is always present.[20][verification needed] A 2020 characterization of mental illnesses noted of the Haltlose that "these people constantly need vigilant control, leadership, authoritarian mentor, encouragement and behavior correction" to avoid an idle lifestyle, involvement in antisocial groups, crime and substance abuse.[34][44] The marked tendencies towards suggestibility are off-set by demonstrations of "abnormal rigidity and intransigence and firmness".[45]
After discovering a guilty conscience due to some act or omission they have committed, "they then live under constant fear of the consequences of their action or inaction, fear of something bad that might strike them" in stark opposition to their apparent carelessness or hyperthymic temperament,[46] which is itself frequently a subconscious reaction to overwhelming fear.[9] They frequently withdraw from society.[47] Given their tendency to "exaggerate, to embroider their narratives, to picture themselves in ideal situations, to invent stories",[27] this fear then manifests as being "apt to blame others for their offences, frequently seeking to avoid responsibility for their actions".[48] They do not hold themselves responsible for their failed life, instead identifying as an ill-treated martyr.[21]
They were characterized as Dégénérés supérieurs,[13] demonstrating normal or heightened intellect but degraded moral standards.[49] Of the ten types of psychopaths defined by Schneider, only the Gemütlose (compassionless) and the Haltlose "had high levels of criminal behavior" without external influence, and thus made up the minority of psychopaths who are "virtually doomed to commit crimes" by virtue only of their own constitution.[50] Frequently changing their determined goals,[9] a haltlose psychopath is "constantly looking for an external hold, it doesn't really matter whether they join occult or fascist movements".[51] The ability to moderate external influence was considered one of three characteristics necessary to form an overall personality, thus leaving Haltlose patients without a functional personality of their own.[52] A study of those with haltlose personality disorder concludes "In all of those cases, the result was a continuous social decline that ended in asocial-parasitic existence or an antisocial-criminal life".[50][53][54]
Haltlose has one of the most unfavorable prognoses of psychopathies.[55] To exist safely, such a psychopath requires "a harsh lifestyle" and constant supervision.[56]
## Contents
* 1 Etymology and criticism
* 2 Physiology
* 3 Symptoms
* 4 Published summaries
* 5 Childhood origins, and later role of family
* 5.1 Schooling
* 5.2 Adolescence, young adulthood and efforts to intervene
* 6 Individual case studies
* 7 Criminology
* 7.1 Domestic violence, incest and molestation of children
* 7.2 Drunk driving, hit-and-run
* 7.3 Suicidality and murder-suicide
* 7.4 Institutionalization
* 8 External links
* 9 References
## Etymology and criticism[edit]
Illustration accompanying the description of Haltlose personality disorder in a Doctoral thesis at Sidi Mohamed Ben Abdellah University.[57]
"Haltlos" is a German word that contextually refers to a floundering, aimless, irresponsible lifestyle,[30] and the diagnosis is named "Haltlose" using the feminine variation on the word.[58] They are commonly clinically termed an "unstable psychopath",[9][4] which is differentiated from emotionally unstable personality disorder (an alternate name for borderline personality disorder). It was remarked in early studies that England, the United States and northern European countries did not use the same typology, not distinguishing between those psychopaths who were unstable and those who were "Unstable Psychopaths".[59][clarification needed]
In 1998, it was remarked that there was not an easily-translated English variation to use for the diagnosis[32] and it has been dubbed a part of "German-speaking psychiatry".[60] The term "Haltlose" is more common in the study of psychiatry, while "Willenlose" is preferred in sociology.[61] Some like Karl Birnbaum prefer the term "Haltlose", while others like Kurt Schneider prefer "Willenlos" shifting focus off their lack of self-control[50] and opposed to the moralist tones of those like Birnbaum who had described the Haltlose as unable to grasp "important ideal values such as honor and morality, duty and responsibility, as well as material ones such as prosperity and health".[50][54] In 1928, Eugen Kahn argued Willenlose was a misnomer, as the patients demonstrated plenty of "will" and simply lacked the ability to translate it into action.[62]
Historically, researchers such as Schneider argued that instability is the symptom, whereas lack of volition is the underlying cause.[19] It is not included in the Diagnostic and Statistical Manual of Mental Disorders, possibly due to a modern belief that the concept of volition is outdated and overshadowed by the concepts of motivation and arousal or drive.[63]
In 1963, Karl Jaspers defined the term as "those who have no willpower at all, the drifters, simply echoing any influence that impinges on them".[2] However, in 1976, the Government of Canada listed the alternate term "Unstable drifter" in a psychiatric criminology context as a problematic term for which they could not readily offer a French translation in accordance with their bilingualism laws.[64][65] Similar issues have arisen trying to translate it to other languages, including Turkish.[66] Ultimately the diagnosis was handicapped by the issues of translation, leading to criticism of "the impoverishment of psychiatric vocabulary" that led to declining research and use.[1][clarification needed]
In the early 20th century, Aschaffenburg distanced himself from accusations that the diagnosis was intended to protect criminals from punishment, emphasizing instead that those with Haltlose personality disorder "generally cannot be exculpated".[67][68]
Dr. Friedrich Stumpfl cautioned against what he saw as a trend of diagnosing haltlose personality disorder without investigating comorbidities that may be even more pronounced.[69] In condemning the idea of personality disorders generally, Joachim-Ernst Meyer suggested in 1976 that Schneider's early description of the Haltlose personality disorder, as a lack of determination in aspects of life including parenting, could just as easily be described as an example of a neurosis rather than a psychopathy if studied only by its aetiology rather than its symptoms,[70] and used it as an example of the nature versus nurture debate that surrounded all personality disorders.[70] Critics ceded that the term "Haltlose" remained of value in educational and therapeutic contexts, while suggesting future collaboration between psychiatric research and sociologists would allow further definition.[71][clarification needed]
Recently,[when?] it has been criticized as a "diagnosis of convenience [that] avoids all further deliberations about a psychopathic personality".[72] Dr. DM Svrakic and Dr. M Divac-Jovanovic suggested the ICD-10 explanations of Haltlose, Immature and Psychoneurotic personality disorders appeared "dubious",[73] and sociologist James Cosgrave found psychiatric use to represent a "fringe figure".[74] A graduate student at Bochumer Stadt & Studierendenzeitung condemned the historical diagnosis from an LGBT perspective, opining that "incredibly oppressive language" had been used by the psychiatrists studying it such as "pathological femininity".[75]
It may be that the evolution of test-batteries have minimized diagnoses of Haltlosen, differentiating it from some newer models in psychiatry.[16]
## Physiology[edit]
Outburst of a Haltlose patient in German, expressing life is hardly worth living since as "war-horses" the Haltlosen suffer from society's efforts to tame them - and he will seek vengeace on the city.[24]
Described as bearing a "pronounced heredity burden",[76] the propensity for Haltlose has also been suggested to be passed only through the maternal genes.[12] Only[dubious – discuss] able to offer "primitive reactions"[77][page needed] and "poor and immature judgement",[48][78] they are noted to display an absolute lack of purpose in their lives "except for the simple biological need to continue living".[79][year needed]
Gustav von Bergmann, a specialist in internal medicine rather than psychiatry, wrote in 1936 that Haltlose personality disorder was entirely biological rather than fostered through psychological experiences.[80] Indeed, Dr. Hans Luxenburger proposed in 1939 that a toxin in the metabolism, when present with Haltlose personality disorder, might be responsible for asthenic difficulties such as shortness of breath, nausea, and cluster headaches.[13] Dr. E.H. Hughes noted that two thirds of Huntington's disease patients had previously been diagnosed as Haltlose or Gemütlose psychopaths.[13]
A study in 1949 of different psychopathies under examination by electroencephalography recordings showed that borderline personalities and haltlose personalities had increased levels of dysrhythmia, whereas other subtypes of psychopathy did not show variation.[81] An individual in 1931 was noted as having initially improved but relapsed "because of encephalitis".[82] As with other personality disorders, a 1923 article suggests it can also be acquired through encephalitis.[83] In 2006, an Essex warehouse employee who suffered head injuries was awarded £3 million compensation on the basis it had caused him to develop Haltlose personality disorder, seeking out prostitutes and pornography which destroyed his marriage.[84]
> Mistakes cannot be fully avoided when placing children under care. even an experienced specialist often cannot distinguish between a blossoming hebephrenia and a Gemutlose or Haltlose personality disorder. Even with weeks of institutional observation, the certainty of our diagnostic aids can remain doubtful...under certain circumstances a doctor will advise medical care even at the risk of learning the patient cannot improve as a result of mental illness and will end up in a madhouse.
>
> — Kurt Schneider[19]
Dr. W. Blankenburg posited in 1968 that those with haltlose personality disorder exhibited less categorical orientation than those patients who were simply unstable.[85] By 1962, lobotomy was being tested as a possible means to limit the chaotic thinking of the Haltlose personality.[86]
Kraepelin, in noting "an increased risk of criminal behavior", estimated that 64% of men and 20% of women with Haltlose descended into alcoholism in the early twentieth century.[16] The frequent intersection between HLPD and alcoholism means modern clinical researchers may use "haltlose" as a grouping when separating subjects by disposition.[87][88][89][specify] Research in 1915 noted an increased propensity for lavish spending, and overconsumption of coffee, tea and medication.[24]
One 1954 study suggested female Haltlose patients may experience "manic excitement" during their menses.[90] According to 1949 research, they have a higher rate of homosexuality,[37] and 1939 evidence suggested that masturbation is more prevalent in Haltlose and Gemütlose (compassionless) psychopaths than in other disorders,[52] and Haltlose erethics leave them "usually very sexually excited" and seeking out "atypical, irregular and unusual" debauchery whether in brothels, adultery or destroying marriages.[24][48][78]
They demonstrate similarities to hysteroid dysphoria.[91][20] In 1928, it was proposed that Fantasy prone personality was likely a subset of Haltlose personalities, suffering from maladaptive daydreaming and Absorption.[92]
The eugenicist Verners Kraulis of the University of Latvia noted[when?] it was frequently comorbid with Histrionic personality disorder.[93]
## Symptoms[edit]
> The most disturbing aspect of this patient's life was his complete selfish, hedonistic, irresponsible, drifting, and aimless lifestyle, along with a complete lack of hold on life or on his self. His life history led us to study the fascinating concept of Bleuler's haltlose personality disorder, which came naturally as a comorbid diagnosis.
>
> — Dr. Gama Marques[94]
According to 1968 research, haltlose personality disorder is frequently comorbid with other mental health diagnoses, and rarely appears isolated on its own.[95] Hans Heinze focused on his belief that Haltlose ultimately stemmed from a sense of inferiority,[52] while Kramer held there was a battling inferiority complex and superiority complex.[47]
The Haltlose were said to have a dynamic instinctual drive to "cling" to others,[when?] to avoid a horrible loneliness they fear[20][year needed] \- but they will always represent a "lurking danger" because they were unable to actually maintain the necessary relationship and were in a class with the "forever abandoned".[96] According to 1926 research, they view all interaction as a means of winning "indulgence from some people, help from other people".[97]
One early study indicated that 7.5% of psychopaths were Haltlose,[98][99] and Kraepelin estimated that his own practice determined fewer than 20% of psychopaths he saw were Haltlose.[16] However more recent studies, after differentiating out newer diagnoses, have suggested that it may be fewer than 1% of psychopaths who are truly Haltlose.[20][year needed][100][clarification needed]
Kraepelin quoted a patient's self-analysis as "a mish-mash of slavish debasement, anxiety, shame, terror, pettiness and fear of people".[24] Krapelin noted generally of such patients that "her own weal and woe plays a huge role in her field of vision, with less interest or participation in the interests of others around them".[24] Described in 1922 as both "moody" and "passive",[101] they quickly switch from over-confidence in victory to sullen defiance.[24]
Their emotional lability[25][18] means they alternate between projecting an optimistic and competent image claiming they are "destined to do great things", and a more honest cynicism and depression.[27] Research in 1925 indicates they display "great emotional irritability, which may result in violent loss of temper...and interpret every limitation as an undeserved insult"[27][102] and have a "pronounced lust for argument".[12] The symptoms are considered to worsen if patients are granted greater independence "in the home and in their work".[9]
Like sociopathy, haltlose personality disorder causes an inability to learn from experience, and an inability to feel genuine remorse[32] as a strong present-time orientation, lacking long-term goals, leaves them detached from the reality of their past - their self schema only encompasses the immediate present.[30] Also described as "living in a random location and moment",[42][year needed] this is commonly seen in Cluster B personality disorders such as Borderline Personality Disorder with which it is frequently comorbid, even though Haltlose is seen as either outside the traditional Cluster organization[103] or a potential Cluster A personality disorder.[104] A common pitfall in therapy is that they proved in 1917 to be "very superficial, they easily acquire knowledge but do not apply it in any way and soon forget it".[27]
> The essence of these people...playthings of external influences, allowing themselves to be carried away by events like a leaf in the wind! ...Impermanence is everything. In one hour, they are happy and excited with the whole world lying open for them in the splendor of the joy of life, but the next hour casts aside this optimism and the future now seems bleak, gray on gray...sympathies and antipathies quickly replace each other, what was worshipped yesterday is burned today, and despite all oaths of eternal loyalty, the best friend is transformed into the deeply-loathed enemy overnight."
>
> — Dr. L. Scholz, Anomale Kinder, Berlin. 1919[105]
Those with HLPD display "a number of endearing qualities, charming with an apparent emotional warmth, but also an enhanced suggestibility and a superficiality of affect", which can lead to unrealistic optimism.[30] and "wandering through life without ever taking firm root".[106] They are also noted as "absolutely indifferent to others...likes to live for [their] pleasure today, does not make plans not only for the future but even for tomorrow, studying and working are not for them".[41] Persons with HLPD typically lack any deep knowledge, and "look for easy life and pleasures".[107] They have been described as "conquerers with an appearance of emotional warmth".[42]
Persons with HLPD were noted as struggling with hypochondria in 1907.[108] They also struggle with alcoholism,[109][30] and identify with antisocial personality disorder.[30][110] In countries that do not use the ICD, the patient might be categorised as Histrionic PD, Borderline PD or Narcissistic PD,[111] or in the manic phase of Bipolar Disorder.[104]
Haltlosen were noted as being among those with a tendency to "disappear, wander and travel about, here, there and everywhere...[including those] known as the Orientkunden, [Middle Eastern] tramps. These are people who are attracted to the Orient on account of the ease with which they are able to live there without steady employment and the freedom from closer supervision of the Western civilization" in 1917.[27] Kraepelin said they were "apt to take senseless journeys, perhaps even becoming vagabonds".[48][78] Kraepelin argued only lifelong wanderlust was tied to Haltlose, whereas Kahn argued that the Haltlose often lost their wanderlust as they aged and preferred to settle into mediocrity.[62] Some make their fortune, but the disappearance of less fortunate travelers is not mentioned by their families who considered them to have been burdensome.[97]
To early twentieth-century researchers, they appeared amiable, well-spoken, self-confident and to be making strong efforts to improve their weaknesses, thus making a misleading first impression and endearing themselves to superiors.[97] The lack of a sense of identity, or internal support, was thought to a lack of resistance to both external and internal impulses in 1927.[9] Their "gradual deterioration in the swamp of neediness and immorality" still does not make a lasting impression on the patients.[24] Thus Haltlose patients who recognize their shortcomings were thought to possibly be overwhelmed by a subconscious fear about participating in the world without restraints in a 1924 account.[19] Similarly, researchers in the early twentieth-century believed that the inauthenticity of their projected self and superficiality of knowledge means that when "someone who is really superior to [them]", after a period of stiffly asserting themselves hoping to avoid submission, will ultimately and without explanation fully embrace the position of the other.[97]
Pathological lying is closely linked to Haltlose personality disorder, with Arthur Kielholz noting "They lie like children...this activity always remains just a game which never satisfies them and leaves them with a guilty conscious because neither the super ego nor the Id get their due...Since they are offering such a daydream as a gift, they consider themselves entitled to extract some symbolic gift in return through fraud or theft".[76][year needed] Adler maintained "Memory is usually poor and untrustworthy...often they seem to have no realization of the truth", [27] while Homburger felt they held "no sense of objectivity, no need for truth or consistency".[97]
According to early accounts, choices are made, often in mirroring others around them, but "do not leave even a passing imprint on the person's identity".[10] Thus, they can "behave properly for a while under good leadership",[9] and are not to be trusted in leadership positions themselves.[45] Gannushkin noted they must be urged, scolded or encouraged "with a stick, as they say".[56] They demonstrate poor mood control and "react quickly to immediate circumstances" since "mood variation can be extreme and fluctuate wildly", which led to the denotation "unstable psychopath".[112]
They have been described as "cold-blooded"[46] and "undisciplined, inclined to ignore the obligations assigned....always needs a strong leader who will direct and show what needs to be done",[34] but must be differentiated from dependent personality disorder, as the two can appear similar, due to the artifice of the Haltlose patient, despite having starkly opposing foundations.[17] Persons with Dependent Personality Disorder are defined by a tendency to embarrassment,[113] and submissiveness[114] which are not genuine facets of those with Haltlose even if they mimic such. Haltlose was thus deemed the "more troublesome" personality in 1955.[115]
## Published summaries[edit]
1915 graph of Haltlose personalities by age and gender[21]
Otto Dornbluth offered the definition in his Clinical Dictionary, that the Haltlose were clinically "Psychopaths without perseverance, always derailing themselves despite good intentions".[116]
In Kramer's lengthy analysis, he proposed that the Haltlose had a "hypersensitivity to sensory perceptions" which led them to deliberately spoil situations into which they actually wished to adapt and settle.[9] This leads to "something quite contradictory in the self-assessment of the Haltlose psychopath, on the one hand they are full of feelings of insufficiency, but on the other hand they have a very high self-assessment...[but] show an astonishing lack of criticism for the inadequacy of their achievements".[9] "They want to at least play-act the role they can't really be internally, they pretend to possess skills and achievements that they do not have...often they want to become actors...they seek out lesser social elements to impress by way of appearing exploited and victimized, and for that they enjoy the reputation that they claim."[9]
Emil Kraepelin's initial belief was that the Haltlose were caught in a transition toward maturity but may ultimately emerge without the disorder.[97] He also wrote that they were recognised as "possessing of lofty though unrealistic ambitions", active imaginations and would routinely "exaggerate, boast and fabricate".[48][78]
Manfred Bleuler wrote "The Haltlosen are characterized by a lack of enduring emotional attachment and, thus, an abnormal tendency for the will to be influenced by various inner and outer stimuli".[58][117]
> [When] convinced of unseemly cases, of committing crimes, such persons [with haltlose personality disorder] transfer their guilt to others, without revealing any shame or embarrassment [and] are prone to pseudology; their lies are rather naive, poorly thought out, implausible, which absolutely does not bother them.
> A group of hysterical psychopathic personalities is characterized[34]
Roth and Slater remarked that "immediate wishes, affections or disgruntlements rule [them] completely, and [they are] indifferent about the future and never consider the past"[115] noting they lack the traditional ability of insight but "are clever at concealing, both from themselves and others, this lack of real understanding by an exercise of verbal agility." and noted "it is tempermentally impossible for him to save, or to maintain any secure financial position...he is always on the brink of a disaster."[4]
Uwe Henrik Peters detailed Haltlose Psychopaths in his psychiatric dictionary as "weak-willed, unreliable, unable to resist external influences, easily led astray, tending to sexual waywardness...if left alone, they cannot set their own goals, they have no inner compass."[58][118]
The 2012 manual "Psychiatric Emergencies in Family Practice" noted these individuals as being "affectionless, egocentric and demanding...show[ing] no realistic ambition or foresight. Often restless, they do not profit from experience or punishment and are frequently impulsive, lacking the awareness of others' needs...appearances in this group can be highly deceptive for they are plausible, likeable and natural. Without a proper history, the doctor can easily be misled by distortions which occasionally amount to pathological lying"[112] An "evasion of reality" is frequently present.[119][97]
## Childhood origins, and later role of family[edit]
> "Whomever is abandoned in youth to the inexorable misery of existence, and at the same time is exposed to all manner of seductions, will find it very difficult to curb their constantly incited desires, and to instead force themselves through to the lofty vantage of moral self-assertion.
>
> — Kraepelin speaking about the Haltlose, 1915[24]
It has been proposed that haltlose personality disorder may arise from "traumatization through maternal indolence" or institutionalization in early life, although without definite conclusion.[10] It may present in childhood simply as a hypomanic reaction to the loss of a parent or incest object.[96] They often display a fear of abandonment that appeared in childhood,[110] a common BPD symptom. Male Haltlose personalities may come out of families with a pampering, over-protective and domineering mother with a weak father.[70] Homburger noted the "childhood and youth of the Haltlose are extraordinarily sad".[97] It is possible, but rare, for Haltlose personalities to develop within healthy family structures.[20]
Gerhardt Nissen referenced the possibility of intrauterine factors in the shaping of anti-social behaviors in Haltlose psychopaths, while noting the concept of psychopathy had been so weakened in modern psychopathology as to be indistinguishable from other conditions.[22] Others have suggested there is a strong heredity correlation, as the parents often also display Haltlose personality disorder, especially the mother.[13][12] Raising a haltlose child can, in some cases, destroy the family structure by forcing relatives to take opposing positions, provoking disagreement and creating an atmosphere of bitterness and dejection.[97] They have been clinically described as disappointments to their families,[22] and are unable to feel actual love for their parents and are indifferent to the hardships of relatives - since all relationships are seen only as potential means towards acquiring pleasure.[20]
Care must be taken in making Haltlose diagnoses of children, since "the traits of instability of purpose, lack of forethought, suggestibility, egoism and superficiality of affect...are to some extent normal in childhood".[4] Children with haltlose personality disorder demonstrate a marked milieu dependency,[120] which may be a cause rather than effect of the Haltlose.[76] It is of great importance that only children with Haltlose have peers and friends to surround themselves to try and learn associations and behaviors.[24] They often become sexually active at a young age but delayed sexual maturity, and as adults retain a psychophysical infantilism.[121][20] Regressive addictions amongst Haltlose psychopaths typically are infantile, and seek to replace the lost "dual union" arising from their parents' rejection, and later morph into a focus on subjects including vengeance or sado-masochism.[11]
The age at which parents or professionals exhibited concern about psychopathy ranged; rarely even at a preschool age.[97] Haltlose children confusingly tend to appear very strong-willed and ambitious, it is only as they age and the lack of perseverance becomes manifest that caretakers become puzzled by their "naughtiness" as it contradicts what had earlier appeared.[97] This arises principally due to their rigid demands for short-term wishes being mistakenly interpreted as having a fixed purpose and persistence.Some patients later shown to be Haltlose, had shown neuropathic traits in childhood such as bedwetting and stuttering.[20] They were also more likely to run away from their home, begin drinking before the socially acceptable age, and were afraid of punishment.[20] Although struggling to make friends in young childhood, they find it easier as they age.[122]
The Russian storybook character Dunno has been noted as an example of a child with Haltlose personality disorder.[123]
A delinquent Austrian youth in 1966 was diagnosed with Haltlose personality disorder, and his case marked that "what he lacks above all is a model to which he would be prepared to submit, just as he lacks the concept of authority".[124] Psychiatrists Lange, Kranz and Stumpfl were agreed that the Haltlose must be "given secure leadership" throughout life in order to remain "socially acceptable".[12]
Kraepelin contended the disorder was "based on a biological predisposition" but also affected by factors such as childrearing practises, social position and state of the parental home.[16] His analysis showed that 49% of diagnosed Haltlose had obvious parental issues such as alcoholism or personality disorders.[16] A 1944 study of children produced by incest by Dr. Alfred Aschenbrenner found a high rate of Haltlose personality disorder, which he suggested might be explained as inherited from overly suggestive mothers.[12] It is not believed to manifest often in children until they have aged.[125] It is possible, although difficult, to diagnose from the age of five[126] and presents one of the stronger psychiatric difficulties if present at such young age.[127] It may be possible to prevent social failure "through welfare measures" akin to early intervention.[127] Italian courts stressed mimicry of positive role models as a means to combat Haltlose youth who had fallen afoul of the law.[128]
### Schooling[edit]
Haltlose can cause educational difficulties,[82] and if parents do not understand the peculiarities of their haltlose child, they may try to through good intentions to force the child into an educational regimen inappropriate for them, which then creates a feeling of isolation in the child which grows into a rebellious tendencies, "which turns out to be disastrous for further development".[9] Students with Haltlose personalities may prefer the arts over the sciences, since the former does not require a consistent sense of truth and entails less disciplined study.[43][105][20] Given their inability to anchor a self-schema and tendency to play-act roles, the theatre and film have great attraction and influence over them.[27]
With proper leadership and controls from teachers, they are able to become "model pupils" in terms of behavior,[37] although Schneider opined that it was worthless to educate an inability to learn from mistakes prevented actual education, and bemoaned that the late onset of anti-social behaviors kept the Haltlose in school when they might otherwise be removed.[19] Walter Moos believed that Haltlose personality disorder and hyperthymia had shown itself to be contagious in rare cases, wherein classmates developed the same disorder from interaction with patients.[129] Homburger argued for removing a Haltlose child from their family of origin as soon as the disorder was confirmed, to resettle in a rural educational centre.[97]
### Adolescence, young adulthood and efforts to intervene[edit]
> [It] is not because the characteristics that cause the abnormal behavior in the late adolescence were not already present in childhood - but we do not yet ask the child to behave independently in life. By a child's nature, it is unstable to a certain extent, and even under normal circumstances will require the support of adults and protection from outside influences. Thus, only when the child reaches the age at which we demand a certain degree of independence and volitional decisions does the defect clearly emerge.
>
> — Dr. Franz Kramer, 1927[9]
Haltlose adolescents may use the internet to seek relief from unpleasant feelings through anonymous virtual relationships and similar activities.[130][131][132]
When required to live independently, they "soon lose interest, become distracted and absent-minded, and commit gross errors and negligence".[27] Ruth von der Leyen noted that "every care provider, teacher and doctor knows the Haltlose Psychopath from their practice", and remarked that caring for such a patient was made more difficult because of the need to lecture and intervene to enlist the psychopath's cooperation in short-term improvements, despite being aware the psychiatric reports have determined such efforts are ultimately useless but should be practised regardless.[133]
The tendency to accumulate debts while seeking pleasure or escaping responsibility is often the attributed cause for their descent into crime, although Kramer noted those who displayed "extreme dexterity, sufficient talent for imagination, and a tendency towards dishonesty" were able to find alternative sources of income without necessarily becoming criminal, although warned that "again and again, their debts have to be paid until the parents no longer can, or want to, do this and leave them to their selves".[9]
Gannushkin noted "Such people involuntarily evoke sympathy and a desire to help them, but the assistance rendered to them rarely lasts, so it is worth abandoning such people for a short while".[56] The wasted good intentions resulted in the summary "probably the most important function of the psychiatrist when dealing with these patients is to protect their relatives and friends from ruining themselves in hopeless attempts at reclamation. With most of these patients a time comes when the relatives will be best advised...to allow the patient to go to prison, or otherwise suffer unsheltered the consequences of his deeds."[4]
By contrast, others have advanced the "rather optimistic" belief that "a suitable [spouse]" or similar "strong-willed" relative could drastically improve the outcome of Haltlosen patients.[56][134] This was echoed by Andrey Yevgenyevich Lichko who, while preferring the term "accentuation of character" to describe the psychopathy rather than "personality disorder", noted "if they fall into the hands of a person with a strong will, for example a wife or husband, they can they live quite happily...but the guardianship must be permanent."[123] When they have been raised by families of origin that tolerated or fed their disorder, they are often confused when other people do not treat them similarly.[97]
## Individual case studies[edit]
Grave marker for Ernst Lossa
In 1902, a criminal complaint in Bern noted regarding a Haltlose-diagnosed offender that "the moral weakness of the accused appears in nearly all his life relationships, and he gives his character their character...[his] principles lack natural strength and stand so haphazardly that, like a house of cards, they will collapse at the first touch with the temptations of life".[135] The commitment papers for an "Ida H.", arrested by Swiss authorities circa 1920, noted that her psychiatric assessment had determined she had Haltlose personality disorder and displayed "a strong fantasy, an inclination to hysteric symptoms and congenital feebleness".[136]
In 1937, a German couple were declined a marriage certificate on the basis one proposed spouse "justif[ied] the conclusion that N. is in a condition of ethical and moral decline, due to a lack of healthy inhibitions...the court is therefore convinced that N is Haltlos and a criminal psychopath who is unable to conduct a marriage in the way in which it is desirable...it is to be feared that the inferior social characteristics that hold sway over [them] will be transmitted to offspring or that [they] would at the very least exert negative educational influences on [the children]".[50]
Willy Roloff was a Pomeranian serial killer diagnosed with Haltlose personality disorder and a higher than average IQ, who was executed by guillotine at Plötzensee Prison in 1937 after his appeal to Adolf Hitler for a commutation was denied.[137][138][139][140]
Wolfgang Scheler, the son of philosopher Max Scheler, was sent to Schneider at his father's request in 1923 and diagnosed as both a Haltlose and Gemütlose psychopath.[141][142] After two decades of an unstable life that involved pimping among other crimes, he was sent to Sachsenhausen concentration camp in 1939; there are no further records of him.[142][141]
Ernst Lossa was a Yenish youth deemed to have a Haltlose personality disorder at the age of 10[143] on account of his theft and treachery.[144] Yenish people were believed to be particularly vulnerable to Haltlose personality disorder on account of inbreeding.[145] He was later euthanized by the Nazis in 1944 at the Irsee sanatorium.[144][146] His death was cited at the Doctors' trials in 1946.[147]
A Haltlose man named Gottlieb K. was repeatedly convicted of crimes such as fraud in 1945, and when Swiss authorities sought to invoke Article 14 of the Criminal Code to house him in a sanatorium or the St. Johannsen Labor Institute, government council noted that his psychiatric report did not suggest medical faculties were needed for the purpose of curing him rather than any source of external control on his actions so he was sent to prison.[135]
In 2011, a Swiss court case noted the defendant had been diagnosed with Haltlose personality disorder, comorbid with ADHD and Narcissistic personality disorder, and that he had been taking benzodiazepines while in freedom but medication was unnecessary once he was institutionalized.[148] Two years later another Swiss case noted another Haltlose diagnosis, comorbid with Generalized Anxiety Disorder and Depression, which required "psychotropic drugs as well as supportive, connected and closely-controlled talk therapy".[149]
In 2017, a Portuguese man with schizoaffective disorder and haltlose personality disorder, and with over 85 hospitalizations over his lifetime, underwent pharmacogenetic testing to determine a way to alleviate his symptoms. Following the results of this testing, his medication regime was accordingly altered. He achieved total remission of symptoms within four weeks.[94]
## Criminology[edit]
> [The Unstable Psychopath] will distinguish [them]self by the glibness and insincerity of [their] protestations...[they] blame [them]self not at all and only hope to be extracted from [their] difficulties in order to continue as before on much the same path. However superficial their affects, personalities of this type often show an apparent warmth...permit[ting] them to impose on their friends and relatives to an almost unbelievable extent.
>
> — Roth and Slater[4]
While some Haltlose have risen to the level of dangerous offenders multiple times over, it is more frequent that they attract attention early from their "vagabond" nature.[145]
G.E. Buda released a study of 72 convicts with haltlose personality disorder, debilitation and psychosis to study their mental degeneration.[150] Heinrich Schulte BVO, a wartime medical judge and consulting psychiatrist for the military, continued advocating for the sterilization of Haltlose and other "Schwachsinnigen" after the war's end.[151] In 1979, the Neue Anthropologie publication referred to a need to sterilize those like alcoholics, "who are often Haltlose psychopaths", from bearing children, to reduce crime.[152]
Although Kraepelin believed those with Haltlose personality disorder represented the antithesis of morality,[135] there is not necessarily a tendency towards deliberate amorality among the demographic despite its frequent criminal violations since they may lack the ability to premeditate.[153] But their demonstrated lack of self-control is "especially manifested in the sphere of morality".[154]
In 1935, it was estimated that 58% of recidivist criminals were diagnosed with Haltlose personality disorder, higher than any other personality disorder.[69] More recently, Haltlose and Histrionic were the most common personality disorders found in female juvenile delinquents by forensic psychologists in Russia in the year 2000.[155]
### Domestic violence, incest and molestation of children[edit]
> "[Patients resembling Haltlose] as a rule show little insight into the peculiarities of their conduct. They do not understand how they could have done these things, or they blame their relatives, neighbors and so forth".
> -Dr. Herman Morris Adler, 1917[27]
Although they enter relationships easily, Andrey Yevgenyevich Lichko contends they are not capable of actual loyalty or selfless love, and sex is treated as a form of entertainment rather than intimacy.[20] They are therefore described as acting as "family tyrants".[24] Their "tendency towards primitive reactions of an explosive nature",[13] means they commonly perpetrate domestic violence including beatings, death threats, and smashing household objects.[24]
Although they may not qualify as "true" pedophiles, Haltlose personalities demonstrate an increased risk of sexually molesting children, since other potential victims would require the realization of greater planning, but children are suggestible and easily overwhelmed.[156][37]
A 1967 German study had suggested over 90% of adult-child incest offenders were diagnosed with Haltlose Personality Disorder.[98] They are also noted for preferring sex in the presence of their children.[24] Female patients may also live vicariously through encouraging and directing the sexual lives of their daughters.[24]
### Drunk driving, hit-and-run[edit]
Haltlose personalities are drawn towards dangerous driving habits "as a source of almost hedonist pleasure".[20] In 1949 the Automobil Revue proposed that additional tests should be necessary for Haltlose personalities to obtain a driver's license.[157] They have been known to steal cars to joyride at high speeds if they are not otherwise able to find satisfy their urge.[20]
The American Journal of Psychiatry published a study of hit and run drivers in 1941, which showed 40% of drivers who fled the scene of a traffic accident tested positive for haltlose personality disorder.[158] This was consistent with the earlier finding that Haltlose Personalities were among the most likely to attempt to flee if caught in commission of any crime.[159]
### Suicidality and murder-suicide[edit]
Research in the early twentieth century on suicidality among the Haltlose indicated several things: they chafe at the notion of any religion as it introduces unwanted inhibitions, especially against parasuicidal demonstrations;[43][97] women Haltlose most frequently indicated suicidality was based upon fear of punishment or reproach, as well as the "excitement" of being institutionalized;[24] and although frequently planning or attempting suicide, including through suicide pacts or murder suicide, Haltlose typically do not succeed since they lacked courage and were easily distracted.[24][27]
### Institutionalization[edit]
Haltlose patients respond very well to institutionalization where their influences can be controlled, becoming "model inmates" of sanitariums even within hours of first arriving despite a chaotic life outside of the regimen, "but if you leave them, through good intentions, to their own devices - they don't last long before collapsing their current state and being seduced back onto the wrong track".[46][160][attribution needed] Kraepelin quoted a patient who noted "Though imprisonment used to seem gruesome to me, if arrested in the future it will become an oasis in my unstable desert".[24] Schneider recommended warning them "through punishing them" as it was the only control on their action.[61] Bleuler said the court system needed to understand such persons were in "urgent need of inhibitions".[161]
Pyotr Gannushkin noted they joined military service due to peer pressure but given the lack of alcohol and stern, hard work required of them were able to function without their normal impairment.[56] A 1942 study of the Wehrmacht found that only Haltlose and Schizoid were not measurable among soldiers despite their presence in the civilian population.[162] A 1976 Soviet naval study came to similar conclusions.[163]
Roth and Slater concluded "the treatment of such a personality is almost hopeless under the present ordering of society. Any treatment would...present difficulties...beyond the powers of these patients. The prospects of psychotherapy are forlorn and the best that can be obtained will be reached through social control."[4]
Some researchers[who?] suggest their moods and insufficient motivation will lead them to "vague feelings of fear and calamity...turning every little thing into big things, excitement, misinterpreting every harmless word, criticizing everything and commiting hostile acts", and in some cases they look back with hindsight and regret the injustices they did.[159] However Kramer held that when caught in wrongdoing, "we find them contrite, self-accusing and assuring that they will improve - but on closer inspection it is feigned and not sincere".[9]
Upon being confronted with their misdeeds, the Haltlose respond "with more or less superficial reasons to excuse them, they claim that their parents treated them incorrectly, that they were the victim of adverse circumstances, seduced by other people and misled. Other Haltlose, especially those with a strong intellect, make up a theoretical schema that would justify their actions."[9]
## External links[edit]
Wikiquote has quotations related to: Haltlose personality disorder
* Kielholz, Arthur, Internationale Zeitschrift für Psychoanalyse XIX 1933 Heft 4, "Weh'dem der lugt! Beitrag zum problem der pseudologia phantastica", an article on pathological lying in the Haltlose patients Max Specke, a Swiss charlatan with a penchant for melodramatic flair and Emil Schuldling, a habitual criminal with childhood sexual perversions
* Story of Robert Wenger, who was diagnosed Haltlose and spent 54 years between institutions and prison for minor crimes until the documentary series Quer exposed his case, leading to an apology from politician Samuel Bhend in 1999.
* Karl Hager, a habitual criminal diagnosed Haltlose who was frequently jailed for homosexual acts and was ultimately killed in Sachsenhausen concentration camp (in German)
* Biography of a man diagnosed Haltlose in 1936 (in German)
* Berlit, Berthold (December 1931). "Erblichkeitsuntersuchungen bei Psychopathen". Zeitschrift für die gesamte Neurologie und Psychiatrie. 134 (1): 382–498. doi:10.1007/BF02897001.
* Article referencing Hermann Lederman, discharged from the Wehrmacht in 1940 having been diagnosed with Haltlose personality disorder and sent to Wehrmachtgefängnis Torgau
* Article about Karl Sieger, a chronic drunkard diagnosed with Haltlose personality disorder in 1936 by Dr. Ferdinand Rechberg of Konstanz
* Thomas Leveritt's novel "The Exchange-Rate Between Love and Money" contains a character, Frito, who has Haltlose personality disorder
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132. ^ Peris, Montserrat; de la Barrera, Usue; Schoeps, Konstanze; Montoya-Castilla, Inmaculada (26 June 2020). "Psychological Risk Factors that Predict Social Networking and Internet Addiction in Adolescents". International Journal of Environmental Research and Public Health. 17 (12): 4598. doi:10.3390/ijerph17124598. PMC 7344613. PMID 32604834. S2CID 220290270.
133. ^ Leyen, Ruth von der. "Ausbildungsfragen", as it appeared in Bericht über die 4. Sachverständigen-Konferenz des Deutschen Vereins zur Fürsorge für jugendliche Psychopathen e.V.: Hamburg 13.–15. September 1928.
134. ^ D. Curran and E. Guttman, Psychological Medicine: A Short Introduction to Psychiatry with an Appendix: War-Time Psychiatry (E. and S. Livingstone, Edinburgh, 1943), p.61
135. ^ a b c Germann, Urs (2004). Psychiatrie und Strafjustiz: Entstehung, Praxis und Ausdifferenzierung der forensischen Psychiatrie in der deutschsprachigen Schweiz 1850-1950 [Psychiatry and criminal justice: emergence, practice and differentiation of forensic psychiatry in German-speaking Switzerland 1850-1950] (in German). Chronos. ISBN 978-3-0340-0678-1.[page needed]
136. ^ Gerodetti, Natalia. "Modernizing Sexualities", page 185 ff.
137. ^ https://www.erichs-kriminalarchiv.de/1921-1940/3-seite-mit-15-faellen.html
138. ^ Kriminalchronik des dritten Reiches Bd. 2: 1938-1945 | Michael Kirchschlager, Wolfgang Krüger | ISBN 9783934277243
139. ^ Berliner Lokal-Anzeiger, July 10, 1937, Evening Edition
140. ^ Berliner Volkszeitung, July 6, 1937 evening edition
141. ^ a b Krahl, A. Schifferdecker, M. "Max Scheler und Kurt Schneider", pg 5
142. ^ a b Cutting, John. History of Psychiatry, "Max Scheler's influence on Kurt Schneider", 2016. Pg 5
143. ^ "Aus dem Gutachten von Dr. Hell, 1940, Ernst ist 10 Jahre und 9 Monate alt", 'From the report by Dr. Hell, 1940, Ernst is 10 years and 9 months old'.
144. ^ a b Schuck, Volker (December 2013). "Vergessenen eine Stimme geben". DNP - der Neurologe und Psychiater. 14 (12): 36–37. doi:10.1007/s15202-013-0545-4. S2CID 180438130.
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Classification
D
* ICD-10: F60.8
* v
* t
* e
Personality disorders
Schizotypal
* Schizotypal
Specific
* Anankastic
* Anxious (avoidant)
* Dependent
* Dissocial
* Emotionally unstable
* Histrionic
* Paranoid
* Schizoid
*
Other
* Eccentric
* Haltlose
* Immature
* Narcissistic
* Passive–aggressive
* Psychoneurotic
Organic
* Organic
Unspecified
* Unspecified
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Haltlose personality disorder | None | 4,943 | wikipedia | https://en.wikipedia.org/wiki/Haltlose_personality_disorder | 2021-01-18T18:41:33 | {"icd-10": ["F60.8"], "wikidata": ["Q5643617"]} |
Cerebellar ataxia - areflexia - pes cavus - optic atrophy - sensorineural hearing loss (CAPOS syndrome) is a rare autosomal dominant neurological disorder characterized by early onset cerebellar ataxia, associated with areflexia, progressive optic atrophy, sensorineural deafness, a pes cavus deformity, and abnormal eye movements.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome | c1832466 | 4,944 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1171 | 2021-01-23T18:56:17 | {"gard": ["1188"], "mesh": ["C535351"], "omim": ["601338"], "umls": ["C1832466"], "icd-10": ["G11.0"], "synonyms": ["CAPOS syndrome", "Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural deafness syndrome"]} |
Aspect of human sexuality
Spinal cord injury affects sexual function, but many people with the condition have fulfilling relationships and sex lives.
Although spinal cord injury (SCI) often causes sexual dysfunction, many people with SCI are able to have satisfying sex lives. Physical limitations acquired from SCI affect sexual function and sexuality in broader areas, which in turn has important effects on quality of life. Damage to the spinal cord impairs its ability to transmit messages between the brain and parts of the body below the level of the lesion. This results in lost or reduced sensation and muscle motion, and affects orgasm, erection, ejaculation, and vaginal lubrication. More indirect causes of sexual dysfunction include pain, weakness, and side effects of medications. Psycho-social causes include depression and altered self-image. Many people with SCI have satisfying sex lives, and many experience sexual arousal and orgasm. People with SCI employ a variety of adaptations to help carry on their sex lives healthily, by focusing on different areas of the body and types of sexual acts. Neural plasticity may account for increases in sensitivity in parts of the body that have not lost sensation, so people often find newly sensitive erotic areas of the skin in erogenous zones or near borders between areas of preserved and lost sensation.
Drugs, devices, surgery, and other interventions exist to help men achieve erection and ejaculation. Although male fertility is reduced, many men with SCI can still father children, particularly with medical interventions. Women's fertility is not usually affected, although precautions must be taken for safe pregnancy and delivery. People with SCI need to take measures during sexual activity to deal with SCI effects such as weakness and movement limitations, and to avoid injuries such as skin damage in areas of reduced sensation. Education and counseling about sexuality is an important part of SCI rehabilitation but is often missing or insufficient. Rehabilitation for children and adolescents aims to promote healthy development of sexuality and includes education for them and their families. Culturally inherited biases and stereotypes negatively affect people with SCI, particularly when held by professional caregivers. Body image and other insecurities affect sexual function, and have profound repercussions on self-esteem and self-concept. SCI causes difficulties in romantic partnerships, due to problems with sexual function and to other stresses introduced by the injury and disability, but many of those with SCI have fulfilling relationships and marriages. Relationships, self-esteem, and reproductive ability are all aspects of sexuality, which encompasses not just sexual practices but a complex array of factors: cultural, social, psychological, and emotional influences.
## Contents
* 1 Sexuality and identity
* 2 Sexual function
* 2.1 Complete and incomplete injury
* 2.2 Level of injury
* 2.3 Psychogenic and reflexogenic responses
* 2.4 Factors in reduced function
* 3 Fertility
* 3.1 Male
* 3.2 Female
* 4 Management
* 4.1 Erectile problems
* 4.2 Ejaculation and male fertility
* 4.3 Women
* 4.4 Education and counseling
* 4.4.1 Children and adolescents
* 4.5 Changes in sexual practices
* 4.6 Considerations for sexual activity
* 5 Long-term adjustment
* 6 Relationships
* 7 Society and culture
* 8 References
* 9 Bibliography
* 10 External links
## Sexuality and identity[edit]
Sexuality is an important part of each person's identity, although some people might have no interest in sex. Sexuality has biological, psychological, emotional, spiritual, social, and cultural aspects.[1] It involves not only sexual behaviors but relationships, self-image, sex drive,[2] reproduction, sexual orientation, and gender expression.[3] Each person's sexuality is influenced by lifelong socialization, in which factors such as religious and cultural background play a part,[4] and is expressed in self-esteem and the beliefs one holds about oneself (identifying as a woman, or as an attractive person).[1]
SCI is extremely disruptive to sexuality, and it most frequently happens to young people, who are at a peak in their sexual and reproductive lives.[3][5] Yet the importance of sexuality as a part of life is not diminished by a disabling injury.[6] Although for years people with SCI were believed to be asexual, research has shown sexuality to be a high priority for people with SCI[7] and an important aspect of quality of life.[8][9] In fact, of all abilities they would like to have return, most paraplegics rated sexual function as their top priority, and most tetraplegics rated it second, after hand and arm function.[10][11] Sexual function has a profound impact on self-esteem and adjustment to life post-injury.[12] People who are able to adapt to their changed bodies and to have satisfying sex lives have better overall quality of life.[5]
## Sexual function[edit]
SCI usually causes sexual dysfunction,[13] due to problems with sensation and the body's arousal responses. The ability to experience sexual pleasure and orgasm are among the top priorities for sexual rehabilitation among injured people.[14]
Much research has been done into erection.[14] By two years post-injury, 80% of men recover at least partial erectile function,[15] though many experience problems with the reliability and duration of their erections if they do not use interventions to enhance them.[16] Studies have found that half[15] or up to 65% of men with SCI have orgasms,[17] although the experience may feel different than it did before the injury.[15] Most men say it feels weaker, and takes longer and more stimulation to achieve.[18]
Common problems women experience post-SCI are pain with intercourse and difficulty achieving orgasm.[19] Around half of women with SCI are able to reach orgasm, usually when their genitals are stimulated.[20] Some women report the sensation of orgasm to be the same as before the injury, and others say the sensation is reduced.[5]
### Complete and incomplete injury[edit]
The severity of the injury is an important aspect in determining how much sexual function returns as a person recovers.[15][21] According to the American Spinal Injury Association grading scale, an incomplete SCI is one in which some amount of sensation or motor function is preserved in the rectum.[10] This indicates that the brain can still send and receive some messages to the lowest parts of the spinal cord, beyond the damaged area. In people with incomplete injury, some or all of the spinal tracts involved in sexual responses remain intact, allowing, for example, orgasms like those of uninjured people.[22] In men, having an incomplete injury improves chances of being able to achieve erections[21][23] and orgasms over those with complete injuries.[24][25]
Even people with complete SCI, in whom the spinal cord cannot transmit any messages past the level of the lesion, can achieve orgasm.[15][17][26] In 1960, in one of the earliest studies to look at orgasm and SCI, the term phantom orgasm was coined to describe women's perception of orgasmic sensations despite SCI—but subsequent studies have suggested the experience is not merely psychological.[10] Men with complete SCI report sexual sensations at the time of ejaculation, accompanied by physical signs normally found at orgasm, such as increased blood pressure.[26] Women can experience orgasm with vibration to the cervix regardless of level or completeness of injury; the sensation is the same as uninjured women experience.[27] The peripheral nerves of the parasympathetic nervous system that carry messages to the brain (afferent nerve fibers) may explain why people with complete SCI feel sexual and climactic sensations.[26] One proposed explanation for orgasm in women despite complete SCI is that the vagus nerve bypasses the spinal cord and carries sensory information from the genitals directly to the brain.[10][25][28][29] Women with complete injuries can achieve sexual arousal and orgasm through stimulation of the clitoris, cervix, or vagina, which are each innervated by different nerve pathways, which suggests that even if SCI interferes with one area, function might be preserved in others.[30] In both injured and uninjured people, the brain is responsible for the way sensations of climax are perceived: the qualitative experiences associated with climax are modulated by the brain, rather than a specific area of the body.[26]
### Level of injury[edit]
The effects of injury depend on the level along the spinal column.
A dermatome is an area of the skin that sends sensory messages to a specific spinal nerve.
In addition to completeness of injury, the location of damage on the spinal cord influences how much sexual function is retained or regained after injury.[19][31] Injuries can occur in the cervical (neck), thoracic (back), lumbar (lower back), or sacral (pelvic) levels.[32] Between each pair of vertebrae, spinal nerves branch off of the spinal cord and carry information to and from specific parts of the body.[32] The location of injury to the spinal cord maps to the body, and the area of skin innervated by a specific spinal nerve, is called a dermatome. All dermatomes below the level of injury to the spinal cord may lose sensation.[33]
An injury at a lower point on the spine does not necessarily mean better sexual function; for example, people with injuries in the sacral region are less likely to be able to orgasm than those with injuries higher on the spine.[34] Women with injuries above the sacral level have a greater likelihood of orgasm in response to stimulation of the clitoris than those with sacral injuries (59% vs 17%).[35] In men, injuries above the sacral level are associated with better function in terms of erections and ejaculation, and fewer and less severe reports of dysfunction.[17] This may be due to reflexes that do not require input from the brain, which sacral injuries might interrupt.[17]
### Psychogenic and reflexogenic responses[edit]
Nerves involved in arousal comprise two major pathways: inhibitory input from the psychogenic pathway is sympathetic, and stimulation by the reflexogenic is parasympathetic.[36]
The body's physical arousal response (vaginal lubrication and engorgement of the clitoris in women and erection in men) occurs due to two separate pathways which normally work together: psychogenic and reflex.[37] Arousal due to fantasies, visual input, or other mental stimulation is a psychogenic sexual experience, and arousal resulting from physical contact to the genital area is reflexogenic.[38] In psychogenic arousal, messages travel from the brain via the spinal cord to the nerves in the genital area.[39] The psychogenic pathway is served by the spinal cord at levels T11–L2.[40] Thus people injured above the level of the T11 vertebra do not usually experience psychogenic erection or vaginal lubrication, but those with an injury below T12 can.[15] Even without these physical responses, people with SCI often feel aroused, just as uninjured people do.[15] The ability to feel the sensation of a pinprick and light touch in the dermatomes for T11–L2 predicts how well the ability to have psychogenic arousal is preserved in both sexes.[41][16] Input from the psychogenic pathway is sympathetic, and most of the time it sends inhibitory signals that prevent the physical arousal response; in response to sexual stimulation, excitatory signals are increased and inhibition is reduced.[42] Removing the inhibition that is normally present allows the spinal reflexes that trigger the arousal response to take effect.[42]
The reflexogenic pathway activates the parasympathetic nervous system in response to the sensation of touch.[43] It is mediated by a reflex arc that goes to the spinal cord (not to the brain)[43] and is served by the sacral segments of the spinal cord at S2–S4.[40][38] A woman with a spinal cord lesion above T11 may not be able to experience psychogenic vaginal lubrication, but may still have reflex lubrication if her sacral segments are uninjured.[27] Likewise, although a man's ability to get a psychogenic erection when mentally aroused may be impaired after a higher-level SCI, he may still be able to get a reflex or "spontaneous" erection.[21][27] These erections may result in the absence of psychological arousal when the penis is touched or brushed, e.g. by clothing,[44] but they do not last long and are generally lost when the stimulus is removed.[15] Reflex erections may increase in frequency after SCI, due to the loss of inhibitory input from the brain that would suppress the response in an uninjured man.[40] Conversely, an injury below the S1 level impairs reflex erections but not psychogenic erections.[21] People who have some preservation of sensation in the dermatomes at the S4 and S5 levels and display a bulbocavernosus reflex (contraction of the pelvic floor in response to pressure on the clitoris or glans penis) are usually able to experience reflex erections or lubrication.[44] Like other reflexes, reflexive sexual responses may be lost immediately after injury but return over time as the individual recovers from spinal shock.[45]
### Factors in reduced function[edit]
Most people with SCI have problems with the body's physical sexual arousal response.[7][36] Problems that result directly from impaired neural transmission are called primary sexual dysfunction.[46] The function of the genitals is almost always affected by SCI, by alteration, reduction, or complete loss of sensation.[47] Neuropathic pain, in which damaged nerve pathways signal pain in the absence of any noxious stimulus, is common after SCI[48] and interferes with sex.[49][50]
Secondary dysfunction results from factors that follow from the injury, such as loss of bladder and bowel control or impaired movement.[46] The main barrier to sexual activity that people with SCI cite is physical limitation; e.g. balance problems and muscle weakness cause difficulty with positioning.[19] Spasticity, tightening of muscles due to increased muscle tone, is another complication that interferes with sex.[51] Some medications have side effects that impede sexual pleasure or interfere with sexual function: antidepressants, muscle relaxants, sleeping pills and drugs that treat spasticity.[52] Hormonal changes that alter sexual function may take place after SCI; levels of prolactin heighten, women temporarily stop menstruating (amenorrhea), and men experience reduced levels of testosterone.[15] Testosterone deficiency causes reduced libido, increased weakness, fatigue, and failure to respond to erection-enhancing drugs.[53][54]
Tertiary sexual dysfunction results from psychological and social factors.[46] Reduced libido, desire, or experience of arousal could be due to psychological or situational factors such as depression, anxiety, and changes in relationships.[44] Both sexes experience reduced sexual desire after SCI,[31] and almost half of men and almost three quarters of women have trouble becoming psychologically aroused.[7][11] Depression is the most common cause of problems with arousal in people with SCI.[55] People frequently experience grief and despair initially after the injury.[56] Anxiety and drug and alcohol abuse may increase after discharge from a hospital as new challenges occur, which can exacerbate sexual difficulties.[57] Drug and alcohol abuse increase unhealthy behaviors, straining relationships and social functioning.[58] SCI can lead to significant insecurities, which have repercussions for sexuality and self-image. SCI often affects body image, either due to the host of changes in the body that affect appearance (e.g. unused muscles in the legs become atrophied), or due to changes in self-perception not directly from physical changes.[59] People frequently find themselves less attractive and expect others not to be attracted to them after SCI.[5] These insecurities cause fear of rejection and deter people from initiating contact or sexual activity[5] or engaging in sex.[59] Feelings of undesirability or worthlessness even lead some to suggest to their partners that they find someone able bodied.[60]
## Fertility[edit]
### Male[edit]
Men with SCI rank the ability to father children among their highest concerns relating to sexuality.[61] Male fertility is reduced after SCI, due to a combination of problems with erections, ejaculation, and quality of the semen.[21][62] As with other types of sexual response, ejaculation can be psychogenic or reflexogenic, and the level of injury affects a man's ability to experience each type.[17] As many as 95% of men with SCI have problems with ejaculation (anejaculation),[15] possibly due to impaired coordination of input from different parts of the nervous system.[19] Erection, orgasm, and ejaculation can each occur independently,[10] although the ability to ejaculate seems linked to the quality of the erection,[24] and the ability to orgasm is linked to the ejaculation facility.[16] Even men with complete injuries may be able to ejaculate, because other nerves involved in ejaculation can effect the response without input from the spinal cord.[8] In general, the higher the level of injury, the more physical stimulation the man needs to ejaculate.[24] Conversely, premature or spontaneous ejaculation can be a problem for men with injuries at levels T12–L1.[24] It can be severe enough that ejaculation is provoked by thinking a sexual thought, or for no reason at all, and is not accompanied by orgasm.[63]
Most men have a normal sperm count, but a high proportion of sperm are abnormal; they are less motile and do not survive as well.[31][62] The reason for these abnormalities is not known, but research points to dysfunction of the seminal vesicles and prostate, which concentrate substances that are toxic to sperm.[64][65] Cytokines, immune proteins which promote an inflammatory response, are present at higher concentrations in semen of men with SCI,[65][66] as is platelet-activating factor acetylhydrolase; both are harmful to sperm.[65][66] Another immune-related response to SCI is the presence of a higher number of white blood cells in the semen.[62]
### Female[edit]
The numbers of women with SCI giving birth and having healthy babies are increasing.[67] Around a half to two-thirds of women with SCI report they might want to have children,[25] and 14–20% do get pregnant at least once.[64] Although female fertility is not usually permanently reduced by SCI, there is a stress response that can happen immediately post-injury that alters levels of fertility-related hormones in the body.[68] In about half of women, menstruation stops after the injury but then returns within an average of five months—it returns within a year for a large majority.[69] After menstruation returns, women with SCI become pregnant at a rate close to that of the rest of the population.[21]
Pregnancy is associated with greater-than-normal risks in women with SCI,[70] among them increased risk of deep vein thrombosis,[71] respiratory infection, and urinary tract infection.[72] Considerations exist such as maintaining proper positioning in a wheelchair,[44] prevention of pressure sores, and increased difficulty moving due to weight gain and changes in center of balance.[73] Assistive devices may need to be altered and medications changed.[74] For women with injuries above T6, a risk during labor and delivery that threatens both mother and fetus is autonomic dysreflexia, in which the blood pressure increases to dangerous levels high enough to cause potentially deadly stroke.[73] Drugs such as nifedipine and captopril can be used to manage an episode if it occurs, and epidural anesthesia helps although it is not very reliable in women with SCI.[75] Anesthesia is used for labor and delivery even for women without sensation, who may only experience contractions as abdominal discomfort, increased spasticity, and episodes of autonomic dysreflexia.[67] Reduced sensation in the pelvic area means women with SCI usually have less painful delivery; in fact, they may fail to realize when they go into labor.[76] If there are deformities in the pelvis or spine caesarian section may be necessary.[77] Babies of women with SCI are more likely to be born prematurely, and, premature or not, they are more likely to be small for their gestational time.[77]
## Management[edit]
### Erectile problems[edit]
A ring can be placed at the base of the penis to maintain erection.
Although erections are not necessary for satisfying sexual encounters, many men see them as important, and treating erectile dysfunction improves their relationships and quality of life.[78] Whatever treatment is used, it works best in combination with talk-oriented therapy to help integrate it into the sex life.[65] Oral medications and mechanical devices are the first choice in treatment because they are less invasive,[79] are often effective, and are well tolerated.[80] Oral medications include sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).[81][65] Penis pumps induce erections without the need for drugs or invasive treatments. To use a pump, the man inserts his penis into a cylinder, then pumps it to create a vacuum which draws blood into the penis, making it erect.[82][65] He then slides a ring from the outside of the cylinder onto the base of the penis to hold the blood in and maintain the erection.[82][53] A man who is able to get an erection but has trouble maintaining it for long enough can use a ring by itself.[63][83] The ring cannot be left on for more than 30 minutes and cannot be used at the same time as anticoagulant medications.[53]
If oral medications and mechanical treatments fail, the second choice is local injections:[79] medications such as papaverine and prostaglandin that alter the blood flow and trigger erection are injected into the penis.[84] This method is preferred for its effectiveness, but can cause pain and scarring.[85] Another option is to insert a small pellet of medication into the urethra, but this requires higher doses than injections and may not be as effective.[85] Topical medications to dilate the blood vessels have been used, but are not very effective or well tolerated.[80] Electrical stimulation of efferent nerves at the S2 level can be used to trigger an erection that lasts as long as the stimulation does.[86] Surgical implants, either of flexible rods or inflatable tubes, are reserved for when other methods fail because of the potential for serious complications, which occur in as many as 10% of cases.[80] They carry the risk of eroding penile tissue (breaking through the skin).[87] Although satisfaction among men who use them is high, if they do need to be removed implants make other methods such as injections and vacuum devices unusable due to tissue damage.[80] It is also possible for erectile dysfunction to exist not as a direct result of SCI but due to factors such as major depression, diabetes, or drugs such as those taken for spasticity.[88] Finding and treating the root cause may alleviate the problem. For example, men who experience erectile problems as the result of a testosterone deficiency can receive androgen replacement therapy.[44]
### Ejaculation and male fertility[edit]
Without medical intervention, the male fertility rate after SCI is 5–14%, but the rate increases with treatments.[89] Even with all available medical interventions, fewer than half of men with SCI can father children.[90] Assisted insemination is usually required.[91] As with erection, therapies used to treat infertility in uninjured men are used for those with SCI.[65] For anejaculation in SCI, the first-line method for sperm retrieval is penile vibratory stimulation (PVS).[8][81][92][93] A high-speed vibrator is applied to the glans penis to trigger a reflex that causes ejaculation, usually within a few minutes.[92] Reports of efficacy with PVS range from 15 to 88%, possibly due to differences in vibrator settings and experience of clinicians, as well as level and completeness of injury.[92] Complete lesions strictly above Onuf's nucleus (S2–S4) are responsive to PVS in 98%, but complete lesions of the S2–S4 segments are not.[8] In case of failure with PVS, spermatozoa are sometimes collected by electroejaculation:[8][92][93] an electrical probe is inserted into the rectum, where it triggers ejaculation.[81] The success rate is 80–100%, but the technique requires anaesthesia and does not have the potential to be done at home that PVS has.[21] Both PVS and electroejaculation carry a risk of autonomic dysreflexia, so drugs to prevent the condition can be given in advance and blood pressure is monitored throughout the procedures for those who are susceptible.[94] Massage of the prostate gland and seminal vesicles is another method to retrieve stored sperm.[65][92] If these methods fail to cause ejaculation or do not yield sufficient usable sperm, sperm can be surgically removed by testicular sperm extraction[21] or percutaneous epididymal sperm aspiration.[8] These procedures yield sperm in 86–100% of cases, but nonsurgical treatments are preferred.[21] Premature or spontaneous ejaculation is treated with antidepressants including selective serotonin reuptake inhibitors, which are known to delay ejaculation as a side effect.[63]
### Women[edit]
Compared with the options available for treating sexual dysfunction in men (for whom results are concretely observable), those available for women are limited.[95] For example, PDE5 inhibitors, oral medications for treating erectile dysfunction in men, have been tested for their ability to increase sexual responses such as arousal and orgasm in women—but no controlled trials have been done in women with SCI, and trials in other women yielded only inconclusive results.[96] In theory, women's sexual response could be improved using a vacuum device made to draw blood into the clitoris, but few studies on treatments for sexual function in women with SCI have been carried out.[83] There is a particular paucity of information outside the area of reproduction.[5]
### Education and counseling[edit]
Counseling about sex and sexuality by medical professionals, psychologists, social workers, and nurses is a part of most SCI rehabilitation programs.[70] Education is part of the follow-up treatment for people with SCI,[20] as are psychotherapy, peer mentorship, and social activities; these are helpful for improving skills needed for socializing and relationships.[15] Rather than addressing sexual dysfunction strictly as a physical problem, appropriate sexual rehabilitation care takes into account the individual as a whole, for example addressing issues with relationships and self-esteem.[97] Sexual counseling includes teaching techniques to manage depression and stress, and to increase attention to preserved sensations during sexual activity.[55] Education includes information about birth control or assistive devices such as those for positioning in sex, or advice and ideas for addressing problems such as incontinence and autonomic dysreflexia.[98]
Many SCI patients have received misinformation about the effects of their injury on their sexual function and benefit from education about it.[10] Although sexual education shortly after injury is known to be helpful and desired, it is frequently missing in rehabilitation settings;[15] a common complaint from those who go through rehabilitation programs is that they offer insufficient information about sexuality.[57] Longer-term education and counseling on sex after discharge from a hospital setting are especially important,[99] yet sexuality is one of the most often neglected areas in long-term SCI rehabilitation, particularly for women.[61] Care providers may refrain from addressing the topic because they feel intimidated or unequipped to handle it.[11] Clinicians must be circumspect in bringing up sexual matters since people may be uncomfortable with or unready for the subject.[44] Many patients wait for providers to broach the topic even if they do want the information.[57]
A person's experience in managing sexuality after the injury relies not only on physical factors like severity and level of the injury, but on aspects of life circumstances and personality such as sexual experience and attitudes about sex.[15] As well as evaluating physical concerns, clinicians must take into account factors that affect each patient's situation: gender, age, cultural, and social factors.[71] Aspects of patients' cultural and religious backgrounds, even if unnoticed before the injury caused sexual dysfunction, affect care and treatments—particularly when cultural attitudes and assumptions of patients and care providers conflict.[100] Health professionals must be sensitive to issues of sexual orientation and gender identity, showing respect and acceptance while communicating, listening, and emotionally supporting.[44] Providers who treat SCI have been found to assume their patients are heterosexual or to exclude LGBTQ patients from their awareness, potentially resulting in substandard care.[101] Academic research on sexuality and disability under-represents LGBTQ perspectives as well.[3]
As well as the patient, the partner of an injured person frequently needs support and counseling.[102] It can help with adjustment to a new relationship dynamic and self-image (such as being placed in the role of caretaker) or with stresses that arise in the sexual relationship.[102] Frequently, partners of injured people must contend with feelings like guilt, anger, anxiety, and exhaustion while dealing with the added financial burden of lost wages and medical expenses.[103] Counseling aims to strengthen the relationship by improving communication and trust.[29]
#### Children and adolescents[edit]
Not only does SCI present children and adolescents with many of the same difficulties adults face, it affects the development of their sexuality.[104] Although substantial research exists on SCI and sexuality in adults, very little exists on the ways in which it affects development of sexuality in young people.[105] Injured children and adolescents need ongoing, age-appropriate sex education that addresses questions of SCI as it relates to sexuality and sexual function.[106] Very young children become aware of their disabilities before their sexuality, but as they age they become curious just as able-bodied children do, and it is appropriate to provide them with increasing amounts of information.[105] Caregivers help the child and family prepare for transition into adulthood, including in sexuality and social interaction, beginning early and intensifying during adolescence.[107] Parents need education about the effects of SCI on sexual function so that they can answer their children's questions.[105] Once patients reach their teens, they need more specific information about pregnancy, birth control, self-esteem, and dating.[77] Teenagers with lost or reduced genital sensation benefit from education about alternative ways to experience pleasure and satisfaction from sexual acts.[108] The teen years are often particularly difficult for those with SCI, in terms of body image and relationships.[109] Given the importance they place on sexuality and privacy, adolescents may experience humiliation when parents or caregivers bathe them or take care of bowel and bladder needs.[110] They can benefit from sexuality counseling, support groups,[109] and mentoring by adults with SCI who can share experiences and lead discussions with peers.[77] With the right care and education from family and professionals, injured children and adolescents can develop into sexually healthy adults.[19]
### Changes in sexual practices[edit]
People make a variety of sexual adaptations to help adjust to SCI. They often change their sexual practices, moving away from genital stimulation and intercourse[5] and toward greater emphasis on touching above the level of injury and other aspects of intimacy such as kissing and caressing.[20] It is necessary to discover new sexual positions if ones used previously have become too difficult.[19] Other factors that enhance sexual pleasure are positive memories, fantasies, relaxation, meditation, breathing techniques, and most importantly, trust with a partner.[83] People with SCI can make use of visual, auditory, olfactory, and tactile stimuli.[111] It is possible to train oneself to be more mindful of the cerebral aspects of sex and of feeling in areas of the body that have sensation; this increases chances of orgasm.[83] The importance of desire and comfort is the reasoning behind the quip "the most important sexual organ is the brain."[112]
Adjusting to post-injury changes in the body's sensation is difficult enough to cause some to give up on the idea of satisfying sex at first.[113] But changes in sensitivity above and at the level of injury occur over time; people may find erogenous zones like the nipples or ears have become more sensitive, enough to be sexually satisfying.[15] They may discover new erogenous zones that were not erotic before the injury; care providers can help direct this discovery.[18] These erogenous areas can even lead to orgasm when stimulated.[44][46] Such changes may result from "remapping" of sensory areas in the brain due to neuroplasticity, particularly when sensation in the genitals is completely lost.[24] Commonly there is an area on the body between the areas where sensation is lost and those where is preserved called a "transition zone" that has increased sensitivity and is often sexually pleasurable when stimulated.[44] Also known as a "border zone", this area may feel the way the penis or clitoris did before injury, and can even give orgasmic sensation.[114] Due to such changes in sensation, people are encouraged to explore their bodies to discover what areas are pleasurable.[115] Masturbation is a useful way to learn about the body's new responses.[116]
Tests exist to measure how much sensation a person has retained in the genitals after an injury, which are used to tailor treatment or rehabilitation.[20] Sensory testing helps people learn to recognize the sensations associated with arousal and orgasm.[117] Injured people who are able to achieve orgasms from stimulation to the genitals may need stimulation for a longer time or at a greater intensity.[10] Sex toys such as vibrators are available, e.g. to enhance sensation in areas of reduced sensitivity, and these can be modified to accommodate disabilities.[44] For example, a hand strap can be added to a vibrator or dildo to assist someone with poor hand function.[45]
### Considerations for sexual activity[edit]
SCI presents extra needs to consider for sexual activity; for example muscle weakness and movement limitations restrict options for positioning.[2] Pillows or devices such as wedges can be placed to help achieve and maintain a desired position for people affected by weakness or movement limitations.[45] Assistive devices exist to aid in motion, such as sliding chairs to provide pelvic thrust.[15] Spasticity and pain also create barriers to sexual activity;[115] these changes may require couples to use new positions, such as seated in a wheelchair.[114] A warm bath can be taken prior to sex,[118] and massage and stretching can be incorporated into foreplay to ease spasticity.[45]
Another consideration is loss of sensation, which puts people at risk for wounds such as pressure sores and injuries that could become worse before being noticed.[44][119] Friction from sexual activity may damage the skin, so it is necessary after sex to inspect areas that could have been hurt, particularly the buttocks and genital area.[44][119] People who already have pressure sores must take care not to make the wounds worse.[44] Irritation to the genitals increases risk for vaginal infections, which get worse if they go unnoticed.[13] Women who do not get sufficient vaginal lubrication on their own can use a commercially available personal lubricant to decrease friction.[45]
Another risk is autonomic dysreflexia (AD), a medical emergency involving dangerously high blood pressure.[120] People at risk for AD can take medications to help prevent it before sex, but if it does occur they must stop and seek treatment.[119] Mild signs of AD such as slightly high blood pressure frequently do accompany sexual arousal and are not cause for alarm.[45] In fact, some interpret the symptoms of AD that occur during sexual activity as pleasant or arousing,[121] or even climactic.[45]
A concern for sexual activity that is not dangerous but that can be upsetting for both partners is bladder or bowel leakage due to urinary or fecal incontinence.[122] Couples can prepare for sex by draining the bladder using intermittent catheterization[5] or placing towels down in advance.[123] People with indwelling urinary catheters must take special care with them, removing them or taping them out of the way.[19][124]
Birth control is another consideration: women with SCI are usually not prescribed oral contraceptives since the hormones in them increase the risk of blood clots,[47][125] for which people with SCI are already at elevated risk. Intrauterine devices could have dangerous complications that could go undetected if sensation is reduced.[47][73] Diaphragms that require something to be inserted into the vagina are not usable by people with poor hand function.[126] An option of choice for women is for partners to use condoms.[126][125]
## Long-term adjustment[edit]
In the first months after an injury, people commonly prioritize other aspects of rehabilitation over sexual matters, but in the long term, adjustment to life with SCI necessitates addressing sexuality.[44] Although physical, psychological and emotional factors militate to reduce the frequency of sex after injury, it increases after time.[15] As years go by, the odds that a person will become involved in a sexual relationship increase.[121] Difficulties adjusting to a changed appearance and physical limitations contribute to reduced frequency of sexual acts, and improved body image is associated with an increase.[5] Like frequency, sexual desire and sexual satisfaction often decrease after SCI.[105] The reduction in women's sexual desire and frequency may be in part because they believe they can no longer enjoy sex, or because their independence or social opportunities are reduced.[5] As time goes by people usually adjust sexually, adapting to their changed bodies.[19] Some 80% of women return to being sexually active,[50] and the numbers who report being sexually satisfied range from 40 to 88%.[127] Although women's satisfaction is usually lower than before the injury,[5] it improves as time passes.[29] Women report higher rates of sexual satisfaction than men post-SCI for as many as 10–45 years.[57] More than a quarter of men have substantial problems with adjustment to their post-injury sexual functioning.[128] Sexual satisfaction depends on a host of factors, some more important than the physical function of the genitals: intimacy, quality of relationships, satisfaction of partners,[15] willingness to be sexually experimental, and good communication.[19] Genital function is not as important to men's sexual satisfaction as are their partners' satisfaction and intimacy in their relationships.[70] For women, quality of relationships, closeness with partners, sexual desire, and positive body image, as well as the physical function of the genitals, contribute sexual satisfaction.[129] For both sexes, long-term relationships are associated with higher sexual satisfaction.[15]
## Relationships[edit]
A catastrophic injury such as SCI puts strain on marriages and other romantic relationships, which in turn has important implications for quality of life. Partners of injured people often feel out of control, overwhelmed, angry, and guilty while having added work related to the injury, less help with responsibilities like parenting, and loss of wages.[130] Relationship stress and excessive dependence in relationships increases risk of depression for the person with SCI; supportive relationships are protective.[131] Relationships change as partners take on new roles, such as that of caregiver,[57] which may conflict with the role of partner and require substantial sacrifice of time and self-care.[103] These changes in responsibilities may mean a reverse in societally determined gender roles within relationships; inability to fulfil these roles affects sexuality in general.[59] Sexual dysfunction is a stressor in relationships. People are often as concerned about failing to keep a partner satisfied as they are about meeting their own sexual needs.[15] In fact, two of the top reasons people with SCI cite for wanting to have sex are for intimacy and to keep a partner.[71] The frequency of sex correlates with the desire of the uninjured partner.[118]
Physical activities and social gatherings are a way to meet people and prevent isolation.
Although problems with sexual function that result from SCI play a part in some divorces, they are not as important as emotional maturity in determining the success of a marriage.[132] People with SCI get divorced more often than the rest of the population,[103] and marriages that took place before the injury fail more often than those that took place after (33% vs. 21%).[133] People married before the injury report less happy marriages and worse sexual adjustment than those married after, possibly indicating that spouses had difficulty adjusting to the new circumstances.[134] For those who chose to become involved with someone after an injury, the disability was an accepted part of the relationship from the outset.[135] Understanding and acceptance of the limitations that result from the injury on the part of the uninjured partner is an important factor in a successful marriage.[136] Many divorces have been found to be initiated by the injured partner, sometimes due to the depression and denial that often occurs early after the injury.[137] Thus counseling is important, not just for managing changes in self-perception but in perceptions about relationships.[137]
Despite the stresses that SCI places on people and relationships, studies have shown that people with SCI are able to have happy and fulfilling romantic relationships and marriages, and to raise well-adjusted children.[138] People with SCI who wish to be parents may question their ability to raise children and opt not to have them, but studies have shown no difference in parenting outcomes between injured and uninjured groups.[139] Children of women with SCI do not have worse self-esteem, adjustment, or attitudes toward their parents.[77] Women who have children post-SCI have a higher quality of life, even though parenting adds demands and challenges to their lives.[140]
For those who are single when injured or who become single, SCI causes difficulties and insecurities with respect to one's ability to meet new partners[141] and start relationships.[142] In some settings, beauty standards cause people to view disabled bodies as less attractive, limiting the options for sexual and romantic partners of people with disabilities like SCI.[143] Furthermore, physical disabilities are stigmatized, causing people to avoid contact with disabled people, particularly those with highly visible conditions like SCI.[144] The stigma may cause people with SCI to experience self-consciousness and embarrassment in public.[144] They can increase their social success by using impression management techniques to change how they are perceived and create a more positive image of themselves in others' eyes.[145] Physical limitations create difficulties; with lowered independence comes reduced social interaction and fewer opportunities to find partners.[5] Difficulties with mobility and the lack of disabled accessibility of social spaces (e.g. lack of wheelchair ramps) create a further barrier to social activity and limit the ability to meet partners. Isolation and its associated risk of depression can be limited by participating in physical activities, social gatherings, clubs, and online chat and dating.[57]
## Society and culture[edit]
The reality television series Push Girls depicts women with SCI addressing matters of sexuality and daily life.
Negative societal attitudes and stereotypes about people with disabilities like SCI affect interpersonal interactions and self-image, with important implications for quality of life. In fact, for women, psychological factors have a more important impact on sexual adjustment and activity than physical ones.[29] Negative attitudes about disability (along with relationships and social support) are more predictive of outcome than even the level or completeness of injury.[146] Stereotypes exist that people with SCI (particularly women) are uninterested in, unsuitable for, or incapable of sexual relationships or encounters.[147] "People think we can only date people in wheelchairs, that we're lucky to get any guy, that we can't be picky", remarked Mia Schaikewitz, who is profiled in Push Girls, a 2012 reality series about four women with SCI.[148] Not only do they affect injured people's self-image, these stereotypes are particularly harmful when held by counselors and professionals involved in rehabilitation.[147] Caregivers affected by these culturally transmitted beliefs may treat their patients as asexual, particularly if the injury occurred at a young age and the patient never had sexual experiences.[4] Failure to recognize injured people's sexual and reproductive capacity restricts their access to birth control, information about sexuality, and sexual health-related medical care such as annual gynecological exams.[3] Another common belief that affects sexual rehabilitation is that sex is strictly about genital function; this could cause caregivers to discount the importance of the rest of the body and of the individual.[34]
Cultural attitudes toward gender roles have profound effects on people with SCI.[149] The injury can cause insecurities surrounding sexual identity, particularly if the disability precludes fulfilment of societally taught gender norms.[150] Female beauty standards propagated by mass media and culture portray the ideal woman as able bodied: as one fashion model with a SCI commented, "when you have a devastating injury or disability, you're not often thought of as sensual or pretty because you don't look like the women in the magazines."[151] Inability to meet these standards can lower self-esteem, even if these ideals are also unattainable for most able-bodied women.[152] Poorer self-esteem is associated with worse sexual adjustment and quality of life, and higher rates of loneliness, stress, and depression.[153] Males are also affected by societal expectations, such as notions about masculinity and sexual prowess.[128][154] Men from some traditional backgrounds may feel performance pressure that emphasizes the ability to have erections and sexual intercourse.[149] Men who have strong sexual desire but who are not able to perform sexually may be at increased risk for depression, particularly when they believe strongly in traditional masculine gender norms with sexual function as core to the male identity.[128][154] Men who strongly believe in these traditional roles may feel sexually inadequate, unmanly, insecure, and less satisfied with life.[128] Since sexual dysfunction has this negative impact on self-esteem, treatment of erectile dysfunction can have a psychological benefit even though it does not help with physical sensation.[149] SCI may necessitate reappraisal and rejection of assumptions about gender norms and sexual function in order to adjust healthily to the disability: those who are able to change the way they think about gender roles may have better life satisfaction and outcomes with rehabilitation.[128] Counseling is helpful in this reassessment process.[128]
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78. ^ Elliott 2009, p. 521.
79. ^ a b Elliott 2010a, p. 416.
80. ^ a b c d Deforge, D.; Blackmer, J.; Moher, D.; Garritty, C.; Cronin, V.; Yazdi, F.; Barrowman, N.; Mamaladze, V.; Zhang, L.; Sampson, M. (2004). "Sexuality and reproductive health following spinal cord injury". Evidence Report/Technology Assessment (Summary) (109): 1–8. doi:10.1037/e439522005-001. PMC 4781438. PMID 15643907.
81. ^ a b c Miller & Marini 2012, p. 140.
82. ^ a b Courtois & Charvier 2015, p. 230.
83. ^ a b c d Elliott 2012, p. 150.
84. ^ The Mayo Clinic 2011, p. 145.
85. ^ a b Elliott 2010a, p. 418.
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92. ^ a b c d e Elliott 2012, p. 147.
93. ^ a b Soler, J.M.; Previnaire, J.G. (2011). "Ejaculatory dysfunction in spinal cord injury men is suggestive of dyssynergic ejaculation" (PDF). European Journal of Physical and Rehabilitation Medicine. 47 (4): 677–81. PMID 22222964.
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101. ^ Burch, A (2008). "Health care providers' knowledge, attitudes, and self-efficacy for working with patients with spinal cord injury who have diverse sexual orientations". Physical Therapy. 88 (2): 191–98. doi:10.2522/ptj.20060188. PMID 18029393.
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103. ^ a b c Sabharwal 2013, p. 406.
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105. ^ a b c d Alexander, M.S.; Alexander, C.J. (2007). "Recommendations for discussing sexuality after spinal cord injury/dysfunction in children, adolescents, and adults". The Journal of Spinal Cord Medicine. 30 Suppl 1: S65–70. doi:10.1080/10790268.2007.11753971. PMC 2031983. PMID 17874689.
106. ^ Vogel, Betz & Mulcahey 2012, p. 140.
107. ^ Vogel, Betz & Mulcahey 2012, p. 131.
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109. ^ a b Sabharwal 2013, pp. 91–92.
110. ^ Vogel, Betz & Mulcahey 2012, p. 141.
111. ^ Bedbrook 2013, p. 153.
112. ^ Fink, Pfaff & Levine 2011, p. 559.
113. ^ Alpert & Wisnia 2009, p. 124.
114. ^ a b Alpert & Wisnia 2009, p. 138.
115. ^ a b The Mayo Clinic 2011, p. 155.
116. ^ Alpert & Wisnia 2009, p. 137.
117. ^ Courtois & Charvier 2015, p. 235.
118. ^ a b Monga 2007, p. 473.
119. ^ a b c Sabharwal 2013, p. 309.
120. ^ Alpert & Wisnia 2009, p. 144.
121. ^ a b Anderson, K.D.; Borisoff, J.F.; Johnson, R.D.; Stiens, S.A.; Elliott, S.L. (2007). "The impact of spinal cord injury on sexual function: concerns of the general population". Spinal Cord. 45 (5): 328–37. doi:10.1038/sj.sc.3101977. PMID 17033620.
122. ^ Naftchi 2012, pp. 260–61.
123. ^ Naftchi 2012, p. 261.
124. ^ Naftchi 2012, p. 259.
125. ^ a b Ohl & Bennett 2013.
126. ^ a b Sabharwal 2013, p. 311.
127. ^ Elliott 2010b, p. 429.
128. ^ a b c d e f Burns, S.M.; Mahalik, J.R.; Hough, S.; Greenwell, A.N. (2008). "Adjustment to Changes in Sexual Functioning Following Spinal Cord Injury: The Contribution of Men's Adherence to Scripts for Sexual Potency". Sexuality and Disability. 26 (4): 197–205. doi:10.1007/s11195-008-9091-y. ISSN 0146-1044. S2CID 145246983.
129. ^ Courtois & Charvier 2015, p. 232.
130. ^ Hammell 2013, p. 79.
131. ^ Kraft, R.; Dorstyn, D. (2015). "Psychosocial correlates of depression following spinal injury: A systematic review". Journal of Spinal Cord Medicine. 38 (5): 571–83. doi:10.1179/2045772314Y.0000000295. PMC 4535798. PMID 25691222.
132. ^ Neumann 2013, p. 337.
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134. ^ Neumann 2013, pp. 352–53.
135. ^ Neumann 2013, p. 354.
136. ^ Neumann 2013, p. 359.
137. ^ a b Neumann 2013, p. 336.
138. ^ Hammell 2013, p. 295.
139. ^ Sabharwal 2013, pp. 311, 406.
140. ^ Kohut et al. 2015, p. 1521.
141. ^ Elliott 2012, p. 153.
142. ^ Hammell 2013, p. 292.
143. ^ Florante & Leyson 2013, p. 366.
144. ^ a b Livneh, Chan & Kaya 2013, p. 98.
145. ^ Livneh, Chan & Kaya 2013, p. 113.
146. ^ Kennedy & Smithson 2012, p. 209.
147. ^ a b Miller & Marini 2012, pp. 136–37.
148. ^ Pfefferman, N. (11 June 2012). "Women in wheelchairs push boundaries in real life and on TV". The Times of Israel. Retrieved 30 December 2015.
149. ^ a b c Francoeur 2013, p. 13.
150. ^ Hammell 2013, pp. 288–89.
151. ^ Taylor, V. (9 October 2014). "'Raw Beauty Project' celebrates women with disabilities". NY Daily News.
152. ^ Panzarino 2013, p. 383.
153. ^ Peter, C.; Müller, R.; Cieza, A.; Geyh, S. (2011). "Psychological resources in spinal cord injury: A systematic literature review". Spinal Cord. 50 (3): 188–201. doi:10.1038/sc.2011.125. ISSN 1362-4393. PMID 22124343.
154. ^ a b Burns, S.M.; Hough, S.; Boyd, B.L.; Hill, J. (2009). "Sexual Desire and Depression Following Spinal Cord Injury: Masculine Sexual Prowess as a Moderator". Sex Roles. 61 (1): 120–29. doi:10.1007/s11199-009-9615-7. ISSN 0360-0025. S2CID 143880790.
## Bibliography[edit]
* Alpert, M.J.; Wisnia, S. (30 June 2009). Spinal Cord Injury and the Family: A New Guide. Harvard University Press. ISBN 978-0-674-02017-7.
* Bedbrook, G.M. (29 June 2013). The Care and Management of Spinal Cord Injuries. Springer Science & Business Media. ISBN 978-1-4613-8087-0.
* Bickenbach, J.; Officer, A.; Shakespeare, T.; von Groote, P.; World Health Organization; The International Spinal Cord Society, eds. (2013). International Perspectives on Spinal Cord Injury (PDF). Geneva: World Health Organization. Retrieved 20 December 2015.
* Courtois, F.; Charvier, K. (21 May 2015). "Sexual dysfunction in patients with spinal cord lesions". In Vodusek, D.B.; Boller, F. (eds.). Neurology of Sexual and Bladder Disorders: Handbook of Clinical Neurology. Handbook of Clinical Neurology. 130. Elsevier Science. pp. 225–245. doi:10.1016/B978-0-444-63247-0.00013-4. ISBN 978-0-444-63254-8. PMID 26003247.
* Creasey, G.H.; Craggs, M.D. (31 December 2012). "Functional electrical stimulation for bowel, bladder, and sexual function". In Verhaagen, J.; McDonald III, J.W. (eds.). Spinal Cord Injury: Handbook of Clinical Neurology Series. Newnes. ISBN 978-0-444-53507-8.
* Ditunno, J.F.; Cardenas, D.D.; Formal, C.; Dalal, K. (31 December 2012). "Advances in the rehabilitation management of acute spinal cord injury". In Verhaagen, J.; McDonald III, J.W. (eds.). Spinal Cord Injury: Handbook of Clinical Neurology Series. Newnes. ISBN 978-0-444-53507-8.
* Daroff, R.B.; Fenichel, G.M.; Jankovic, J.; Mazziotta, J.C. (29 March 2012). Neurology in Clinical Practice. Elsevier Health Sciences. ISBN 978-1-4557-2807-7.
* Elliott, S. (26 March 2009). "Sexuality after spinal cord injury". In Field-Fote, E. (ed.). Spinal Cord Injury Rehabilitation. F.A. Davis. ISBN 978-0-8036-2319-4.
* Elliott, S. (19 March 2010). "Sexual dysfunction and infertility in men with spinal cord injury". In Bono, C.M.; Cardenas, D.D.; Frost, F.S. (eds.). Spinal Cord Medicine, Second Edition: Principles & Practice. Demos Medical Publishing. ISBN 978-1-935281-77-1.
* Elliott, S. (19 March 2010). "Sexual dysfunction in women with spinal cord injury". In Bono, C.M.; Cardenas, D.D.; Frost, F.S. (eds.). Spinal Cord Medicine, Second Edition: Principles & Practice. Demos Medical Publishing. ISBN 978-1-935281-77-1.
* Elliott, S. (29 October 2012). "Sexuality and fertility after spinal cord injury". In Fehlings, M.G.; Vaccaro, A.R.; Maxwell B. (eds.). Essentials of Spinal Cord Injury: Basic Research to Clinical Practice. Thieme. ISBN 978-1-60406-727-9.
* Field-Fote, E. (26 March 2009). "Spinal cord injury: An overview". In Field-Fote, E. (ed.). Spinal Cord Injury Rehabilitation. F.A. Davis. ISBN 978-0-8036-2319-4.
* Fink, G.; Pfaff, D.W.; Levine, J. (31 August 2011). Handbook of Neuroendocrinology. Academic Press. ISBN 978-0-12-378554-1.
* Florante, J.; Leyson, J.F.J. (9 March 2013). "Male homosexuality and other varieties of sexual lifestyles". In Leyson, J.F.J. (ed.). Sexual Rehabilitation of the Spinal-Cord-Injured Patient. Springer Science & Business Media. ISBN 978-1-4612-0467-1.
* Kohut, R.M.; Seftel, A.D.; Ducharme, S.H.; Fogel, B.S.; Bodner, D.R. (30 July 2015). "Sexual and psychological aspects of rehabilitation after spinal cord injury". In Fogel, B.S.; Greenberg, D.B. (eds.). Psychiatric Care of the Medical Patient. Oxford University Press. ISBN 978-0-19-022629-9.
* Francoeur, R. (9 March 2013). "Cross-cultural and religious perspectives". In Leyson, J.F.J. (ed.). Sexual Rehabilitation of the Spinal-Cord-Injured Patient. Springer Science & Business Media. ISBN 978-1-4612-0467-1.
* Hammell, K.W. (11 December 2013). Spinal Cord Injury Rehabilitation. Springer. ISBN 978-1-4899-4451-1.
* Harvey, L. (2008). Management of Spinal Cord Injuries: A Guide for Physiotherapists. Elsevier Health Sciences. ISBN 978-0-443-06858-4. Retrieved 19 March 2016.
* Kennedy, P. (12 March 2007). Psychological Management of Physical Disabilities: A Practitioner's Guide. Routledge. ISBN 978-1-135-44984-1.
* Kennedy, P.; Smithson, E.F. (29 October 2012). "Psychosocial aspects of spinal cord injury". In Fehlings, M.G.; Vaccaro, A.R.; Maxwell B. (eds.). Essentials of Spinal Cord Injury: Basic Research to Clinical Practice. Thieme. ISBN 978-1-60406-727-9.
* Livneh, H.; Chan, F.; Kaya, C. (1 December 2013). "Stigma related to physical and sensory disabilities". In Corrigan, P.W. (ed.). The Stigma of Disease and Disability: Understanding Causes and Overcoming Injustices. American Psychological Association. ISBN 978-1-4338-1583-6.
* The Mayo Clinic (May 2011). Mayo Clinic's Guide to Living with a Spinal Cord Injury. ReadHowYouWant.com. ISBN 978-1-4587-5865-1.
* McKay-Moffat, S.F. (10 October 2007). "The interaction between specific conditions and the childbirth continuum". In McKay-Moffat, S.F. (ed.). Disability in Pregnancy and Childbirth. Elsevier Health Sciences. ISBN 978-0-7020-3967-6.
* Miller, E.; Marini, I. (24 February 2012). "Sexuality and spinal cord injury counseling implications". In Marini, I.; Stebnicki, M.A. (eds.). The Psychological and Social Impact of Illness and Disability, 6th Edition. Springer Publishing Company. ISBN 978-0-8261-0655-1.
* Monga, M. (22 May 2007). "Treatment of sexual dysfunction in men with spinal cord injury and other neurologic disabling disorders". In Kandeel, F.R. (ed.). Male Sexual Dysfunction: Pathophysiology and Treatment. CRC Press. ISBN 978-1-4200-1508-9.
* Naftchi, N.E. (6 December 2012). Spinal Cord Injury. Springer Science & Business Media. ISBN 978-94-011-6305-7.
* Neumann, R.J. (9 March 2013). "The forgotten others: Partners of the spinal-cord-injured". In Leyson, J.F.J. (ed.). Sexual Rehabilitation of the Spinal-Cord-Injured Patient. Springer Science & Business Media. ISBN 978-1-4612-0467-1.
* Ohl, D.A.; Bennett, C.J. (29 June 2013). "Sexual and fertility concerns: Surgical practices". In Parsons K.F.; Fitzpatrick, J.M. (eds.). Practical Urology in Spinal Cord Injury. Springer Science & Business Media. ISBN 978-1-4471-1860-2.
* Panzarino, C.J. (9 March 2013). "Female homosexuality". In Leyson, J.F.J. (ed.). Sexual Rehabilitation of the Spinal-Cord-Injured Patient. Springer Science & Business Media. ISBN 978-1-4612-0467-1.
* Sabharwal, S. (10 December 2013). Essentials of Spinal Cord Medicine. Demos Medical Publishing. ISBN 978-1-61705-075-6.
* Vogel, L.C.; Betz, R.R.; Mulcahey, M.J. (31 December 2012). "Spinal cord injuries in children and adolescents". In Verhaagen, J.; McDonald III, J.W. (eds.). Spinal Cord Injury: Handbook of Clinical Neurology Series. Newnes. ISBN 978-0-444-53507-8.
* Wegener, S.T.; Adams, L.L.; Rohe, D. (31 December 2012). "Promoting optimal functioning in spinal cord injury: The role of rehabilitation psychology". In Verhaagen, J.; McDonald III, J.W. (eds.). Spinal Cord Injury: Handbook of Clinical Neurology Series. Newnes. ISBN 978-0-444-53507-8.
* Wein, A.J.; Kavoussi, L.R.; Novick, A.C.; Partin, A.W.; Peters, C.A. (28 September 2011). Campbell-Walsh Urology. Elsevier Health Sciences. ISBN 978-1-4557-2298-3.
* Whipple, B. (9 March 2013). "Female sexuality". In Leyson, J.F.J. (ed.). Sexual Rehabilitation of the Spinal-Cord-Injured Patient. Springer Science & Business Media. ISBN 978-1-4612-0467-1.
## External links[edit]
* Medicine portal
* Human sexuality portal
* PleasureABLE: Sexual Device Manual for Persons with Disabilities.
* SCI Forum Reports: Dating and Relationships after SCI. University of Washington
* Sexuality & Sexual Function following SCI. University of Alabama at Birmingham Spinal Cord Injury Model System video series
* Sexuality and spinal cord injury: Where we are and where we are going. The Free Library
* Sexuality in Spinal Cord Injury. University of Miami School of Medicine
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
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*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Sexuality after spinal cord injury | None | 4,945 | wikipedia | https://en.wikipedia.org/wiki/Sexuality_after_spinal_cord_injury | 2021-01-18T18:39:05 | {"wikidata": ["Q21452236"]} |
Soff et al. (1981) reported 4 families with combined deficiency of coagulation factors VIII, IX and XI. Family 1 had several persons with dislocations, e.g., of patella and hips, and several who had possible hemarthrosis related to trauma. Other probands were referred because of the finding of prolonged partial thromboplastin time (PTT) on preoperative testing. Two generations were affected in 2 families, and males and females had similar procoagulant levels and histories of abnormal hemostasis. No male-to-male transmission was observed. The pathogenesis of FMFD V is unknown. The 3 factors are biochemically and functionally different and the possibility of a common precursor or subunit is highly unlikely. Possibly a common regulator is deficient. Angelopoulos et al. (1964) described combined deficiency of factors VIII, IX and XI in a male with a history of recurrent hemarthroses, hematomas, and ecchymoses. A sister died from excessive hemorrhage, and some others in the family had hemorrhagic tendencies.
Joints \- Joint dislocations \- Hemarthrosis Inheritance \- Autosomal dominant Lab \- Combined coagulation factor VIII, IX and XI deficiency \- Prolonged partial thromboplastin time (PTT) Heme \- Abnormal hemostasis \- Hematomas \- Ecchymoses \- Excessive hemorrhage ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| FACTORS VIII, IX AND XI, COMBINED DEFICIENCY OF | c1851375 | 4,946 | omim | https://www.omim.org/entry/134520 | 2019-09-22T16:41:14 | {"mesh": ["C565023"], "omim": ["134520"], "synonyms": ["Alternative titles", "FAMILIAL MULTIPLE COAGULATION FACTOR DEFICIENCY V", "MULTIPLE COAGULATION FACTOR DEFICIENCY V"]} |
Congenital disorder of nervous system
Zellweger syndrome
Other namesCerebrohepatorenal syndrome
Zellweger syndrome is inherited in an autosomal recessive manner
SpecialtyMedical genetics
Complicationspneumonia and respiratory distress.
Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual.[1] It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.[2][3]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 References
* 7 External links
## Signs and symptoms[edit]
Zellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).[4] The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD).[5][6] Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders.[7]
Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development.[4] In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.[4]
Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts.[4] Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat.[4][7]
## Cause[edit]
Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes.[8] In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.[citation needed]
As a result of impaired peroxisome function, an individual's tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.[citation needed]
## Diagnosis[edit]
In addition to genetic tests involving the sequencing of PEX genes,[9][10] biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma. Cultured primarily skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid beta-oxidation, phytanic acid alpha-oxidation, pristanic acid alpha-oxidation, and plasmalogen biosynthesis.[4]
## Treatment[edit]
The malabsorption resulting from lack of bile acid has resulted in elemental formula being suggested, which are low in fat with < 3% of calories derived from long chain triglycerides (LCT). However, reduced very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels,[11][12] likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients.[13] Since docosahexaenoic acid (DHA) synthesis is impaired [14] [59], DHA supplementation was recommended, but a placebo-controlled study has since showed no clinical efficacy.[15] Due to the defective bile acid synthesis, fat soluble supplements of vitamins A, D, E, and K are recommended.[citation needed]
## Prognosis[edit]
Currently, no cure for Zellweger syndrome is known, nor is a course of treatment made standard. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.[4]
## References[edit]
1. ^ Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R.; Schram, A.; Heymans, H.; Schutgens, R.; Van Den Bosch, H.; Tager, J. (June 1988). "Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis". Journal of Clinical Investigation (Free full text). 81 (6): 1710–1715. doi:10.1172/JCI113510. PMC 442615. PMID 2454948.
2. ^ Zellweger's syndrome at Who Named It?
3. ^ Wiedemann, H. R. (1991). "Hans-Ulrich Zellweger (1909-1990)". European Journal of Pediatrics. 150 (7): 451. doi:10.1007/BF01958418. PMID 1915492. S2CID 34905299.
4. ^ a b c d e f g Steinberg, S.; Dodt, G.; Raymond, G.; Braverman, N.; Moser, A.; Moser, H. (2006). "Peroxisome biogenesis disorders". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (12): 1733–48. doi:10.1016/j.bbamcr.2006.09.010. PMID 17055079.
5. ^ GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
6. ^ Krause, C.; Rosewich, H.; Thanos, M.; Gärtner, J. (2006). "Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients". Human Mutation. 27 (11): 1157. doi:10.1002/humu.9462. PMID 17041890.
7. ^ a b Raymond, G. V.; Watkins, P.; Steinberg, S.; Powers, J. (2009). "Peroxisomal Disorders". Handbook of Neurochemistry and Molecular Neurobiology. pp. 631–670. doi:10.1007/978-0-387-30378-9_26. ISBN 978-0-387-30345-1.
8. ^ Online Mendelian Inheritance in Man (OMIM): Zellweger syndrome; ZS - 214100
9. ^ Steinberg, S.; Chen, L.; Wei, L.; Moser, A.; Moser, H.; Cutting, G.; Braverman, N. (2004). "The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum". Molecular Genetics and Metabolism. 83 (3): 252–263. doi:10.1016/j.ymgme.2004.08.008. PMID 15542397.
10. ^ Yik, W. Y.; Steinberg, S. J.; Moser, A. B.; Moser, H. W.; Hacia, J. G. (2009). "Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders". Human Mutation. 30 (3): E467–E480. doi:10.1002/humu.20932. PMC 2649967. PMID 19105186.
11. ^ Van Duyn, MA; Moser, AE; Brown FR, 3rd; et al. (August 1984). "The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy". The American Journal of Clinical Nutrition. 40 (2): 277–84. doi:10.1093/ajcn/40.2.277. PMID 6465061.
12. ^ Brown FR, 3rd; Van Duyn, MA; Moser, AB; et al. (October 1982). "Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids". The Johns Hopkins Medical Journal. 151 (4): 164–72. PMID 7120720.
13. ^ Moser, AB; Borel, J; Odone, A; et al. (March 1987). "A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients". Annals of Neurology. 21 (3): 240–9. doi:10.1002/ana.410210305. PMID 2440378. S2CID 29043456.
14. ^ Martinez, M (26 June 1992). "Abnormal profiles of polyunsaturated fatty acids in the brain, liver, kidney and retina of patients with peroxisomal disorders". Brain Research. 583 (1–2): 171–82. doi:10.1016/s0006-8993(10)80021-6. PMID 1504825. S2CID 20508763.
15. ^ Paker, AM; Sunness, JS; Brereton, NH; et al. (31 August 2010). "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial". Neurology. 75 (9): 826–30. doi:10.1212/WNL.0b013e3181f07061. PMC 3013498. PMID 20805528.
## External links[edit]
* Zellweger-Syndrome at NINDS
* Zellweger syndrome at NIH's Office of Rare Diseases
Classification
D
* ICD-10: Q87.8
* ICD-9-CM: 277.86, 759.8
* OMIM: 214100
* MeSH: D015211
* DiseasesDB: 14248
External resources
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Congenital abnormality syndromes
Craniofacial
* Acrocephalosyndactylia
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Short stature
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Combined/other,
known locus
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* 15 (Marfan syndrome)
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* Multiple
* Fryns syndrome
* v
* t
* e
Genetic disorder, organelle: Peroxisomal disorders and lysosomal structural disorders
Peroxisome biogenesis disorder
* Zellweger syndrome
* Neonatal adrenoleukodystrophy
* Infantile Refsum disease
* Adult Refsum disease-2
* RCP 1
Enzyme-related
* Acatalasia
* RCP 2&3
* Mevalonate kinase deficiency
* D-bifunctional protein deficiency
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Transporter-related
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Lysosomal
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See also: proteins, intermediates
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
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*[LIT]: Lithuania
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*[CZE]: Czech Republic
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| Zellweger syndrome | c0043459 | 4,947 | wikipedia | https://en.wikipedia.org/wiki/Zellweger_syndrome | 2021-01-18T19:04:16 | {"gard": ["7917"], "mesh": ["D015211"], "umls": ["C0043459"], "icd-9": ["277.86", "759.8"], "orphanet": ["912", "1271"], "wikidata": ["Q189167"]} |
Nail-patella syndrome causes changes in the nails, elbows, kneecaps (patellae), and hip bone. The most common symptom of the syndrome is having missing or underdeveloped fingernails and toenails. Other symptoms may include having small or missing kneecaps, underdeveloped elbows, and an extra small piece of bone on both sides of the hip (called iliac horns). People with nail-patella syndrome are at an increased risk for developing high fluid pressure in the eye (glaucoma) and kidney disease.
Nail-patella syndrome is caused by genetic changes (pathogenic variants or mutations) in the LMX1B gene. The syndrome is inherited in an autosomal dominant manner. Diagnosis is usually suspected when a person has symptoms of the syndrome. The diagnosis can be confirmed by genetic testing. Treatment for nail-patella syndrome may include physical therapy or surgery for joint problems. Other treatments depend on the symptoms present in each person.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Nail-patella syndrome | c0027341 | 4,948 | gard | https://rarediseases.info.nih.gov/diseases/7160/nail-patella-syndrome | 2021-01-18T17:58:48 | {"mesh": ["D009261"], "omim": ["161200"], "umls": ["C0027341"], "orphanet": ["2614"], "synonyms": ["NPS 1", "Onychoosteodysplasia", "Turner-Kieser syndrome", "Fong disease", "Osteo-Onychodysplasia", "Arthro-Onychodysplasia"]} |
A number sign (#) is used with this entry because of evidence that the disorder can be caused by mutation in several mitochondrial genes, including MTTL1 (590050), MTTE (590025), and MTTK (590060).
The most common mutation is a 3243A-G transition in the MTTL1 gene (590050.0001).
Description
Maternally inherited diabetes-deafness syndrome (MIDD) is a mitochondrial disorder characterized by onset of sensorineural hearing loss and diabetes in adulthood. Some patients may have additional features observed in mitochondrial disorders, including pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, renal problems, and neuropsychiatric symptoms (Ballinger et al., 1992; Reardon et al., 1992; Guillausseau et al., 2001).
The association of diabetes and deafness is observed with Wolfram syndrome (see 222300), Rogers syndrome (249270), and Herrmann syndrome (172500), but all 3 of these disorders have other clinical manifestations.
Clinical Features
Kressmann (1976) reported a large family in which diabetes and deafness were transmitted over 4 generations, with a total of 13 affected individuals. The clinical history was the same for all affected patients: the first manifestation was deafness, beginning at 20 to 30 years of age, with a rapid and severe increase in bilateral sensory hearing loss. Diabetes mellitus developed later in the third decade, and insulin was required either immediately or at a later date. At that time, persons from the fourth generation who were less than 20 years of age presented no deafness or diabetes. No pedigree member had ptosis, ophthalmoplegia, or muscle weakness. Reexamination of members of the family by Negrier et al. (1998) demonstrated no ragged-red fibers on skeletal muscle biopsy specimens and very limited lipid storage on electron microscopy.
Ballinger et al. (1992) described a family in which a mother, all of her 6 children by 2 husbands, and a granddaughter of 1 daughter had diabetes and deafness. The onset of diabetes was between ages 20 and 30 years except for 1 male in whom diabetes was first diagnosed at about age 43 years. The characteristics of the deafness were not specified. (Wallace (1992) indicated that the hearing loss was neurosensory and relatively late in onset; however, deafness generally preceded diabetes.) No member of the pedigree had ptosis, ophthalmoplegia or muscle weakness, features of other mitochondrial deletion syndromes. Infarcts occurred in the first generation and in 1 member of the second generation. In 1 of the patients, administration of Zidovudine (400-500 mg/d), a known inhibitor of mitochondrial replication, was associated with pancytopenia.
Van den Ouweland et al. (1992) observed maternally transmitted type II diabetes mellitus and deafness in 3 generations of a Dutch family. All 9 children of a woman with noninsulin-dependent diabetes mellitus had NIDDM and deafness; 2 grandchildren through a female also had the combination. None of the diabetic subjects showed optic atrophy, mental retardation, photomyoclonus, epilepsy, or myopathy.
Reardon et al. (1992) described a family with MIDD. Diabetes was associated with deafness in 7 individuals in 3 generations, only some of whom were available for study. Reduction of circulating insulin levels was a presenting feature of a multisystem disorder without significant neurologic involvement in this kindred. The proband presented with diabetes in his mid-twenties and received insulin therapy. Progressive bilateral hearing impairment was noted in his late thirties. ECG showed left bundle branch block and an echocardiographic diagnosis of cardiomyopathy was made shortly before his death at age 43. A salt-and-pepper retinopathy was noted in some affected members of the family.
Schulz et al. (1993) reported the case of a 47-year-old deaf man who was admitted for his first acute manifestation of hyperglycemia. Progressive bilateral sensorineural hearing loss had started in his early twenties. He had a 2-year history of dizziness, unsteady gait, and epilepsy. He also had pigmentary retinal degeneration with normal visual acuity but concentric narrowing of visual fields, external ophthalmoplegia, impaired vestibular function, and dysarthria.
Velho et al. (1996) reported 5 French pedigrees with the common 3243A-G mutation associated with variable clinical features, ranging from normal glucose tolerance to insulin-requiring diabetes. They described the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in 7 mutation-positive individuals who had a range of glucose tolerance from normal to impaired to NIDDM. All subjects, including those with normal glucose tolerance, demonstrated abnormal insulin secretion on at least 1 test. The data suggested to Velho et al. (1996) that a defect of glucose-regulated insulin secretion is an early and possible primary abnormality in carriers of the mutation. They speculated that this defect may result from the progressive reduction of oxidative phosphorylation and may implicate the glucose-sensing mechanism of beta cells.
Guillausseau et al. (2001) ascertained 54 patients with type II diabetes mellitus and the 3243 mtDNA mutation through 16 departments of internal medicine and diabetes and metabolic diseases in France. On average, patients with maternally inherited diabetes and deafness were young at diabetes onset and presented with a normal or low body mass index. None was obese. Maternal family history of diabetes was found in 73% of probands. Diabetes was noninsulin-dependent at onset in 87% of patients; however, 46% of patients had noninsulin-dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. In 86% of patients who had received an ophthalmologic examination, macular pattern dystrophy (a specific retinal lesion of MIDD) was found. Myopathy was present in 43%, cardiomyopathy in 15%, and neuropsychiatric symptoms in 18% (9 of 51). Although the prevalence of diabetic retinopathy was 8% among patients who had received an ophthalmologic examination, a lower than expected percentage after a mean 12-year duration of diabetes, the prevalence of kidney disease was 28%. This suggested that a specific renal involvement results from mitochondrial disease. Fischel-Ghodsian (2001) suggested that early treatment with nephroprotective agents, such as angiotensin-converting enzyme inhibitors, may be beneficial in heading off the renal disease.
Ogun et al. (2012) reported a 54-year-old woman with the 3243A-G MTTL1 mutation in heteroplasmic state (40% in skeletal muscle) who had ptosis since her early teens, with worsening in her forties. She had hearing loss since her early twenties. Although visual acuity was normal, funduscopy showed macular dystrophy with a perimacular ring of retinal atrophy in both eyes, characteristic of MIDD. She did not have cardiac disease or diabetes, but her mother and brother both had deafness, and her brother had diabetes.
Inheritance
The transmission pattern in the family with MIDD reported by Ballinger et al. (1992) was consistent with mitochondrial inheritance, only through the female line.
The implication of mitochondrial mutations in diabetes mellitus is suggested by the fact that patients with noninsulin-dependent diabetes mellitus are more likely to have affected mothers than affected fathers (Alcolado and Alcolado, 1991).
Pathogenesis
Ballinger et al. (1994) restudied their original family and demonstrated that the mtDNA deletion was associated with the cotransmission of a related mtDNA duplication. The levels of 3 mtDNA forms, normal, deleted, and duplicated, varied between family members and between tissues within family members. The duplicated and deleted molecules shared the same breakpoint junction, np4398/14822. The duplicated molecule was thought to have a 6.1-kb insertion which duplicated the heavy-strand origin, O(H), but not the light-strand origin, O(L). It appeared that the deleted molecules accumulated in postmitotic tissues with age, presumably causing a progressive decline in tissue OXPHOS. When the mitochondrial ATP production of the pancreatic beta cells falls below the level necessary for glucose 'sensing,' diabetes mellitus ensues.
Molecular Genetics
In affected members of a family with maternally inherited diabetes and deafness, Ballinger et al. (1992) found a 10.4-kb mtDNA deletion (nucleotides 4398-14822), which was unique in being inherited through 3 generations at high levels and by the fact that the deletion lacked O(L), the origin of the light chain for mtDNA replication. The maternal inheritance of the deletion and, hence, its clear replication was strongly at variance with biochemical studies which suggested that O(L) is essential for mammalian mtDNA replication. Mitochondrial protein synthesis was inhibited in these patients. The deleterious effects of OXPHOS inhibition on pancreatic islet cell function was suggested by the finding that, in rats, streptozotocin, which impairs mtDNA replication, transcription, and OXPHOS function, results in diabetes.
Negrier et al. (1998) reported a partial tandem triplication of 9.2 kb mtDNA in 1 member of a family presenting maternally inherited diabetes and deafness associated with a tandem duplication of 4.6 kb. The family had previously been reported by Kressmann (1976).
### Mutation in the MTTL1 Gene
In 3 generations of a Dutch family with MIDD, van den Ouweland et al. (1992) demonstrated cosegregation of a single point mutation in the MTTL1 gene (3243A-G; 590050.0001). The 3243-bp mtDNA mutation has most commonly been observed in patients with MELAS syndrome (540000). The reason for the differences in phenotype was not clear. In their family, van den Ouweland et al. (1992) found a second mtDNA mutation in tRNA(lys) at the conserved nucleotide position 8334. This homoplasmic mutation was absent in 75 controls. Since it was present in 1 unaffected member of the family, a sister of the grandmother, it did not associate with the disease but might contribute to the phenotype in combination with the tRNA(leu-UUR) mutation. The same Dutch group ('t Hart et al., 1996) examined whether the levels of heteroplasmy of the 3243 mutation changed with aging. They compared DNA samples from peripheral blood collected recently and those collected 1.5 to 6 years ago, from 18 individuals carrying the mutation. They found that 17 of these 18 individuals showed a decrease on aging (p = 0.001). Data indicated a continuous selection against hematopoietic cells carrying high levels of the 3243 mutation. Thus 't Hart et al. (1996) concluded that the levels of heteroplasmy may decline below the detection level if DNA from peripheral blood is analyzed from elderly individuals. They found DNA from oral mucosa cells to be a good alternative as heteroplasmy levels for the 3243 mutation were on the average 1.5-fold higher than in DNA from peripheral blood.
Reardon et al. (1992) identified the 3243A-G mutation in the MTTL1 gene in a family with MIDD. The mutation was found in all 3 diabetic patients and in postmortem tissues from the proband. It was also found in 7 offspring of female patients, but not in the 2 children of the male proband.
To determine if the percentage level of a pathogenic mtDNA molecule is caused by a purely random process, Chinnery et al. (1999) studied the tissue distribution of the 3243A-G point mutation in 5 members of a family with maternally inherited diabetes and deafness. These individuals showed a nonrandom tissue distribution of the mutation, with highest levels in the skeletal muscle, followed by hair follicles and buccal mucosa, and with the lowest level in blood. The probability of observing any strict hierarchy in a family was calculated to be very small, leading the authors to suggest that the distribution of the 3243A-G mutation is not solely determined by random processes. Since the level of mutated mtDNA in hair follicles was most similar to the level in muscle, the authors suggested that hair follicles may be the best tissue for noninvasive quantitation of the 3243A-G mutation.
Sue et al. (1993) and Schulz et al. (1993) identified the 3243A-G mutation in affected individuals.
Velho et al. (1996) detected the mt3243 mutation in 25 of 50 tested members of 5 white French pedigrees.
### Mutation in the MTTE Gene
Vialettes et al. (1997) identified a 14709T-C mutation in the MTTE gene (590025.0001) in a proband with adult-onset IDDM and severe myopathy. The patient was also found to have a subclinical hearing impairment of high frequencies, suggesting maternally inherited diabetes and deafness.
### Mutation in the MTTK Gene
Kameoka et al. (1998) identified an 8396A-G mutation in the MTTK gene (590060.0005) in patients with maternally inherited diabetes and deafness.
INHERITANCE \- Mitochondrial HEAD & NECK Ears \- Deafness, neurosensory \- Impaired vestibular function Eyes \- Pigmentary retinal degeneration \- Macular pattern dystrophy \- Normal visual acuity \- Concentric narrowing of visual fields \- External ophthalmoplegia \- Ptosis (less common) CARDIOVASCULAR Heart \- Cardiomyopathy (in some) NEUROLOGIC Central Nervous System \- Dizziness \- Unsteady gait \- Seizures \- Dysarthria ENDOCRINE FEATURES \- Diabetes mellitus (NIDDM) LABORATORY ABNORMALITIES \- Hyperglycemia MISCELLANEOUS \- Variable features \- Onset of deafness and diabetes in adulthood MOLECULAR BASIS \- Caused by mutation in the mitochondrial tRNA-glutamic acid gene (MTTE, 590025.0001 ) \- Caused by mutation in the mitochondrial tRNA-leucine 1 gene (MTTL1, 590050.0001 ) \- Caused by mutation in the mitochondrial tRNA-lysine gene (MTTK, 590060.0005 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| DIABETES AND DEAFNESS, MATERNALLY INHERITED | c0342289 | 4,949 | omim | https://www.omim.org/entry/520000 | 2019-09-22T16:16:49 | {"mesh": ["C536246"], "omim": ["520000"], "orphanet": ["225"], "synonyms": ["Alternative titles", "DIABETES-DEAFNESS SYNDROME, MATERNALLY TRANSMITTED", "BALLINGER-WALLACE SYNDROME", "DIABETES MELLITUS, TYPE II, WITH DEAFNESS", "NONINSULIN-DEPENDENT DIABETES MELLITUS WITH DEAFNESS", "NIDDM WITH DEAFNESS"]} |
Zinc deficiency
Zinc
SpecialtyEndocrinology
Causesa diet high in phytate-containing whole grains
Zinc deficiency is defined either as insufficient zinc to meet the needs of the body, or as a serum zinc level below the normal range. However, since a decrease in the serum concentration is only detectable after long-term or severe depletion, serum zinc is not a reliable biomarker for zinc status.[1] Common symptoms include increased rates of diarrhea. Zinc deficiency affects the skin and gastrointestinal tract; brain and central nervous system, immune, skeletal, and reproductive systems.
Zinc deficiency in humans is caused by reduced dietary intake, inadequate absorption, increased loss, or increased body system use. The most common cause is reduced dietary intake. In the U.S., the Recommended Dietary Allowance (RDA) is 8 mg/day for women and 11 mg/day for men.[2]
The highest concentration of dietary zinc is found in oysters, meat, beans, and nuts. Increasing the amount of zinc in the soil and thus in crops and animals is an effective preventive measure. Zinc deficiency may affect up to 2 billion people worldwide.[3]
## Contents
* 1 Signs and symptoms
* 1.1 Skin, nails and hair
* 1.2 Mouth
* 1.3 Vision, smell and taste
* 1.4 Immune system
* 1.5 Diarrhea
* 1.6 Appetite
* 1.7 Cognitive function and hedonic tone
* 1.8 Psychological disorders
* 1.9 Growth
* 1.10 During pregnancy
* 1.11 Testosterone production
* 2 Causes
* 2.1 Dietary deficiency
* 2.2 Inadequate absorption
* 2.3 Increased loss
* 2.4 Chronic disease
* 3 Mechanism
* 4 Diagnosis
* 5 Classification
* 6 Prevention
* 7 Epidemiology
* 8 History
* 9 Soils and crops
* 9.1 Biofortification
* 10 References
* 11 Further reading
* 12 External links
## Signs and symptoms[edit]
### Skin, nails and hair[edit]
Zinc deficiency may manifest as acne,[4] eczema, xerosis (dry, scaling skin), seborrheic dermatitis,[5] or alopecia (thin and sparse hair).[5][6] It may also impair or possibly prevent wound healing.[6]
### Mouth[edit]
Zinc deficiency can manifest as non-specific oral ulceration, stomatitis, or white tongue coating.[5] Rarely it can cause angular cheilitis (sores at the corners of the mouth).[7]
### Vision, smell and taste[edit]
Severe zinc deficiency may disturb the sense of smell[6] and taste.[8][9][10][11][12][13] Night blindness may be a feature of severe zinc deficiency,[6] although most reports of night blindness and abnormal dark adaptation in humans with zinc deficiency have occurred in combination with other nutritional deficiencies (e.g. vitamin A).[14]
### Immune system[edit]
Impaired immune function in people with zinc deficiency can lead to the development of respiratory, gastrointestinal, or other infections, e.g., pneumonia.[6][15][16] The levels of inflammatory cytokines (e.g., IL-1β, IL-2, IL-6, and TNF-α) in blood plasma are affected by zinc deficiency and zinc supplementation produces a dose-dependent response in the level of these cytokines.[17] During inflammation, there is an increased cellular demand for zinc and impaired zinc homeostasis from zinc deficiency is associated with chronic inflammation.[17]
### Diarrhea[edit]
Zinc deficiency contributes to an increased incidence and severity of diarrhea.[15][16]
### Appetite[edit]
Zinc deficiency may lead to loss of appetite.[18] The use of zinc in the treatment of anorexia has been advocated since 1979 by Bakan. At least 15 clinical trials have shown that zinc improved weight gain in anorexia. A 1994 trial showed that zinc doubled the rate of body mass increase in the treatment of anorexia nervosa. Deficiency of other nutrients such as tyrosine, tryptophan and thiamine could contribute to this phenomenon of "malnutrition-induced malnutrition".[19]
### Cognitive function and hedonic tone[edit]
Cognitive functions, such as learning and hedonic tone, are impaired with zinc deficiency.[3][20] Moderate and more severe zinc deficiencies are associated with behavioral abnormalities, such as irritability, lethargy, and depression (e.g., involving anhedonia).[21] Zinc supplementation produces a rapid and dramatic improvement in hedonic tone (i.e., general level of happiness or pleasure) under these circumstances.[21] Zinc supplementation has been reported to improve symptoms of ADHD and depression.[3][22][23]
### Psychological disorders[edit]
Low plasma zinc levels have been alleged to be associated with many psychological disorders. Schizophrenia has been linked to decreased brain zinc levels.[24] Evidence suggests that zinc deficiency could play a role in depression.[24][25][26] Zinc supplementation may be an effective treatment in major depression.[27][28]
### Growth[edit]
Zinc deficiency in children can cause delayed growth[5] and has been claimed to be the cause of stunted growth in one third of the world's population.[29]
### During pregnancy[edit]
Zinc deficiency during pregnancy can negatively affect both the mother and fetus. Animal studies indicate that maternal zinc deficiency can upset both the sequencing and efficiency of the birth process. An increased incidence of difficult and prolonged labor, hemorrhage, uterine dystocia and placental abruption has been documented in zinc deficient animals.[30] These effects may be mediated by the defective functioning of estrogen via the estrogen receptor, which contains a zinc finger protein.[30] A review of pregnancy outcomes in women with acrodermatitis enteropathica, reported that out of every seven pregnancies, there was one abortion and two malfunctions, suggesting the human fetus is also susceptible to the teratogenic effects of severe zinc deficiency. However, a review on zinc supplementation trials during pregnancy did not report a significant effect of zinc supplementation on neonatal survival.[30]
Zinc deficiency can interfere with many metabolic processes when it occurs during infancy and childhood, a time of rapid growth and development when nutritional needs are high.[31] Low maternal zinc status has been associated with less attention during the neonatal period and worse motor functioning.[32] In some studies, supplementation has been associated with motor development in very low birth weight infants and more vigorous and functional activity in infants and toddlers.[32]
### Testosterone production[edit]
Zinc is required to produce testosterone. Thus, zinc deficiency can lead to reduced circulating testosterone, which could lead to sexual immaturity (Ananda Parsad, et al.) hypogonadism, and delayed puberty.[5]
## Causes[edit]
### Dietary deficiency[edit]
Zinc deficiency can be caused by a diet high in phytate-containing whole grains, foods grown in zinc deficient soil, or processed foods containing little or no zinc.[33][34] Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency.[35]
In the U.S., the Recommended Dietary Allowance (RDA) is 8 mg/day for women and 11 mg/day for men. RDA for pregnancy is 11 mg/day. RDA for lactation is 12 mg/day. For infants up to 12 months the RDA is 3 mg/day. For children ages 1–13 years the RDA increases with age from 3 to 8 mg/day.[2] The following table summarizes most of the foods with significant quantities of zinc, listed in order of quantity per serving, unfortified.[36] Note that all of the top 10 entries are meat, beans, or nuts.
Food mg in one serving Percentage of 11 mg recommended daily intake
Oysters, cooked, breaded and fried, 3 ounces (about 5 average sized oysters) 74.0 673%
Beef chuck roast, braised, 3 ounces 7.0 64%
Crab, Alaska king, cooked, 3 ounces 6.5 59%
Beef patty, broiled, 3 ounces 5.3 48%
Cashews, dry roasted, 3 ounces 4.8 44%
Lobster, cooked, 3 ounces 3.4 31%
Pork chop, loin, cooked, 3 ounces 2.9 26%
Baked beans, canned, plain or vegetarian, ½ cup 2.9 26%
Almonds, dry roasted, 3 ounces 2.7 25%
Chicken, dark meat, cooked, 3 ounces 2.4 22%
Yogurt, fruit, low fat, 8 ounces 1.7 15%
Shredded wheat, unfortified, 1 cup[37] 1.5 14%
Chickpeas, cooked, ½ cup 1.3 12%
Cheese, Swiss, 1 ounce 1.2 11%
Oatmeal, instant, plain, prepared with water, 1 packet 1.1 10%
Milk, low-fat or non-fat, 1 cup 1.0 9%
Kidney beans, cooked, ½ cup 0.9 8%
Chicken breast, roasted, skin removed, ½ breast 0.9 8%
Cheese, cheddar or mozzarella, 1 ounce 0.9 8%
Peas, green, frozen, cooked, ½ cup 0.5 5%
Flounder or sole, cooked, 3 ounces 0.3 3%
Recent research findings suggest that increasing atmospheric carbon dioxide concentrations will exacerbate zinc deficiency problems in populations that consume grains and legumes as Staple foods. A meta-analysis of data from 143 studies comparing the nutrient content of grasses and legumes grown in ambient and elevated CO2 environments found that the edible portions of wheat, rice, peas and soybeans grown in elevated CO2 contained less zinc and iron.[38] Global atmospheric CO2 concentration is expected to reach 550 p.p.m. in the late 21st century. At this CO2 level the zinc content of these crops was 3.3 to 9.3% lower than that of crops grown in the present atmosphere. A model of the nutritional impact of these lower zinc quantities on the populations of 151 countries predicts that an additional 175 million people could face dietary zinc deficiency as the result of increasing atmospheric CO2.[39]
### Inadequate absorption[edit]
Acrodermatitis enteropathica is an inherited deficiency of the zinc carrier protein ZIP4 resulting in inadequate zinc absorption.[6] It presents as growth retardation, severe diarrhea, hair loss, skin rash (most often around the genitalia and mouth) and opportunistic candidiasis and bacterial infections.[6]
Numerous small bowel diseases which cause destruction or malfunction of the gut mucosa enterocytes and generalized malabsorption are associated with zinc deficiency.[citation needed]
### Increased loss[edit]
Exercising, high alcohol intake, and diarrhea all increase loss of zinc from the body.[5][40] Changes in intestinal tract absorbability and permeability due, in part, to viral, protozoal, or bacteria pathogens may also encourage fecal losses of zinc.[41]
### Chronic disease[edit]
The mechanism of zinc deficiency in some diseases has not been well defined; it may be multifactorial.
Wilson's disease, sickle cell disease, chronic kidney disease, chronic liver disease have all been associated with zinc deficiency.[42][43] It can also occur after bariatric surgery, mercury exposure[44][45] and tartrazine.[citation needed]
Although marginal zinc deficiency is often found in depression, low zinc levels could either be a cause or a consequence of mental disorders and their symptoms. [25]
## Mechanism[edit]
As biosystems are unable to store zinc, regular intake is necessary. Excessively low zinc intake can lead to zinc deficiency, which can negatively impact an individual's health.[46] The mechanisms for the clinical manifestations of zinc deficiency are best appreciated by recognizing that zinc functions in the body in three areas: catalytic, structural, and regulatory.[2][47] Zinc (Zn) is only common in its +2 oxidative state, where it typically coordinates with tetrahedral geometry. It is important in maintaining basic cellular functions such as DNA replication, RNA transcription, cell division and cell activations. However, having too much or too little zinc can cause these functions to be compromised.
Zinc is a critical component of the catalytic site of hundreds of kinds of different metalloenzymes in each human being. In its structural role, zinc coordinates with certain protein domains, facilitating protein folding and producing structures such as 'zinc fingers'. In its regulatory role, zinc is involved in the regulation of nucleoproteins and the activity of various inflammatory cells. For example, zinc regulates the expression of metallothionein, which has multiple functions, such as intracellular zinc compartmentalization[48] and antioxidant function.[49][50] Thus zinc deficiency results in disruption of hundreds of metabolic pathways, causing numerous clinical manifestations, including impaired growth and development, and disruption of reproductive and immune function.[5][51][52]
Pra1 (pH regulated antigen 1) is a candida albicans protein that scavenges host zinc.[53]
## Diagnosis[edit]
Diagnosis is typically made based on clinical suspicion and a low level of zinc in the blood. Any level below 70 mcg/dl (normal 70-120 mcg/dl)is considered as zinc deficiency. Zinc deficiency could be also associated with low alkaline phosphatase since it acts a cofactor for this enzyme.
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## Classification[edit]
Zinc deficiency can be classified as acute, as may occur during prolonged inappropriate zinc-free total parenteral nutrition; or chronic, as may occur in dietary deficiency or inadequate absorption.[29]
## Prevention[edit]
Zinc gluconate tablets
Five interventional strategies can be used:
* Adding zinc to soil, called agronomic biofortification, which both increases crop yields and provides more dietary zinc.
* Adding zinc to food, called food fortification. The Republic of China, India, Mexico and about 20 other countries, mostly on the east coast of sub-Saharan Africa, fortify wheat flour and/or maize flour with zinc.[54]
* Adding zinc rich foods to diet. The foods with the highest concentration of zinc are proteins, especially animal meats, the highest being oysters.[5] Per ounce, beef, pork, and lamb contain more zinc than fish. The dark meat of a chicken has more zinc than the light meat. Other good sources of zinc are nuts, whole grains, legumes, and yeast.[55] Although whole grains and cereals are high in zinc, they also contain chelating phytates which bind zinc and reduce its bioavailability.[5]
* Oral repletion via tablets (e.g. zinc gluconate) or liquid (e.g. zinc acetate). Oral zinc supplementation in healthy infants more than six months old has been shown to reduce the duration of any subsequent diarrheal episodes by about 11 hours.[56]
* Oral repletion via multivitamin/mineral supplements containing zinc gluconate, sulfate, or acetate. It is not clear whether one form is better than another.[55]
## Epidemiology[edit]
Zinc deficiency affects about 2.2 billion people around the world.[3] Severe zinc deficiency is rare, and is mainly seen in persons with acrodermatitis enteropathica, a severe defect in zinc absorption due to a congenital deficiency in the zinc carrier protein ZIP4 in the enterocyte.[5] Mild zinc deficiency due to reduced dietary intake is common.[5] Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency.[35] Zinc deficiency is thought to be a leading cause of infant mortality.[citation needed]
Providing micronutrients, including zinc, to humans is one of the four solutions to major global problems identified in the Copenhagen Consensus from an international panel of economists.[57]
## History[edit]
Significant historical events related to zinc deficiency began in 1869 when zinc was first discovered to be essential to the growth of an organism Aspergillus niger.[58] In 1929 Lutz measured zinc in numerous human tissues using the dithizone technique and estimated total body zinc in a 70 kg man to be 2.2 grams. Zinc was found to be essential to the growth of rats in 1933.[59] In 1939 beriberi patients in China were noted to have decreased zinc levels in skin and nails. In 1940 zinc levels in a series of autopsies found it to be present in all tissues examined. In 1942 a study showed most zinc excretion was via the feces. In 1950 a normal serum zinc level was first defined, and found to be 17.3–22.1 micromoles/liter. In 1956 cirrhotic patients were found to have low serum zinc levels. In 1963 zinc was determined to be essential to human growth, three enzymes requiring zinc as a cofactor were described, and a report was published of a 21-year-old Iranian man with stunted growth, infantile genitalia, and anemia which were all reversed by zinc supplementation.[60] In 1972 fifteen Iranian rejected army inductees with symptoms of zinc deficiency were reported: all responded to zinc. In 1973 the first case of acrodermatitis enteropathica due to severe zinc deficiency was described. In 1974 the National Academy of Sciences declared zinc to be an essential element for humans and established a recommended daily allowance. In 1978 the Food and Drug Administration required zinc to be in total parenteral nutrition fluids. In the 1990s there was increasing attention on the role of zinc deficiency in childhood morbidity and mortality in developing countries.[61] In 2002 the zinc transporter protein ZIP4 was first identified as the mechanism for absorption of zinc in the gut across the basolateral membrane of the enterocyte. By 2014 over 300 zinc containing enzymes have been identified, as well as over 1000 zinc containing transcription factors.[citation needed]
Phytate was recognized as removing zinc from nutrients given to chicken and swine in 1960. That it can cause human zinc deficiency however was not recognized until Reinhold's work in Iran in the 1970s. This phenomenon is central to the high risk of zinc deficiency worldwide.[62]
## Soils and crops[edit]
See also: Zinc deficiency (plant disorder)
Soil zinc is an essential micronutrient for crops. Almost half of the world's cereal crops are deficient in zinc, leading to poor crop yields.[63] Many agricultural countries around the world are affected by zinc deficiency.[64] In China, zinc deficiency occurs on around half of the agricultural soils, affecting mainly rice and maize. Areas with zinc deficient soils are often regions with widespread zinc deficiency in humans. A basic knowledge of the dynamics of zinc in soils, understanding of the uptake and transport of zinc in crops and characterizing the response of crops to zinc deficiency are essential steps in achieving sustainable solutions to the problem of zinc deficiency in crops and humans.[65]
### Biofortification[edit]
Soil and foliar application of zinc fertilizer can effectively increase grain zinc and reduce the phytate:zinc ratio in grain.[66][67] People who eat bread prepared from zinc enriched wheat have a significant increase in serum zinc.[citation needed]
Zinc fertilization not only increases zinc content in zinc deficient crops, it also increases crop yields.[65] Balanced crop nutrition supplying all essential nutrients, including zinc, is a cost effective management strategy. Even with zinc-efficient varieties, zinc fertilizers are needed when the available zinc in the topsoil becomes depleted.
Plant breeding can improve zinc uptake capacity of plants under soil conditions with low chemical availability of zinc. Breeding can also improve zinc translocation which elevates zinc content in edible crop parts as opposed to the rest of the plant.
Central Anatolia, in Turkey, was a region with zinc-deficient soils and widespread zinc deficiency in humans. In 1993, a research project found that yields could be increased by 6 to 8-fold and child nutrition dramatically increased through zinc fertilization.[68] Zinc was added to fertilizers. While the product was initially made available at the same cost, the results were so convincing that Turkish farmers significantly increased the use of the zinc-fortified fertilizer (1 percent of zinc) within a few years, despite the repricing of the products to reflect the added value of the content. Nearly ten years after the identification of the zinc deficiency problem, the total amount of zinc-containing compound fertilizers produced and applied in Turkey reached a record level of 300,000 tonnes per annum. It is estimated that the economic benefits associated with the application of zinc fertilizers on zinc deficient soils in Turkey is around US$100 million per year. Zinc deficiency in children has been dramatically reduced.
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52. ^ Rink L, Gabriel P (November 2000). "Zinc and the immune system". The Proceedings of the Nutrition Society. 59 (4): 541–52. doi:10.1017/S0029665100000781. PMID 11115789.
53. ^ Citiulo F, Jacobsen ID, Miramón P, Schild L, Brunke S, Zipfel P, et al. (2012). "Candida albicans scavenges host zinc via Pra1 during endothelial invasion". PLOS Pathogens. 8 (6): e1002777. doi:10.1371/journal.ppat.1002777. PMC 3386192. PMID 22761575.
54. ^ "Map: Count of Nutrients in Fortification Standards". Food Fortification Initiative. 2018. Retrieved 24 January 2019.
55. ^ a b "Zinc in diet: MedlinePlus Medical Encyclopedia". medlineplus.gov. 2 February 2015. Retrieved 21 February 2017.
56. ^ Lazzerini M, Wanzira H (December 2016). "Oral zinc for treating diarrhoea in children". The Cochrane Database of Systematic Reviews. 12: CD005436. doi:10.1002/14651858.CD005436.pub5. PMC 5450879. PMID 27996088.
57. ^ "Copenhagen Consensus Center". Retrieved 30 August 2014.
58. ^ Raulin J (1869). "Chemical studies on vegetation". Annales des Sciences Naturelles. 11: 293–299.
59. ^ Todd WR, Elvejheim CA, Hart EB (1934). "Zinc in the nutrition of the rat". Am J Physiol. 107: 146–156. doi:10.1152/ajplegacy.1933.107.1.146.
60. ^ Prasad AS, Miale A, Farid Z, Sandstead HH, Schulert AR (April 1963). "Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypognadism". The Journal of Laboratory and Clinical Medicine. 61: 537–49. PMID 13985937.
61. ^ Duggan C, Watkins JB, Walker WA (2008). Nutrition in pediatrics : basic science, clinical application (4th ed.). Hamilton: BC Decker. pp. 69–71. ISBN 9781550093612.
62. ^ Sandstead HH (January 2013). "Human zinc deficiency: discovery to initial translation". Advances in Nutrition. 4 (1): 76–81. doi:10.3945/an.112.003186. PMC 3648742. PMID 23319126.
63. ^ Korayem, A.M. (1993). "Effect of zinc fertilization on rice plants and on the population of the rice-root nematode Hirschmanniella oryzae". Anz. Schadlingskde., Pflanzenschutz, Umweltschutz. 66: 18–21. doi:10.1007/BF01903608. S2CID 33142627.
64. ^ "Archived copy". Archived from the original on 19 December 2008. Retrieved 23 April 2009.CS1 maint: archived copy as title (link)
65. ^ a b Alloway BJ (2008). "Zinc in Soils and Crop Nutrition, International Fertilizer Industry Association, and International Zinc Association". Archived from the original on 19 February 2013. Retrieved 15 December 2012.
66. ^ Hussain S, Maqsood MA, Rengel Z, Aziz T (March 2012). "Biofortification and estimated human bioavailability of zinc in wheat grains as influenced by methods of zinc application". Plant and Soil. 361 (1–2): 279–290. doi:10.1007/s11104-012-1217-4. S2CID 16068957.
67. ^ Fang Y, Wang L, Xin Z, Zhao L, An X, Hu Q (March 2008). "Effect of foliar application of zinc, selenium, and iron fertilizers on nutrients concentration and yield of rice grain in China". Journal of Agricultural and Food Chemistry. 56 (6): 2079–84. doi:10.1021/jf800150z. PMID 18311920.
68. ^ Cakmak, I. (2008). "Enrichment of cereal grains with zinc: Agronomic or genetic biofortification?". Plant Soil. 302 (1–2): 1–17. doi:10.1007/s11104-007-9466-3. S2CID 34821888.
## Further reading[edit]
* Maret W (2013). "Chapter 14 Zinc and the Zinc Proteome". In Banci L (ed.). Metallomics and the Cell. Metal Ions in Life Sciences. 12. Springer. pp. 479–501. doi:10.1007/978-94-007-5561-1_14. ISBN 978-94-007-5560-4. ISSN 1559-0836. PMID 23595681.
## External links[edit]
Classification
D
* ICD-10: E60
* ICD-9-CM: 269.3
* DiseasesDB: 14272
* DermAtlas 228
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* HarvestZinc: HarvestPlus Zinc Fertilizer Project
* Proceedings from the Zinc Crops Conference on Improving Crop Production and Human Health, Istanbul, Turkey, 24–26 May 2007
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Zinc deficiency | c0235950 | 4,950 | wikipedia | https://en.wikipedia.org/wiki/Zinc_deficiency | 2021-01-18T18:59:10 | {"umls": ["C0235950"], "icd-9": ["269.3"], "icd-10": ["E60"], "wikidata": ["Q8072298"]} |
A number sign (#) is used with this entry because of evidence that isolated microphthalmia and/or coloboma (MCOPCB10) is caused by heterozygous mutation in the RBP4 gene (180250) on chromosome 10q23.
Clinical Features
Chou et al. (2015) studied a 7-generation pedigree in which 11 family members had microphthalmia or clinical anophthalmia and/or coloboma. The first proband was an 8-year-old girl with bilateral clinical anophthalmia in whom MRI at day 1 of life showed bilateral absence of the eyeballs, with only cystic remnants in the orbits, thin optic nerves, and a small chiasm; there were no brain abnormalities. The right orbital cyst was surgically removed at 8 months; pathology revealed rudimentary eye structures. The second proband was an 11-year-old boy, a second cousin of the first proband, with left clinical anophthalmia and right microphthalmia with ventronasal iris and chorioretinal coloboma. Brain MRI and echocardiography at age 7 years were normal. His mother, who was a monozygous twin, had inferior iris and chorioretinal coloboma. The colobomas in both mother and son involved the entire uveal and neuroretinal axis, from the pupillary margin to the optic nerve head. The mother's twin sister, who had normal eyes, was the mother of a 13-year-old boy who had a left-sided iris and chorioretinal coloboma, as well as an atrial septal defect. In another branch of the family, a 61-year-old man had bilateral clinical anophthalmia but was otherwise healthy. In the third generation of the pedigree, 6 deceased individuals reportedly had had anophthalmia/microphthalmia and/or coloboma. Chou et al. (2015) described a second family in which a 41-year-old man had bilateral clinical anophthalmia as well as developmental delay and seizures; his 21-year-old male first cousin once removed also had severe bilateral microphthalmia and similar developmental delay and seizures. In a third family, a mother exhibited only unilateral optic pit, but her 12-year-old daughter had left-sided microphthalmia and ventronasal iris coloboma.
Mapping
In a 7-generation family in which 11 members had microphthalmia or clinical anophthalmia and/or coloboma, Chou et al. (2015) excluded 23 known loci associated with microphthalmia and coloboma. By genomewide multipoint linkage analysis, the authors identified a nonrecombinant 8.2-Mb interval on chromosome 10q23 with a peak lod score of 3.01.
Inheritance
The transmission pattern of microphthalmia or clinical anophthalmia and/or coloboma in the 7-generation family reported by Chou et al. (2015) was consistent with autosomal dominant inheritance. Maternal penetrance was significantly greater than paternal inheritance (0.7 vs 0.1).
Molecular Genetics
In a 7-generation family segregating microphthalmia or clinical anophthalmia and/or coloboma mapping to chromosome 10q23, Chou et al. (2015) analyzed 3 candidate genes in the critical region that have roles in vitamin A transport. They identified a missense mutation in the RBP4 gene (A75T; 180250.0004) that segregated with the disease and was not found in more than 11,330 control chromosomes. All but 1 of the 11 affected individuals inherited the trait from their mother; thus, maternal penetrance was significantly greater than paternal penetrance (0.7 vs 0.1). In the 1 instance of paternal transmission, only 1 of 2 monozygous twins was affected. Screening of DNA samples from 75 unrelated microphthalmia/coloboma cases revealed another RBP4 missense mutation (A73T; 180250.0005) in 2 patients; the mutation occurred on distinct haplotypes, indicating recurrence, and there was maternal transmission in both families. Functional analysis demonstrated that both mutant retinol-binding proteins (RBPs) bind the STRA6 (610745) receptor with much higher affinity than wildtype yet carry little or no vitamin A. Consistent with these findings, all 3 A75T heterozygous carriers who were tested had fasting serum vitamin A levels below normal limits, and plasma retinol fluorescence was also reduced. Chou et al. (2015) suggested that the significantly greater penetrance in this disorder when the RBP4 mutation is maternally transmitted results from decreased vitamin A delivery both at the placenta, involving maternal-derived RBP, and later at the developing eye primordia, involving fetal-derived RBP.
INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Microphthalmia \- Clinical anophthalmia \- Iris coloboma \- Chorioretinal coloboma \- Microcoria (rare) \- Optic pit (rare) LABORATORY ABNORMALITIES \- Low serum vitamin A levels \- Reduced plasma retinol fluorescence MISCELLANEOUS \- Increased penetrance of phenotype when there is maternal transmission of the mutant allele MOLECULAR BASIS \- Caused by mutation in the retinol-binding protein-4 gene (RBP4, 180250.0004 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| MICROPHTHALMIA, ISOLATED, WITH COLOBOMA 10 | c2931501 | 4,951 | omim | https://www.omim.org/entry/616428 | 2019-09-22T15:48:55 | {"mesh": ["C537463"], "omim": ["616428"], "orphanet": ["98938"]} |
Facioscapulohumeral muscular dystrophy
Other namesLandouzy–Dejerine muscular dystrophy, FSHMD, FSH
A diagram showing in red the muscles commonly involved in FSHD
Pronunciation
* /fæʃiːoʊskæpjəloʊˈhjumərəl/
SpecialtyNeurology, neuromuscular medicine
SymptomsFacial weakness, scapular winging, foot drop
Usual onsetAdolescence
DurationLong term
TypesFSHD1, FSHD2
CausesGenetic (inherited or new mutation)
Diagnostic methodGenetic testing
Differential diagnosisLimb-girdle muscular dystrophy (especially calpainopathy), Pompe disease, mitochondrial myopathy, polymyositis[1]
ManagementPhysical therapy, bracing, reconstructive surgery
Frequency1 in 8333 to 1 in 15000[1]
Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy that preferentially weakens the skeletal muscles of the face (Latin: facio), those that position the scapula (scapulo), and those in the upper arm, overlying the humerus bone (humeral).[1] Weakness of the scapular muscles causes an abnormally positioned scapula (winged scapula). Other areas of the body usually develop weakness as well, such as the abdomen and lower leg, causing foot drop. The two sides of the body are often affected unequally. Symptoms typically begin in early childhood and become noticeable in the teenage years, with 95% of affected individuals manifesting disease by age 20 years.[2] Non-muscular manifestations of FSHD include hearing loss and blood vessel abnormalities in the back of the eye.
FSHD is caused by complex genetic changes involving the DUX4 gene.[3] In those without FSHD, DUX4 is expressed (ie: turned on) in early human development and later repressed (ie: turned off) in mature tissues.[4] In FSHD, DUX4 is inadequately turned off, which can be caused by several different mutations, the most common being deletion of DNA in the region surrounding DUX4.[5] This mutation is termed "D4Z4 contraction" and defines FSHD type 1 (FSHD1), making up 95% of FSHD cases. FSHD due to other mutations is classified as FSHD type 2 (FSHD2). Regardless of which mutation is present, disease can only result if the individual has a 4qA allele, which is a common variation in the DNA next to DUX4.[6] Up to 30% of FSHD cases are due to a new mutation, which then is able to be passed on to children.[7] FSHD1 follows an autosomal dominant inheritance pattern, meaning each child of an affected individual has a 50% chance of also being affected.[1] How DUX4 expression causes muscle damage is unclear.[1] Expression of DUX4 gene produces DUX4 protein, whose function is to modulate hundreds of other genes, many of which are involved in muscle function.[1][3] Diagnosis is by genetic testing.[1]
There is no known cure for FSHD. No pharmaceuticals have proven effective for altering the disease course. Symptoms can be addressed with physical therapy, bracing, and reconstructive surgery. Surgical fixation of the scapula to the thorax is effective in reducing shoulder symptoms in select cases.[8] FSHD is the third most common genetic disease of skeletal muscle (Duchenne/Becker muscular dystrophy being first and myotonic dystrophy being second), affecting 1 in 8,333 to 1 in 15,000 people.[1] Prognosis is extremely variable, with many never facing significant limitations, although up to 20% of affected individuals become severely disabled, requiring use of a wheel chair or mobility scooter.[2] Life expectancy is generally not affected, except in rare cases of respiratory insufficiency.[9]
The first description of an individual with FSHD is an autopsy report from 1852,[10][11] although FSHD wasn't distinguished as a disease until the 1870s and 1880s when French physicians Landouzy and Dejerine followed a family affected by it; thus FSHD is sometimes referred to as Landouzy–Dejerine muscular dystrophy.[12][11] In 1991, the association of most cases with the tip of chromosome 4 was established, which was discovered to be due to D4Z4 contraction in 1993. DUX4 was discovered in 1999, but it wasn't until 2010 that the genetic mechanism causing its expression was elucidated. In 2012, the predominant mutation of FSHD2 was discovered. In 2014, researchers published the first proposed pathophysiology definition of the disease and four viable therapeutic targets for possible intervention points.[13]
## Contents
* 1 Signs and symptoms
* 1.1 Face and shoulder
* 1.2 Upper arm and lower body
* 1.3 Muscle involvement from medical imaging perspective
* 1.4 Non-musculoskeletal
* 2 Genetics
* 2.1 DUX4 and the D4Z4 repeat array
* 2.2 FSHD1
* 2.3 FSHD2
* 2.4 Two ends of a disease spectrum
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Genetic testing
* 4.1.1 Assessing D4Z4 length
* 4.2 Alternative testing
* 5 Management
* 5.1 Surgical intervention
* 6 Epidemiology
* 7 History
* 7.1 Chronology of important FSHD-related genetic research
* 7.2 Past pharmaceutical development
* 8 Society and culture
* 8.1 FSHD Society
* 8.2 FSHD-EUROPE
* 9 Research directions
* 9.1 Current pharmaceutical development
* 9.2 Potential pharmaceutical development
* 9.3 Outcome measures
* 10 References
* 11 External links
## Signs and symptoms[edit]
Two brothers with FSHD followed by Landouzy and Dejerine
Drawing of one brother at age 17. Visible is lumbar hyperlordosis, and atrophy of the upper arm and pectoral muscles.
Photograph of another brother at age 21. The right scapula appears protracted, downwardly rotated, and laterally displaced.
Muscles of the face, shoulder girdle, and upper arm are classically affected, although these muscles can be spared and other muscles usually are affected. Distribution and degree of muscle weakness is extremely variable, even between identical twins.[14][15] Individual muscles can weaken while adjacent muscles remain healthy.[citation needed] Muscle weakness usually becomes noticeable on one side of the body before the other, a hallmark of the disease.[citation needed] The right shoulder muscles are more often affected than the left shoulder muscles, independent of handedness.[16]:139[17] Musculoskeletal pain is very common, most often described in the neck, shoulders, lower back, and the back of the knee.[18] Classically, symptoms appear in those 15 – 30 years of age, although infantile onset, adult onset, and absence of symptoms despite having the causal genetics also occur.[7] Long static phases, in which no progression is apparent, is not uncommon.[19] FSHD1 and FSHD2 have similar signs and symptoms, although very large D4Z4 deletions in FSHD1 (EcoRI 10-11 kb) are more strongly associated with infantile onset, progressive hearing loss, retinal disease, and various rare manifestations.[20]
### Face and shoulder[edit]
Weakness typically begins in the muscles of the face.[19] At least mild facial weakness can be found in 90% or more with FSHD, although it is rarely the initial complaint.[21] The muscles surrounding the eyes (orbicularis oculi muscle) are commonly affected, which can result in sleeping with eyelids open.[citation needed] The muscle surrounding the mouth (orbicularis oris muscle) is also commonly affected, resulting in inability to pucker the lips or whistle.[citation needed] There can be difficulty pronouncing the letters M, B, and P, or facial expressions that appear diminished, depressed, angry, or fatigued.[citation needed] After the facial weakness, weakness usually develops in the muscles of the upper torso, especially those connecting shoulder girdle to the thorax. Weakness of the shoulder girdle muscles is the initial complaint in 80% of cases, and the disease doesn't progress further in 30% of familial cases.[21] Predominantly, the serratus anterior muscle and middle and lower trapezius fibers are affected; the upper trapezius fibers often are spared.[citation needed]. This weakness causes the scapulas to become downwardly rotated and protracted, resulting in winged scapulas, horizontal clavicles, and sloping shoulders. In advanced cases, the scapula appears to "herniate" up and over the rib cage. A common complaint is difficulty working with the arms overhead. The rotator cuff muscles are usually spared, even late in the disease course.[22][23] Another commonly affected upper torso muscle is the pectoralis major muscle, particularly the sterno costal portion, atrophy of which can contribute to a prominent horizontal anterior axillary fold.[24][7]
### Upper arm and lower body[edit]
After facial and upper torso weakness, weakness can "descend" to the upper arms (biceps muscle and triceps muscle) and the pelvic girdle.[19] The forearms are usually spared, resulting in an appearance some compare to the fictional character Popeye.[7] Sometimes, the weakness is observed to "skip" the pelvis and involve the tibialis anterior (shin muscle), causing foot drop. Weakness can also occur in the abdominal muscles, which can manifest as a protuberant abdomen, lumbar hyperlordosis, the inability to do a sit-up, or the inability to turn from one side to the other while lying down. The lower fibers of the rectus abdominis muscle are more often affected than the upper fibers, manifesting as a positive Beevor's sign.[7] Weakness in the legs can manifest as difficulty walking or hips held in slight flexion.
### Muscle involvement from medical imaging perspective[edit]
Medical imaging (CT and MRI) has shown muscle damage that doesn't cause obvious symptoms.[22] A single MRI study shows the teres major muscle to be commonly affected.[23] The semimembranosus muscle, part of the hamstrings, is commonly affected,[17][25][26] with one author stating it to be "the most frequently and severely affected muscle."[1] Also, MRI shows that the rectus femoris is more often affected than the other muscles of the quadriceps,[25] the medial gastrocnemius is more often affected than the lateral gastrocnemius,[25][26] and the iliopsoas muscle is very often spared.[26][1]
### Non-musculoskeletal[edit]
The most common non-musculoskeletal manifestation of FSHD is mild retinal blood vessel abnormalities, such as telangiectasias or microaneurysms, with one study placing the incidence at 50%.[citation needed] These abnormal blood vessels generally do not affect vision or health, although a severe form of it mimics Coat's disease, a condition found in about 1% of FSHD cases and more frequently associated with large 4q35 deletions.[1][27] High-frequency hearing loss can occur in those with large 4q35 deletions, but otherwise is no more common compared to the general population.[1] Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-bound patients.[citation needed] However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases.[1][28]
## Genetics[edit]
The genetics of FSHD are complex, culminating in abnormal expression of the DUX4 gene.[1][5] In those without FSHD, DUX4 is expressed during embryogenesis and, at some point, becomes repressed in all tissues except the testes. In FSHD, there is inadequate repression of DUX4, allowing ectopic production of DUX4 protein in muscles, causing muscle damage. Two genetic elements are required for inadequate repression of DUX4. First, there must be a mutation that causes hypomethylation of the DNA surrounding DUX4, allowing transcription of DUX4 into messenger RNA (mRNA). Several mutations cause hypomethylation, upon which FSHD is subclassified into FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2).[13]
The second genetic element needed is a polyadenylation sequence downstream to DUX4 that allows stability to DUX4 mRNA, which allows DUX4 mRNA to persist long enough to be translated into DUX4 protein, the causal agent of muscle damage.[5] There are at least 17 variations, or haplotype polymorphisms, of 4q35 (DNA encompassing D4Z4 repeat array) observed in the population.[29] These 17 variations can be roughly divided into the groups 4qA and 4qB.[29] It are the 4qA alleles that contain polyadenylation signals, allowing stability to DUX4 mRNA.[5] The 4qB alleles do not have polyadenylation sequences.[5]
### DUX4 and the D4Z4 repeat array[edit]
D4Z4 array with three D4Z4 repeats and the 4qA allele.[13] CEN centromeric end TEL telomeric end
NDE box non-deleted element PAS polyadenylation site
triangle D4Z4 repeat trapezoid partial D4Z4 repeat
white box pLAM gray boxes DUX4 exons 1, 2, 3
arrows
corner promoters straight RNA transcripts
black sense red antisense
blue DBE-T dashes dicing sites
DUX4 resides within the D4Z4 macrosatellite repeat array, a series of tandemly repeated DNA segments in the subtelomeric region (4q35) of chromosome 4. Each D4Z4 repeat is 3.3 kilobase pairs (kb) long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures.[30][31] In FSHD, the heterochromatin structure is lost, becoming euchromatin.[30] The name "D4Z4" is derived from an obsolete nomenclature system used for DNA segments of unknown significance during the human genome project: D for DNA, 4 for chromosome 4, Z indicates it is a repetitive sequence, and 4 is a serial number assigned based on the order of submission.[32][33]
DUX4 consists of three exons. Exons 1 and 2 are in each repeat. Exon 3 is in the pLAM region telomeric to the last partial repeat.[5][4] Multiple RNA transcripts are produced from the D4Z4 repeat array, both sense and antisense. Some transcripts might be degraded in areas to produce si-like small RNAs.[13] Some transcripts that originate centromeric to the D4Z4 repeat array at the non-deleted element (NDE), termed D4Z4 regulatory element transcripts (DBE-T), could play a role in DUX4 derepression.[13][34] One proposed mechanism is that DBE-T leads to the recruitment of the trithorax-group protein Ash1L, an increase in H3K36me2-methylation, and ultimately de-repression of 4q35 genes.[35]
### FSHD1[edit]
FSHD involving deletion of D4Z4 repeats (termed 'D4Z4 contraction') is classified as FSHD1, which accounts for 95% of FSHD cases.[1] Typically, chromosome 4 includes between 11 and 150 repetitions of D4Z4.[30][5] In FSHD1, there are 1–10 repetitions of D4Z4.[5] The number of repeats roughly inversely correlates with disease severity. Namely, those with 1 - 3 repeats are more likely to have severe, atypical, and early onset disease; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms.[36] D4Z4 contraction causes D4Z4 hypomethylation, allowing DUX4 transcription. Deletion of the entire D4Z4 repeat array does not result in FSHD because then there are no complete copies of DUX4 to be expressed, although other birth defects result.[37][5] Inheritance is autosomal dominant, although 10 - 30% of cases are from de novo (new) mutations.[7]
The subtelomeric region of chromosome 10q contains a tandem repeat structure highly homologous (99% identical) to 4q35.[5][29] The repeats of 10q are termed "D4Z4-like" repeats.[5] Because 10q usually lacks a polyadenylation sequence, it is generally not implicated in disease, except in the instance of chromosomal rearrangements between 4q and 10q leading to 4q D4Z4 contraction, or the other instance of transfer of a 4q D4Z4 repeat and polyadenylation signal onto 10q.[38][5][39]
It has been posited that FSHD1 undergoes anticipation, a phenomenon classically associated with trinucleotide repeat disorders in which disease manifestation worsens with each subsequent generation.[40] As of 2019, more detailed studies are needed to definitively show whether or not anticipation plays a role.[41] If anticipation does occur in FSHD, the mechanism is different than that of trinucleotide repeat disorders, since the D4Z4 repeats are not trinucleotide repeats, and the repeat array size in FSHD is stable across generations.[42]
Each triangle represents a D4Z4 repeat. The circles above the triangles represent DNA methylation: high methylation resulting in heterochromatic DNA and low methylation resulting in euchromatic DNA.
### FSHD2[edit]
FSHD without D4Z4 contraction is classified as FSHD2, which constitutes 5% of FSHD cases.[1] Various mutations cause FSHD2, all resulting in D4Z4 hypomethylation, at which the genetic mechanism converges with FSHD1.[43] Approximately 80% of FSHD2 cases are due to deactivating mutations in the gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18. SMCHD1 is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array.[1] Another cause of FSHD2 is mutation in DNMT3B (DNA methyltransferase 3B), which also plays a role in DNA methylation.[44][45] As of 2020, early evidence indicates that a third cause of FSHD2 is mutation in both copies of the LRIF1 gene, which encodes the protein ligand-dependent nuclear receptor-interacting factor 1 (LRIF1).[46] LRIF1 is known to interact with the SMCHD1 protein.[46] As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause FSHD2.[1]
Mutation of a single allele of SMCHD1 or DNMT3B can cause disease. Mutation of both copies LRIF1 has been tentatively shown to cause disease in a single person as of 2020.[46] As in FSHD1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in FSHD2 are not in proximity with the 4qA allele, and so they are inherited independently from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without FSHD can pass on an SMCHD1 mutation, and the other parent, also without FSHD, can pass on a 4qA allele, bearing a child with FSHD2.[43][45]
### Two ends of a disease spectrum[edit]
Initially, FSHD1 and FSHD2 were described as two separate genetic causes of the same disease. However, they can also be viewed not as distinct causes, but rather as risk factors. Not rarely do both contribute to disease in the same individual.[36]
In those with FSHD2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still often have one less than 17 (relatively short compared to the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation.[36] Further studies need to be done to determine the upper limit of D4Z4 repeats in which FSHD2 can occur.[36]
In those with a 4qA allele and 10 or fewer repeats, an additional SMCHD1 mutation has shown to worsen disease, classifying them as both FSHD1 and FSHD2.[47] In these FSHD1/FSHD2 individuals, the methylation pattern of the D4Z4 repeat array resembles that seen in FSHD2.[36] This combined FSHD1/FSHD2 presentation is most common in those with 9 - 10 repeats, and is seldom found in those with 8 or less repeats. The relative abundance of SMCHD1 mutations in the 9 - 10 repeat group is likely because a sizable portion of the general population has 9 - 10 repeats with no disease, yet with the additive effect of an SMCHD1 mutation, symptoms develop and a diagnosis is made. In those with 8 or fewer repeats, symptoms are more likely than in those with 9 - 10 repeats, leading to diagnosis regardless of an additional SMCHD1 mutation.[36]
The apparent frequency of FSHD1/FSHD2 cases in the 9 - 10 repeat range, combined with the FSHD2-like methylation pattern, suggest the 9 - 10 repeat size to be an overlap zone between FSHD1 and FSDH2.[36]
## Pathophysiology[edit]
DUX4 signaling in FSHD-affected skeletal muscle.
As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of FSHD.[48] DUX4 is expressed in extremely small amounts, detectable in 1 out of every 1000 immature muscle cells (myoblast), which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single nucleus expressing DUX4 can provide DUX4 protein to neighboring nuclei from fused cells.[49]
It remains an area of active research how DUX4 causes muscle damage. DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin. It seems that DUX4 makes muscle cells more prone to apoptosis, although details of the mechanism are still unknown and contested. Other DUX4 regulated genes are involved in oxidative stress, and it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of FSHD. DUX4 downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7. DUX4 has shown to reduce muscle cell proliferation, differentiation, and fusion. Estrogen seems to play a role on in modifying DUX4 effects on muscle differentiation, which could explain why females are less affected than males. DUX4 regulates a few genes that are involved in RNA quality control, and DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis.[48]
The cellular hypoxia response has been reported in a single study to be the main driver of DUX4-induced muscle cell death. The hypoxia-inducible factors (HIFs) are upregulated by DUX4, possibly causing pathologic signaling leading to cell death.[50]
Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue.[49]
## Diagnosis[edit]
### Genetic testing[edit]
Genetic testing is the gold standard for FSHD diagnosis, as it is the most sensitive and specific test available.[1] Commonly, FSHD1 is tested for first.[1] A shortened D4Z4 array length (EcoRI length of 10 kb to 38 kb) with an adjacent 4qA allele supports FSHD1.[1] If FSHD1 is not present, commonly FSHD2 is tested for next by assessing methylation at 4q35.[1] Low methylation (less than 20%) in the context of a 4qA allele is sufficient for diagnosis.[1] The specific mutation, usually one of various SMCHD1 mutations, can be identified with next-generation sequencing (NGS).[51]
#### Assessing D4Z4 length[edit]
Measuring D4Z4 length is technically challenging due to the D4Z4 repeat array consisting of long, repetitive elements.[52] For example, NGS is not useful for assessing D4Z4 length, because it breaks DNA into fragments before reading them, and it is unclear from which D4Z4 repeat each sequenced fragment came.[7] In 2020, optical mapping became available for measuring D4Z4 array length, which is more precise and less labor intensive than southern blot.[53] Molecular combing is also available for assessing D4Z4 array length.[54] Sometimes 4q or 10q will have a combination of D4Z4 and D4Z4-like repeats due to DNA exchange between 4q and 10q, which can yield erroneous results, requiring more detailed workup.[29]
Restriction enzyme sites on 4q and 10q subtelomeric repeat arrays
Restriction fragment length polymorphism (RFLP) analysis was the first genetic test developed and is still used as of 2020, although it is being phased out by newer methods. It involves dicing the DNA with restriction enzymes and sorting the resulting restriction fragments by size using southern blot. The restriction enzymes EcoRI and BlnI are commonly used. EcoRI isolates the 4q and 10q repeat arrays, and BlnI dices the 10q sequence into small pieces, allowing 4q to be distinguished.[7][29] The EcoRI restriction fragment is composed of three parts: 1) 5.7 kb proximal part, 2) the central, variable size D4Z4 repeat array, and 3) the distal part, usually 1.25 kb.[55] The proximal portion has a sequence of DNA stainable by the probe p13E-11, which is commonly used to visualize the EcoRI fragment during southern blot.[29] The name "p13E-11" reflects that it is a subclone of a DNA sequence designated as cosmid 13E during the human genome project.[56][57] Sometimes D4Z4 repeat array deletions can include the p13E-11 binding site, warranting use of alternate probes.[29] Considering that each D4Z4 repeat is 3.3 kb, and the EcoRI fragment contains 6.9 kb of DNA that is not part of the D4Z4 repeat array, the number of D4Z4 units can be calculated.
D4Z4 repeats = (EcoRI length - 6.9) / 3.3
### Alternative testing[edit]
MRI showing asymmetrical involvement of various muscles in FSHD
When cost is prohibitive or a diagnosis of FSHD is not suspected as the cause of symptoms, patients and doctors may rely on one or more of the following tests, all of which are less sensitive and less specific than genetic testing.[58]
* Creatine kinase (CK) blood level is often ordered when muscle damage is suspected. CK is an enzyme found in muscle, and it is released into the blood when muscles become damaged. However, CK levels are only mildly elevated, or even normal, in FSHD.[1]
* Electromyogram (EMG) measures the electrical activity in the muscle. EMG shows nonspecific signs of muscle damage or irritability.[1]
* Nerve conduction velocity (NCV) measures the how fast signals travel from one part of a nerve to another. The nerve signals are measured with surface electrodes (similar to those used for an electrocardiogram) or needle electrodes.
* Muscle biopsy involves surgical removal of a small piece of muscle, usually from the arm or leg. The biopsy is evaluated with a variety of biochemical tests. Biopsies from FSHD-affected muscles show nonspecific signs, such as presence of white blood cells and variation in muscle fiber size. This test is rarely indicated.[1]
* Muscle MRI is sensitive for detecting muscle damage, even in paucisymptomatic cases. Because of the particular muscle involvement patterns of FSHD, MRI can help differentiate FSHD from other muscle diseases, directing molecular diagnosis.[22][23]
## Management[edit]
As of 2020, there is no cure for FSHD, and no pharmaceuticals have definitively proven effective for altering the disease course. Aerobic exercise has been shown to reduce chronic fatigue and decelerate fatty infiltration of muscle in FSHD.[59][60] The American Academy of Neurology (ANN) recommends that people with FSHD engage in low-intensity aerobic exercise to promote energy levels, muscle health, and bone health.[1] Moderate-intensity strength training appears to do no harm, although it hasn't been shown to be beneficial.[61] Physical therapy can address specific symptoms; there is no standardized protocol for FSHD. Anecdotal reports suggest that appropriately applied kinesiology tape can reduce pain.[62] Occupational therapy can be used for training in activities of daily living (ADLs) and to help adapt to new assistive devices. Cognitive behavioral therapy (CBT) has been shown to reduce chronic fatigue in FSHD, and it also decelerates fatty infiltration of muscle when directed towards increasing daily activity.[59][60]
Braces are often used to address muscle weakness. Scapular bracing can improve scapular positioning, which improves shoulder function, although it is often deemed as ineffective or impractical.[63] Ankle-foot orthoses can improve walking, balance, and quality of life.[64]
Multiple medical tests can be done to detect complications. A dilated eye exam to look for retinal abnormalities is recommended in those newly diagnosed with FSHD. Those with large D4Z4 deletions should be referred to a retinal specialist for yearly exams.[65][1] A hearing test should be done in individuals with early-onset FSHD, prior to starting school, or any other FSHD-affected individual with symptoms of hearing loss.[65][1] Pulmonary function testing (PFT) should be done in those newly diagnosed to establish baseline pulmonary function.[1] PFT should also be done recurrently for those with risks for or symptoms of pulmonary insufficiency.[65][1]
### Surgical intervention[edit]
Various manifestations of facial weakness are amenable to surgical correction. Upper eyelid gold implants have been used for those unable to close their eyes.[66] Drooping lower lip has been addressed with plastic surgery.[67] Select cases of foot drop can be surgically corrected with tendon transfer, such as the Bridle procedure.[68][69][62] Severe scoliosis caused by FSHD can be corrected with spinal fusion.
Several procedures can address scapular winging, the best known being scapulothoracic fusion (arthrodesis), an orthopedic procedure that achieves bony fusion between the scapula and the ribs. It increases shoulder active range of motion, improves shoulder function, decreases pain, and improves cosmetic appearance.[70][71] Active range of motion increases most in the setting of severe scapular winging with an unaffected deltoid muscle;[8] however, passive range of motion decreases. Namely, the patient gains the ability to slowly flex and abduct their shoulders to 90+ degrees, but they lose the ability to "throw" their arm up to a full 180 degrees.[1] A second procedure type is scapulopexy, which involves tethering the scapula to the ribs, vertebrae, or other scapula using tendon grafts, wire, or other means. Unlike the scapulothoracic fusion, no fusion between bones is achieved. Several types of scapulopexy exist, and outcomes are different for each. Compared to scapulothoracic fusions, scapulopexies are considered to be less invasive, but also more susceptible to long-term failure. An alternative treatment, not commonly done, is tendon transfer, which involves rearranging the attachments of muscles to bone. Examples include pectoralis major transfer and the Eden-Lange procedure.[72]
* Scapular winging management
* Kinesiology tape applied across the scapulas.
* A cloth brace to hold the scapulas in retraction to reduce shoulder symptoms, such as collarbone pain.
* Scapula-to-scapula scapulopexy, pre- and post-operation. The scapulas are tethered together with an Achilles tendon graft, holding them in a retracted position. In the right image, the rhomboid major muscles are easily visible.
## Epidemiology[edit]
The prevalence of FSHD ranges from 1 in 8,333 to 1 in 15,000.[1] The Netherlands reports a prevalence of 1 in 8,333, after accounting for the undiagnosed.[73] The prevalence in the United States is commonly quoted as 1 in 15,000.[9]
After genetic testing became possible in 1992, average prevalence was found to be around 1 in 20,000, a large increase compared to before 1992.[74][21][73] However, 1 in 20,000 is likely an underestimation, since many with FSHD have mild symptoms and are never diagnosed, or they are siblings of affected individuals and never seek diagnosis.[73]
Race and ethnicity have not been shown to affect FSHD incidence or severity.[9]
Although the inheritance of FSHD shows no predilection for biological sex, the disease manifests less often in women, and even when it manifests in women, they on average are less severely affected than affected males.[9] Estrogen has been suspected to be a protective factor that accounts for this discrepancy. One study found that estrogen reduced DUX4 activity.[75] However, another study found no association between disease severity and lifetime estrogen exposure in females. The same study found that disease progression wasn't different through periods of hormonal changes, such as menarche, pregnancy, and menopause.[76]
## History[edit]
The first description of a person with FSHD in medical literature appears in an autopsy report by Jean Cruveilhier in 1852.[10][11] In 1868, Duchenne published his seminal work on Duchenne muscular dystrophy, and as part of its differential was a description of FSHD.[77][11] First in 1874, then with a more commonly cited publication in 1884, and again with pictures in 1885, the French physicians Louis Landouzy and Joseph Dejerine published details of the disease, recognizing it as a distinct clinical entity, and thus FSHD is sometimes referred to as Landouzy Dejerine disease.[12][11] In their paper of 1886, Landouzy and Dejerine drew attention to the familial nature of the disorder and mentioned that four generations were affected in the kindred that they had investigated.[78] Formal definition of FSHD's clinical features didn't occur until 1952 when a large Utah family with FSHD was studied. Beginning about 1980 an increasing interest in FSHD led to increased understanding of the great variability in the disease and a growing understanding of the genetic and pathophysiological complexities. By the late 1990s, researchers were finally beginning to understand the regions of chromosome 4 associated with FSHD.[30]
Since the publication of the unifying theory in 2010, researchers continued to refine their understanding of DUX4. With increasing confidence in this work, researchers proposed the first a consensus view in 2014 of the pathophysiology of the disease and potential approaches to therapeutic intervention based on that model.[13]
Over the years, FSHD has, at various times, been referred to as:
* facioscapulohumeral disease[16]
* faciohumeroscapular[citation needed]
* Landouzy-Dejerine disease[16]
* Landouzy-Dejerine syndrome[78]
* Landouzy-Dejerine type of muscular dystrophy[16]
* Erb-Landouzy-Dejerine syndrome[citation needed]
### Chronology of important FSHD-related genetic research[edit]
1884
* Landouzy and Dejerine describe a form of childhood progressive muscle atrophy with a characteristic involvement of facial muscles and distinct from pseudohypertrophic (Duchenne’s MD) and spinal muscle atrophy in adults.[79]
1886
* Landouzy and Dejerine describe progressive muscular atrophy of the scapulo-humeral type.[80]
1950
* Tyler and Stephens study 1249 individuals from a single kindred with FSHD traced to a single ancestor and describe a typical Mendelian inheritance pattern with complete penetrance and highly variable expression. The term facioscapulohumeral dystrophy is introduced.[81]
1982
* Padberg provides the first linkage studies to determine the genetic locus for FSHD in his seminal thesis "Facioscapulohumeral disease."[16]
1987
* The complete sequence of the Dystrophin gene (Duchenne’s MD) is determined.[82]
1991
* The genetic defect in FSHD is linked to a region (4q35) near the tip of the long arm of chromosome 4.[83]
1992
* FSHD, in both familial and de novo cases, is found to be linked to a recombination event that reduces the size of 4q EcoR1 fragment to < 28 kb (50–300 kb normally).[56]
1993
* 4q EcoR1 fragments are found to contain tandem arrangement of multiple 3.3-kb units (D4Z4), and FSHD is associated with the presence of < 11 D4Z4 units.[55]
* A study of seven families with FSHD reveals evidence of genetic heterogeneity in FSHD.[84]
1994
* The heterochromatic structure of 4q35 is recognized as a factor that may affect the expression of FSHD, possibly via position-effect variegation.[85]
* DNA sequencing within D4Z4 units shows they contain an open reading frame corresponding to two homeobox domains, but investigators conclude that D4Z4 is unlikely to code for a functional transcript.[85][86]
1995
* The terms FSHD1A and FSHD1B are introduced to describe 4q-linked and non-4q-linked forms of the disease.[87]
1996
* FSHD Region Gene1 (FRG1) is discovered 100 kb proximal to D4Z4.[88]
1998
* Monozygotic twins with vastly different clinical expression of FSHD are described.[14]
1999
* Complete sequencing of 4q35 D4Z4 units reveals a promoter region located 149 bp 5' from the open reading frame for the two homeobox domains, indicating a gene that encodes a protein of 391 amino acid protein (later corrected to 424 aa[89]), given the name DUX4.[90]
2001
* Investigators assessed the methylation state (heterochromatin is more highly methylated than euchromatin) of DNA in 4q35 D4Z4. An examination of SmaI, MluI, SacII, and EagI restriction fragments from multiple cell types, including skeletal muscle, revealed no evidence for hypomethylation in cells from FSHD1 patients relative to D4Z4 from unaffected control cells or relative to homologous D4Z4 sites on chromosome 10. However, in all instances, D4Z4 from sperm was hypomethylated relative to D4Z4 from somatic tissues.[91]
2002
* A polymorphic segment of 10 kb directly distal to D4Z4 is found to exist in two allelic forms, designated 4qA and 4qB. FSHD1 is associated solely with the 4qA allele.[92]
* Three genes (FRG1, FRG2, ANT1) located in the region just centromeric to D4Z4 on chromosome 4 are found in isolated muscle cells from individuals with FSHD at levels 10 to 60 times greater than normal, showing a linkage between D4Z4 contractions and altered expression of 4q35 genes.[93]
2003
* A further examination of DNA methylation in different 4q35 D4Z4 restriction fragments (BsaAI and FseI) showed significant hypomethylation at both sites for individuals with FSHD1, non-FSHD-expressing gene carriers, and individuals with phenotypic FSHD relative to unaffected controls.[94]
2004
* Contraction of the D4Z4 region on the 4qB allele to < 38 kb does not cause FSHD.[95]
2006
* Transgenic mice overexpressing FRG1 are shown to develop severe myopathy.[96]
2007
* The DUX4 open reading frame is found to have been conserved in the genome of primates for over 100 million years, supporting the likelihood that it encodes a required protein.[97]
* Researchers identify DUX4 mRNA in primary FSHD myoblasts and identify in D4Z4-transfected cells a DUX4 protein, the overexpression of which induces cell death.[89]
* DUX4 mRNA and protein expression are reported to increase in myoblasts from FSHD patients, compared to unaffected controls. Stable DUX4 mRNA is transcribed only from the most distal D4Z4 unit, which uses an intron and a polyadenylation signal provided by the flanking pLAM region. DUX4 protein is identified as a transcription factor, and evidence suggests overexpression of DUX4 is linked to an increase in the target paired-like homeodomain transcription factor 1 (PITX1).[98]
2009
* The terms FSHD1 and FSHD2 are introduced to describe D4Z4-deletion-linked and non-D4Z4-deletion-linked genetic forms, respectively. In FSHD1, hypomethylation is restricted to the short 4q allele, whereas FSHD2 is characterized by hypomethylation of both 4q and both 10q alleles.[99]
* Splicing and cleavage of the terminal (most telomeric) 4q D4Z4 DUX4 transcript in primary myoblasts and fibroblasts from FSHD patients is found to result in the generation of multiple RNAs, including small noncoding RNAs, antisense RNAs and capped mRNAs as new candidates for the pathophysiology of FSHD.[100]
2010
* A unifying genetic model of FSHD is established: D4Z4 contractions only cause FSHD when in the context of a 4qA allele due to stabilization of DUX4 RNA transcript, allowing DUX4 expression.[5] Several organizations including The New York Times highlighted this research[101] (See FSHD Society).
Dr. Francis Collins, who oversaw the first sequencing of the Human Genome with the National Institutes of Health stated:[101]
> “If we were thinking of a collection of the genome’s greatest hits, this would go on the list,”
Daniel Perez, co-founder of the FSHD Society, hailed the new findings saying:[citation needed]
> "This is a long-sought explanation of the exact biological workings of [FSHD]”
The MDA stated that:[citation needed]
> "Now, the hunt is on for which proteins or genetic instructions (RNA) cause the problem for muscle tissue in FSHD."
One of the report's co-authors, Silvère van der Maarel of the University of Leiden, stated that[citation needed]
> “It is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. We finally have a target that we can go after.”
* DUX4 is found actively transcribed in skeletal muscle biopsies and primary myoblasts. FSHD-affected cells produce a full length transcript, DUX4-fl, whereas alternative splicing in unaffected individuals results in the production of a shorter, 3'-truncated transcript (DUX4-s). The low overall expression of both transcripts in muscle is attributed to relatively high expression in a small number of nuclei (~ 1 in 1000). Higher levels of DUX4 expression in human testis (~100 fold higher than skeletal muscle) suggest a developmental role for DUX4 in human development. Higher levels of DUX4-s (vs DUX4-fl) are shown to correlate with a greater degree of DUX-4 H3K9me3-methylation.[4]
2012
* Some instances of FSHD2 are linked to mutations in the SMCHD1 gene on chromosome 18, and a genetic/mechanistic intersection of FSHD1 and FSHD2 is established.[43]
* The prevalence of FSHD-like D4Z4 deletions on permissive alleles is significantly higher than the prevalence of FSHD in the general population, challenging the criteria for molecular diagnosis of FSHD.[102]
* When expressed in primary myoblasts, DUX4-fl acted as a transcriptional activator, producing a > 3-fold change in the expression of 710 genes.[103] A subsequent study using a larger number of samples identified DUX4-fl expression in myogenic cells and muscle tissue from unaffected relatives of FSHD patients, per se, is not sufficient to cause pathology, and that additional modifiers are determinants of disease progression.[104]
* Mechanism proposed of DBE-T (D4Z4 Regulatory Element transcript) leading to de-repression of 4q35 genes.[35]
2013
* Mutations in SMCHD1 are shown to increase the severity of FSHD1.[47]
* Transgenic mice carrying D4Z4 arrays from an FSHD1 allele (with 2.5 D4Z4 units), although lacking an obvious FSHD-like skeletal muscle phenotype, are found to recapitulate important genetic expression patterns and epigenetic features of FSHD.[105]
2014
* DUX4-fl and downstream target genes are expressed in skeletal muscle biopsies and biopsy-derived cells of fetuses with FSHD-like D4Z4 arrays, indicating that molecular markers of FSHD are already expressed during fetal development.[106]
* Researchers "review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease" and articulate how the unifying genetic model and subsequent research represent a "pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology." They describe the consensus mechanism of pathophysiology for FSHD as a "inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle." [13]
### Past pharmaceutical development[edit]
Early drug trials, before the pathogenesis involving DUX4 was discovered, were untargeted and largely unsuccessful.[107] Most compounds were trialed on the basis of increasing muscle mass or decreasing inflammation.[107] Drugs that failed to show efficacy include:
* Prednisone, a steroid, was trialed due to its therapeutic effect in Duchenne muscular dystrophy.[108]
* Oral albuterol, a β2 agonist, although it improved muscle mass and certain measures of strength in clinical trials, it did not improve global strength or function.[109][110][111] Interestingly, after DUX4 was identified as an integral part of FSHD pathophysiology, drug screens showed that β2 agonists reduce DUX4 expression.[112]
* Diltiazem, a calcium channel blocker, was trialed in FSHD on the bases of anecdotal reports of it being beneficial and the theory that calcium dysregulation may play a part in muscle cell death (this was before identification of DUX4 as part of pathophysiology).[113]
* MYO-029 (Stamulumab) was developed to promote muscle growth. It is an antibody that inhibits myostatin, a protein that inhibits the growth of muscle tissue.[114]
* ACE-083 is a TGF-β inhibitor was developed to promote muscle growth.[115]
## Society and culture[edit]
* In the Amazon Video series The Man in the High Castle, Obergruppenführer John Smith's son, Thomas, is diagnosed with Landouzy-Dejerine syndrome.
* In the biography Stuart: A Life Backwards, the protagonist was affected by FSHD.
* Chris Carrino, the radio voice of the Brooklyn Nets, is affected by FSHD. He created the Chris Carrino Foundation for FSHD.
### FSHD Society[edit]
In 1991 the FSHD Society (named "FSH Society" until 2019)[116] was founded by two individuals with FSHD, Daniel Perez and Stephen Jacobsen. The FSHD Society raised funding to provide seed grants for FSHD research, advocated for the field to standardize the name of the disease as facioscapulohumeral muscular dystrophy and FSHD, and co-wrote the MD-CARE Act, passed into law in 2001, which for the first time mandated federal resources, including National Institutes of Health funding, for all muscular dystrophies. The FSHD Society has grown into the world's largest grassroots organization advocating for patient education and scientific and medical research.[117]
### FSHD-EUROPE[edit]
In 2009 the FSHD-EUROPE was founded by European associations.[118]
## Research directions[edit]
Play media
Timelapse of DUX4 being expressed in FSHD muscle cells[119]
Based on the consensus model of pathophysiology, researchers propose four approaches for therapeutic intervention:[13]
1. enhance the epigenetic repression of the D4Z4
2. target the DUX4 mRNA, including altering splicing or polyadenylation;
3. block the activity of the DUX4 protein
4. inhibit the DUX4-induced process, or processes, that leads to pathology.
### Current pharmaceutical development[edit]
* Losmapimod, a selective inhibitor of p38α/β mitogen-activated protein kinases, was identified by Fulcrum Therapeutics as a potent suppressor of DUX4 in vitro.[120] A phase IIb clinical trial started in July 2019 and is expected to end in August 2020.[121]
* Antisense nucleotides directed against DUX4 messenger RNA are in the preclinical stage. Antisense nucleotides have been shown to reduce DUX4 and downregulate DUX4 target genes, with few off-target effects. The current challenge is delivering the nucleotides to the muscle cells; these antisense nucleotides have poor ability to penetrate muscle.[1]
* Gene therapy consisting of microRNAs (miRNAs) directed against DUX4, delivered by viral vectors, are in the preclinical stage. In mouse FSHD models, miRNAs have shown to reduce DUX4, protect against muscle pathology, and prevent loss of grip strength.[1]
### Potential pharmaceutical development[edit]
* Inhibition of the hyaluronic acid (HA) pathway is a potential therapy. One study found that many DUX4-induced molecular pathologies are mediated by HA signaling, and inhibition of HA biosynthesis with 4-methylumbelliferone prevented these molecular pathologies.[122]
* P300 inhibition has shown to inhibit the deleterious effects of DUX4[123]
* BET inhibitors have been shown to reduce DUX4 expression.[112]
* Casein kinase 1 (CK1) inhibitors have been identified by Facio Therapies, a Dutch pharmaceutical company, as repressors of DUX4 expression. Facio Therapies claims that CK1 inhibition leaves myotube fusion intact, unlike BET inhibitors, p38 MAPK inhibitors, and β2 agonists.[124][125]
* Antioxidants could potentially reduce the effects of FSHD. One study found that vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation increased endurance and strength of the quadriceps, but had no significant benefit on walking performance.[126] Further study is warranted.[1]
### Outcome measures[edit]
Ways of measuring the disease are important for assessing the efficacy of drugs in clinical trials.
* Electrical impedance myography is being studied as a way to measure muscle damage.[1]
* Quality of life can be measured with questionnaires, such as the FSHD Health Index.[127][1]
* Muscle MRI is useful for assessment of all the muscles in the body. Muscles can be scored based on the degree of fat infiltration.[1]
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## External links[edit]
* list of clinical trials for FSHD, Clinicaltrials.gov.
* fsh at NIH/UW GeneTests
Classification
D
* ICD-10: G71.0
* ICD-10-CM: G71.02
* ICD-9-CM: 359.1
* OMIM: 158900 158901
* MeSH: D020391
* DiseasesDB: 7247
External resources
* MedlinePlus: 000707
* eMedicine: neuro/133
* Patient UK: Facioscapulohumeral muscular dystrophy
* GeneReviews: Facioscapulohumeral muscular dystrophy
* Orphanet: 269
Wikimedia Commons has media related to FSHD.
* v
* t
* e
Muscular dystrophy
Types
* Congenital
* Dystrophinopathy
* Becker's
* Duchenne
* Distal
* Emery-Dreifuss
* Facioscapulohumeral
* Limb-girdle muscular dystrophy
* Calpainopathy
* Myotonic
* Oculopharyngeal
National/International Organizations
* Muscular Dystrophy Association (USA)
* Muscular Dystrophy Canada
* Myotonic Dystrophy Foundation
* Muskelsvindfonden (Denmark)
National/International Events
* MDA Muscle Walk (USA)
* Labor Day Telethon (defunct; USA/Canada)
* Décrypthon (France)
* Grøn Koncert (Denmark)
Clinical trials
* Stamulumab (MYO-029)
Category
* v
* t
* e
Diseases of muscle, neuromuscular junction, and neuromuscular disease
Neuromuscular-
junction disease
* autoimmune
* Myasthenia gravis
* Lambert–Eaton myasthenic syndrome
* Neuromyotonia
Myopathy
Muscular dystrophy
(DAPC)
AD
* Limb-girdle muscular dystrophy 1
* Oculopharyngeal
* Facioscapulohumeral
* Myotonic
* Distal (most)
AR
* Calpainopathy
* Limb-girdle muscular dystrophy 2
* Congenital
* Fukuyama
* Ullrich
* Walker–Warburg
XR
* dystrophin
* Becker's
* Duchenne
* Emery–Dreifuss
Other structural
* collagen disease
* Bethlem myopathy
* PTP disease
* X-linked MTM
* adaptor protein disease
* BIN1-linked centronuclear myopathy
* cytoskeleton disease
* Nemaline myopathy
* Zaspopathy
Channelopathy
Myotonia
* Myotonia congenita
* Thomsen disease
* Neuromyotonia/Isaacs syndrome
* Paramyotonia congenita
Periodic paralysis
* Hypokalemic
* Thyrotoxic
* Hyperkalemic
Other
* Central core disease
Mitochondrial myopathy
* MELAS
* MERRF
* KSS
* PEO
General
* Inflammatory myopathy
* Congenital myopathy
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Facioscapulohumeral muscular dystrophy | c0238288 | 4,952 | wikipedia | https://en.wikipedia.org/wiki/Facioscapulohumeral_muscular_dystrophy | 2021-01-18T18:44:04 | {"gard": ["9941"], "mesh": ["D020391"], "umls": ["C0238288"], "icd-9": ["359.1"], "wikidata": ["Q1399182"]} |
Kleine-Levin syndrome (KLS) is a rare neurological disorder of unknown origin characterised by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioural disturbances.
## Epidemiology
It affects around 1/500 000 individuals. Patients are mostly male (68-78% of cases) and adolescents (81% of patients), with a mean age of onset of 15 years (range 4-82 years).
## Clinical description
The first episode is triggered by an infection in 72% of patients. Patients experience 7-19 neurological episodes with a duration of 10-13 days/episode and relapses every 3.5 months. One third of patients have episodes lasting longer than one month. Episodes recur more quickly in patients with childhood onset. During episodes, all patients have hypersomnia (with sleep periods lasting 15-21 hours per day), cognitive impairment (apathy, confusion, slowness and amnesia) and a specific feeling of derealization (a dream-like state with altered perception). Less frequently, patients experience hyperphagia (66% of patients), hypersexuality (53% of patients, principally men), anxiety, compulsive or mood disorders and depression (53% of patients, predominantly women). Sleep, vigilance, mood, and eating habits are similar to those of controls between episodes. The median disease course is 8-14 years, but tends to be longer in men, in patients with hypersexuality, and when onset occurs after 20 years of age.
## Etiology
Susceptibility factors include perinatal and developmental problems. Familial clustering occurs in 5% of cases with multiplex families and similar symptoms. An association of KLS with HLA-DQ2 positivity was found in a small series but not replicated in larger independent sample groups. There is no family history of neuropsychiatric disorders. In 10% of cases, KLS arises secondary to various genetic, inflammatory, vascular or paraneoplastic conditions. In these cases the patients are older and have more frequent and longer episodes, but clinical symptoms, disease course and treatment response are similar to those of primary cases.
## Diagnostic methods
Structural brain imaging, cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is noted in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypoarousal with low sleep efficiency. Functional brain imaging (brain scintigraphy or TEP scan) frequently show hypoperfusion/hypometabolism, mainly focused in the thalamic, hypothalamic and frontotemporal associative areas, especially when compared to images obtained between episodes. Reduced metabolism at the parietotemporal junction is marked during episodes, correlates with the intensity of derealization and persists during asymptomatic periods.
## Differential diagnosis
The disorder should mainly be differentiated from epilepsy, migraine with aura, and bipolar disorder.
## Management and treatment
The prevention of episodes is mainly based on lithium therapy, combined with regular sleep-wake habits, as well as avoidance of alcohol intake and infections. Lithium therapy stops episodes in 37% patients (vs. 3.4% if no treatment is given) and reduces the frequency/duration of episodes in 46% of other patients. The treatment is usually given to patients with frequent, prolonged or very severe episodes. Patients with rare (e.g., 1/y) episodes may not need any treatment. Antiepileptics (valproate, carbamazepine, lamotrigine) have marginal benefits. During episodes, patients feel better resting at home under parental supervision, unless psychotic or depressive symptoms require hospitalization. Stimulants are not effective. Trials of IV steroids may help terminate long episodes in around 40% of patients.
## Prognosis
The prognosis is generally good, with most patients presenting less frequent and less severe episodes with advancing age and disappearance of the syndrome around 30-35 y old. During asymptomatic periods, around 20-30% of patients have mild difficulties focusing or remembering. Persistent psychiatric disorders occur in a minority of patients.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Kleine-Levin syndrome | c0206085 | 4,953 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33543 | 2021-01-23T18:29:27 | {"gard": ["3117"], "mesh": ["D017593"], "omim": ["148840"], "umls": ["C0206085"], "icd-10": ["G47.8"]} |
Vitiligo ponctué
SpecialtyDermatology
Vitiligo ponctué is a cutaneous condition, an unusual form of vitiligo, characterized by small confetti-like or tiny, discrete macules that may occur on otherwise normal or unusually darkened skin.[1]
## See also[edit]
* Quadrichrome vitiligo
* List of cutaneous conditions
## References[edit]
1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
* v
* t
* e
Pigmentation disorders/Dyschromia
Hypo-/
leucism
Loss of
melanocytes
Vitiligo
* Quadrichrome vitiligo
* Vitiligo ponctué
Syndromic
* Alezzandrini syndrome
* Vogt–Koyanagi–Harada syndrome
Melanocyte
development
* Piebaldism
* Waardenburg syndrome
* Tietz syndrome
Loss of melanin/
amelanism
Albinism
* Oculocutaneous albinism
* Ocular albinism
Melanosome
transfer
* Hermansky–Pudlak syndrome
* Chédiak–Higashi syndrome
* Griscelli syndrome
* Elejalde syndrome
* Griscelli syndrome type 2
* Griscelli syndrome type 3
Other
* Cross syndrome
* ABCD syndrome
* Albinism–deafness syndrome
* Idiopathic guttate hypomelanosis
* Phylloid hypomelanosis
* Progressive macular hypomelanosis
Leukoderma w/o
hypomelanosis
* Vasospastic macule
* Woronoff's ring
* Nevus anemicus
Ungrouped
* Nevus depigmentosus
* Postinflammatory hypopigmentation
* Pityriasis alba
* Vagabond's leukomelanoderma
* Yemenite deaf-blind hypopigmentation syndrome
* Wende–Bauckus syndrome
Hyper-
Melanin/
Melanosis/
Melanism
Reticulated
* Dermatopathia pigmentosa reticularis
* Pigmentatio reticularis faciei et colli
* Reticulate acropigmentation of Kitamura
* Reticular pigmented anomaly of the flexures
* Naegeli–Franceschetti–Jadassohn syndrome
* Dyskeratosis congenita
* X-linked reticulate pigmentary disorder
* Galli–Galli disease
* Revesz syndrome
Diffuse/
circumscribed
* Lentigo/Lentiginosis: Lentigo simplex
* Liver spot
* Centrofacial lentiginosis
* Generalized lentiginosis
* Inherited patterned lentiginosis in black persons
* Ink spot lentigo
* Lentigo maligna
* Mucosal lentigines
* Partial unilateral lentiginosis
* PUVA lentigines
* Melasma
* Erythema dyschromicum perstans
* Lichen planus pigmentosus
* Café au lait spot
* Poikiloderma (Poikiloderma of Civatte
* Poikiloderma vasculare atrophicans)
* Riehl melanosis
Linear
* Incontinentia pigmenti
* Scratch dermatitis
* Shiitake mushroom dermatitis
Other/
ungrouped
* Acanthosis nigricans
* Freckle
* Familial progressive hyperpigmentation
* Pallister–Killian syndrome
* Periorbital hyperpigmentation
* Photoleukomelanodermatitis of Kobori
* Postinflammatory hyperpigmentation
* Transient neonatal pustular melanosis
Other
pigments
Iron
* Hemochromatosis
* Iron metallic discoloration
* Pigmented purpuric dermatosis
* Schamberg disease
* Majocchi's disease
* Gougerot–Blum syndrome
* Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis
* Lichen aureus
* Angioma serpiginosum
* Hemosiderin hyperpigmentation
Other
metals
* Argyria
* Chrysiasis
* Arsenic poisoning
* Lead poisoning
* Titanium metallic discoloration
Other
* Carotenosis
* Tar melanosis
Dyschromia
* Dyschromatosis symmetrica hereditaria
* Dyschromatosis universalis hereditaria
See also
* Skin color
* Skin whitening
* Tanning
* Sunless
* Tattoo
* removal
* Depigmentation
This dermatology article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Vitiligo ponctué | None | 4,954 | wikipedia | https://en.wikipedia.org/wiki/Vitiligo_ponctu%C3%A9 | 2021-01-18T18:56:43 | {"wikidata": ["Q7937094"]} |
A number sign (#) is used with this entry because of evidence that pyridoxamine 5-prime-phosphate oxidase deficiency (PNPOD) is caused by homozygous or compound heterozygous mutation in the PNPO gene (603287) on chromosome 17q21.
Description
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).
Clinical Features
Brautigam et al. (2002) described twins, born of first-cousin parents, who were born at 29 weeks' gestation and suffered from birth from severe convulsions, myoclonus, rotatory eye movements, sudden clonic contractions, burst suppression electroencephalogram (EEG), hypoglycemia, and acidosis. The patients showed an improvement of the clonic contractions with vitamin B6 supplementation, but died in the third week of life. Biochemical analysis of cerebrospinal fluid and urine suggested aromatic L-amino acid decarboxylase (AADC) deficiency (608643), but molecular analysis excluded genetic defect in the AADC gene (107930). Brautigam et al. (2002) suggested that the epileptic encephalopathy in the twins was in the pathway of vitamin B6 metabolism.
Clayton et al. (2003) presented a boy born at 35 weeks' gestation by cesarean section for fetal distress. His consanguineous parents were of East African Asian origin. Seizures commenced on day 1 and rapidly progressed to status epilepticus. Electroencephalogram showed severe generalized burst suppression. Biochemistry was suggestive of reduced AADC activity; seizures responded dramatically to pyridoxal phosphate (PLP).
In a study of 5 patients, including those of Brautigam et al. (2002) and Clayton et al. (2003), with PNPO deficiency, Mills et al. (2005) reviewed the phenotype. All patients were born prematurely and all but one had low Apgar scores and/or required intubation. Early acidosis was also common. Thus, PNPO deficiency must enter the differential diagnosis of hypoxic-ischemic encephalopathy in a prematurely born infant. Seizures commenced on the first day of life, with EEG showing a burst suppression pattern. Biochemical abnormalities in CSF and urine were as for AADC deficiency with the additional features of raised glycine (in all 5), threonine (4 of 5), taurine (4 of 5), histidine (all 5), and low arginine (3 of 5).
Ruiz et al. (2008) reported a male infant with PNPO deficiency. The mother reported repetitive fetal rhythmic movements 2 weeks before delivery, thought to be related to seizures. At birth he had a faltering cry, hypersalivation with orobuccal rhythmic movements accompanied by myoclonus and marked hyperexcitability requiring intubation and ventilation. EEG showed severe myoclonic epilepsy. Brain imaging at 23, 25, and 35 days showed progressive hypomyelination and global atrophy. Laboratory studies showed anemia, leukopenia, thrombocytopenia, and coagulopathy. Analysis of urinary organic acids, plasma amino acids, and CSF neurotransmitters suggested PNPO deficiency. He died of multiorgan failure due to uncontrollable fungal infection at 48 days of life. Genetic analysis identified a homozygous mutation in the PNPO gene (603287.0004). Prenatal diagnosis using chorionic villus sampling in a subsequent pregnancy identified the same homozygous mutation in the fetus.
Plecko et al. (2014) reported 11 children from 7 families with PNPOD, confirmed by genetic analysis, who had a complete or partial response to pyridoxine treatment. All patients presented in the neonatal period with recurrent myoclonic and tonic jerks accompanied by rolling eye movements and desaturation. EEG showed burst-suppression patterns and/or discontinuous tracings. Ten of 11 patients had pyridoxine administration in the first week of life, and 1 had pyridoxine treatment at age 6 weeks. Pyridoxine led to prompt cessation of seizures in 4 patients, delayed seizure reduction in 2, initial EEG improvement only in 2, and no effect in 2, although 1 of these last patients had remission after subsequent treatment with pyridoxine. Two patients developed status epilepticus after pyridoxine was replaced with PLP. Breakthrough seizures while on pyridoxine were observed in 5 of 9 living patients. Five patients had a favorable overall outcome, 2 had global developmental delay, 2 had severe neurologic sequelae, and 2 died in the absence of continuous pyridoxine treatment.
Ware et al. (2014) reported 2 unrelated boys with PNPOD. Both developed multifocal myoclonic seizures on the first day of life. One of the boys showed hemiclonic seizures, hypertonia, mild encephalopathy, and high-pitched cry until pyridoxine therapy was added on day 7 of life. Breakthrough seizures occurred whenever pyridoxine doses were missed. At age 4 years, the patient had autism spectrum disorder. EEG showed centrotemporal spikes with rare generalized spike-wave bursts. Sequencing of the ALDH7A1 gene was normal, and a trial of monotherapy with pyridoxal 5-prime phosphate (PLP) was commenced, but seizures recurred. After a pathogenic mutation in the PNPO gene was found, the patient had combination therapy with both pyridoxine and PLP, with subsequent reduction of the pyridoxine. At age 7, the patient took only PLP and experienced no significant additional seizures. The second patient had a good initial and subsequent response to monotherapy with high-dose PLP beginning in infancy. At age 21 months, he had moderate global developmental delay and hemiparesis. The report indicated that some patients with PNPOD can respond to pyridoxine treatment.
Inheritance
The transmission pattern of PNPOD in the families reported by Plecko et al. (2014) was consistent with autosomal recessive inheritance.
Molecular Genetics
Among 5 patients in 3 families with neonatal epileptic encephalopathy, Mills et al. (2005) found evidence in cerebrospinal fluid and urine for reduced activity of aromatic L-amino acid decarboxylase (AADC; 107930) and other PLP-dependent enzymes. Seizures ceased with the administration of PLP, having been resistant to treatment with pyridoxine, suggesting a defect of pyridox(am)ine 5-prime-phosphate oxidase (PNPO; 603287). Sequencing of the PNPO gene identified homozygous missense, splice site, and stop codon mutations. Expression studies in Chinese hamster ovary cells showed that the splice site (IVS3-1G-A; 603287.0002) and stop codon (X262Q; 603287.0003) mutations were null activity mutations and that the missense mutation (R229W; 603287.0001) markedly reduced pyridox(am)ine phosphate oxidase activity. The authors suggested that maintenance of optimal PLP levels in the brain may be important in many neurologic disorders in which neurotransmitter metabolism is disturbed (either as a primary or as a secondary phenomenon). Only one infant, treated with PLP, survived the newborn period, but exhibited seizures, dystonic spasms, microcephaly, and severe developmental delay at 2 years of age.
In 11 patients from 7 unrelated families with PNPOD, Plecko et al. (2014) identified 3 different biallelic mutations in the PNPO gene; 6 of the families carried the same homozygous missense mutation (R225H; 603287.0005). In vitro functional expression studies in CHO cells showed that the R225H mutant protein had no detectable enzyme activity. Most of the patients had a partial or even complete response to pyridoxine treatment. The 6 families derived from the former Yugoslavia.
In 2 unrelated boys with PNPOD, Ware et al. (2014) identified 2 different homozygous missense mutations in the PNPO gene (603287.0005 and 603287.0006). Functional studies of the variants were not performed.
INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly, progressive Eyes \- Eye movement abnormalities ABDOMEN Gastrointestinal \- Feeding problems NEUROLOGIC Central Nervous System \- Neonatal epileptic encephalopathy (NEE) \- Global developmental delay, variable severity \- Burst suppression on EEG \- Seizures \- Myoclonus \- Partial response to pyridoxine \- Response to pyridoxal phosphate \- Hypotonia, truncal \- Hypertonia \- Unsteady gait METABOLIC FEATURES \- Metabolic acidosis HEMATOLOGY \- Anemia PRENATAL MANIFESTATIONS Delivery \- Preterm delivery \- Low APGAR scores LABORATORY ABNORMALITIES \- Increased blood lactate \- Hypoglycemia \- Normal to increased plasma glycine \- Normal to increased plasma threonine \- Decreased plasma arginine \- Increased urine vanillactic acid (VLA) \- Decreased CSF homovanillic acid (HVA) \- Decreased CSF 5-hydroxyindoleacetic acid (5HIAA) \- Increased CSF 3-methoxytyrosine (3-MT) \- Increased CSF glycine \- Increased CSF threonine \- Increased CSF taurine \- Increased CSF histidine \- Decreased CSF arginine \- Decreased CSF pyridoxal 5-prime-phosphate (PLP) MISCELLANEOUS \- Onset 0-12 hours after birth \- Variable features and severity MOLECULAR BASIS \- Caused by mutation in the pyridoxamine 5-prime-phosphate oxidase gene (PNPO, 603287.0001 ) ▲ Close
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY | c1864723 | 4,955 | omim | https://www.omim.org/entry/610090 | 2019-09-22T16:05:11 | {"doid": ["0111329"], "mesh": ["C566449"], "omim": ["610090"], "orphanet": ["79096"], "synonyms": ["Alternative titles", "PNPO DEFICIENCY", "SEIZURES, PYRIDOXINE-RESISTANT, PLP-SENSITIVE", "EPILEPTIC ENCEPHALOPATHY, NEONATAL, PNPO-RELATED"]} |
Folic acid plays an important role in normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (see 601634), as well as for vascular disease of later life. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, Mitchell et al. (1997) evaluated red blood cell folate levels in 440 pairs of monozygotic twins in 331 pairs of dizygotic twins. The data were best described by a model in which 46% of the variance in RBC folate was due to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% was due to random environmental effects. Moreover, the correlations for RBC folate in MZ cotwins (r = 0.46) and in repeat measures from the same individual (r = 0.51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. Mitchell et al. (1997) suggested that specific genes that influence RBC folate level in the general population should be sought. Such genes might be useful in identifying individuals at an increased risk for neural tube defects and other folate-related diseases.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| FOLATE LEVEL IN ERYTHROCYTES | c1866295 | 4,956 | omim | https://www.omim.org/entry/601775 | 2019-09-22T16:14:21 | {"omim": ["601775"]} |
Cat eye syndrome (CES) is a rare chromosomal disorder with a highly variable clinical presentation. Most patients have multiple malformations affecting the eyes (iris coloboma), ears (preauricular pits and/or tags), anal region (anal atresia), heart and kidneys. Intellectual disability is usually mild or borderline normal.
## Epidemiology
CES has an estimated prevalence of 1/50,000 to 1/150,000 live births. Males and females appear to be affected equally.
## Clinical description
CES covers a very wide clinical spectrum in terms of features and severity, ranging from a normal phenotype to severe multisystemic disease. The 3 main visible characteristics are preauricular anomalies, anal atresia, and iris coloboma but none are found consistently. Preauricular skin tags and/or pits are the most consistent feature. The typical eye anomaly is absent in up to 50% of patients. Eye coloboma may involve the iris, the choroid and/or the retina. Less frequently, unilateral microphtalmia, aniridia, cornea clouding, cataract and/or Duane anomaly are observed. In addition to preauricular tags and/or pits, the external ears may be low-set and severely reduced with possible atresia of the external ear canal. Characteristic facial features are down-slanting palpebral fissures, inner epicanthic folds, hypertelorism, flat nasal bridge, and small mandible. Cleft lip/palate (see this term) is sometimes observed. In some individuals, the anal canal is narrow or absent with a fistula from the rectum into an abnormal location (the bladder, vagina or perineum). The most frequently reported congenital heart defect is congenital total pulmonary venous return anomaly and, less frequently, tetralogy of Fallot (see these terms). Congenital kidney abnormalities include absence of one or both kidneys, hydronephrosis, supernumerary kidneys, and/or renal hypoplasia. Skeletal abnormalities include spinal defects and limb malformations. Possible gastrointestinal malformations are biliary atresia, intestinal malrotation and/or Hirschsprung disease (see this term). Other variable features include hernias, cryptorchidism and hypospadias in males. Rarer malformations may affect almost every organ. Most patients have mild intellectual disability (although some moderate to severe) but a few have normal cognitive development. Short stature with growth hormone deficiency is possible in some cases.
## Etiology
Most patients harbor a small supernumerary bisatellited marker chromosome (sSMC) that results in partial tetrasomy of 22pter-22q11. In one third of cases, this extra chromosome is present in a mosaic state. Other cytogenetic anomalies have been rarely reported, including partial trisomy of chromosome 22 and intrachromosomal triplication of the 22q11 region.
## Diagnostic methods
The diagnosis, suspected on the basis of clinical manifestations, is based on cytogenetic testing showing the presence of extra material derived from chromosome 22q11. Fluorescence in situ hybridization (FISH) with specific probes is needed to detect a low level mosaicism.
## Differential diagnosis
Differential diagnosis includes other chromosomal disorders with overlapping phenotypes such as CHARGE syndrome and VACTERL/VATER association (see these terms).
## Antenatal diagnosis
Prenatal diagnosis is possible through karyotyping and FISH analysis of prenatal samples.
## Genetic counseling
The extra chromosome usually arises de novo.
## Management and treatment
Multidisciplinary management is necessary and depends on the specific symptoms that are apparent in each patient. Surgical correction is necessary for anal atresia and severe cardiac malformations. Bacterial infections should be anticipated and treated vigorously. Patients should be screened for visual and hearing impairment. Early intervention with educational support can be beneficial.
## Prognosis
Some patients die from severe malformations in early infancy. Otherwise, life expectancy is generally not significantly reduced.
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
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*[E2]: estradiol
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*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
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| Cat-eye syndrome | c0265493 | 4,957 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=195 | 2021-01-23T18:43:34 | {"gard": ["26"], "mesh": ["C535918"], "omim": ["115470"], "umls": ["C0265493"], "icd-10": ["Q92.8"], "synonyms": ["CES"]} |
A number sign (#) is used with this entry because of evidence that Prader-Willi syndrome (PWS) is in effect a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene (182279), the NDN gene (602117), and possibly other genes within the chromosome region 15q11-q13.
Description
Prader-Willi syndrome is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet. It can be considered to be an autosomal dominant disorder and is caused by deletion or disruption of a gene or several genes on the proximal long arm of the paternal chromosome 15 or maternal uniparental disomy 15, because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting. Horsthemke and Wagstaff (2008) provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome (105830) region.
See also the chromosome 15q11-q13 duplication syndrome (608636), which shows overlapping clinical features.
Clinical Features
The original paper by Prader et al. (1956) described the full clinical picture.
### Prenatal
Mothers with prior experience of normal pregnancies almost without exception report distinctly delayed onset and reduced fetal activity during the pregnancies involving Prader-Willi children. Obstetricians often fail to detect diminished fetal activity with ultrasound investigation. When reduced fetal activity is observed, prenatal cytogenetic examination produces normal results because cytogeneticists were not instructed to look for the characteristic chromosomal changes of PWS (Schinzel, 1986). Alert clinicians should refer CVS material from pregnancies with fetuses that demonstrate poor activity for molecular diagnosis of the syndrome (see below). Other candidates for prenatal diagnosis of PWS are fetuses of pregnancies in which trisomy 15 or mosaic trisomy 15 was determined from CVS, and in which subsequent amniocyte or fetal blood examinations disclosed a normal diploid karyotype. Theoretically, one-third of trisomy 15 fetuses initially with 2 maternal chromosomes 15 and 1 paternal chromosome 15 should give rise to Prader-Willi syndrome patients exhibiting maternal uniparental disomy (Cassidy et al., 1992; Purvis-Smith et al., 1992; Hall, 1992).
### Perinatal
Neonates are profoundly hypotonic, which often causes asphyxia. In addition, there is mild prenatal growth retardation with a mean birth weight of about 6 lbs (2.8 kg) at term, hyporeflexia, poor feeding due to diminished swallowing and sucking reflexes, which in many cases necessitates gavage feeding for about 3 to 4 months. Cryptorchidism occurs with hypoplastic penis and scrotum in boys and hypoplastic labiae in girls (Stephenson, 1980). Chitayat et al. (1989) commented on the normal size of hands and feet at birth and in the first year of life.
Miller et al. (1999) described 6 newborns evaluated for hypotonia who were later diagnosed with Prader-Willi syndrome. These newborns lacked the classic neonatal features of the syndrome (peculiar cry, characteristic craniofacial features, and clinical evidence of hypogonadism). The authors suggested that specific genetic testing for PWS be considered for all neonates with undiagnosed central hypotonia even in the absence of the other major features of the syndrome.
Oiglane-Shlik et al. (2006) studied 5 newborns with hypotonia, poor arousal, weak or absent cry, and no interest in food, in whom PWS was confirmed by the abnormal methylation test. All had a distinctive facial appearance, with high prominent forehead, narrow bifrontal diameter, downturned corners of the mouth, micrognathia, and dysplastic ears. Three neonates had a high-arched palate, and 4 had arachnodactyly. In the first few days of life, 4 of the 5 patients demonstrated a peculiar position of the hands, with the thumb constantly adducted over the index and middle finger. All 5 patients had transient bradycardia, thermolability, and acrocyanosis; and 3 also showed marked skin mottling, as previously reported by Chitayat et al. (1989).
### Infancy and Childhood
Feeding difficulties generally improve by the age of 6 months. From 12 to 18 months onward, uncontrollable hyperphagia causes major somatic as well as psychologic problems. Diminished growth is observed in the majority of infants (Butler and Meaney, 1987). Small hands with delicate and tapering fingers and small feet (acromicria) are seen in most infants and adolescents; hand and foot sizes correlate well with length, but not with age, and foot size tends to be lower than hand size. However, patients of normal height tend to have normally sized hands (Hudgins and Cassidy, 1991). The face is characterized by a narrow bifrontal diameter, almond-shaped eyes (often in mild upslanted position), strabismus, full cheeks, and diminished mimic activity due to muscular hypotonia. Plethoric obesity becomes the most striking feature. From the age of about 6 years onward, many children present scars from scratching due to itching, and later, almost all show abdominal striae.
Depigmentation relative to the familial background is a feature in about three-quarters of the patients. Butler (1989), Hittner et al. (1982), and several authors remarked that this sign is confined to cases with deletions and absent in those with maternal disomy 15. Phelan et al. (1988) presented a black female child with oculocutaneous albinism, PWS, and an interstitial deletion of 15q11.2. Patients with classic albinism (203100) have misrouting of optic fibers, with fibers from 20 degrees or more of the temporal retina crossing at the chiasm instead of projecting to the ipsilateral hemisphere. Misrouting can result in strabismus and nystagmus. Because patients with PWS have hypopigmentation and strabismus, Creel et al. (1986) studied 6 patients, selected for a history of strabismus, with pattern-onset visual evoked potentials on binocular and monocular stimulation. Of the 4 with hypopigmentation, 3 had abnormal evoked potentials indistinguishable from those recorded in albinos. The 2 with normal pigmentation had normal responses. Wiesner et al. (1987) found that 14 of 29 patients with PWS had ocular hypopigmentation. There was possible correlation between hypopigmentation and a deletion of 15q.
MacMillan et al. (1972) described 2 unrelated girls with the features of PWS who additionally showed precocious puberty. They suggested that this is a variant and that a hypothalamic disturbance is responsible for this disorder. Hall and Smith (1972) pointed out narrow bifrontal cranial diameter as a feature. Hall (1985) pointed to a possibly increased risk of leukemia in PWS.
A frequent feature generally overlooked is thick saliva at the edges of the mouth. Patients tend to be relatively insensitive to pain (including that caused by obtaining blood samples)(Prader, 1991).
Eiholzer et al. (1999) presented data on body composition and leptin (164160) levels of 13 young, still underweight children and 10 older overweight children with Prader-Willi syndrome. Both groups showed elevated skinfold standard deviation scores for body mass index and elevated body mass index-adjusted leptin levels, suggesting relatively increased body fat even in underweight children. Leptin production appeared to be intact. The authors concluded that body composition in PWS is already disturbed in infancy, long before the development of obesity.
Van Mil et al. (2001) compared body composition in 17 patients with PWS with 17 obese control patients matched for gender and bone age. In children with PWS, adiposity was associated with reduced fat-free mass, and extracellular-to-intracellular water ratio was increased. Both findings are related to growth hormone (GH; 139250) function and physical activity. Bone mineral density, especially in the limbs, tends to be reduced in patients with PWS and is related to growth hormone function.
Gunay-Aygun et al. (2001) reviewed the sensitivity of PWS diagnostic criteria and proposed revised criteria for DNA testing. From birth to 2 years any infant with hypotonia and poor suck should have DNA testing for the PWS deletion. From age 2 to 6 years any child with hypotonia and a history of poor suck and global developmental delay should have DNA testing. From 6 years to 12 years any child with history of hypotonia and poor suck, global developmental delay, and excessive eating with central obesity should be tested for PWS.
### Adolescence and Adulthood
Greenswag (1987) reported on a survey of 232 adults with PWS, ranging in age from 16 to 64 years. Of 106 patients whose chromosomes were analyzed, 54 had an abnormality of chromosome 15, primarily a deletion. Physical characteristics, health problems, intelligence, psychosocial adjustment, and impact on the family were reviewed. Emotional lability, poor gross motor skills, cognitive impairment, and insatiable hunger were especially remarkable features.
Olander et al. (2000) pointed to the occurrence of 3 PWS phenotypes: patients with paternal deletions have the typical PWS phenotype; patients with maternal UPD have a slightly milder phenotype with better cognitive function; and patients with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. They described a patient with the severe phenotype with maternal isodisomy rather than the more common maternal heterodisomy. They concluded that the more severe PWS phenotype was due to trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes.
In contrast to infants, adults invariably are small compared to their family members (Butler and Meaney, 1987). Due to high caloric intake, alimentary diabetes frequently sets in during or soon after the period of puberty. Puberty itself is diminished in PWS patients of both sexes. Adolescents and young adults often require digitalization because of cardiac insufficiency; however, it has been shown that substantial weight reduction relieves the need of cardiac therapy. Any attempt to reduce food intake in these adolescents often leads to serious psychologic and behavioral problems, and in some children, the situation in their home environment becomes intolerable (Curfs et al., 1991). Patients rarely survive beyond 25 to 30 years of age, the cause of death being diabetes and cardiac failure. However, if strict weight control is achieved, both diabetes and cardiac failure are greatly reduced and survival is either not or only mildly reduced. Johnsen et al. (1967) studied 7 mentally retarded patients, aged 4 to 19 years. Studies showed that fat synthesis from acetate during fasting was 10 times greater in patients than in unaffected sibs, and that hormone-stimulated lipolysis was depressed. These workers suggested that the condition is comparable to the genetic obese-hyperglycemic mouse. Since during fasting substrate continues to be used for new fat and lipolysis is deficient, survival depends on a continuous supply of exogenous calories. The abundant fat, muscle hypotonia, and small feet and hands are exactly the opposite of the sparse fat, muscle hypertrophy, and large hands and feet in Seip syndrome (269700).
Hoybye et al. (2002) studied the clinical, genetic, endocrinologic, and metabolic findings in 10 male and 9 female adult PWS patients (mean age, 25 years). The PWS karyotype was demonstrated in 13 patients. The mean BMI was 35.6 kg/m2, and total body fat was increased. Two-thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency. Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9, and modest dyslipidemia in 7. IGF-binding protein-1 (146730) correlated negatively with insulin (176730) levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, BMI, waist-to-hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a) (152200), which was significantly higher in the group with the negative karyotype. Hoybye et al. (2002) concluded that the risk factors found predicting cardiovascular disease were secondary to GHD and emphasized the importance of evaluating treatment of GHD in adults with PWS.
Curfs et al. (1991) concluded that PWS patients score better on visual motor discrimination skills than on auditory verbal processing skills.
Wise et al. (1991) described 5 patients with PWS who experienced recurrent hyperthermia in infancy. On the basis of these patients and other reports of abnormal temperature regulation in PWS patients, particularly hypothermia with exposure to cold, they concluded that defects in temperature regulation may be a manifestation of hypothalamic dysfunction in PWS. On the other hand, Cassidy and McKillop (1991) concluded on the basis of a survey that clinically significant abnormal temperature control is not a common finding in this disorder. Similarly, Williams et al. (1994) concluded on the basis of a survey that the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F were not unique to PWS but can occur in any neurodevelopmentally handicapped individual and do not necessarily reflect syndrome-specific hypothalamic abnormalities.
Individuals with Prader-Willi syndrome manifest severe skin picking behavior. Bhargava et al. (1996) described 3 adolescent patients in whom an extension of this behavior to rectal picking resulted in significant lower gastrointestinal bleeding and anal rectal disease. Recognition of this behavior is important to avoid misdiagnosing inflammatory bowel disease in PWS patients.
Wharton et al. (1997) presented 6 patients with PWS with dramatic acute gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy was performed in 2 cases; in 1, gastrectomy was subtotal and distal, whereas in the other, gastrectomy was combined with partial duodenectomy and pancreatectomy. All specimens showed ischemic gastroenteritis. There was diffuse mucosal infarction with multifocal transmural necrosis.
From a study of 10 African Americans with PWS, Hudgins et al. (1998) pointed out that the clinical features differ from those of white patients. Growth is less affected, hand and foot lengths usually are normal, and the facies are atypical; as a result, PWS may be underdiagnosed in this population.
Lindgren et al. (2000) studied the microstructure of eating behavior in patients with PWS and compared it with that of members of obese and normal weight control groups of the same age. PWS patients had a mean age of 10 +/- 4 years, while the control groups were 12 +/- 3 years (normal weight) and 12 +/- 4 years (obese). Subjects with PWS had a longer duration of eating rate compared with members of both obese and normal weight groups. In subjects with PWS, 56% of the eating curves were non-decelerating, compared with 10% of the normal weight group and 30% of the obese group. Lindgren et al. (2000) concluded that the eating behavior found in subjects with PWS might be due to decreased satiation rather than increased hunger.
Nagai et al. (2000) reported standard growth curves for height and weight among Japanese children with Prader-Willi syndrome. No difference in height was seen between those with and those without chromosome 15q deletion.
Cassidy et al. (1997) personally examined and studied using molecular techniques 54 individuals with PWS to determine whether there are phenotypic differences between patients with the syndrome due to deletion (present in 37) or uniparental disomy (present in 17) as the mechanism. Previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the 2 groups, those with UPD were less likely to have a 'typical' facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average.
Gunay-Aygun et al. (2001) proposed new revised criteria for DNA testing for individuals in adolescence and adulthood. Anyone with cognitive impairment (usually mild mental retardation), excessive eating with central obesity, and hypothalamic hypogonadism, and/or typical behaviors, including temper tantrums and obsessive-compulsive features, should be referred for DNA testing for PWS.
Among 25 patients with PWS aged 18 years or older, Boer et al. (2002) found that 7 (28%) had severe affective disorder with psychotic features, with a mean age of onset of 26 years. The 7 affected persons, all aged 28 years or older, included all 5 with disomies of chromosome 15, 1 with a deletion in this chromosome, and 1 with an imprinting center mutation in the same chromosome. They postulated that in PWS, an abnormal pattern of expression of a sex-specific imprinted gene on chromosome 15 is associated with psychotic illness in early adult life.
Vogels et al. (2004) detailed the psychopathologic manifestations of 6 adults with PWS and a history of psychotic episodes. Characteristics of the psychotic disorder included early and acute onset, polymorphous and shifting symptoms, psychiatric hospitalization along with precipitating stress factors, and a prodromal phase of physiologic symptoms.
To evaluate the risk of cancer in patients with PWS, Davies et al. (2003) conducted a retrospective questionnaire survey of its occurrence among patients registered with the PWS Association compared with cases in the general US population based on the SEER program. The median age of 1,024 PWS patients was 19.0 years (range, 0.1-63 years) with 2 older than age 50. The ratio of observed (8) to expected (4.8) cancers was 1.67 (p = 0.1610; 95% CI = 0.72-3.28). Three myeloid leukemias were confirmed, resulting in a ratio of observed to expected of 40.18 (p = 0.0001; 95% CI = 8.0-117). The authors speculated that a gene within the 15q11-q13 region may be involved in the biology of myeloid leukemia or that secondary manifestations of PWS, such as obesity, may be associated with an increased risk of certain cancers.
Wey et al. (2005) described a woman with features consistent with PWS due to a mosaic imprinting defect. Three independent assays revealed a reduced proportion of nonmethylated SNURF-SNRPN alleles in peripheral blood DNA. Microsatellite analysis and FISH revealed apparently normal chromosomes 15 of biparental origin. Wey et al. (2005) estimated that approximately 50% of the patient's blood cells had an imprinting defect. Apart from a rather normal facial appearance, the proband had typical features of PWS in terms of truncal obesity, small hands with tapered fingers, and small feet. Operation for strabismus had been performed. When evaluated at 21 years of age, she presented with the major signs of PWS, except for the relatively normal facial appearance. Wey et al. (2005) suggested that the patient, although presenting with atypical PWS features at birth and in infancy, had progressively acquired more pronounced PWS features during childhood and adolescence.
Sinnema et al. (2012) reported the clinical features of 12 patients over the age of 50 years with genetically confirmed PWS. Eleven patients lived in a facility, and 1 lived with his elderly mother. Half of the patients had diabetes mellitus with an average age at diagnosis of 41.6 years. Three patients had hypertension, 3 had a history of stroke, 6 had a history of fractures, 10 had foot problems, 5 had scoliosis, 9 had edema, and 6 had erysipelas. Older patients had significantly lower functioning, particularly in activities of daily living, compared to younger control patients, and the decline began around age 40. All 8 patients with maternal uniparental disomy used psychotropic medications, 7 of whom had a psychiatric disorder. None of the 4 patients with a paternal deletion had a psychiatric illness. Sinnema et al. (2012) suggested that age-associated medical problems may be exacerbated by temperature instability, decreased mobility, and high pain threshold in PWS. Overall, the constellation of features suggested premature aging in PWS, which may also result from abnormalities in sex hormone levels. Sinnema et al. (2012) noted that the life expectancy of individuals with PWS had increased in recent years, and that these individuals have specific medical and social needs as they age.
To examine survival trends and risk factors in PWS, Manzardo et al. (2018) performed a survival analysis of the Prader-Willi Syndrome Association's 40-year mortality syndrome-specific database of 486 deaths. They compared 331 deaths that occurred between the years 2000 and 2015 (Recent) with 94 deaths that occurred before 2000 (Early). The risk for all-cause mortality in PWS was 1.5 (95% CI = 1.2-1.9) times higher for the Early than for the Recent cohort, reflected in female cardiac failure (hazard ratio (HR) = 1.8; 95% CI = 1.3-2.6), pulmonary embolism (HR = 6.1; 95% CI = 1.7-22), and gastrointestinal-related (HR = 3.2; 95% CI = 1.1-7.4) causes. Accidental deaths in males increased in the Recent cohort (HR = 5.7; 95% CI = 1.2-27.1), possibly due to enhanced weight management and mobility. Risk of death from respiratory failure was unchanged.
Butler et al. (2017) reviewed causes of death in Prader-Willi syndrome using the US Prader-Willi Syndrome Association 40-year mortality survey ranging from 1973 to 2015. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 +/- 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype.
### Prader-Willi-like Syndrome Associated with Chromosome 6
Fryns et al. (1986) described an 8-month-old girl with a de novo 5q/6q autosomal translocation resulting in loss of the distal part of the long arm of chromosome 6 (6q23.3-qter). Clinical manifestations included abnormal facies with broad, flat nasal bridge, small nose with broad tip, bilateral epicanthus, narrow palpebral fissures, small anteverted ears, and small mouth. Other features included truncal obesity, short hands and feet, and delayed psychomotor development. Prader-Willi syndrome was suspected initially.
Villa et al. (1995) reported a 23-month-old boy with mental and psychomotor delay, minor craniofacial abnormalities, and obesity who had a de novo interstitial deletion of chromosome 6q16.2-q21. The authors noted the phenotypic similarities to Prader-Willi syndrome. In a boy with clinical features mimicking Prader-Willi syndrome, but with a normal chromosome 15, Stein et al. (1996) found a de novo interstitial deletion of 6q22.2-q23.1. The boy showed delayed development, hypotonia, seizures, hyperactive behavior, a bicuspid aortic valve with mild aortic stenosis, small hands and feet, hypogonadism, and obesity since about 4 years of age. In a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, small mouth, and obesity, Smith et al. (1999) found a duplication of 6q24.3-q27. The authors noted that the phenotype showed similarities to Prader-Willi syndrome.
As reviewed by Gilhuis et al. (2000), several obese patients with cytogenetic alterations in the same region of 6q had been reported; all had in common some clinical features, including obesity, hypotonia, and developmental delays, resembling Prader-Willi syndrome. However, their behavior, facial features, and additional neurologic abnormalities, as well as a lack of cytogenetic changes or imprinting mutations on chromosome 15, clearly distinguished this PWS-like phenotype from PWS patients.
Holder et al. (2000) studied a girl with early-onset obesity and a balanced translocation between 1p22.1 and 6q16.2. At 67 months of age she weighed 47.5 kg (+9.3 SD) and was 127.2 cm tall (+3.2 SD); her weight for height was +6.3 SD. The child displayed an aggressive, voracious appetite, and the obesity was thought to be due to high intake, since measured energy expenditure was normal. However, the authors noted that apart from her obesity, there were no features suggestive of PWS. Genetic analysis of the region on chromosome 6 showed that the translocation disrupted the SIM1 gene (603128). Holder et al. (2000) hypothesized that haploinsufficiency of the SIM1 gene may be responsible for the obesity. In a boy with a Prader-Willi-like phenotype, Faivre et al. (2002) identified a deletion of chromosome 6q16.1-q21. Intrauterine growth retardation, oligohydramnios, and a left clubfoot were noted during the third trimester of pregnancy. Later, generalized obesity, slightly dysmorphic facial features, small hands and feet, clumsiness, and mental retardation were observed. Molecular analysis showed that the deletion was paternal in origin and resulted in a deletion of the SIM1 gene.
Other Features
Miller et al. (2007) evaluated 3-dimensional brain MRI scans of 20 individuals with PWS aged 3 months to 39 years. Intracranial morphologic abnormalities included ventriculomegaly (100%), decreased volume of the parietal-occipital lobe (50%), sylvian fissure polymicrogyria (60%), and incomplete insular closure (65%).
Fan et al. (2009) found that 10 of 56 PWS patients had seizures, 9 of whom had generalized seizures attributable to PWS. The remaining patient was born with intraventricular hemorrhage and had focal epileptic discharges, which was thought to be responsible for the seizures. Eight of the 9 with PWS-related seizures had a 15q11-q13 deletion, suggesting that decreased inhibitory effects of the GABA receptor cluster in this region may play a role in epileptogenesis. Six additional patients of the 56 had paroxysmal events such as staring spells, tremor spells, and collapsing spells.
Inheritance
Familial inheritance of PWS has been described frequently. Gabilan (1962) reported a family with affected brother and sister, as well as a second in which the parents of the proband were first cousins, but his patients were not entirely typical.
Jancar (1971) reported familial incidence. Hall and Smith (1972) reported 2 affected male maternal first cousins. One was of normal stature and intelligence. DeFraites et al. (1975) observed 5 cases in 3 sibships of an inbred Louisiana Acadian kindred. Clarren and Smith (1977) reported affected sibs and affected first cousins. They found a recurrence risk of 1.6% in sibs of probands.
It is clear that chromosomal mechanisms are principally responsible for PWS and that the syndrome is caused by lack of the paternal segment 15q11.2-q12. Basically, there are 2 mechanisms by which such a loss can occur: either through deletion of just the paternal 'critical' segment or through loss of the entire paternal chromosome 15 with presence of 2 maternal homologs (uniparental maternal disomy). The opposite, i.e., maternal deletion or paternal uniparental disomy, causes another characteristic phenotype, the Angelman syndrome (AS; 105830). This indicates that both parental chromosomes are differentially imprinted, and that both are necessary for normal embryonic development.
Ming et al. (2000) described 2 cousins with Prader-Willi syndrome resulting from a submicroscopic deletion detected by fluorescence in situ hybridization. Although the karyotype was cytogenetically normal, FISH analysis showed a submicroscopic deletion of SNRPN (182279), but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3 (137192). The affected female and male were offspring of brothers who carried the deletion but were clinically normal, as were also 2 paternal aunts of the probands who likewise had the deletion. The grandmother was deceased and not available for study; the grandfather did not show deletion of SNRPN. DNA methylation analysis of D15S63 was consistent with an abnormality of the imprinting center associated with PWS. Ming et al. (2000) referred to this as grandmatrilineal inheritance, which occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In such an instance, PWS does not become evident as long as the deletion is passed through the female line.
### Occurrence of the Prader-Willi Syndrome
The vast majority of PWS cases occur sporadically. These instances include virtually all interstitial deletions, the large majority of de novo unbalanced translocations, all instances of maternal uniparental disomy with normal karyotype or with a de novo rearrangement involving chromosome 15, and almost all cases of maternal uniparental disomy with a familial rearrangement involving chromosome 15. There is no parental age effect whatsoever in the deletion cases.
For full discussion on the mode of inheritance, see Cytogenetics, below.
### Recurrence Risk
Monozygotic twins are concordantly affected. However, affected sibs and cousins have repeatedly been reported, and even if a publication bias is considered, their incidence is obviously higher than the estimated incidence in the population of about 1 in 25,000 would suggest. Clarren and Smith (1977) reported affected sibs and first cousins. They found a recurrence risk of 1.6% in sibs of probands. Cassidy (1987) stated that the Prader-Willi Syndrome Association maintained a registry of PWS individuals which, as of December 1986, contained 1,595 names of affected persons in the United States and Canada. While in some of these cases the diagnosis had not been fully confirmed, in only 1 family, that reported by Lubinsky et al. (1987), was there a well-documented recurrence. Thus, it is reasonable to assume that the recurrence risk for PWS is less than 1 in 1,000 and that such recurrence is not likely to occur when a 15q interstitial deletion is identified in the proband. (As pointed out by Kennerknecht (1992), the membership of the PWS association is not limited to affected persons; 'two thirds are families and one third professionals'.)
Ledbetter et al. (1987) summarized a scientific conference on PWS. Of 195 cases studied by high resolution cytogenetic methods, deletion of chromosome 15 was detected in 116 (59.5%); other chromosome 15 abnormalities were found in 7 additional cases (3.6%). It was suggested that the recurrence risk may be as low as 1 in 1,000.
Kennerknecht (1992) used the diagnostic criteria given by Cassidy (1987) to evaluate reported cases of PWS with a view to estimating recurrence risk. Since a deletion at 15q has not been found in familial cases of PWS, except in those where del(15q) is due to familial structural chromosome rearrangement, the recurrence risk with de novo deletion should be nearly zero. In cases with familial translocation, risk estimates depend on the nature of the translocations concerned. If only 1 child is affected and the karyotype is apparently normal, Kennerknecht (1992) estimated an overall recurrence risk of 0.4%. However, if 2 or more sibs are affected, he estimated that the risk to the next sib would be 50%. If every proband were investigated cytogenetically (to ascertain unbalanced chromosome rearrangements), molecularly (with probes to detect invisible deletions and to determine the methylation pattern), and if in each instance of a paternal deletion an examination of the father was carried out, then the few instances with a high recurrence risk could be ascertained before a second child was born.
### Mutagenic Factors
Strakowski and Butler (1987) found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations. Among 81 patients with PWS, Cassidy et al. (1989) compared the frequency of possible periconceptional occupational hydrocarbon exposure in those fathers who demonstrated a 15q deletion with the frequency in those who did not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half the fathers had been employed in hydrocarbon-exposing jobs. The data provided additional support for the possibility that hydrocarbon exposure is causally related to the disorder and further suggested lack of etiologic heterogeneity between the cytogenetically different groups.
Cytogenetics
Deletions account for 70 to 80% of cases; the majority are interstitial deletions, many of which can be visualized by prometaphase banding examination. A minority consist of unbalanced translocations, mostly de novo, which are easily detected by routine chromosome examination. The remainder of cases are the result of maternal uniparental disomy. In most of these latter cases, cytogenetic examinations yield normal results. However, in a few cases, either balanced translocations, familial or de novo, or supernumerary small marker chromosomes, are observed.
### Deletions
Butler et al. (1986) found an interstitial deletion of chromosome 15 (breakpoints q11 and q13) in 21 of 39 cases and an apparently normal karyotype in the remainder. By studying chromosome 15 heteromorphisms, the del(15q) was demonstrably paternal in origin in all cases, although both parents were normal and all deletions were de novo events. Paternal age was not increased. The exclusively paternal origin of deletions was subsequently confirmed cytogenetically and by molecular marker analysis (Magenis et al., 1990; Zori et al., 1990; Robinson et al., 1991). Examination of other series of patients by different groups resulted in the figures that two-thirds to three-fourths of PWS patients have a deletion of 15q11-q13. In less than 10%, this is due to an unbalanced translocation while the remainder have interstitial deletions.
To analyze the mechanism underlying the interstitial de novo deletions at 15q11-q13 that underlie approximately 70% of PWS cases, Carrozzo et al. (1997) genotyped 10 3-generation families of PWS-deletion patients using microsatellite markers flanking the common deletion region. By FISH and/or other molecular techniques, each patient was known to be deleted for the interval from D15S11 to GABRB3. In 5 of 7 cases, a different grandparental origin was identified for the alleles flanking the deletion, a finding significantly different from the expected frequency in light of the close position of the markers. This finding was considered highly suggestive of an unequal crossover occurring in the paternal meiosis at the breakpoint as the mechanism leading to deletion. The authors noted that asymmetric exchanges between nonsister chromatids in meiosis I have previously been demonstrated and are the basis of a number of genetic diseases. When the related sequences are part of tandemly arrayed homologous genes, nonhomologous recombination may lead to the formation of chimeric genes, such as those of Lapore hemoglobin and of the red-green pigment genes involved in abnormalities of color vision. In other instances, the deletion/duplication event may arise from the unequal recombination between repetitive elements interspersed throughout a genomic region. A misalignment between Alu-repetitive sequences has been demonstrated in duplications of the LDL-receptor gene (606945; Lehrman et al., 1987) and the HPRT gene (308000; Marcus et al., 1993).
In 2 PWS families studied by Carrozzo et al. (1997), the data were consistent with an intrachromosomal mechanism being responsible for the deletion. One of the few precedents for intrachromosomal recombination leading to human disease is provided by the recombination that occurs between the small intronless gene within intron 22 of the factor VIII gene (300841), and a copy of gene A (FSA; 305423) located 500 kb telomeric to the F8 gene, a recombination that causes severe hemophilia (306700) (Lakich et al., 1993). This rearrangement arises almost exclusively in male meioses, indicating that it is intrachromosomal. Carrozzo et al. (1997) suggested that the in-cis mechanism leading to the deletions in PWS patients may be related either to an exchange of chromosomal material between sister chromatids or to the formation of an intrachromosomal loop, either during meiosis or as a somatic event, followed by an excision of the chromosomal material lying between the recombining regions.
Deletions in PWS and AS are subdivided into 2 main groups based on their proximal breakpoints: type 1 deletions encompass the region between BP1 and BP3 (about 6 Mb) and type 2 deletions encompass the region from BP2 to BP3 (about 5.3 Mb). However, some patients have atypical deletions. Using methylation-specific multiplex ligation-dependent probe amplification to analyze the type of deletion in 88 PWS patients, Kim et al. (2012) found that 32 (36.4%) had a type 1 deletion and 49 (55.7%) had a type 2 deletion. Seven patients (8%) had atypical larger (2) or smaller (5) de novo deletions that were associated with unique phenotypic features, although there were no unifying characteristics across the group. Variable atypical clinical features in these patients included macrocephaly, microcephaly, large hands, no hypopigmentation, lack of facial gestalt, and variable cognitive impairment. Kim et al. (2012) discussed the possible role of different genes in the manifestation of different features.
In a 23-year-old woman with Prader-Willi syndrome, Bieth et al. (2015) identified a paternally transmitted 118-kb deletion of the SNORD116 gene cluster. The authors stated that this was the smallest deletion described to that time. SNORD109A and IPW (601491) were also deleted in the patient. SNORD116 expression was absent in patient cells, but present in her unaffected father's cells.
### Maternal Uniparental Disomy
Nicholls et al. (1989), studying cases of PWS in which no deletion was cytologically evident using RFLP analysis, were the first to demonstrate maternal uniparental disomy (UPD) in 2 families. Two different, apparently intact, maternal chromosomes were present ('heterodisomy'), and, as with deletion cases of PWS, there was an absence of paternal genes from the 15q11-q13 segment. Robinson et al. (1991) used cytogenetic and molecular techniques to examine 37 patients with features of PWS. Clinical features in 28 of the patients were thought to fulfill diagnostic criteria for typical PWS. In 21 of these, a deletion of the 15q11.2-q12 region could be identified molecularly, including several cases in which the cytogenetic results were inconclusive. Five cases of maternal heterodisomy and 2 of isodisomy for 15q11-q13 were observed. All 9 patients who did not fulfill clinical criteria for typical PWS showed normal maternal and paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. Thus, all typical PWS cases showed either a deletion or maternal uniparental disomy of 15q11.2-q12. As the disomy patients did not show any additional or more severe features than did the typical deletion patients, it is likely that there is only one imprinted region on chromosome 15. A significantly increased mean maternal age was found in the disomy cases, suggesting an association between increased maternal age and nondisjunction.
Mascari et al. (1992) demonstrated maternal uniparental disomy for chromosome 15 in 18 of 30 patients (60%) without a cytogenetic deletion. Furthermore, they confirmed the observation of Robinson et al. (1991) that the phenomenon was associated with advanced maternal age. In another 8 patients (27%), they identified large molecular deletions. The remaining 4 patients (13%) had evidence of normal biparental inheritance for chromosome 15; 3 of these patients were the only ones in the study which had some atypical clinical features. All told, they estimated that about 20% of cases of PWS result from maternal uniparental disomy and that, by the combined use of cytogenetic and molecular techniques, the genetic basis of PWS can be identified in at least 95% of patients.
Mitchell et al. (1996) compared 79 cases of PWS with UPD and 43 cases with deletions. Although there were no major clinical differences between the 2 classes of patients analyzed as a whole, mean maternal and paternal age were significantly higher in the UPD patients. The UPD group had a predominance of males, yet a gender bias was not seen in the deletion group. Hypopigmentation was found in 77% of the deletion group compared to only 39% of the UPD children. When the groups were analyzed by gender, females with UPD tended to be less severely affected than female deletion patients.
Mutirangura et al. (1993) demonstrated maternal heterodisomy in 10 PWS patients. Since the markers used were 13 cM from the centromere, heterodisomy indicated that maternal meiosis I nondisjunction was primarily involved in the origin of UPD. In contrast, 2 paternal disomy cases of Angelman syndrome (AS) showed isodisomy for all markers tested along the length of chromosome 15. This suggested a paternal meiosis II nondisjunction event (without crossing over) or, more likely, monosomic conception (due to maternal nondisjunction) followed by chromosome duplication. The latter mechanism would indicate that at least some instances of uniparental disomy in PWS and AS initiate as reciprocal products of maternal nondisjunction events.
Robinson et al. (1993) reported data indicating that the majority (82%) of maternal nondisjunction events leading to UPD and causing PWS involve a meiosis I error, whereas most paternal UPD Angelman syndrome cases are meiosis II or, more likely, mitotic errors. Robinson et al. (1993) made the interesting statement that the proportion of UPD cases among all PWS patients in Switzerland is higher than in the United States, which could reflect the higher mean maternal age at birth in Switzerland versus the United States.
Gold et al. (2014) studied the frequency of Prader-Willi syndrome in births conceived via assisted reproductive technology (ART). The overall incidence in those who used ART was 1.1%; the population frequency for the United States was 1.0%. However, the proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than that in the total sample, 55.6% (10 of 18) and 34.5% (431 of 1,250), respectively. As compared with naturally conceived individuals with Prader-Willi syndrome, those who were ART-conceived were more likely to have uniparental disomy and imprinting defects than deletions. This study also demonstrated no association between twinning and Prader-Willi syndrome when ART-conceived pregnancies were excluded.
### Rescuing of Trisomy 15
Maternal nondisjunction does not itself directly lead to uniparental disomy but must also involve a further nondisjunction event to produce a euploid embryo. Purvis-Smith et al. (1992) have confirmed such an origin of uniparental disomy 15 resulting from 'correction' of an initial trisomy 15. Routine chorionic villus sampling performed for advanced maternal age led to detection of placental mosaicism for trisomy 15. Follow-up studies on amniotic fluid indicated a normal 46,XY karyotype with no evidence of trisomy 15, and the pregnancy continued to term. At birth, the baby was found to have PWS. Molecular analysis indicated that the mother was the sole contributor of the chromosome 15 pair in the child. Centromere/short-arm heteromorphisms were different in the 2 chromosome 15 homologs, consistent with meiosis I error. Cassidy et al. (1992) reported a similar case that supported the idea that maternal disomy can result from a 'corrected' trisomy 15 and that maternal age was a predisposing factor to nondisjunction. Thus, in any case in which trisomy or mosaic trisomy 15 has been prenatally determined through CVS examination, a molecular study should follow to exclude uniparental (paternal or) maternal disomy. This type of examination should also be considered in case of pregnancies of translocation carrier parents involving chromosome 15.
Devriendt et al. (1997) proposed partial zygotic trisomy rescue as a mechanism for mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter in a patient with PWS. A maternal uniparental heterodisomy for chromosome 15 was present in all cells and was responsible for the PWS phenotype. The translocated 15q segment was of paternal origin and was present as a jumping translocation, involving chromosomes 14q, 4q, and 16p. The recipient chromosomes were cytogenetically intact. Devriendt et al. (1997) reported that mental retardation was more marked in their patient than is usually observed in PWS, and proposed that this was due to partial trisomy for distal 15q.
### Multiple Affected Relatives
There are several mechanisms that explain the simultaneous occurrence of affected first- and second-degree relatives in PWS families. These include translocations that give rise to maternal nondisjunction and hence effective maternal uniparental disomy for the PWS region and translocations which give rise to paternally derived deletions.
The first report of involvement of a D group translocation in PWS (later identified as a 15-15 translocation) dates back to 1963 (Buehler et al., 1963). Additional translocations were found subsequently, and after the introduction of chromosome banding it became obvious that at least one chromosome 15 was involved in all instances (Zuffardi et al., 1978; Kucerova et al., 1979; Guanti, 1980). However, the situation was further complicated by cases in which not only the proband had a translocation involving chromosome 15, but the mother and 2 normal sibs showed the seemingly identical translocation as well (Smith and Noel, 1980). In addition, there were a few cases that did not show a translocation involving chromosome 15, but had a small supernumerary chromosome, presumably an isochromosome for the short arm of an acrocentric (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980).
Smith and Noel (1980) described a family in which a Prader-Willi girl had the same balanced 4;15 translocation as her mother and other phenotypically normal family members. A second such family was observed by Smith et al. (1983). Nicholls et al. (1989) reported a similar family and demonstrated that the Prader-Willi proband had inherited the maternal translocation chromosome plus the normal maternal homolog, but no paternal 15. Therefore, having a balanced translocation involving chromosome 15 predisposes to PWS offspring via nondisjunction, and this is a much more frequent cause than spontaneous nondisjunction, which may arise from chromosomally normal individuals. The opposite, i.e., Angelman syndrome, could also occur with paternal translocation carriers.
The simplest instance is that of a balanced rearrangement with a breakpoint in 15q13 in related male carriers. Fernandez et al. (1987) reported a family with a 15;22 translocation carrier father who had 2 children with PWS because of an unbalanced segregation. Hulten et al. (1991) described a family in which a balanced translocation involving 15q13 was segregating. Females with the translocation appeared to have an increased risk of having children with AS, whereas male carriers of the translocation had an increased risk of having children with PWS.
Ledbetter et al. (1980) pointed out that apparent balanced translocations involving chromosome 15 have been found. The defect may be an alteration in gene expression, i.e., a regulatory defect. Ledbetter et al. (1981), assuming a small deletion of proximal 15q as the cause of the clinical features in the translocated cases, studied 45 persons with the clinical diagnosis of PWS. Of the 45, 25 had an abnormality of chromosome 15 (which in 23 was an interstitial deletion affecting the q11-q12 region). No relatives of probands showed chromosomal changes.
Orstavik et al. (1992) described 3 sibs thought to have the Prader-Willi syndrome but with no abnormality in the 15q11-q13 region detectable by cytogenetic or molecular genetic methods. One of the sibs, a boy, was born at 32 weeks by cesarean section. He was extremely hypotonic and died at 7 days of age from respiratory distress. The other sibs, a 12-year-old brother and a 7-year-old sister, had an accessory nipple and seemingly typical PWS. A paternally inherited submicroscopic deletion was suggested as one possibility. A very small deletion was later molecularly detected in affected members of this family (Tommerup, 1993).
Ishikawa et al. (1987) described 2 sisters with PWS. No interstitial deletion of 15q was detected in either; 1 sister had a possibly unrelated partial deletion of one X chromosome. No molecular investigations were performed in this family.
Lubinsky et al. (1987) reported the cases of 2 brothers and 2 sisters in a single sibship with PWS but apparently normal chromosomes. Results of chromosome studies in the parents and surviving sibs were normal. The diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs. The fourth child had died at the age of 10 months with a history and clinical findings typical of the first phase of PWS. Again, no molecular or fluorescence in situ hybridization (FISH) studies were performed. It seems likely that an undetected structural chromosome rearrangement is the cause for this multiple occurrence of PWS.
McEntagart et al. (2000) described a brother and sister with PWS in whom there was no microscopically visible deletion in 15q11-q13 or maternal disomy. Methylation studies at D15S63 and at the SNRPN locus confirmed the diagnosis of PWS. Molecular studies revealed biparental inheritance in both sibs with the exception of 2 markers where no paternal contribution was present, indicating a deletion of the imprinting center. Family studies indicated that the father of the sibs carried the deletion which he had inherited from his mother. Recurrence risk of PWS in his offspring was 50%.
### Co-Occurrence of Prader-Willi and Angelman Syndromes
Hasegawa et al. (1984) studied a family in which 2 cousins were claimed to have the Prader-Willi syndrome and found a reciprocal translocation t(14;15)(q11.2;q13) in a single parent of each cousin and in their common grandmother. The affected cousins had the same unbalanced translocation including monosomy of the 15pter-q13 segment. Schinzel et al. (1992) pointed out that the unbalanced karyotype with deletion of 15q11-q13 came from the mother in the case of the proband who had been described to have classic Prader-Willi syndrome and from the father in the case of the cousin; the mother of the proband and the father of the cousin were sister and brother. However, the proband was not hypotonic and had seizures. Schinzel et al. (1992) suggested that the diagnosis in the proband actually may have been Angelman syndrome, consistent with the finding that there has been no reported instance of a patient in which absence of the paternal segment 15q11-q13 does not cause PWS, while the absence of the maternal segment leads to AS.
Another mechanism by which the Prader-Willi syndrome and Angelman syndrome can occur in cousins was reported by Smeets et al. (1992). Two female first cousins were offspring of brothers, both of whom had a familial translocation between chromosome 6 and 15, t(6;15)(p25.3;q11.1). The cousin with the Prader-Willi syndrome had the karyotype 45,XX,-6,-15+t(6;15)(p25.3;q13); DNA studies indicated that there was a large paternally derived deletion of all loci from the Prader-Willi chromosomal region tested. The cousin with Angelman syndrome had the karyotype 45,XX,-6,-15,+t(6;15)(p25.3;q11.1) and DNA studies indicated that she had uniparental heterodisomy, having inherited both the (6;15) translocation and the normal chromosome 15 from her father, but no chromosome 15 from her mother. In an editorial, Hall (1992) suggested that the cousin with Angelman syndrome had started out life as a trisomy and survived only through the loss of extra chromosomal material.
Greenstein (1990) presented a kindred in which both the Prader-Willi and the Angelman syndromes were found; the inheritance pattern was consistent with genetic imprinting.
### Marker Chromosomes
Finally, additional small marker chromosomes representing isochromosomes or isodicentric chromosomes from the short arms of acrocentrics have repeatedly been observed (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980) before Robinson et al. (1993) demonstrated maternal uniparental disomy 15 in a Prader-Willi child mosaic for such a marker and paternal UPD 15 in an Angelman patient also mosaic for a small metacentric marker chromosome.
Investigation of PWS and AS patients with a small inv dup(15) chromosome attributes the abnormal phenotype to uniparental disomy rather than to the extra chromosome (Robinson et al., 1993). The small chromosome may represent either the remnant of the missing parental chromosome 15 or could be associated with nondisjunction.
Park et al. (1998) described an example of maternal disomy and Prader-Willi syndrome consistent with gamete complementation. They considered that the probable event was adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient, a 17-year-old white male with PWS, had 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15 fused to distal 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescence in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion in the PWS region on the normal pair of 15s present in the patient. Maternal disomy was confirmed by 2 methods.
Mapping
Kirkilionis et al. (1991) constructed a long-range restriction map of the PWS region, 15q11.1-q12, using a combination of pulsed-field gel techniques and rare cutting restriction enzymes.
A preliminary YAC contig map was reported by Kuwano et al. (1992), which also localized many common proximal and distal deletion breakpoints to two YACs. Ozcelik et al. (1992) refined the localization of the small nuclear ribonucleoprotein N gene (SNRPN; 182279) within the minimum deletion region. FISH ordering of reference markers in this region was also reported by Knoll et al. (1993) who placed D15S63 in the minimum PWS deletion region between D15S13 and D15S10. Mutirangura et al. (1993) published a complete YAC contig of the PWS/AS critical region and discussed the potential role of uniparental disomy (UPD) in PWS and AS. Buiting et al. (1993) constructed a YAC restriction map of the entire minimum PWS critical region defined by the shortest region of overlap between two key PWS deletion patients. This region is 320 kb and includes D15S63 and SNRPN.
Molecular Genetics
Latt et al. (1987) isolated probes from the proximal region of the long arm of chromosome 15 that are useful in the study of PWS.
Buiting et al. (1992) isolated a putative gene family and candidate genes by microdissection and microcloning from the 15q11-q13 region. One microclone, designated MN7, detected multiple loci in 15q11-q13 and 16p11.2. There were 4 or 5 different MN7 copies spread over a large distance within 15q11-q13. The presence of multiple copies of the MN7 gene family in proximal 15q may be related to the instability of this region and thus to the etiology of PWS and Angelman syndrome.
Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, Driscoll et al. (1992) systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion cases and 20 cases of uniparental disomy) and those with AS (26 deletion cases and 1 case of uniparental disomy). They found that the sequences identified by the cDNA DN34, which is highly conserved in evolution, demonstrate distinct differences in DNA methylation of the parental alleles at the D15S9 locus. Clayton-Smith et al. (1993) used DN34 to perform methylation analysis of 2 first-cousin males, one with AS and the other with PWS. The methylation pattern varied according to the parent of origin, providing further evidence for the association of methylation with genomic imprinting. Thus, DNA methylation can be used as a reliable postnatal diagnostic tool. Dittrich et al. (1992) found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-q13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, they devised a rapid diagnostic test for patients suspected of having PWS or AS.
The human homolog for the mouse pink-eyed dilution locus (p locus) was found to be equivalent to the D15S12 locus which maps within the PWS/AS deletion region (Rinchik et al., 1993). Mutations in both copies of the P gene were found in a patient with type II oculocutaneous albinism, and it is suggested that deletion of 1 copy of this gene is the cause of hypopigmentation in PWS and AS.
The SNRPN gene was shown by RT-PCR to be expressed in normal and AS individuals, but not in fibroblasts from either deletion or maternal UPD PWS patients who lack a paternal copy of this gene (Glenn et al., 1993). Parent-specific DNA methylation was also identified for the SNRPN gene. Reed and Leff (1994) showed that in the human, as in the mouse, there is maternal imprinting of SNRPN, thus supporting the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype. See SNRPN (182279) for discussion of evidence indicating that this is a candidate gene in PWS and suggesting that PWS may be caused, in part, by defects in mRNA processing. In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by FISH.
A DNA transcript, OP2, was identified just centromeric to D15S10 by Woodage et al. (1994). Multiple expressed genes were identified by Sutcliffe (1994) in the region between SNRPN and D15S10. They showed that at least 4 genes are expressed only on the paternal chromosome including SNRPN, PAR1 (600161), PAR5 (600162), and PAR7. A PWS patient with a small paternal deletion showed no expression of these genes, even though the deletion occurs proximal to but not including these maternally imprinted genes, implying a common element involved in regulation of these genes. Wevrick et al. (1994) identified another expressed gene in the region, designated IPW (601491) for 'imprinted gene in the Prader-Willi syndrome region,' that is expressed only from the paternal chromosome 15.
DNA replication was shown by FISH to be asynchronous between maternal and paternal alleles within 15q11-q13 (Knoll et al., 1993). Loci in the PWS-critical region were shown to be early replicating on the paternal chromosome, and alleles within the AS critical region were early replicating on the maternal chromosome. A mosaic replication pattern with maternal and paternal alleles alternatively expressed was noted at the P locus, and is consistent with the presence of hypopigmentation in both PWS and AS due to decreased product.
Schulze et al. (1996) reported a boy with PWS who had a rare translocation and a normal methylation pattern at SNRPN. Although the boy fulfilled the diagnostic criteria for PWS defined by Holm et al. (1993), he had a normal methylation pattern due to the position of the translocation breakpoint.
Cassidy (1997) provided a comprehensive review of the clinical and molecular aspects of Prader-Willi syndrome. Cassidy and Schwartz (1998) provided a similar review of both Prader-Willi syndrome and Angelman syndrome.
PWS and AS are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2 to 4% of patients, this loss of function is the result of an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Buiting et al. (1998) described the molecular analysis of 13 PWS patients and 17 AS patients who had an imprinting defect but no IC deletion. Furthermore, heteroduplex and partial sequence analyses did not reveal any point mutations in the known IC elements. All of these patients represented sporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggested that the grandmaternal imprint was not erased in the father's germline. In 7 informative AS patients reported by Buiting et al. (1998) and in 3 previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, but it suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error; (2) these cases have a low recurrence risk; and (3) the paternal imprint may be the default imprint.
Buiting et al. (2003) described a molecular analysis of 51 patients with PWS and 85 patients with AS. A deletion of an IC was found in 7 patients with PWS (14%) and 8 patients with AS (9%). Sequence analysis of 32 PWS patients and 66 AS patients, neither with an IC deletion, did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggested that these patients were mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggested that this imprinting defect resulted from a failure to erase the maternal imprint during spermatogenesis.
Microdeletions of the imprinting center in 15q11-q13 have been identified in several families with PWS or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in this region of 15q during gametogenesis. Ohta et al. (1999) identified a large series of cases of familial PWS, including 1 case with a deletion of only 7.5 kb, that narrowed the PWS critical region to less than 4.3 kb spanning the SNRPN gene CpG island and exon 1. The identification of a strong DNase I hypersensitive site, specific for the paternal allele, and 6 evolutionarily conserved (human-mouse) sequences that are potential transcription factor binding sites is consistent with a conclusion that this region defines the SNRPN gene promoter. These findings suggested that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. Ohta et al. (1999) also identified 3 patients with sporadic PWS who had an imprinting mutation (IM) and no known detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental gametogenesis. These studies allowed a better understanding of the novel mechanism of human disease, since the epigenetic effect of an imprinting mutation in parental germline determines the phenotypic effect in the patient.
To elucidate the mechanism underlying the deletions that lead to PWS and Angelman syndrome, Amos-Landgraf et al. (1999) characterized the regions containing 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from large genomic duplications of the HERC2 gene (605837) (Ji et al., 1999). Many copies of the HERC2 gene are transcriptionally active in germline tissues. Amos-Landgraf et al. (1999) postulated that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, they proposed that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.
To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, Lee and Wevrick (2000) constructed an imprinted transcript map of the PWS-AS deletion interval. They found 7 new paternally expressed transcripts localized to a domain of approximately 1.5 Mb surrounding the SNRPN-associated imprinting center, which already included 4 imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggested strong regional control of the imprinting process. Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.
Boccaccio et al. (1999) and Lee et al. (2000) independently cloned and characterized MAGEL2 (605283), a gene within the PWS deletion region. They demonstrated that the MAGEL2 gene is transcribed only from the paternal allele.
Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of PWS or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation t(X;15)(q28;q12) in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85/PWCR1 (SNORD116-1; 605436), as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype.
Meguro et al. (2001) determined the allelic expression profiles of 118 cDNA clones using monochromosomal hybrids retaining either a paternal or maternal human chromosome 15. There was a preponderance of unusual transcripts lacking protein-coding potential that were expressed exclusively from the paternal copy of the critical interval. This interval also encompassed a large direct repeat (DR) cluster displaying a potentially active chromatin conformation of paternal origin, as suggested by enhanced sensitivity to nuclease digestion. Database searches revealed an organization of tandemly repeated consensus elements, all of which possessed well-defined C/D box sequences characteristic of small nucleolar RNAs (snoRNAs). Southern blot analysis further demonstrated a considerable degree of phylogenetic conservation of the DR locus in the genomes of all mammalian species tested. The authors suggested that there may be a potential direct contribution of the DR locus, representing a cluster of multiple snoRNA genes, to certain phenotypic features of PWS.
Fulmer-Smentek and Francke (2001) explored whether differences in histone acetylation exist between the 2 parental alleles of SNRPN and other paternally expressed genes in the region by using a chromatin immunoprecipitation assay with antibodies against acetylated histones H3 (see 601058) and H4 (see 602822). SNRPN exon 1, which is methylated on the silent maternal allele, was associated with acetylated histones on the expressed paternal allele only. SNRPN intron 7, which is methylated on the paternal allele, was not associated with acetylated histones on either allele. The paternally expressed genes NDN, IPW, PWCR1/HBII-85, and MAGEL2 were not associated with acetylated histones on either allele. Treatment of the lymphoblastoid cells with trichostatin A, a histone deacetylase inhibitor, did not result in any changes to SNRPN expression or association of acetylated histones with exon 1. Treatment with 5-aza-deoxycytidine, which inhibits DNA methylation, resulted in activation of SNRPN expression from the maternal allele, but was not accompanied by acetylation of histones. The authors hypothesized that histone acetylation at this site may be important for regulation of SNRPN and of other paternally expressed genes in the region, and that histone acetylation may be a secondary event in the process of gene reactivation by CpG demethylation.
The Prader-Willi syndrome/Angelman syndrome region on chromosome 15q11-q13 exemplifies coordinate control of imprinted gene expression over a large chromosomal domain. Establishment of the paternal state of the region requires the PWS imprinting center (PWS-IC); establishment of the maternal state requires the AS-IC. Cytosine methylation of the PWS-IC, which occurs during oogenesis in mice, occurs only after fertilization in humans, so this modification cannot be the gametic imprint for the PWS/AS region in humans. Xin et al. (2001) demonstrated that the PWS-IC shows parent-specific complementary patterns of histone H3 (see 602810) lysine-9 (lys9) and H3 lysine-4 (lys4) methylation. H3 lys9 is methylated on the maternal copy of PWS-IC and H3 lys4 is methylated on the paternal copy. Xin et al. (2001) suggested that H3 lys9 methylation is a candidate maternal gametic imprint for this region, and they showed how changes in chromatin packaging during the life cycle of mammals provide a means of erasing such an imprint in the male germline.
Bittel et al. (2003) performed cDNA microarray analysis of 73 genes/transcripts from the 15q11-q13 region in actively growing lymphoblastoid cell lines established from 9 young adult males: 6 with PWS (3 with deletion and 3 with UPD) and 3 controls. They detected no difference in expression of genes with known biallelic expression located outside the 15q11-q13 region in all cell lines studied. When comparing UPD cell lines with controls, there was no difference in expression levels of biallelically expressed genes from within 15q11-q13 (e.g., OCA2; 611409). Two genes previously identified as maternally expressed, UBE3A (601623) and ATP10C (605855), showed a significant increase in expression in UPD cell lines compared with those from control and PWS deletion patients. The results suggested that differences in expression of candidate genes may contribute to phenotypic differences between the deletion and UPD types of PWS.
Horsthemke et al. (2003) described a girl with PWS who was mosaic for maternal uniparental disomy 15 [upd(15)mat] in blood and skin. The upd event occurred prior to X inactivation. DNA microarray experiments on cloned normal and upd fibroblasts detected several chromosome 15 genes known to be imprinted, but there was no evidence for novel 15q genes showing imprinted expression. Differentially expressed genes on other chromosomes were considered candidates for downstream genes regulated by an imprinted gene and may play a role in the pathogenesis of PWS. Upon finding strongly reduced mRNA levels in upd(15)mat cells of the gene encoding secretogranin II (SCG2; 118930), a precursor of the dopamine-releasing factor secretoneurin, the authors speculated that the hyperphagia in patients with PWS might be due to a defect in dopamine-modulated food reward circuits.
Kantor et al. (2004) constructed a transgene including both the 4.3-kb SNRPN promoter/exon 1 (PWS-SRO) sequence and the 880-bp sequence (AS-SRO) located 35 kb upstream of the SNRPN transcription start site and determined that the transgene carried out the entire imprinting process. The epigenetic features of this transgene resembled those previously observed on the endogenous locus, thus allowing analyses in mouse gametes and early embryos. In gametes, they identified a differentially methylated CpG cluster (DMR) on AS-SRO that was methylated in sperm and unmethylated in oocytes. This DMR specifically bound a maternal allele-discrimination protein that was involved in DMR maintenance through implantation when methylation of PWS-SRO on the maternal allele takes place. While the AS-SRO was required in gametes to confer methylation on PWS-SRO, it was dispensable later in development.
The Prader-Willi deleted region on chromosome 15q11 contains a small nucleolar RNA (snoRNA), HBII-52 (SNORD115-1; 609837), that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor HTR2C (312861). Kishore and Stamm (2006) found that HBII-52 regulates alternative splicing of HTR2C by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different HTR2C mRNA isoforms than healthy individuals. Kishore and Stamm (2006) concluded that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.
Runte et al. (2005) found that individuals with complete deletion of all copies of HBII-52 had no obvious clinical phenotype, suggesting that HBII-52 does not play a major role in PWS.
Sahoo et al. (2008) reported a boy with all of 7 major clinical criteria for Prader-Willi syndrome, including neonatal hypotonia, feeding difficulties and failure to thrive during infancy, excessive weight gain after 18 months, hyperphagia, hypogonadism, and global developmental delay; facial features were considered equivocal, with bitemporal narrowing and almond-shaped eyes. Additional minor features included behavioral problems, sleep apnea, skin picking, speech delay, and small hands and feet relative to height. High-resolution chromosome and array comparative genomic hybridization showed an atypical deletion of the paternal chromosome within the snoRNA region at chromosome 15q11.2. The deletion encompassed HBII-438A, all 29 snoRNAs comprising the HBII-85 cluster, and the proximal 23 of the 42 snoRNAs comprising the HBII-52 cluster. The data suggested that paternal deficiency of the HBII-85 cluster may cause key manifestations of the PWS phenotype, although some atypical features suggested that other genes in the region may make lesser phenotypic contributions.
De Smith et al. (2009) reported a 19-year-old male with hyperphagia, severe obesity, mild learning difficulties, and hypogonadism, in whom diagnostic tests for PWS had been negative. The authors identified a 187-kb deletion at chromosome 15q11-q13 that encompassed several exons of SNURF-SNRPN, the HBII-85 cluster (SNORD116-1; 605436), and IPW but did not include the HBII-52 cluster. HBII-85 snoRNAs were not expressed in peripheral lymphocytes from the patient. Characterization of the clinical phenotype revealed increased ad libitum food intake, normal basal metabolic rate when adjusted for fat-free mass, partial hypogonadotropic hypogonadism, and growth failure. These findings provided direct evidence for the role of a particular family of noncoding RNAs, the HBII-85 snoRNA cluster, in human energy homeostasis, growth, and reproduction.
Using bioinformatic predictions and experimental verification, Kishore et al. (2010) identified 5 pre-mRNAs (DPM2, 603564; TAF1, 313650; RALGPS1, 614444; PBRM1, 606083; and CRHR1, 122561) containing alternative exons that are regulated by MBII-52, the mouse homolog of HBII-52. Analysis of a single member of the MBII-52 cluster of snoRNAs by RNase protection and Northern blot analysis showed that the MBII-52 expressing unit generated shorter RNAs that originate from the full-length MBII-52 snoRNA through additional processing steps. These novel RNAs associated with hnRNPs and not with proteins associated with canonical C/D box snoRNAs. Kishore et al. (2010) concluded that not a traditional C/D box snoRNA MBII-52, but a processed version lacking the snoRNA stem, is the predominant MBII-52 RNA missing in Prader-Willi syndrome. This processed snoRNA functions in alternative splice site selection.
Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 15q11.2-q13 (BP2-BP3) deletion was identified in 41 cases and no controls for a p value of 2.77 x 10(-9) and a frequency of 1 in 384 cases.
Diagnosis
Seven clinicians experienced with PWS, in consultation with national and international experts, proposed 2 scoring systems as diagnostic criteria: one for children aged 0-36 months and another for children aged 3 years to adults (Holm et al., 1993).
The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee (1996) outlined approaches to the laboratory diagnosis of PWS and Angelman syndrome.
White et al. (1996) exploited the allele-specific replication differences that had been observed in imprinted chromosomal regions to obtain a diagnostic test for detecting uniparental disomy. They used FISH of D15S9 and SNRPN (182279) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples with uniparental disomy of 15q11-q13 and those with biparental inheritance. They found that the familial recurrence risks are low when the child has de novo uniparental disomy and may be as high as 50% when the child has biparental inheritance. The frequency of interphase cells with asynchronous replication was significantly lower in patients with uniparental disomy than in patients with biparental inheritance. Within the sample population of patients with biparental inheritance, those with altered methylation and presumably imprinting center mutations could not be distinguished from those with no currently detectable mutation. White et al. (1996) considered the test cost-effective because it could be performed on interphase cells from the same hybridized cytologic preparation in which a deletion was included, and additional specimens were not required to determine the parental origin of chromosome 15.
Kubota et al. (1996) noted that neither FISH nor uniparental disomy (UPD) analysis with microsatellite markers will detect rare PWS patients with imprinting mutations, including small deletions or point mutations in the imprinting center region. They reported that as an initial screening test, methylation analysis has the advantage of detecting all of the major classes of molecular defects involved in PWS (deletions, uniparental disomy, and imprinting mutations) without the need for parental blood. Kubota et al. (1996) reported that in 67 patients examined clinically, the methylation results for PW71 were consistent with the clinical diagnosis. They concluded that SNRPN methylation analysis, similar to PW71 methylation analysis, constitutes a reliable diagnostic test for PWS. They emphasized the importance of conventional cytogenetic analysis in parallel with DNA methylation analysis. They noted that a few patients with signs of PWS have balanced translocations within or distal to SNRPN and normal methylation patterns. They noted also that conventional cytogenetic analysis is important to rule out other cytogenetic anomalies in patients who may have similar clinical manifestations but who do not have PWS.
Since the SNRPN gene is not expressed in any patient with PWS regardless of the underlying cytogenetic or molecular cause, Wevrick and Francke (1996) tested for expression of the SNRPN gene and a control gene in 9 patients with PWS and 40 control individuals by PCR analysis of reverse transcribed mRNA from blood leukocytes. SNRPN expression could readily be detected in blood leukocytes by PCR analysis in all control samples but not in samples from known PWS patients. Four suspected PWS cases were negative for SNRPN expression and were found to have chromosome 15 rearrangements, while the diagnosis of PWS was excluded in 7 other patients with normal SNRPN expression based on clinical, molecular, and cytogenetic findings. Thus, Wevrick and Francke (1996) concluded that the SNRPN-expression test is rapid and reliable in the molecular diagnosis of PWS.
The diagnostic criteria arrived at by a consensus group (Holm et al., 1993) were presented in a table by Schulze et al. (1996). In a point system, 1 point each was allowed for each of 5 major criteria, such as feeding problems in infancy and failure to thrive, and one-half point each for 7 minor criteria, such as hypopigmentation. A minimum of 8.5 points was considered necessary for the diagnosis of PWS.
Hordijk et al. (1999) reported a boy with a PWS-like phenotype who was found to have maternal heterodisomy for chromosome 14. The authors noted that while previous reports of this phenotype had been associated with a Robertsonian translocation involving chromosome 14, in this case the karyotype was normal. Hordijk et al. (1999) concluded that patients with a PWS-like phenotype and normal results of DNA analysis for PWS should be reexamined for uniparental disomy for maternal chromosome 14.
Whittington et al. (2002) compared clinical and genetic laboratory diagnoses of PWS. The genetic diagnosis was established using the standard investigation of DNA methylation of SNRPN, supplemented with cytogenetic studies. The 5 clinical features of floppy at birth, weak cry or inactivity, poor suck, feeding difficulties, and hypogonadism were present in 100% of persons with positive genetic findings, the absence of any 1 predicting a negative genetic finding. The combination of poor suck at birth, weak cry or inactivity, decreased vomiting, and thick saliva correctly classified 92% of all cases. Whittington et al. (2002) hypothesized that these criteria ('core criteria') invariably present when genetic findings are positive and are necessary accompaniments of the genetics of PWS. No subset of clinical and behavioral criteria was sufficient to predict with certainty a positive genetic diagnosis, but the absence of any 1 of the core criteria predicted a negative genetic finding.
Clinical Management
The suggestion of a hypothalamic defect located in the ventromedial or ventrolateral nucleus is plausible, but no such lesion has been reported, nor was such found on careful search in a typical case (Warkany, 1970). Hamilton et al. (1972) showed that the hypogonadism is the hypogonadotropic type and the result of hypothalamic dysfunction. Treatment with clomiphene citrate raised plasma luteinizing hormone, testosterone, and urinary gonadotropin levels to normal and resulted in normal spermatogenesis and physical signs of puberty.
Vagotomy has been successful in correcting obesity in experimental obesity produced by hypothalamic lesions (Hirsch, 1984). Fonkalsrud and Bray (1981) performed truncal vagotomy without pyloroplasty in a 17-year-old boy who had maintained a weight of approximately 264 lb (120 kg) for several years. Initially, he lost weight satisfactorily but by 11 months postoperative he had regained most of the weight. Prader (1991) reported a 17-year-old boy weighing 264 lb (120 kg) who had developed diabetes, required digitalization for cardiac failure, and presented with intolerable behavior problems. Strict dietary control in combination with psychotherapy in a foster environment resulted in a weight reduction to 143 lb (65 kg), cessation of hyperglycemia and glucosuria, and cardiac normalization.
Carrel et al. (1999) presented the results of a randomized controlled study of growth hormone treatment in children with Prader-Willi syndrome. They showed that growth hormone treatment accelerated growth, decreased percent body fat, and increased fat oxidation, but did not significantly increase resting energy expenditure. Improvements in respiratory muscle strength, physical strength, and agility also were observed, leading the authors to suggest that growth hormone treatment may have value in reducing disability in children with PWS. Lindgren et al. (1999) measured resting ventilation, airway occlusion pressure, and respiratory response to CO(2) in 9 children, aged 7 to 14 years, before and 6 to 9 months after the start of growth hormone therapy. Treatment resulted in a significant increase in all 3 measurements.
Studies had shown that GH (139250) therapy with doses of GH typically used for childhood growth improves growth, body composition, physical strength and agility, and fat utilization in children with PWS. However, these measurements remained far from normal after up to 2 years of GH therapy. Carrel et al. (2002) assessed the effects of 24 additional months of GH treatment at varying doses on growth, body composition, strength and agility, pulmonary function, resting energy expenditure, and fat utilization in 46 children with PWS, who had previously been treated with GH therapy for 12 to 24 months. During months 24 to 48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and resting energy expenditure occurred with higher GH therapy doses, but not with the lowest dose. Bone mineral density continued to improve at all doses of GH (P less than 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. They authors concluded that salutary and sustained GH-induced changes in growth, body composition, bone mineral density, and physical function in children with PWS can be achieved with daily administration of GH doses greater than or equal to 1 mg/m2.
Marzullo et al. (2007) evaluated the cardiovascular response to GH therapy in 13 adult PWS patients. GH therapy increased cardiac mass devoid of diastolic consequences. The observation of a slight deterioration of right heart function as well as the association between IGF-I and left ventricular function during GH therapy suggested the need for appropriate cardiac and hormonal monitoring.
With regard to genetic counseling, the type of cytogenetic aberration and molecular results determine the recurrence risk. Prenatal molecular investigation from chorionic villi should be recommended in every case despite very low recurrence risk. Prenatal ultrasonographic studies of fetal activity may be useful for a first screening since Prader-Willi fetuses will show diminished fetal movement during the second trimester (Schinzel, 1986). Furthermore, a molecular examination for uniparental disomy is indicated in any pregnancy in which a CVS examination disclosed (mosaic) trisomy 15 and a subsequent cytogenetic examination from amniocytes or fetal blood revealed a normal diploid karyotype.
Treatment with octreotide, a somatostatin (182450) agonist, decreases ghrelin (605353) concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. To investigate whether the high fasting ghrelin concentrations of children with PWS could be suppressed by short-term octreotide administration, Haqq et al. (2003) treated 4 subjects with PWS with octreotide (5 microg/kg-d) for 5 to 7 days and studied ghrelin concentration, body composition, resting energy expenditure, and GH markers. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P less than 0.05). Meal-related ghrelin suppression was still present after intervention but was blunted. Body weight, body composition, leptin, insulin (176730), resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. The authors concluded that short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin.
Festen et al. (2006) studied the effects of GH treatment on respiratory parameters in prepubertal children with PWS. At baseline, the median apnea hypopnea index (AHI) was 5.1 per hour, mainly due to central apneas. Six months of GH treatment did not aggravate the sleep-related breathing disorders in young PWS children. Festen et al. (2006) concluded that monitoring during upper respiratory tract infection in PWS children should be considered.
Because of the very high (3%) annual death rate of PWS patients, with most deaths occurring during moderate infections, and because PWS patients have hypothalamic dysregulations and show no or few signs of illness, de Lind van Wijngaarden et al. (2008) investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. They found that 15 (60%) of 25 randomly selected PWS patients had CAI. De Lind van Wijngaarden et al. (2008) concluded that the high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress; the authors suggested that treatment with hydrocortisone during acute illness should be considered in PWS patients unless CAI had been ruled out with a metyrapone test.
From a multicenter study of 38 diverse GH-deficient PWS adults, Mogul et al. (2008) concluded that GH improves body composition, normalizes triiodothyronine (T3), and is well tolerated without glucose impairment. Mildly progressive ankle edema in 5 patients was the most serious treatment-emergent adverse event.
Pathogenesis
### Relationship of Ghrelin to Hyperphagia
To determine whether ghrelin, a GH (139250) secretagogue with orexigenic properties, is elevated in PWS, Delparigi et al. (2002) measured fasting plasma ghrelin concentration, body composition, and subjective ratings of hunger in 7 subjects with PWS and 30 healthy subjects who had fasted overnight. The mean plasma ghrelin concentration was higher in PWS than in the reference population and this difference remained significant after adjustment for percentage of body fat. A positive correlation was found between plasma ghrelin and subjective ratings of hunger. The authors concluded that ghrelin is elevated in subjects with PWS. They also suggested that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.
Haqq et al. (2003) measured fasting serum ghrelin levels in 13 children with PWS with an average age of 9.5 years and body mass index (BMI) of 31.3 kilograms per square meter. The PWS group was compared with 4 control groups: normal weight controls, obese children, and children with melanocortin-4 receptor (155541) mutations and leptin (164160) deficiency. Ghrelin levels in children with PWS were significantly elevated (3-4 fold) compared with BMI-matched obese controls. The authors concluded that elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.
Feigerlova et al. (2008) studied total plasma ghrelin levels in 40 children with PWS and 84 controls from 2 months to 17 years. Plasma ghrelin levels were higher in children with PWS than controls, both in the youngest children below 3 years who were not receiving GH (771 vs 233 pg/ml, P less than 0.0001) and in the children older than 3 years, all of whom were treated with GH (428 vs 159 pg/ml, P less than 0.0001). The authors concluded that plasma ghrelin levels in children with PWS are elevated at any age, including during the first years of life, thus preceding the development of obesity.
Population Genetics
In a review, Butler (1990) estimated the frequency of PWS at about 1 in 25,000 and suggested that it is the most common syndromal cause of human obesity. In a comprehensive survey of PWS in North Dakota, Burd et al. (1990) identified 17 affected persons, from which they derived a prevalence rate of 1 per 16,062.
Whittington et al. (2001) identified all definite or possible PWS cases in the Anglia and Oxford Health Region of the U.K. (population approximately 5 million people). From a total of 167 people referred with possible PWS, 96 were classified as having PWS on genetic and/or clinical grounds. From this, Whittington et al. (2001) estimated a lower limit of population prevalence of 1 in 52,000 with a proposed true prevalence of 1 in 45,000; a lower limit of birth incidence of 1 in 29,000 was also estimated.
Animal Model
Nakatsu et al. (1992) found that the mouse homolog of a human gene within the PWCR is tightly linked to the p locus, which is the site of mutations affecting pigmentation and is often associated with neurologic abnormalities as well. The p locus is located on mouse chromosome 7 near a chromosomal region associated with imprinting effects. Nakatsu et al. (1992) suggested that the hypopigmentation in both PWS and Angelman syndrome may result from an imprinting effect on the human cognate of the mouse p locus.
Although representing only indirectly an animal model in the usual sense, studies focusing on the effects of imprinted genes on brain development by examining the fate of androgenetic (Ag; duplicated paternal genome) and parthenogenetic/gynogenetic (Pg/Gg; duplicated maternal genome) cells in chimeric mouse embryos (Keverne et al., 1996) sheds interesting light on the pathogenesis of the distinctive neuropsychologic features of PWS and Angelman syndrome. Keverne et al. (1996) observed striking cell-autonomous differences in the role of the 2 types of uniparental cells in brain development. Ag cells with a duplicated paternal genome contributed substantially to the hypothalamic structures and not the cerebral cortex. By contrast, Pg/Gg cells with a duplicated maternal genome contributed substantially to the cortex, striatum, and hippocampus but not to the hypothalamic structures. Furthermore, growth of the brain was enhanced by Pg/Gg and retarded by Ag cells. Keverne et al. (1996) proposed that genomic imprinting may represent a change in strategy controlling brain development in mammals. In particular, genomic imprinting may have facilitated a rapid nonlinear expansion of the brain, especially the cortex, during development over evolutionary time. It is noteworthy that Ag cells were seen predominantly in the medial preoptic area and hypothalamus, regions of the brain concerned with neuroendocrine function and primary motivated behavior, including feeding and sexual behavior, which are disturbed in PWS. Contrariwise, MRI shows that the sylvian fissures are anomalous in Angelman patients, who are severely mentally retarded with speech and movement disorders, findings not inconsistent with the distribution of Pg cells.
Yang et al. (1998) created 2 deletion mutations in mice to understand PWS and the mechanism of the 'imprinting center,' or IC, which maps in part to the promoter and first exon of the SNRPN gene (182279). Mice harboring an intragenic deletion of Snrpn were phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lacked expression of the imprinted genes Zfp127 (mouse homolog of ZNF127; 176270), Ndn (602117), and lpw, and manifested several phenotypes common to PWS infants. Mice heterozygous for the paternally inherited IC-deletion died as neonates, 72% within 48 hours. At birth, the heterozygous mutant mice were present in the expected mendelian ratio. On the day of birth, the affected mice appeared normal but underweight. There was little hypotonia, but one consistently observed difference was that mutant mice were unable to support themselves on their hind feet, resting on their knees instead. No genital or gonadal hypoplasia was observed at the time of birth.
Gabriel et al. (1999) reported the characterization of a transgene insertion into mouse chromosome 7C, which resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicated that the transgene-induced mutation had generated a complete deletion of the PWS/AS homologous region but had not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintained the correct imprint in somatic cells of PWS and AS mice and established the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model could be particularly useful for the identification of the etiologic genes and mechanisms, phenotypic basis, and therapeutic approaches for PWS.
Muscatelli et al. (2000) also produced mice deficient for necdin (602117), and suggested that postnatal lethality associated with loss of the paternal gene may vary dependent on the strain. Viable necdin mutants showed a reduction in both oxytocin (167050)-producing and luteinizing hormone-releasing hormone (LHRH; 152760)-producing neurons in hypothalamus, increased skin scraping activity, and improved spatial learning and memory. The authors proposed that underexpression of necdin is responsible for at least a subset of the multiple clinical manifestations of PWS.
Chamberlain et al. (2004) reported survival of PWS-IC deletion mice on a variety of strain backgrounds. Expression analysis of genes affected in the PWS region suggested that while there was low expression from both parental alleles in PWS-IC deletion pups, this expression did not explain their survival on certain strain backgrounds. Rather, the data provided evidence for strain-specific modifier genes that supported the survival of PWS-IC deletion mice.
Lee et al. (2005) demonstrated that morphologic abnormalities in axonal outgrowth and fasciculation manifested in several regions of the nervous system in Ndn (602117)-null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic, and catecholaminergic neurons. Lee et al. (2005) concluded that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin may impinge on axonal outgrowth, and further suggested that loss of necdin may contribute to the neurologic phenotype of PWS. They speculated that codeletion of necdin and the related protein Magel2 (605283) may explain the lack of single gene mutations in PWS.
History
Langdon-Down (1828-1896), who described 'mongolism' (Down syndrome), also described PWS (Down, 1887) about 70 years before Prader et al. (1956), and called it polysarcia (see account by Brain, 1967). The patient was a mentally subnormal girl who, when 13 years old, was 4 feet 4 inches tall (1.32 m) and weighed 196 lbs (84 kg). At 25 years of age she weighed 210 lbs (95.4 kg). 'Her feet and hands remained small, and contrasted remarkably with the appendages they terminated. She had no hair in the axillae, and scarcely any on the pubis. She had never menstruated, nor did she exhibit the slightest sexual instinct.'
INHERITANCE \- Autosomal dominant (loss of paternal allele) GROWTH Height \- Normal birth length \- Length deceleration in first few months \- Mean adult male height, 155 cm \- Mean adult female height, 147 cm \- Steady childhood growth \- Fall-off in adolescent growth Weight \- Failure to thrive in infancy \- Onset of obesity from 6 months to 6 years \- Central obesity HEAD & NECK Head \- Dolichocephaly Face \- Narrow bitemporal diameter Eyes \- Almond-shaped eyes \- Strabismus \- Upslanting palpebral fissures \- Myopia \- Hyperopia Mouth \- Thin upper lip \- Small-appearing mouth \- Down-turned corners of mouth \- Thick, viscous saliva Teeth \- Early dental caries RESPIRATORY \- Hypoventilation \- Hypoxia \- Sleep apnea (obstructive, central, or mixed) ABDOMEN Gastrointestinal \- Feeding problems in infancy requiring gavage feeds \- Decreased vomiting GENITOURINARY External Genitalia (Male) \- Hypogonadotropic hypogonadism \- Small penis \- Scrotal hypoplasia External Genitalia (Female) \- Hypoplastic labia minora \- Hypoplastic clitoris Internal Genitalia (Male) \- Cryptorchidism Internal Genitalia (Female) \- Amenorrhea \- Oligomenorrhea SKELETAL \- Osteoporosis \- Osteopenia Spine \- Scoliosis \- Kyphosis Hands \- Small hands (<25th percentile for height age) \- Narrow hands with straight ulnar border \- Clinodactyly \- Syndactyly Feet \- Small feet (<10th percentile for height age) SKIN, NAILS, & HAIR \- Hypopigmentation Skin \- Fair skin \- Sun sensitivity Hair \- Blonde to light brown hair \- Frontal hair upsweep NEUROLOGIC Central Nervous System \- Mild to moderate mental retardation (~90%) \- Learning disabilities \- Severe neonatal hypotonia improving with age \- Normal neuromuscular studies \- Seizures \- Poor gross motor coordination \- Poor fine motor coordination \- Global developmental delay \- High pain threshold \- Sleep disturbances \- High pain threshold \- Poor neonatal suck and swallow reflexes \- Speech articulation problems Behavioral Psychiatric Manifestations \- Childhood polyphagia (excessive appetite and obsession with eating) \- Behavioral problems \- Stubbornness \- Rage \- Excessive skin picking of sores VOICE \- Hypernasal speech \- Weak or squeaky cry in infancy METABOLIC FEATURES \- Temperature instability ENDOCRINE FEATURES \- Hyperinsulinemia \- Growth hormone deficiency \- Hypogonadotropic hypogonadism PRENATAL MANIFESTATIONS Movement \- Decreased fetal activity Delivery \- Breech position LABORATORY ABNORMALITIES \- Microdeletion of 15q11 in 70% of patients confirmed by fluorescent in situ hybridization MISCELLANEOUS \- Imprinted disorder \- Unusual skill with jigsaw puzzle \- Most cases due to interstitial deletions, the remainder of cases are secondary to maternal disomy \- Rare cases secondary to chromosome translocation MOLECULAR BASIS \- Contiguous gene syndrome caused by deletion of the paternal allele of the imprinted region at 15q11.2 ▲ Close
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| PRADER-WILLI SYNDROME | c0032897 | 4,958 | omim | https://www.omim.org/entry/176270 | 2019-09-22T16:35:51 | {"doid": ["11983"], "mesh": ["D011218"], "omim": ["176270"], "icd-9": ["759.81"], "icd-10": ["Q87.1"], "orphanet": ["739"], "synonyms": ["Alternative titles", "PRADER-LABHART-WILLI SYNDROME"], "genereviews": ["NBK1330"]} |
## Description
Glucose is the major source of energy in humans, with levels in vivo determined by a balance of glucose absorption via the gut, production primarily by the liver, and utilization by both insulin-sensitive and insulin-insensitive tissues. Blood and plasma fasting glucose levels are tightly regulated within a narrow physiologic range by a feedback mechanism that targets a particular fasting glucose set point for each individual. Within healthy, nondiabetic populations there is substantial variation in fasting glucose levels. Approximately one-third of this variation is genetic. Disruption of normal glucose homeostasis and substantial elevations of fasting glucose are hallmarks of type 2 diabetes (T2D) and typically result from sustained reduction in pancreatic beta-cell function and insulin secretion (summary by Chen et al., 2008 and Prokopenko et al., 2009).
### Genetic Heterogeneity
Genetic loci influencing fasting plasma glucose have been identified on 2q24-q32 (FGQTL1), related to single-nucleotide polymorphisms (SNPs) in the vicinity of the G6PC2 gene (608058); on 7p15-p13 (FGQTL2; 613219), related to SNPs in the vicinity of the glucokinase gene (GCK; 138079); on 11q21-q22 (FGQTL3; 613233), related to SNPs in the vicinity of the MTNR1B gene (600804); on 7p21.2 (FGQTL4; 613462), in the vicinity of the DGKB gene (604070); on 2p23.3-p23.2 (FGQTL5; 613463) due to variation in the GCKR gene (600842); and on 3q21 (FGQTL6; 613460), in the vicinity of the ADCY5 gene (600293).
See 613219 for a discussion of birth weight as a quantitative trait, another glycemic-influenced trait with an effect on T2D risk. See also 606035 for a discussion of a fasting insulin quantitative trait locus on chromosome 6q22-q24.
Mapping
To identify genetic determinants that contribute to interindividual variation in fasting plasma glucose, Bouatia-Naji et al. (2008) tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with fasting plasma glucose, and replicated the most strongly associated SNP, rs560887 (p = 4 x 10(-7)), in 9,353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene (608058), which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with fasting plasma glucose (linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined p = 4 x 10(-23)) and with pancreatic beta cell function (Homa-B model, combined P = 3 x 10(-13)) in 3 populations; however, it was not associated with risk of type 2 diabetes (125853) or body mass index (BMI). Bouatia-Naji et al. (2008) noted that the observed association signal might be caused by an unidentified SNP in high LD with rs560887 and stated that further investigation would be required to define the functional consequences on G6PC2 splicing or gene expression.
Chen et al. (2008) performed 2 genomewide association scans in a total of 5,088 nondiabetic individuals from Finland and Sardinia and found a significant association between the rs563694 SNP on chromosome 2q24 and fasting glucose concentrations (p = 3.5 x 10(-7)), which was confirmed in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies (combined p = 6.9 x 10(-26)); combining results from all the studies yielded an overall p value of 6.3 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01 to 0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The authors noted that rs563694 is located in an extended region of linkage disequilibrium between 2 biologically plausible candidate genes, G6PC2 and ABCB11 (603201).
Prokopenko et al. (2009) examined the leading association signals in 10 genomewide association studies involving a total of 36,610 individuals of European descent. They confirmed previous associations of fasting glucose with variants at the G6PC2 locus (rs560887, p = 1.1 x 10(-57)).
To identify new loci influencing glycemic traits, Dupuis et al. (2010) performed metaanalyses of 21 genomewide association studies informative for fasting glucose, fasting insulin, and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and 2 loci associated with fasting insulin and HOMA-IR. Dupuis et al. (2010) found the C allele of rs560887 associated with elevated fasting glucose, with a global p value of 8.7 x 10(-218). The SNP was also associated with HOMA-B (global p = 1.5 x 10(-66)).
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| FASTING PLASMA GLUCOSE LEVEL QUANTITATIVE TRAIT LOCUS 1 | c2677501 | 4,959 | omim | https://www.omim.org/entry/612108 | 2019-09-22T16:02:20 | {"omim": ["612108"]} |
Occurs when a reservoir population causes an epidemic in a novel host population
Spillover infection, also known as pathogen spillover and spillover event, occurs when a reservoir population with a high pathogen prevalence comes into contact with a novel host population. The pathogen is transmitted from the reservoir population and may or may not be transmitted within the host population.[1]
## Contents
* 1 Spillover zoonoses
* 2 Intraspecies spillover
* 3 See also
* 4 References
* 5 External links
## Spillover zoonoses[edit]
Spillover is a common event; in fact, more than two-thirds of human viruses are zoonotic.[2] Most spillover events result in self-limited cases with no further human to human transmission, as occurs, for example, with rabies, anthrax, histoplasmosis or hidatidosis. Other zoonotic pathogens are able to be transmitted by humans to produce secondary cases and even to establish limited chains of transmission. Some examples are the Ebola and Marburg filoviruses, the MERS and SARS coronaviruses or some avian flu viruses. Finally, some few spillover events can result in the final adaptation of the microbe to the humans, who became a new stable reservoir, as occurred with the HIV virus resulting in the AIDS epidemic. In fact, most of the pathogens which are presently exclusive of humans were probably transmitted by other animals sometime in the past.[3] If the history of mutual adaptation is long enough, permanent host-microbe associations can be established resulting in co-evolution, and even on permanent integration of the microbe genome in the human genome, as it is the case of endogenous viruses. The closer the two species are in phylogenetic terms, the easier it is for microbes to overcome the biological barrier to produce successful spillovers. For this reason, other mammals are the main source of zoonotic agents for humans.
Zoonotic spillover has increased in the last 50 years, mainly due to the environmental impact of agriculture, that promotes deforestation, changing wildlife habitat, and the impacts of increased land use.[4]
## Intraspecies spillover[edit]
Commercially bred bumblebees used to pollinate greenhouses can be reservoirs for several pollinator parasites including the protozoans Crithidia bombi, and Apicystis bombi,[5] the Microsporidians Nosema bombi and Nosema ceranae,[5][6] plus viruses such as Deformed wing virus and the tracheal mites Locustacarus buchneri.[6] Commercial bees that escape the glasshouse environment may then infect wild bee populations. Infection may be via direct interactions between managed and wild bees or via shared flower use and contamination.[7][8] One study found that half of all wild bees found near greenhouses were infected with C. bombi. Rates and incidence of infection decline dramatically the further away from the greenhouses the wild bees are located.[9][10] Instances of spillover between bumblebees are well documented across the world but particularly in Japan, North America and the United Kingdom.[11][12]
## See also[edit]
* Viruses portal
* Medicine portal
* 1993 Four Corners hantavirus outbreak
* Cross-species transmission
* Epidemic
* Infection
* List of Legionellosis outbreaks
* Outbreak
* Severe acute respiratory syndrome coronavirus 2
## References[edit]
1. ^ Power, AG; Mitchell, CE (Nov 2004). "Pathogen spillover in disease epidemics". Am Nat. 164 (Suppl 5): S79–89. doi:10.1086/424610. PMID 15540144.
2. ^ Woolhouse M, Scott F, Hudson Z, Howey R, Chase-Topping M. Human viruses: discovery and emergence. Phil. Trans. R. Soc. B (2012) 367, 2864–2871
3. ^ Wolfe ND, Dunavan CP, Diamond J Origins of major human infectious diseases. Nature, 477: 279-283.
4. ^ Berger, Kevin (2020-03-12). "The Man Who Saw the Pandemic Coming". Nautilus. Retrieved 2020-03-16.
5. ^ a b Graystock, P; Yates, K; Evison, SEF; Darvill, B; Goulson, D; Hughes, WOH (2013). "The Trojan hives: pollinator pathogens, imported and distributed in bumblebee colonies". Journal of Applied Ecology. 50 (5): 1207–15. doi:10.1111/1365-2664.12134.
6. ^ a b Sachman-Ruiz, Bernardo; Narváez-Padilla, Verónica; Reynaud, Enrique (2015-03-10). "Commercial Bombus impatiens as reservoirs of emerging infectious diseases in central México". Biological Invasions. 17 (7): 2043–53. doi:10.1007/s10530-015-0859-6. ISSN 1387-3547.
7. ^ Durrer, Stephan; Schmid-Hempel, Paul (1994-12-22). "Shared Use of Flowers Leads to Horizontal Pathogen Transmission". Proceedings of the Royal Society of London B: Biological Sciences. 258 (1353): 299–302. Bibcode:1994RSPSB.258..299D. doi:10.1098/rspb.1994.0176. ISSN 0962-8452.
8. ^ Graystock, Peter; Goulson, Dave; Hughes, William O. H. (2015-08-22). "Parasites in bloom: flowers aid dispersal and transmission of pollinator parasites within and between bee species". Proc. R. Soc. B. 282 (1813): 20151371. doi:10.1098/rspb.2015.1371. ISSN 0962-8452. PMC 4632632. PMID 26246556.
9. ^ Otterstatter, MC; Thomson, JD (2008). "Does Pathogen Spillover from Commercially Reared Bumble Bees Threaten Wild Pollinators?". PLOS ONE. 3 (7): e2771. Bibcode:2008PLoSO...3.2771O. doi:10.1371/journal.pone.0002771. PMC 2464710. PMID 18648661.
10. ^ Graystock, Peter; Goulson, Dave; Hughes, William O.H. (2014). "The relationship between managed bees and the prevalence of parasites in bumblebees". PeerJ. 2: e522. doi:10.7717/peerj.522. PMC 4137657. PMID 25165632.
11. ^ Graystock, Peter; Blane, Edward J.; McFrederick, Quinn S.; Goulson, Dave; Hughes, William O. H. (2016). "Do managed bees drive parasite spread and emergence in wild bees?". International Journal for Parasitology: Parasites and Wildlife. 5 (1): 64–75. doi:10.1016/j.ijppaw.2015.10.001. PMC 5439461. PMID 28560161.
12. ^ Imported bumblebees pose risk to UK's wild and honeybee population. Damian Carrington. theguardian.com, Thursday 18 July 2013
## External links[edit]
* Infection Information Resource
* European Center for Disease Prevention and Control
* U.S. Centers for Disease Control and Prevention,
* Infectious Disease Society of America (IDSA)
* v
* t
* e
Concepts in infectious disease
Transmission
Basic concepts
* Asymptomatic carrier
* Host
* Incubation period
* Index case
* Infectious period
* Latent period
* Natural reservoir
* Subclinical infection
* Super-spreader
Modes
* Human-to-human transmission
* Horizontal
* Vertical
* Cross-species transmission
* Spillover infection
* Vector
* Zoonosis
* Reverse zoonosis
Routes
* Airborne disease
* Blood-borne disease
* Foodborne illness
* Waterborne disease
* Hospital-acquired infection
* Fomite
* Fecal-oral route
* Sexual
Modelling
* Attack rate
* Basic reproduction number
* Compartmental models in epidemiology
* Critical community size
* Herd immunity
* Infection rate
* Serial interval
* Transmission risks and rates
Medication
* Antimicrobial
* Antibiotic
* Antiviral drug
* Antimicrobial resistance
* Immunotherapy
* Phage therapy
* Vaccination
Emerging infections
* Disease X
* Emergent virus
Other
* Discovery of disease-causing pathogens
* Eradication of infectious diseases
* Pandemic
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Spillover infection | None | 4,960 | wikipedia | https://en.wikipedia.org/wiki/Spillover_infection | 2021-01-18T19:08:49 | {"wikidata": ["Q16000336"]} |
Idiopathic and/or familial pulmonary arterial hypertension (IFPAH) is a form or pulmonary arterial hypertension (PAH, see his term) characterized by elevated pulmonary arterial resistance leading to right heart failure; it is progressive and potentially fatal. About 75% of heritable pulmonary arterial hypertension (HPAH, see this term) have an identified mutation. HPAH has been linked to mutations in BMPR2 in 75% of cases; other genes implicated in HPAH include ACVR1, BMPR1, CAV1, ENG and SMAD9 and CBLN2. (However, the majority of patients carrying an HPAH mutation do not develop PAH). Idiopathic pulmonary arterial hypertension (IFPAH; see this term) refers to those cases of pulmonary arterial hypertension in which etiology remains unknown .
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Idiopathic/heritable pulmonary arterial hypertension | c4552070 | 4,961 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=422 | 2021-01-23T18:25:42 | {"mesh": ["D065627"], "omim": ["178600", "265400", "615342", "615343", "615344"], "icd-10": ["I27.0"], "synonyms": ["Idiopathic and/or familial pulmonary arterial hypertension"]} |
Rapid, irregular beating of the atria of the heart
Atrial fibrillation
Other namesAuricular fibrillation[1]
Leads V4 and V5 of an electrocardiogram showing atrial fibrillation with somewhat irregular intervals between heart beats, no P waves, and a heart rate of about 150 beats per minute.
SpecialtyCardiology
SymptomsNone, heart palpitations, fainting, shortness of breath, chest pain[2][3]
ComplicationsHeart failure, dementia, stroke[3]
Usual onset> age 50[4]
Risk factorsHigh blood pressure, valvular heart disease, coronary artery disease, cardiomyopathy, congenital heart disease, COPD, obesity, smoking, sleep apnea[3][5][6][7]
Diagnostic methodFeeling the pulse, electrocardiogram[8]
Differential diagnosisIrregular heartbeat[9]
TreatmentLifestyle modifications, rate control, rhythm control, anticoagulation[5]
Frequency2.5% (developed world), 0.5% (developing world)[4]
Deaths193,300 with atrial flutter (2015)[10]
Atrial fibrillation (AF or A-fib) is an abnormal heart rhythm (arrhythmia) characterized by the rapid and irregular beating of the atrial chambers of the heart.[11] It often begins as short periods of abnormal beating, which become longer or continuous over time.[4] It may also start as other forms of arrhythmia such as atrial flutter that then transform into AF.[12] Often episodes have no symptoms.[3] Occasionally there may be heart palpitations, fainting, lightheadedness, shortness of breath, or chest pain.[2] The disease is associated with an increased risk of heart failure, dementia, and stroke.[3] It is a type of supraventricular tachycardia.[13]
High blood pressure and valvular heart disease are the most common alterable risk factors for AF.[5][6] Other heart-related risk factors include heart failure, coronary artery disease, cardiomyopathy, and congenital heart disease.[5] In the developing world, valvular heart disease often occurs as a result of rheumatic fever.[14] Lung-related risk factors include COPD, obesity, and sleep apnea.[3] Other factors include excess alcohol intake, tobacco smoking, diabetes mellitus, and thyrotoxicosis.[3][7][14] However, half of the cases are not associated with any of these risks.[3] Healthcare professionals may suspect AF by feeling the pulse and confirm the diagnosis by interpreting an electrocardiogram (ECG).[8] A typical ECG in AF shows no P waves and an irregular ventricular rate.[8]
Healthy lifestyle changes, such as weight loss in people with obesity, increased physical activity, and drinking less alcohol, can lower the risk for atrial fibrillation and reduce its burden if it occurs.[15] AF is often treated with medications to slow the heart rate to a near-normal range (known as rate control) or to convert the rhythm to normal sinus rhythm (known as rhythm control).[5] Electrical cardioversion can convert AF to normal heart rhythm and is often necessary for emergent use if the person is unstable.[16] Ablation may prevent recurrence in some people.[17] For those at low risk of stroke, AF does not necessarily require blood-thinning though some healthcare providers may prescribe aspirin or an anti-clotting medication.[18] For those at more than low risk, experts generally recommend an anti-clotting medication.[18] Anti-clotting medications include warfarin and direct oral anticoagulants.[18] Most people are at higher risk of stroke.[19] While these medications reduce stroke risk, they increase rates of major bleeding.[20]
Atrial fibrillation is the most common serious abnormal heart rhythm and, as of 2020, affects more than 33 million people worldwide.[3][15] As of 2014, it affected about 2 to 3% of the population of Europe and North America.[4] This was an increase from 0.4 to 1% of the population around 2005.[21] In the developing world, about 0.6% of males and 0.4% of females are affected.[4] The percentage of people with AF increases with age with 0.1% under 50 years old, 4% between 60 and 70 years old, and 14% over 80 years old being affected.[4] A-fib and atrial flutter resulted in 193,300 deaths in 2015, up from 29,000 in 1990.[10][22] The first known report of an irregular pulse was by Jean-Baptiste de Sénac in 1749.[3] Thomas Lewis was the first doctor to document this by ECG in 1909.[3]
## Contents
* 1 Signs and symptoms
* 1.1 Rapid heart rate
* 2 Causes
* 2.1 Genetics
* 2.2 Sedentary lifestyle
* 2.3 Tobacco
* 2.4 Alcohol
* 2.5 High blood pressure
* 2.6 Other diseases
* 2.7 Medications
* 3 Pathophysiology
* 3.1 Pathology
* 3.2 Electrophysiology
* 4 Diagnosis
* 4.1 Screening
* 4.2 Minimal evaluation
* 4.2.1 History and physical examination
* 4.2.2 Routine bloodwork
* 4.2.3 Electrocardiogram
* 4.2.4 Echocardiography
* 4.3 Extended evaluation
* 4.3.1 Chest X-ray
* 4.3.2 Transesophageal echocardiogram
* 4.3.3 Ambulatory Holter monitoring
* 4.3.4 Exercise stress testing
* 4.4 Classification
* 5 Prevention
* 5.1 Lifestyle modification
* 6 Management
* 6.1 Lifestyle modification
* 6.2 Comorbidity treatment
* 6.3 Anticoagulants
* 6.4 Rate versus rhythm control
* 6.5 Rate control
* 6.6 Cardioversion
* 6.7 Surgery
* 6.7.1 Ablation
* 6.7.2 Left atrial appendage occlusion
* 6.7.3 After surgery
* 7 Prognosis
* 7.1 Blood clots
* 7.1.1 Prediction of embolism
* 7.1.2 Mechanism of thrombus formation
* 7.2 Dementia
* 8 Epidemiology
* 8.1 Sex
* 8.2 Ethnicity
* 8.3 Young people
* 9 History
* 10 Other animals
* 11 References
* 12 External links
## Signs and symptoms[edit]
Normal rhythm tracing (top) Atrial fibrillation (bottom)
How a stroke can occur during atrial fibrillation
AF is usually accompanied by symptoms related to a rapid heart rate. Rapid and irregular heart rates may be perceived as the sensation of the heart beating too fast, irregularly, or skipping beats (palpitations) or exercise intolerance and occasionally may produce anginal chest pain (if the high heart rate causes the heart's demand for oxygen to increase beyond the supply of available oxygen (ischemia)). Other possible symptoms include congestive heart failure symptoms such as fatigue, shortness of breath, or swelling. The abnormal heart rhythm (arrhythmia) is sometimes only identified with the onset of a stroke or a transient ischemic attack (TIA). It is not uncommon for a person to first become aware of AF from a routine physical examination or ECG, as it often does not cause symptoms.[21]
Since most cases of AF are secondary to other medical problems, the presence of chest pain or angina, signs and symptoms of hyperthyroidism (an overactive thyroid gland) such as weight loss and diarrhea, and symptoms suggestive of lung disease can indicate an underlying cause. A history of stroke or TIA, as well as high blood pressure, diabetes, heart failure, or rheumatic fever, may indicate whether someone with AF is at a higher risk of complications.[21] The risk of a blood clot forming in the left atrial chamber of the heart, breaking off, and then traveling in the bloodstream can be assessed using the CHADS2 or CHA2DS2-VASc score.
### Rapid heart rate[edit]
Presentation is similar to other forms of rapid heart rate and may be asymptomatic.[23] Palpitations and chest discomfort are common complaints.[23] The rapid uncoordinated heart rate may result in reduced output of blood pumped by the heart (cardiac output), resulting in inadequate blood flow, and therefore oxygen delivery to the rest of the body. Common symptoms of uncontrolled atrial fibrillation may include shortness of breath,[23] shortness of breath when lying flat, dizziness, and sudden onset of shortness of breath during the night. This may progress to swelling of the lower extremities, a manifestation of congestive heart failure. Due to inadequate cardiac output, individuals with AF may also complain of light-headedness,[23] may feel like they are about to faint, or may lose consciousness.
AF can cause respiratory distress due to congestion in the lungs. By definition, the heart rate will be greater than 100 beats per minute. Blood pressure may be variable, and often difficult to measure as the beat-by-beat variability causes problems for most digital (oscillometric) non-invasive blood pressure monitors. For this reason, when determining the heart rate in AF, direct cardiac auscultation is recommended. Low blood pressure is most concerning, and a sign that immediate treatment is required. Many of the symptoms associated with uncontrolled atrial fibrillation are a manifestation of congestive heart failure due to the reduced cardiac output. The affected person's respiratory rate often increases in the presence of respiratory distress. Pulse oximetry may confirm the presence of too little oxygen reaching the body's tissues, related to any precipitating factors such as pneumonia. Examination of the jugular veins may reveal elevated pressure (jugular venous distention). Examination of the lungs may reveal crackles, which are suggestive of pulmonary edema. Examination of the heart will reveal a rapid irregular rhythm.
## Causes[edit]
Non-modifiable risk factors (top left box) and modifiable risk factors (bottom left box) for atrial fibrillation. The main outcomes of atrial fibrillation are in the right box. BMI=Body Mass Index.
AF is linked to several forms of cardiovascular disease but may occur in otherwise normal hearts. Cardiovascular factors known to be associated with the development of AF include high blood pressure, coronary artery disease, mitral valve stenosis (e.g., due to rheumatic heart disease or mitral valve prolapse), mitral regurgitation, left atrial enlargement, hypertrophic cardiomyopathy (HCM), pericarditis, congenital heart disease, and previous heart surgery.[24] Congenital heart disease is a strong risk factor for developing atrial fibrillation—a 20-year-old adult with congenital heart disease has a comparable lifetime risk of developing atrial fibrillation when compared to a 55-year-old adult with no history of congenital heart disease.[24] People with congenital heart disease tend to develop atrial fibrillation at a younger age, that is more likely to be of right atrial origin (atypical) than of left origin, and have a greater risk of progressing to permanent atrial fibrillation.[25]
Additionally, lung diseases (such as pneumonia, lung cancer, pulmonary embolism, and sarcoidosis) may play a role in certain people. Sepsis also increases the risk of developing new-onset atrial fibrillation.[26][27] Disorders of breathing during sleep, such as obstructive sleep apnea (OSA), are also associated with AF.[28] Obesity is a risk factor for AF.[29] Hyperthyroidism and subclinical hyperthyroidism are associated with AF development.[30]
Caffeine consumption does not appear to be associated with AF;[15][31] excessive alcohol consumption ("binge drinking" or "holiday heart syndrome") is linked to AF.[32] Low-to-moderate alcohol consumption also appears to be associated with an increased risk of developing atrial fibrillation, although the increase in risk associated with drinking less than two drinks daily appears to be small.[32][33] Tobacco smoking and secondhand tobacco smoke exposure are associated with an increased risk of developing atrial fibrillation.[7][34] Long-term endurance exercise that far exceeds the recommended amount of exercise (e.g., long-distance cycling or marathon running) appears to be associated with a modest increase in the risk of atrial fibrillation in middle-aged and elderly people.[19][35][36]
### Genetics[edit]
A family history of AF may increase the risk of AF. A study of more than 2,200 people found an increased risk factor for AF of 1.85 for those that had at least one parent with AF.[37][38][39] Various genetic mutations may be responsible.[40][41]
Four types of genetic disorder are associated with atrial fibrillation:[42]
* Familial AF as a monogenic disease
* Familial AF presenting in the setting of another inherited cardiac disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, familial amyloidosis)
* Inherited arrhythmic syndromes (congenital long QT syndrome, short QT syndrome, Brugada syndrome)
* Non-familial AF associated with genetic backgrounds (polymorphism in the ACE gene) that may predispose to atrial fibrillation
Family history in a first degree relative is associated with a 40% increase in risk of AF. This finding led to the mapping of different loci such as 10q22-24, 6q14-16 and 11p15-5.3 and discover mutations associated with the loci. Fifteen mutations of gain and loss of function have been found in the genes of K+ channels, including mutations in KCNE1-5, KCNH2, KCNJ5 or ABCC9 among others. Six variations in genes of Na+ channels that include SCN1-4B, SCN5A and SCN10A have also been found. All of these mutations affect the processes of polarization-depolarization of the myocardium, cellular hyper-excitability, shortening of effective refractory period favoring re-entries.[43] Other mutations in genes, such as GJA5, affect gap junctions, generating a cellular uncoupling that promotes re-entries and a slow conduction velocity.[44] Using genome-wide association study, which screen the entire genome for single nucleotide polymorphism (SNP), three susceptibility loci have been found for AF (4q25, 1q21 and 16q22).[45] In these loci there are SNPs associated with a 30% increase in risk of recurrent atrial tachycardia after ablation. There are also SNPs associated with loss of function of the Pitx2c gene (involved in cellular development of pulmonary valves), responsible for re-entries. There are also SNPs close to ZFHX3 genes involved in the regulation of Ca2+.[43] A GWAS meta-analysis study conducted in 2018 revealed the discovery of 70 new loci associated with AF. Different variants have been identified. They are associated with genes that encode transcription factors, such as TBX3 and TBX5, NKX2-5 or PITX2, involved in the regulation of cardiac conduction, modulation of ion channels and in cardiac development. Have been also identified new genes involved in tachycardia (CASQ2) or associated with an alteration in cardiomyocyte communication (PKP2).[46] Rare mutations in the cardiomyopathy gene TTN may also increase the risk of AF, even in individuals without signs of heart failure.[47][48] Small genetic deletions on the X chromosome around the STS (steroid sulfatase) gene are associated with increased rates of AF in males [49]
### Sedentary lifestyle[edit]
A sedentary lifestyle increases the risk factors associated with AF, such as obesity, hypertension, or diabetes mellitus. This favors remodeling processes of the atrium due to inflammation or alterations in the depolarization of cardiomyocytes by elevation of sympathetic nervous system activity.[43][50] A sedentary lifestyle is associated with an increased risk of AF compared to physical activity. In both men and women, the practice of moderate exercise reduces the risk of AF progressively;[51] intense sports may increase the risk of developing AF, as seen in athletes.[52] It is due to a remodeling of cardiac tissue,[53] and an increase in vagal tone, which shortens the effective refractory period (ERP) favoring re-entries from the pulmonary veins.[51]
### Tobacco[edit]
The rate of AF in smokers is 1.4 times higher than in non-smokers.[54] However, snus consumption, which delivers nicotine at a dose equivalent to that of cigarettes and is debated as a harm-reduction product, is not correlated with AF.[55]
### Alcohol[edit]
Acute alcohol consumption can directly trigger an episode of atrial fibrillation.[32] Regular alcohol consumption also increases the risk of atrial fibrillation in several ways.[32] The long-term use of alcohol alters the physical structure and electrical properties of the atria.[32] Alcohol consumption does this by repeatedly stimulating the sympathetic nervous system, increasing inflammation in the atria, raising blood pressure, lowering the levels of potassium and magnesium in the blood, worsening obstructive sleep apnea, and by promoting harmful structural changes (remodeling) in the atria and ventricles of the heart.[32] This remodeling leads to abnormally increased pressure in the left atrium, inappropriately dilates it, and increases scarring (fibrosis) in the left atrium.[32] The aforementioned structural changes increase the risk of developing atrial fibrillation when paired with the harmful changes in how the left atrium conducts electricity.[32]
### High blood pressure[edit]
According to the CHARGE Consortium, both systolic and diastolic blood pressure are predictors of the risk of AF. Systolic blood pressure values close to normal limit the increase in the risk associated with AF. Diastolic dysfunction is also associated with AF, which increases left atrial pressure, left atrial volume, size, and left ventricular hypertrophy, characteristic of chronic hypertension. All atrial remodeling is related to heterogeneous conduction and the formation of re-entrant electric conduction from the pulmonary veins.[43][54]
### Other diseases[edit]
There is a relationship between risk factors such as obesity and hypertension, with the appearance of diseases such as diabetes mellitus and sleep apnea-hypopnea syndrome, specifically, obstructive sleep apnea (OSA). These diseases are associated with an increased risk of AF due to their remodeling effects on the left atrium.[43]
### Medications[edit]
Several medications are associated with an increased risk of developing atrial fibrillation.[56] Few studies have examined this phenomenon, and the exact incidence of medication-induced atrial fibrillation is unknown.[56] Medications that are commonly associated with an increased risk of developing atrial fibrillation include dobutamine and the chemotherapy agent cisplatin.[56] Agents associated with a moderately increased risk include nonsteroidal anti-inflammatory drugs (e.g., ibuprofen), bisphosphonates, and other chemotherapeutic agents such as melphalan, interleukin 2, and anthracyclines.[56] Other medications that rarely increase the risk of developing atrial fibrillation include adenosine, aminophylline, corticosteroids, ivabradine, ondansetron, and antipsychotics.[56] This form of atrial fibrillation occurs in people of all ages but is most common in the elderly, in those with other atrial fibrillation risk factors, and after heart surgery.[56]
## Pathophysiology[edit]
The normal electrical conduction system of the heart allows electrical impulses generated by the heart's own pacemaker (the sinoatrial node) to spread to and stimulate the muscular layer of the heart (myocardium) in both the atria and the ventricles. When the myocardium is stimulated it contracts, and if this occurs in an orderly manner allows blood to be pumped to the body. In AF, the normal regular electrical impulses generated by the sinoatrial node are overwhelmed by disorganized electrical waves, usually originating from the roots of the pulmonary veins. These disorganized waves conduct intermittently through the atrioventricular node, leading to irregular activation of the ventricles that generate the heartbeat.
### Pathology[edit]
The primary pathologic change seen in atrial fibrillation is the progressive fibrosis of the atria. This fibrosis is due primarily to atrial dilation; however, genetic causes and inflammation may be factors in some individuals. Dilation of the atria can be due to almost any structural abnormality of the heart that can cause a rise in the pressure within the heart. This includes valvular heart disease (such as mitral stenosis, mitral regurgitation, and tricuspid regurgitation), hypertension, and congestive heart failure. Any inflammatory state that affects the heart can cause fibrosis of the atria. This is typically due to sarcoidosis but may also be due to autoimmune disorders that create autoantibodies against myosin heavy chains. Mutation of the lamin AC gene is also associated with fibrosis of the atria that can lead to atrial fibrillation.
Once dilation of the atria has occurred, this begins a chain of events that leads to the activation of the renin–angiotensin–aldosterone system (RAAS) and subsequent increase in matrix metalloproteinases and disintegrin, which leads to atrial remodeling and fibrosis, with loss of atrial muscle mass. This process occurs gradually, and experimental studies have revealed patchy atrial fibrosis may precede the occurrence of atrial fibrillation and may progress with prolonged durations of atrial fibrillation.
Fibrosis is not limited to the muscle mass of the atria and may occur in the sinus node (SA node) and atrioventricular node (AV node), correlating with sick sinus syndrome. Prolonged episodes of atrial fibrillation have been shown to correlate with prolongation of the sinus node recovery time;[21] this suggests that dysfunction of the SA node is progressive with prolonged episodes of atrial fibrillation.
### Electrophysiology[edit]
Conduction
Sinus rhythm
Atrial fibrillation
There are multiple theories about the cause of atrial fibrillation. An important theory is that, in atrial fibrillation, the regular impulses produced by the sinus node for a normal heartbeat are overwhelmed by rapid electrical discharges produced in the atria and adjacent parts of the pulmonary veins. Sources of these disturbances are either automatic foci, often localized at one of the pulmonary veins, or a small number of localized sources in the form of either a re-entrant leading circle or electrical spiral waves (rotors); these localized sources may be found in the left atrium near the pulmonary veins or a variety of other locations through both the left or right atrium. Three fundamental components favor the establishment of a leading circle or a rotor: slow conduction velocity of the cardiac action potential, a short refractory period, and a small wavelength. Meanwhile, the wavelength is the product of velocity and refractory period. If the action potential has fast conduction, with a long refractory period and/or conduction pathway shorter than the wavelength, an AF focus would not be established. In multiple wavelet theory, a wavefront will break into smaller daughter wavelets when encountering an obstacle, through a process called vortex shedding. But, under the proper conditions, such wavelets can reform and spin around a center, forming an AF focus.[57]
In a heart with AF, the increased calcium release from the sarcoplasmic reticulum and increased calcium sensitivity can lead to an accumulation of intracellular calcium and causes downregulation of L-type calcium channels. This reduces the duration of action potential and refractory period, thus favorable for the conduction of re-entrant waves. Increased expression of inward-rectifier potassium ion channels can cause a reduced atrial refractory period and wavelength. The abnormal distribution of gap junction proteins such as GJA1 (also known as Connexin 43), and GJA5 (Connexin 40) causes non-uniformity of electrical conduction, thus causing the arrhythmia.[58]
AF can be distinguished from atrial flutter (AFL), which appears as an organized electrical circuit usually in the right atrium. AFL produces characteristic saw-toothed F-waves of constant amplitude and frequency on an ECG, whereas AF does not. In AFL, the discharges circulate rapidly at a rate of 300 beats per minute (bpm) around the atrium. In AF, there is no regularity of this kind, except at the sources where the local activation rate can exceed 500 bpm. Although AF and atrial flutter are distinct arrhythmias, atrial flutter may degenerate into AF, and an individual may experience both arrhythmias at different times.[12]
Although the electrical impulses of AF occur at a high rate, most of them do not result in a heartbeat. A heartbeat results when an electrical impulse from the atria passes through the atrioventricular (AV) node to the ventricles and causes them to contract. During AF, if all of the impulses from the atria passed through the AV node, there would be severe ventricular tachycardia, resulting in a severe reduction of cardiac output. This dangerous situation is prevented by the AV node since its limited conduction velocity reduces the rate at which impulses reach the ventricles during AF.[59]
## Diagnosis[edit]
A 12-lead ECG showing atrial fibrillation at approximately 132 beats per minute
Diagram of normal sinus rhythm as seen on ECG. In atrial fibrillation the P waves, which represent depolarization of the top of the heart, are absent.
The evaluation of atrial fibrillation involves a determination of the cause of the arrhythmia, and classification of the arrhythmia. Diagnostic investigation of AF typically includes a complete history and physical examination, ECG, transthoracic echocardiogram, complete blood count, and serum thyroid stimulating hormone level.[23]
### Screening[edit]
Limited evidence suggests that screening for atrial fibrillation in those 65 years and older increases the number of cases of atrial fibrillation detected.[60] A Scottish inquiry into atrial fibrillation estimated that as many as one-third of people with AF are undiagnosed.[61] Despite this, in 2018, the United States Preventive Services Task Force found insufficient evidence to determine the usefulness of routine screening.[62]
### Minimal evaluation[edit]
In general, the minimal evaluation of atrial fibrillation should be performed in all individuals with AF. The goal of this evaluation is to determine the general treatment regimen for the individual. If the results of the general evaluation warrant it, further studies may then be performed.
#### History and physical examination[edit]
The history of the individual's atrial fibrillation episodes is probably the most important part of the evaluation. Distinctions should be made between those who are entirely asymptomatic when they are in AF (in which case the AF is found as an incidental finding on an ECG or physical examination) and those who have gross and obvious symptoms due to AF and can pinpoint whenever they go into AF or revert to sinus rhythm.
#### Routine bloodwork[edit]
While many cases of AF have no definite cause, it may be the result of various other problems. Hence, kidney function and electrolytes are routinely determined, as well as thyroid-stimulating hormone (commonly suppressed in hyperthyroidism and of relevance if amiodarone is administered for treatment) and a blood count.[21]
In acute-onset AF associated with chest pain, cardiac troponins, or other markers of damage to the heart muscle may be ordered. Coagulation studies (INR/aPTT) are usually performed, as anticoagulant medication may be commenced.[21]
#### Electrocardiogram[edit]
ECG of atrial fibrillation (top) and normal sinus rhythm (bottom). The purple arrow indicates a P wave, which is lost in atrial fibrillation.
Atrial fibrillation is diagnosed on an electrocardiogram (ECG), an investigation performed routinely whenever an irregular heartbeat is suspected. Characteristic findings are the absence of P waves, with disorganized electrical activity in their place, and irregular R–R intervals due to irregular conduction of impulses to the ventricles.[21] At very fast heart rates, atrial fibrillation may look more regular, which may make it more difficult to separate from other supraventricular tachycardias or ventricular tachycardia.[63]
QRS complexes should be narrow, signifying that they are initiated by normal conduction of atrial electrical activity through the intraventricular conduction system. Wide QRS complexes are worrisome for ventricular tachycardia, although, in cases where there is a disease of the conduction system, wide complexes may be present in A-fib with rapid ventricular response.
If paroxysmal AF is suspected, but an ECG during an office visit shows only a regular rhythm, AF episodes may be detected and documented with the use of ambulatory Holter monitoring (e.g., for a day). If the episodes are too infrequent to be detected by Holter monitoring with reasonable probability, then the person can be monitored for longer periods (e.g., a month) with an ambulatory event monitor.[21]
#### Echocardiography[edit]
In general, a non-invasive transthoracic echocardiogram (TTE) is performed in newly diagnosed AF, as well as if there is a major change in the person's clinical state. This ultrasound-based scan of the heart may help identify valvular heart disease (which may greatly increase the risk of stroke and alter recommendations for the appropriate type of anticoagulation), left and right atrial size (which predicts the likelihood that AF may become permanent), left ventricular size and function, peak right ventricular pressure (pulmonary hypertension), presence of left atrial thrombus (low sensitivity), presence of left ventricular hypertrophy and pericardial disease.[21]
Significant enlargement of both the left and right atria is associated with long-standing atrial fibrillation and, if noted at the initial presentation of atrial fibrillation, suggests that the atrial fibrillation is likely to be of a longer duration than the individual's symptoms.
### Extended evaluation[edit]
In general, an extended evaluation is not necessary for most individuals with atrial fibrillation and is performed only if abnormalities are noted in the limited evaluation, if a reversible cause of the atrial fibrillation is suggested, or if further evaluation may change the treatment course.
#### Chest X-ray[edit]
In general, a chest X-ray is performed only if a pulmonary cause of atrial fibrillation is suggested, or if other cardiac conditions are suspected (in particular congestive heart failure). This may reveal an underlying problem in the lungs or the blood vessels in the chest.[21] In particular, if an underlying pneumonia is suggested, then treatment of the pneumonia may cause the atrial fibrillation to terminate on its own.
#### Transesophageal echocardiogram[edit]
A regular echocardiogram (transthoracic echo/TTE) has a low sensitivity for identifying blood clots in the heart. If this is suspected (e.g., when planning urgent electrical cardioversion), a transesophageal echocardiogram/TEE (or TOE where British spelling is used) is preferred.[21]
The TEE has much better visualization of the left atrial appendage than transthoracic echocardiography.[64] This structure, located in the left atrium, is the place where a blood clot forms in more than 90% of cases in non-valvular (or non-rheumatic) atrial fibrillation.[65][66] TEE has a high sensitivity for locating thrombi in this area and can also detect sluggish blood flow in this area that is suggestive of blood clot formation.[64]
If a blood clot is seen on TEE, then cardioversion is contraindicated due to the risk of stroke, and anticoagulation is recommended.
#### Ambulatory Holter monitoring[edit]
A Holter monitor is a wearable ambulatory heart monitor that continuously monitors the heart rate and heart rhythm for a short duration, typically 24 hours. In individuals with symptoms of significant shortness of breath with exertion or palpitations regularly, a Holter monitor may be of benefit to determine whether rapid heart rates (or unusually slow heart rates) during atrial fibrillation are the cause of the symptoms.
#### Exercise stress testing[edit]
Some individuals with atrial fibrillation do well with normal activity but develop shortness of breath with exertion. It may be unclear whether the shortness of breath is due to a blunted heart rate response to exertion caused by excessive atrioventricular node-blocking agents, a very rapid heart rate during exertion, or other underlying conditions such as chronic lung disease or coronary ischemia. An exercise stress test will evaluate the individual's heart rate response to exertion and determine whether the AV node blocking agents are contributing to the symptoms.
### Classification[edit]
Classification system AF category Defining characteristics
First detected only one diagnosed episode
Paroxysmal recurrent episodes that stop on their own in less than seven days
Persistent recurrent episodes that last more than seven days
Permanent an ongoing long-term episode
The American College of Cardiology (ACC), American Heart Association (AHA), and the European Society of Cardiology (ESC) recommend in their guidelines the following classification system based on simplicity and clinical relevance.[21]
All people with AF are initially in the category called first detected AF. These people may or may not have had previous undetected episodes. If a first detected episode stops on its own in less than seven days and then another episode begins, later on, the category changes to paroxysmal AF. Although people in this category have episodes lasting up to seven days, in most cases of paroxysmal AF, the episodes will stop in less than 24 hours. If the episode lasts for more than seven days, it is unlikely to stop on its own and is then known as persistent AF. In this case, cardioversion can be used to stop the episode. If cardioversion is unsuccessful, or not attempted and the episode continues for a long time (e.g., a year or more), the person's AF is then known as permanent.[67]
Episodes that last less than 30 seconds are not considered in this classification system. Also, this system does not apply to cases where the AF is a secondary condition that occurs in the setting of a primary condition that may be the cause of the AF.
About half of people with AF have permanent AF, while a quarter has paroxysmal AF, and a quarter has persistent AF.[4]
In addition to the above four AF categories, which are mainly defined by episode timing and termination, the ACC/AHA/ESC guidelines describe additional AF categories in terms of other characteristics of the person.[21]
* Lone atrial fibrillation (LAF) – the absence of clinical or echocardiographic findings of other cardiovascular diseases (including hypertension), related pulmonary diseases, or cardiac abnormalities such as enlargement of the left atrium, and age under 60 years
* Nonvalvular AF (NVAF) – the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair
* Secondary AF – occurs in the setting of a primary condition that may be the cause of the AF, such as acute myocardial infarction, cardiac surgery, pericarditis, myocarditis, hyperthyroidism, pulmonary embolism, pneumonia, or another acute pulmonary disease
Lastly, atrial fibrillation is also classified by whether or not it is caused by valvular heart disease. Valvular atrial fibrillation refers to atrial fibrillation attributable to moderate to severe mitral valve stenosis or atrial fibrillation in the presence of a mechanical artificial heart valve.[68] This distinction is necessary since it has implications on appropriate treatment, including differing recommendations for anticoagulation.
## Prevention[edit]
Prevention of atrial fibrillation focuses primarily on preventing or controlling its risk factors. Many of its risk factors, such as obesity, smoking, lack of physical activity, and excessive alcohol consumption, are modifiable and preventable with lifestyle modification or can be managed by a healthcare professional.[56]
### Lifestyle modification[edit]
Several healthy lifestyle behaviors are associated with a lower likelihood of developing atrial fibrillation. Accordingly, consensus guidelines recommend abstaining from alcohol and recreational drugs, stopping tobacco use, maintaining a healthy weight, and regularly participating in moderate-intensity physical activities.[56] Consistent moderate-intensity aerobic exercise, defined as achieving 3.0-5.9 METs of intensity, for at least 150 minutes per week may reduce the risk of developing new-onset atrial fibrillation.[15] Few studies have examined the role of specific dietary changes and how it relates to the prevention of atrial fibrillation.[56]
## Management[edit]
Main article: Management of atrial fibrillation
The main goals of treatment are to prevent circulatory instability and stroke. Rate or rhythm control is used to achieve the former, whereas anticoagulation is used to decrease the risk of the latter.[69] If cardiovascularly unstable due to uncontrolled tachycardia, immediate cardioversion is indicated.[21] Many antiarrhythmics, when used long term, increase the risk of death without any meaningful benefit.[70] An integrated management approach, which includes stroke prevention, symptoms control and management of associated comorbdities [71] was associated with better outcomes in patients with atrial fibrillation.[72][73][74]
### Lifestyle modification[edit]
Regular aerobic exercise improves atrial fibrillation symptoms and AF-related quality of life.[15] The effect of high-intensity interval training on reducing atrial fibrillation burden is unclear.[15] Weight loss of at least 10% is associated with reduced atrial fibrillation burden in people who are overweight or obese.[15]
### Comorbidity treatment[edit]
For people who have both atrial fibrillation and obstructive sleep apnea, observational studies suggest that continuous positive airway pressure (CPAP) treatment appears to lower the risk of atrial fibrillation recurrence after undergoing ablation.[15] Randomized controlled trials examining the role of obstructive sleep apnea treatment on atrial fibrillation incidence and burden are lacking.[15] Guideline-recommended lifestyle and medical interventions are recommended for people with atrial fibrillation and coexisting conditions such as hyperlipidemia, diabetes mellitus, or hypertension without specific blood sugar or blood pressure targets for people with atrial fibrillation.[15] Bariatric surgery may reduce the risk of new-onset atrial fibrillation in people with obesity without AF and may reduce the risk of a recurrence of AF after an ablation procedure in people with coexisting obesity and atrial fibrillation.[15] It is important for all people with atrial fibrillation to optimize the control of all coexisting medical conditions that can worsen their atrial fibrillation, such as hyperthyroidism, congestive heart failure, high blood pressure, stimulant use (e.g., methamphetamine dependence), and excessive alcohol consumption.[75]
### Anticoagulants[edit]
Anticoagulation can be used to reduce the risk of stroke from AF. Anticoagulation is recommended in most people other than those at low risk of stroke[76] or those at high risk of bleeding. The risk of falls and consequent bleeding in frail elderly people should not be considered a barrier to initiating or continuing anticoagulation since the risk of fall-related brain bleeding is low and the benefit of stroke prevention often outweighs the risk of bleeding.[77][78] Similarly, the presence or absence of AF symptoms does not determine whether a person warrants anticoagulation and is not an indicator of stroke risk.[33] Oral anticoagulation is underused in atrial fibrillation, while aspirin is overused in many who should be treated with a direct oral anticoagulant (DOAC) or warfarin.[79][80][81] In 2019, DOACs were often recommended over warfarin by the American Heart Association.[82]
The risk of stroke from non-valvular AF can be estimated using the CHA2DS2-VASc score. In the 2019 AHA/ACC/HRS guidelines anticoagulation is recommended in non-valvular AF if there is a score of two or more in men and three or more in women and may be considered if there is a score of one in men or two in women, and not using anticoagulation is reasonable if there is a score of zero in men or one in women.[82] Guidelines from the American College of Chest Physicians, Asia-Pacific Heart Rhythm Society, Canadian Cardiovascular Society, European Society of Cardiology, Japanese Circulation Society, Korean Heart Rhythm Society, and the National Institute for Health and Care Excellence recommend the use of novel oral anticoagulants or warfarin with a CHA2DS2-VASc score of one over aspirin and some directly recommend against aspirin.[81][83][84][85][86][87][88][89] Experts generally advocate for most people with atrial fibrillation with CHA2DS2-VASc scores of one or more receiving anticoagulation though aspirin is sometimes used for people with a score of one (moderate risk for stroke).[79] There is little evidence to support the idea that the use of aspirin significantly reduces the risk of stroke in people with atrial fibrillation.[79] Furthermore, aspirin's major bleeding risk (including bleeding in the brain) is similar to that of warfarin and DOACs despite its inferior efficacy.[80][87]
Anticoagulation can be achieved through several means including warfarin,[90] heparin, dabigatran, rivaroxaban,[91] edoxaban,[92] and apixaban.[93] Many issues should be considered related to their comparative effectiveness, including the cost of DOACs, risk of stroke, risk of falls, comorbidities (such as chronic liver or kidney disease), the presence of significant mitral stenosis or mechanical heart valves, compliance, and speed of the desired onset of anticoagulation.[94][68][95] The optimal approach to anticoagulation in people with AF and who simultaneously have other diseases (e.g., cirrhosis and end-stage kidney disease on dialysis) that predispose a person to both bleeding and clotting complications is unclear.[96][97]
For those with non-valvular atrial fibrillation, DOACs (rivaroxaban, dabigatran, apixaban) are at least as effective as warfarin for preventing strokes and blood clots embolizing to the systemic circulation (if not more so) and are generally preferred over warfarin.[68][98][99][100] DOACs carry a lower risk of bleeding in the brain compared to warfarin,[78] although dabigatran is associated with a higher risk of intestinal bleeding.[98][99] Dual antiplatelet therapy with aspirin and clopidogrel is inferior to warfarin for preventing strokes and has comparable bleeding risk in people with atrial fibrillation.[101] In those who are also on aspirin, however, DOACs appear to be better than warfarin.[102]
Warfarin is the recommended anticoagulant choice for persons with valvular atrial fibrillation (atrial fibrillation in the presence of a mechanical heart valve and/or moderate-severe mitral valve stenosis).[68] The exception to this recommendation is in people with valvular atrial fibrillation who are unable to maintain a therapeutic INR on warfarin therapy; in such cases, treatment with a DOAC is then recommended.[68]
### Rate versus rhythm control[edit]
There are two ways to approach atrial fibrillation using medications: rate control and rhythm control. Both methods have similar outcomes.[103] Rate control lowers the heart rate closer to normal, usually 60 to 100 bpm, without trying to convert to a regular rhythm. Rhythm control tries to restore a normal heart rhythm in a process called cardioversion and maintains the normal rhythm with medications. Studies suggest that rhythm control is more important in the acute setting AF, whereas rate control is more important in the chronic phase.
The risk of stroke appears to be lower with rate control versus attempted rhythm control, at least in those with heart failure.[104] AF is associated with a reduced quality of life, and, while some studies indicate that rhythm control leads to a higher quality of life, some did not find a difference.[105]
Neither rate nor rhythm control is superior in people with heart failure when they are compared in various clinical trials. However, rate control is recommended as the first-line treatment regimen for people with heart failure. On the other hand, rhythm control is only recommended when people experience persistent symptoms despite adequate rate control therapy.[106]
In those with a fast ventricular response, intravenous magnesium significantly increases the chances of achieving successful rate and rhythm control in the urgent setting without major side-effects.[107] A person with poor vital signs, mental status changes, preexcitation, or chest pain often will go to immediate treatment with synchronized DC cardioversion.[21] Otherwise, the decision of rate control versus rhythm control using medications is made. This is based several criteria that include whether or not symptoms persist with rate control.
### Rate control[edit]
Rate control to a target heart rate of fewer than 110 beats per minute is recommended in most people.[108] Lower heart rates may be recommended in those with left ventricular hypertrophy or reduced left ventricular function.[109] Rate control is achieved with medications that work by increasing the degree of the block at the level of the AV node, decreasing the number of impulses that conduct into the ventricles. This can be done with:[21][110]
* Beta blockers (preferably the "cardioselective" beta blockers such as metoprolol, bisoprolol, or nebivolol)
* Non-dihydropyridine calcium channel blockers (e.g., diltiazem or verapamil)
* Cardiac glycosides (e.g., digoxin) – have less use, apart from in older people who are sedentary. They are not as effective as either beta blockers or calcium channel blockers.[5]
In those with chronic AF either beta blockers or calcium channel blockers are recommended.[108]
In addition to these agents, amiodarone has some AV node blocking effects (in particular when administered intravenously) and can be used in individuals when other agents are contraindicated or ineffective (particularly due to hypotension).
### Cardioversion[edit]
Cardioversion is the attempt to switch an irregular heartbeat to a normal heartbeat using electrical or chemical means.[21]
* Electrical cardioversion involves the restoration of normal heart rhythm through the application of a DC electrical shock. The exact placement of the pads does not appear to be important.[111]
* Chemical cardioversion is performed with medications, such as amiodarone, dronedarone,[112] procainamide (especially in pre-excited atrial fibrillation), dofetilide, ibutilide, propafenone, or flecainide.
After successful cardioversion, the heart may be stunned, which means that there is a normal rhythm, but the restoration of normal atrial contraction has not yet occurred.[113]
### Surgery[edit]
#### Ablation[edit]
Catheter ablation (CA) is a procedure performed by an electrophysiologist, a cardiologist who specializes in heart rhythm problems, to restore the heart's normal rhythm by destroying, or electrically isolating, specific parts of the atria. Most commonly, CA electrically isolates the left atrium from the pulmonary veins, where most of the abnormal electrical activity promoting atrial fibrillation originates.[75] CA is a form of rhythm control that restores normal sinus rhythm and reduces AF-associated symptoms more reliably than antiarrhythmic medications.[75] Electrophysiologists generally use two forms of catheter ablation—radiofrequency ablation and cryoablation. In young people with little-to-no structural heart disease where rhythm control is desired and cannot be maintained by medication or cardioversion, radiofrequency catheter ablation or cryoablation may be attempted and is preferred over several years of medical therapy.[21][114] Although radiofrequency ablation is becoming an accepted intervention in selected younger people, evidence is lacking that ablation reduces all-cause mortality, stroke, or heart failure.[75] Some evidence indicates CA may be particularly helpful for people with AF who also have heart failure.[115] AF may recur in people who have undergone CA and nearly half of people who undergo it will require a repeat procedure to achieve long-term control of their AF.[75] In general, CA is more successful at preventing AF recurrence if AF is paroxysmal as opposed to persistent or permanent.[116] CA is useful to reduce AF symptoms and reduce AF burden, but does not reduce the risk of stroke, therefore many are advised to continue their anticoagulation.[75] Possible complications include common, minor complications such as the formation of a collection of blood at the site where the catheter goes into the vein (access site hematoma), but also more dangerous complications including bleeding around the heart (cardiac tamponade), stroke, damage to the esophagus (atrio-esophageal fistula), or even death.[75][117]
The Maze procedure, first performed in 1987, is an effective invasive surgical treatment that is designed to create electrical blocks or barriers in the atria of the heart, forcing electrical impulses that stimulate the heartbeat to travel down to the ventricles. The idea is to force abnormal electrical signals to move along one, uniform path to the lower chambers of the heart (ventricles), thus restoring the normal heart rhythm.[118] People with AF often undergo cardiac surgery for other underlying reasons and are frequently offered concomitant AF surgery to reduce the frequency of short- and long-term AF. Concomitant AF surgery is more likely to lead to the person being free from atrial fibrillation and off medications three months after surgery, but these same people are more likely to need a pacemaker following the procedure.[119]
AF often occurs after cardiac surgery and is usually self-limiting. It is strongly associated with age, preoperative hypertension, and the number of vessels grafted. Measures should be taken to control hypertension preoperatively to reduce the risk of AF. Also, people with a higher risk of AF, e.g., people with pre-operative hypertension, more than three vessels grafted, or greater than 70 years of age, should be considered for prophylactic treatment. Postoperative pericardial effusion is also suspected to be the cause of atrial fibrillation. Prophylaxis may include prophylactic postoperative rate and rhythm management. Some authors perform posterior pericardiotomy to reduce the incidence of postoperative AF.[120] When AF occurs, management should primarily be rate and rhythm control. However, cardioversion may be employed if the person is hemodynamically unstable, highly symptomatic, or persists for six weeks after discharge. In persistent cases, anticoagulation should be used.
#### Left atrial appendage occlusion[edit]
There is tentative evidence that left atrial appendage occlusion therapy may reduce the risk of stroke in people with non-valvular AF as much as warfarin.[121]
3D Medical Animation still shot of Left Atrial Appendage Occlusion
#### After surgery[edit]
After catheter ablation, people are moved to a cardiac recovery unit, intensive care unit, or cardiovascular intensive care unit where they are not allowed to move for 4–6 hours. Minimizing movement helps prevent bleeding from the site of the catheter insertion. The length of time people stay in the hospital varies from hours to days. This depends on the problem, the length of the operation, and whether or not general anesthetic was used. Additionally, people should not engage in strenuous physical activity – to maintain a low heart rate and low blood pressure – for around six weeks.[122]
## Prognosis[edit]
Atrial fibrillation increases the risk of heart failure by 11 per 1000, kidney problems by 6 per 1000, death by 4 per 1000, stroke by 3 per 1000, and coronary heart disease by 1 per 1000.[123] Women have a worse outcome overall than men.[124] Evidence increasingly suggests that atrial fibrillation is independently associated with a higher risk of developing dementia.[125]
### Blood clots[edit]
See also: CHA2DS2-VASc score
#### Prediction of embolism[edit]
Among Danish men aged 50, with no risk factors, the 5-year risk of stroke was 1.1% and with AF alone 2.5%. For women the risks were slightly less, 0.7% and 2.1%. For men aged 70, the 5-year risk of stroke was 4.8% and with AF alone 6.8%. For women aged 70 the risk was again lower than for men, 3.4% with no added risk factor and 8.2% with AF.[126]
Determining the risk of an embolism causing a stroke is important for guiding the use of anticoagulants. The most accurate clinical prediction rules are:[127]
* CHADS2
* CHA2DS2-VASc score
Both the CHADS2 and the CHA2DS2-VASc score predict future stroke risk in people with A-fib with CHA2DS2-VASc score being more accurate. Some that had a CHADS2 score of zero had a CHA2DS2-VASc score of three, with a 3.2% annual risk of stroke. Thus, a CHA2DS2-VASc score of zero is considered very low risk.[128]
#### Mechanism of thrombus formation[edit]
In atrial fibrillation, the lack of an organized atrial contraction can result in some stagnant blood in the left atrium (LA) or left atrial appendage (LAA). This lack of movement of blood can lead to thrombus formation (blood clotting). If the clot becomes mobile and is carried away by the blood circulation, it is called an embolus. An embolus proceeds through smaller and smaller arteries until it plugs one of them and prevents blood from flowing through the artery. This process results in end organ damage due to the loss of nutrients, oxygen, and the removal of cellular waste products. Emboli in the brain may result in an ischemic stroke or a transient ischemic attack (TIA).
More than 90% of cases of thrombi associated with non-valvular atrial fibrillation evolve in the left atrial appendage.[65] However, the LAA lies in close relation to the free wall of the left ventricle, and thus the LAA's emptying and filling, which determines its degree of blood stagnation, may be helped by the motion of the wall of the left ventricle if there is good ventricular function.[129]
### Dementia[edit]
Atrial fibrillation has been independently associated with a higher risk of developing cognitive impairment, vascular dementia, and Alzheimer disease.[125][130] Several mechanisms for this association have been proposed, including silent small blood clots (subclinical microthrombi) traveling to the brain resulting in small ischemic strokes without symptoms, altered blood flow to the brain, inflammation, clinically silent small bleeds in the brain, and genetic factors.[125][130] Tentative evidence suggests that effective anticoagulation with direct oral anticoagulants or warfarin may be somewhat protective against AF-associated dementia and evidence of silent ischemic strokes on MRI but this remains an active area of investigation.[125][130]
## Epidemiology[edit]
Atrial fibrillation is the most common arrhythmia and affects more than 33 million people worldwide.[15][21] In Europe and North America, as of 2014[update], it affects about 2% to 3% of the population.[4] This is an increase from 0.4 to 1% of the population around 2005.[21] In the developing world, rates are about 0.6% for males and 0.4% for females.[4] The number of people diagnosed with AF has increased due to better detection of silent AF and increasing age and conditions that predispose to it.[131]
It also accounts for one-third of hospital admissions for cardiac rhythm disturbances,[21] and the rate of admissions for AF has risen in recent years.[132] Strokes from AF account for 20–30% of all ischemic strokes.[131] After a transient ischemic attack or stroke, about 11% are found to have a new diagnosis of atrial fibrillation.[133] Between 3 and 11% of those with AF have structurally normal hearts.[134] Approximately 2.2 million individuals in the United States and 4.5 million in the European Union have AF.[21]
The number of new cases each year of atrial fibrillation increases with age. In individuals over the age of 80, it affects about 8%.[21] In contrast, atrial fibrillation is relatively rare in younger individuals with an estimated prevalence of 0.05% and is associated with the presence of congenital heart disease or structural heart disease in this demographic.[135] As of 2001, it was anticipated that in developed countries, the number of people with atrial fibrillation was likely to increase during the following 50 years, owing to the growing proportion of elderly individuals.[136]
### Sex[edit]
It is more common in men than in women, in European and North American populations.[137] In Asian populations and both developed and developing countries, there is also a higher rate in men than in women. The risk factors associated with AF are also distributed differently according to sex. In men, coronary disease is more frequent, while in women, high systolic blood pressure and valvular heart disease are more prevalent.[43]
### Ethnicity[edit]
Rates of AF are lower in populations of African descent than in populations of European descent. The African descent is associated with a protective effect of AF, due to the low presence of SNPs with guanine alleles, in comparison with the European ancestry. European ancestry has more frequent mutations.[43] The variant rs4611994 for the gene PITX2 is associated with the risk of AF in African and European populations.[43][46] Other studies reveal that Hispanic and Asian populations have a lower risk of AF compared to populations of European descent. Also, they demonstrate that the risk of AF in non-European populations is associated with characteristic risk factors of these populations, such as hypertension.[138]
### Young people[edit]
Atrial fibrillation is an uncommon condition in children but sometimes occurs in association with certain inherited and acquired conditions. Congenital heart disease and rheumatic fever are the most common causes of atrial fibrillation in children. Other inherited heart conditions associated with the development of atrial fibrillation in children include Brugada syndrome, short QT syndrome, Wolff Parkinson White syndrome, and other forms of supraventricular tachycardia (e.g., AV nodal reentrant tachycardia).[135] Adults who survived congenital heart disease have an increased risk of developing AF. In particular, people who had atrial septal defects, Tetralogy of Fallot, or Ebstein's anomaly, and those who underwent the Fontan procedure, are at higher risk with prevalence rates of up to 30% depending on the heart's anatomy and the person's age.[25]
## History[edit]
Because the diagnosis of atrial fibrillation requires measurement of the electrical activity of the heart, atrial fibrillation was not truly described until 1874, when Edmé Félix Alfred Vulpian observed the irregular atrial electrical behavior that he termed "fremissement fibrillaire" in dog hearts.[139] In the mid-eighteenth century, Jean-Baptiste de Sénac made note of dilated, irritated atria in people with mitral stenosis.[140] The irregular pulse associated with AF was first recorded in 1876 by Carl Wilhelm Hermann Nothnagel and termed "delirium cordis", stating that "[I]n this form of arrhythmia the heartbeats follow each other in complete irregularity. At the same time, the height and tension of the individual pulse waves are continuously changing".[141] Correlation of delirium cordis with the loss of atrial contraction, as reflected in the loss of a waves in the jugular venous pulse, was made by Sir James MacKenzie in 1904.[142] Willem Einthoven published the first ECG showing AF in 1906.[143] The connection between the anatomic and electrical manifestations of AF and the irregular pulse of delirium cordis was made in 1909 by Carl Julius Rothberger, Heinrich Winterberg, and Sir Thomas Lewis.[144][145][146]
## Other animals[edit]
Atrial fibrillation occurs in other animals, including cats, dogs, and horses.[147][148] Unlike humans, dogs rarely suffer from the complications that stem from blood clots breaking off from inside the heart and traveling through the arteries to distant sites (thromboembolic complications).[147] Cats rarely develop atrial fibrillation but appear to have a higher risk of thromboembolic complications than dogs.[147] Cats and dogs with atrial fibrillation often have underlying structural heart disease that predisposes them to the condition.[147] The medications used in animals for atrial fibrillation are largely similar to those used in humans.[147] Electrical cardioversion is occasionally performed in these animals, but the need for general anesthesia limits its use.[147] Standardbred horses appear to be genetically susceptible to developing atrial fibrillation.[148] Horses that develop atrial fibrillation often have minimal or no underlying heart disease, and the presence of atrial fibrillation in horses can adversely affect physical performance.[148]
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134. ^ Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA, Weyman AE (1990). "Atrial enlargement as a consequence of atrial fibrillation A prospective echocardiographic study". Circulation. 82 (3): 792–97. doi:10.1161/01.CIR.82.3.792. PMID 2144217.
135. ^ a b Gourraud, JB; Khairy, P; Abadir, S; Tadros, R; Cadrin-Tourigny, J (July 2018). "Atrial fibrillation in young patients". Expert Review of Cardiovascular Therapy. 16 (7): 489–500. doi:10.1080/14779072.2018.1490644. PMID 29912584. S2CID 49305621.
136. ^ Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (May 2001). "Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study". primary source. JAMA. 285 (18): 2370–75. doi:10.1001/jama.285.18.2370. PMID 11343485.
137. ^ Schnabel RB, Yin X, Gona P (2015). "50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study". Lancet. 386 (9989): 154–162. doi:10.1016/S0140-6736(14)61774-8. PMC 4553037. PMID 25960110.
138. ^ Dewland TA, Olgin JE, Vittinghoff E (2013). "Incident atrial fibrillation among Asians, Hispanics, blacks, and whites". Circulation. 128 (23): 2470–2477. doi:10.1161/CIRCULATIONAHA.113.002449. PMID 24103419.
139. ^ Vulpian A (1874). "Note sur les effets de la faradisation directe des ventricules du coeur chez le chien". Archives de Physiologie Normale et Pathologique. 6: 975.
140. ^ McMichael J (1982). "History of atrial fibrillation 1628–1819 Harvey – de Senac – Laënnec". Br Heart J. 48 (3): 193–97. doi:10.1136/hrt.48.3.193. PMC 481228. PMID 7049202.
141. ^ Nothnagel H (1876). "Ueber arythmische Herzthatigkeit". Deutsches Archiv für Klinische Medizin. 17: 190–220.
142. ^ MacKenzie J (1904). "Observations on the Inception of the Rhythm of the Heart by the Ventricle: As the cause of Continuous Irregularity of the Heart". Br Med J. 1 (2253): 529–36. doi:10.1136/bmj.1.2253.529. PMC 2353402. PMID 20761393.
143. ^ Einthoven W (1906). "Le telecardiogramme". Archives Internationales de Physiologie. 4: 132–64.
144. ^ Rothberger CJ, Winterberg H (1909). "Vorhofflimmern und Arhythmia perpetua". Wiener Klinische Wochenschrift. 22: 839–44.
145. ^ Lewis T (1909). "Auricular fibrillation: a common clinical condition". Br Med J. 2 (2552): 1528. doi:10.1136/bmj.2.2552.1528. PMC 2321318. PMID 20764769.
146. ^ Flegel KM (1995). "From delirium cordis to atrial fibrillation: historical development of a disease concept". Ann. Intern. Med. 122 (11): 867–73. doi:10.7326/0003-4819-122-11-199506010-00010. PMID 7741373. S2CID 10629315.
147. ^ a b c d e f Pariaut, R (September 2017). "Atrial Fibrillation: Current Therapies". The Veterinary Clinics of North America. Small Animal Practice. 47 (5): 977–88. doi:10.1016/j.cvsm.2017.04.002. PMID 28645513.
148. ^ a b c van Loon, G (April 2019). "Cardiac Arrhythmias in Horses". The Veterinary Clinics of North America. Equine Practice. 35 (1): 85–102. doi:10.1016/j.cveq.2018.12.004. PMID 30871832.
## External links[edit]
Classification
D
* ICD-10: I48.0, I48.1, I48.2, I48.9
* ICD-9-CM: 427.31
* MeSH: D001281
* DiseasesDB: 1065
External resources
* MedlinePlus: 000184
* eMedicine: med/184 emerg/46
* Patient UK: Atrial fibrillation
Wikimedia Commons has media related to Atrial fibrillation.
* Atrial fibrillation at Curlie
* Wann LS; Curtis AB; Ellenbogen KA; Estes NA; Ezekowitz MD; Jackman WM; January CT; Lowe JE; Page RL; Slotwiner DJ; Stevenson WG; Tracy CM; Fuster V; Rydén LE; Cannom DS; Crijns HJ; Curtis AB; Ellenbogen KA; Halperin JL; Le Heuzey J; Kay GN; Lowe JE; Olsson SB; Prystowsky EN; Tamargo JL (7 May 2013). "Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines". Circulation. 127 (18): 1916–26. doi:10.1161/CIR.0b013e318290826d. PMID 23545139.
* Atrial fibrillation toolkit – American College of Cardiology
* v
* t
* e
Cardiovascular disease (heart)
Ischaemic
Coronary disease
* Coronary artery disease (CAD)
* Coronary artery aneurysm
* Spontaneous coronary artery dissection (SCAD)
* Coronary thrombosis
* Coronary vasospasm
* Myocardial bridge
Active ischemia
* Angina pectoris
* Prinzmetal's angina
* Stable angina
* Acute coronary syndrome
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* Unstable angina
Sequelae
* hours
* Hibernating myocardium
* Myocardial stunning
* days
* Myocardial rupture
* weeks
* Aneurysm of heart / Ventricular aneurysm
* Dressler syndrome
Layers
Pericardium
* Pericarditis
* Acute
* Chronic / Constrictive
* Pericardial effusion
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* Hemopericardium
Myocardium
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* Alcoholic
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* Cardiac amyloidosis
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* Arrhythmogenic right ventricular dysplasia
Endocardium /
valves
Endocarditis
* infective endocarditis
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Valves
* mitral
* regurgitation
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* stenosis
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* stenosis
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* tricuspid
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* insufficiency
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* stenosis
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arrhythmia
Bradycardia
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* AV
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(paroxysmal and sinus)
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* Accelerated idioventricular rhythm
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* Atrial
* Junctional
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Pre-excitation syndrome
* Lown–Ganong–Levine
* Wolff–Parkinson–White
Flutter / fibrillation
* Atrial flutter
* Ventricular flutter
* Atrial fibrillation
* Familial
* Ventricular fibrillation
Pacemaker
* Ectopic pacemaker / Ectopic beat
* Multifocal atrial tachycardia
* Pacemaker syndrome
* Parasystole
* Wandering atrial pacemaker
Long QT syndrome
* Andersen–Tawil
* Jervell and Lange-Nielsen
* Romano–Ward
Cardiac arrest
* Sudden cardiac death
* Asystole
* Pulseless electrical activity
* Sinoatrial arrest
Other / ungrouped
* hexaxial reference system
* Right axis deviation
* Left axis deviation
* QT
* Short QT syndrome
* T
* T wave alternans
* ST
* Osborn wave
* ST elevation
* ST depression
* Strain pattern
Cardiomegaly
* Ventricular hypertrophy
* Left
* Right / Cor pulmonale
* Atrial enlargement
* Left
* Right
* Athletic heart syndrome
Other
* Cardiac fibrosis
* Heart failure
* Diastolic heart failure
* Cardiac asthma
* Rheumatic fever
Authority control
* GND: 4278966-7
* NDL: 01103770
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Atrial fibrillation | c0004238 | 4,962 | wikipedia | https://en.wikipedia.org/wiki/Atrial_fibrillation | 2021-01-18T19:05:01 | {"mesh": ["D001281"], "umls": ["C0004238"], "wikidata": ["Q815819"]} |
Rolando fracture
SpecialtyHand surgery
The Rolando fracture is a comminuted intra-articular fracture through the base of the first metacarpal bone (the first bone forming the thumb[1]). It was first described in 1910 by Silvio Rolando.[2] This is a fracture consisting of 3 distinct fragments; it is typically T- or Y-shaped.
## Contents
* 1 Treatment
* 2 Prognosis
* 3 See also
* 4 References
* 5 Further reading
* 6 External links
## Treatment[edit]
There are several proposed methods of treatment. The quality of reduction does not correlate with late symptoms and osteoarthritic changes. Despite this fact, the joint surface should be restored as close to its anatomical position as possible.[citation needed] Some advocate fixation with Kirschner wires, or plate and screw constructions. Another accepted treatment is an external fixator accompanied by the tension band wiring technique.[3]
Tension band wiring is a technique in which the bone fragments are transfixed by Kirschner wires, which are then also used as an anchor for a loop of flexible wire. As the loop is tightened the bone fragments are compressed together.[citation needed]
## Prognosis[edit]
The Rolando fracture is less common than the Bennett's fracture, and is associated with a worse prognosis.[citation needed]
## See also[edit]
* Bennett's fracture
* Boxer's fracture
* Gamekeeper's thumb
## References[edit]
1. ^ "Wheeless' Textbook of Orthopaedics".
2. ^ Rolando S. Fracture de la base du premier metacarpien et principalement sur une variete` non encore e`crite. Presse Med 1910;33:303–4 [in French].
3. ^ Howard, FM (Jul 1987). "Fractures of the basal joint of the thumb". Clinical Orthopaedics and Related Research (220): 46–51. doi:10.1097/00003086-198707000-00007. PMID 3595009.
Bibliography
* Canale, S. Terry; Beaty, James H., eds. (2008). "64". Campbell's operative orthopaedics. 4 (11th ed.). Philadelphia, PA: Mosby/Elsevier. pp. 3927–3931. ISBN 978-0-323-03329-9.
## Further reading[edit]
* Edmunds, JO (Aug 2006). "Traumatic dislocations and instability of the trapeziometacarpal joint of the thumb" (PDF). Hand Clinics. 22 (3): 365–92. doi:10.1016/j.hcl.2006.05.001. PMID 16843802. Archived from the original (PDF) on 2011-07-17.
## External links[edit]
Classification
D
* ICD-10: S62.2
External resources
* eMedicine: orthoped/288
* v
* t
* e
Fractures and cartilage damage
General
* Avulsion fracture
* Chalkstick fracture
* Greenstick fracture
* Open fracture
* Pathologic fracture
* Spiral fracture
Head
* Basilar skull fracture
* Blowout fracture
* Mandibular fracture
* Nasal fracture
* Le Fort fracture of skull
* Zygomaticomaxillary complex fracture
* Zygoma fracture
Spinal fracture
* Cervical fracture
* Jefferson fracture
* Hangman's fracture
* Flexion teardrop fracture
* Clay-shoveler fracture
* Burst fracture
* Compression fracture
* Chance fracture
* Holdsworth fracture
Ribs
* Rib fracture
* Sternal fracture
Shoulder fracture
* Clavicle
* Scapular
Arm fracture
Humerus fracture:
* Proximal
* Supracondylar
* Holstein–Lewis fracture
Forearm fracture:
* Ulna fracture
* Monteggia fracture
* Hume fracture
* Radius fracture/Distal radius
* Galeazzi
* Colles'
* Smith's
* Barton's
* Essex-Lopresti fracture
Hand fracture
* Scaphoid
* Rolando
* Bennett's
* Boxer's
* Busch's
Pelvic fracture
* Duverney fracture
* Pipkin fracture
Leg
Tibia fracture:
* Bumper fracture
* Segond fracture
* Gosselin fracture
* Toddler's fracture
* Pilon fracture
* Plafond fracture
* Tillaux fracture
Fibular fracture:
* Maisonneuve fracture
* Le Fort fracture of ankle
* Bosworth fracture
Combined tibia and fibula fracture:
* Trimalleolar fracture
* Bimalleolar fracture
* Pott's fracture
Crus fracture:
* Patella fracture
Femoral fracture:
* Hip fracture
Foot fracture
* Lisfranc
* Jones
* March
* Calcaneal
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Rolando fracture | None | 4,963 | wikipedia | https://en.wikipedia.org/wiki/Rolando_fracture | 2021-01-18T18:47:10 | {"umls": ["CL427952"], "icd-10": ["S62.2"], "wikidata": ["Q7360596"]} |
Gallstone ileus
SpecialtyGastroenterology
Gallstone ileus is a rare form of small bowel obstruction caused by an impaction of a gallstone within the lumen of the small intestine. Such a gallstone enters the bowel via a cholecysto-enteric fistula. The presence of large stones, >2.5 cm in diameter, within the gallbladder are thought to predispose to fistula formation by gradual erosion through the gallbladder fundus.[1] Once a fistula has formed, a stone may travel from the gallbladder into the bowel and become lodged almost anywhere along the gastrointestinal tract. Obstruction occurs most commonly at the near the distal ileum, within 60 cm proximally to the ileocecal valve.[2][3] Rarely, gallstone ileus may recur if the underlying fistula is not treated.[4]
First described by Thomas Bartholin in 1654, the name "gallstone ileus" is a misnomer because an ileus is, by definition, a non-mechanical bowel motility failure (as opposed to a mechanical obstruction by a stone).
## Contents
* 1 Diagnosis
* 2 Treatment
* 3 Eponym
* 4 References
* 5 External links
## Diagnosis[edit]
Diagnosis of gallstone ileus requires radiographic studies. Classic radiographic findings are known as Rigler's triad:[5]
* pneumobilia (air within the biliary tree)
* evidence of small bowel obstruction
* radiopaque gallstone on abdominal radiograph
## Treatment[edit]
Initial management involves fluid resuscitation and potentially nasogastric suctioning.[1] Since gallstone ileus constitutes a form of mechanical small bowel obstruction, it can be a surgical emergency and requires open or laparoscopic surgery to remove an impacted stone.[1] The different strategies for surgical management are either enterolithotomy alone, allowing a delayed cholecystectomy after an inflammation-free period of 4–6 weeks (and therefore two-stage surgery) or enterolithotomy in combination with a cholecystectomy and fistula division (one-stage surgery). The different strategies for surgical management are controversial, and depend on factors such as patient fitness for surgery and comorbidities.[4]
## Eponym[edit]
Bouveret's syndrome refers to reverse gallstone ileus where the gallstone propagates proximally and causes gastric outlet obstruction by being impacted in first part of duodenum.
## References[edit]
1. ^ a b c Longo, DL; Fauci, AS; Kasper, DL; Hauser, SL; Jameson, JL; Loscalzo, J (2015). Harrison's Principles of Internal Medicine (19 ed.). New York: McGraw-Hill. pp. 2081–2082. ISBN 978-0-07-180216-1. Retrieved 3 March 2017.
2. ^ Gaillard, Frank. "Gallstone Ileus". Radiopaedia. Retrieved 17 December 2013.
3. ^ Williams, N.; O'Connell, P. R., eds. (2013). Bailey & Love's Short Practice of Surgery (26th ed.). CRC Press. ISBN 978-1444121278.
4. ^ a b Fitzgerald J, Fitzgerald L, Maxwell-Armstrong C, Brooks A (2009). "Recurrent gallstone ileus: time to change our surgery?". Journal of Digestive Diseases. 10 (2): 149–151. doi:10.1111/j.1751-2980.2009.00378.x. PMID 19426399.
5. ^ Ibrahim, Dalia; Gaillard, Frank. "Rigler's Triad". Radiopaedia. Retrieved 17 December 2013.
## External links[edit]
Classification
D
* ICD-10: K56.3
* ICD-9-CM: xxx
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Gallstone ileus | c0156156 | 4,964 | wikipedia | https://en.wikipedia.org/wiki/Gallstone_ileus | 2021-01-18T19:00:54 | {"umls": ["C0156156"], "icd-10": ["K56.3"], "wikidata": ["Q1492299"]} |
Cleft palate-lateral synechia syndrome (CPLS) is a congenital malformation syndrome characterized by the association of cleft palate and intra-oral lateral synechiae connecting the free borders of the palate and the floor of the mouth. CPLS is presumed to be inherited in an autosomal dominant manner.
## Epidemiology
11 cases have been reported in the worldwide literature.
## Clinical description
Patients present with cleft palate at birth and on examination are found to have multiple cord-like adhesions running from the free internal borders of the palate to the lateral parts of the tongue and floor of the mouth. Babies manifest symptoms of cleft palate such as disrupted sucking and swallowing, recurrent ear infections and speech impairment. Lateral synechiae may be asymptomatic or cause feeding difficulty due to restricted opening of mouth. In some cases the synechiae undergo spontaneous resolution.
## Etiology
Etiology is unclear but interposition of the tongue between the palatal shelves in the embryo due to genetic, teratogenic or mechanical insults could result in a cleft palate while close contact between the floor of the mouth and the palate could predispose to the formation of intraoral synechiae. This can be either due to failed regression of buccopharyngeal membrane or formation of subglossopalatal membrane during the 7th week of embryonic life. Less than normal movement of the mandible and tongue is presumed to predispose to the formation of this subglossopalatal membrane.
## Diagnostic methods
Diagnosis is clinical. When necessary, computed tomography can help to detect the presence of any bony fusion.
## Differential diagnosis
Phenotypic features of CLPS can occur with other congenital anomalies, particularly the Van der Woude (VDW), orofaciodigital syndrome and popliteal pterygium syndrome (see these terms). In one reported family with CPLS, the monozygotic twin of the index case had classic phenotypic features of Fryns syndrome (see this term) suggesting that CPLS may represent a mild phenotypic expression of this syndrome.
## Antenatal diagnosis
Prenatal diagnosis of cleft palate can be made by prenatal ultrasonogram.
## Genetic counseling
An autosomal dominant inheritance pattern with variable expressivity has been proposed.
## Management and treatment
Management includes excision of synechiae and palatal closure. Immediate excision of the synechiae may be necessary due to breathing or feeding problems; obtaining a safe airway for the release of the bands may be difficult. When immediate release of synechiae is not warranted, excision is done during palatal closure. The synechiae has been used to provide additional tissue for the surgical closure of soft palate.
## Prognosis
The prognosis depends on the presence of associated anomalies (especially, congenital syngnathia (see this term)), quality of initial repair and regular follow-up.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Cleft palate-lateral synechia syndrome | c0795898 | 4,965 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2016 | 2021-01-23T17:33:10 | {"gard": ["1391"], "mesh": ["C563047"], "omim": ["119550"], "umls": ["C0795898"], "icd-10": ["Q87.8"], "synonyms": ["CPLS syndrome"]} |
## Mapping
Liu et al. (2009) tested 379,319 SNPs in 1,000 unrelated Caucasian individuals and found that 2 intronic SNPs within the TRHR gene (188545) on chromosome 8q23, rs16892496 and rs7832552, were significantly associated with lean body mass (LBM; corrected p = 7.55 x 10(-8) and 7.58 x 10(-8), respectively). Individuals carrying unfavorable genotypes at rs16892496 and rs7832552 had, on average, 2.70 and 2.55 kg lower LBM, respectively, compared to those with alternative genotypes. The significant associations were replicated in 3 independent samples, including 1,488 unrelated Caucasian individuals, 2,955 unrelated Chinese individuals, and 593 nuclear families comprising 1,972 Caucasian individuals. Metaanalysis of the genomewide scan and the replication studies yielded p values of 5.53 x 10(-9) for rs16892496 and 3.88 x 10(-10) for rs7832552. Liu et al. (2009) also found significant interactions between rs16892496 and polymorphisms of several other genes involved in the hypothalamic-pituitary-thyroid axis and the growth hormone (139250)-IGF1 (147440) axis.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| LEAN BODY MASS QUANTITATIVE TRAIT LOCUS 1 | c2674799 | 4,966 | omim | https://www.omim.org/entry/612729 | 2019-09-22T16:00:41 | {"omim": ["612729"]} |
Fletcher et al. (1997) mapped to mouse chromosome 11 a leucine zipper protein gene (Cdr3) that shows considerable homology to cerebellar degeneration-related autoantigen-2 (CDR2; 117340). From the location of the Cdr3 gene on chromosome 11, the homologous human gene, CDR3, was predicted to be located on 17q25.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| CEREBELLAR DEGENERATION-RELATED AUTOANTIGEN 3 | c1865782 | 4,967 | omim | https://www.omim.org/entry/602197 | 2019-09-22T16:13:53 | {"omim": ["602197"], "synonyms": ["Alternative titles", "CDR3"]} |
This article is about infection of the tip of the finger. For infection at the side or base of the fingernail, see Paronychia. For other uses, see Whitlow (disambiguation).
Infection of the fingertip
A whitlow or felon is an infection of the tip of the finger.[1][2][a] Herpetic whitlow and melanotic whitlow (subungual melanoma) are subtypes that are not synonymous with the term felon. A felon is an "extremely painful abscess on the palmar aspect of the fingertip".[6] Whitlow usually refers to herpetic whitlow, though it can also refer to melanotic whitlow (subungual melanoma),[7] which somewhat resembles acral lentiginous melanoma. The terms whitlow and felon are also sometimes misapplied to paronychia, which is an infection of the tissue at the side or base of the nail. Felon presents with a throbbing pain, clinically.
## Notes[edit]
1. ^ The term whitlow derives from the Scandinavian whickflaw, combining a variant of quick (a sensitive spot) and flaw.[3][4] Felon comes from the Old French, derived from the Latin root fel-, literally meaning "bile" and referring to the toxic content of the abscess.[5]
## References[edit]
Wikisource has the text of the 1911 Encyclopædia Britannica article Whitlow.
1. ^ "whitlow" at Dorland's Medical Dictionary
2. ^ Fitzpatrick, Thomas B.; Klauss Wolff; Wolff, Klaus Dieter; Johnson, Richard R.; Suurmond, Dick; Richard Suurmond (2005). Fitzpatrick's color atlas and synopsis of clinical dermatology. McGraw-Hill Medical Pub. Division. ISBN 0-07-144019-4.
3. ^ Walter William Skeat (1895). A Concise Etymological Dictionary of the English Language. Harper & Bros. pp. 560–. Retrieved March 5, 2013.
4. ^ 2flaw and 2quick from "Free Dictionary". Merriam-Webster. Retrieved March 5, 2013.
5. ^ Diab, Mohammad (1999). Lexicon of Orthopaedic Etymology. Taylor & Francis. p. 115. ISBN 978-90-5702-597-6. Retrieved March 6, 2013.
6. ^ Dorland's Medical Dictionary: 29th Edition.
7. ^ Haneke E, Baran R (June 2001). "Longitudinal melanonychia". Dermatol Surg. 27 (6): 580–4. doi:10.1111/j.1524-4725.2001.01916.x. PMID 11442597.
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Bacterial skin disease
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This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it.
* v
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* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Whitlow | c0152448 | 4,968 | wikipedia | https://en.wikipedia.org/wiki/Whitlow | 2021-01-18T18:52:17 | {"umls": ["C0152448"], "icd-9": ["681.01"], "wikidata": ["Q659001"]} |
Ichthyosis prematurity syndrome is a rare, syndromic congenital ichthyosis characterized by premature birth (at gestational weeks 30-32, in general) in addition to thick, caseous and desquamating epidermis, neonatal respiratory asphyxia, and persistent eosinophilia. After the perinatal period, a spontaneous improvement in the health of affected patients is observed and skin features (vernix caseosa-like scale) evolve into a mild presentation of flat follicular hyperkeratosis with atopy.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Ichthyosis-prematurity syndrome | c1837610 | 4,969 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88621 | 2021-01-23T18:25:35 | {"gard": ["9886"], "mesh": ["C536271"], "omim": ["608649"], "umls": ["C1837610"], "synonyms": ["Congenital ichthyosis type 4", "IPS"]} |
Gorlin-Chaudhry-Moss (GCM) syndrome is a multiple congenital anomaly syndrome characterized by craniofacial dysostosis, facial dysmorphism, conductive hearing loss, generalized hypertrichosis, and extremity, ocular and dental anomalies.
## Epidemiology
To date, 7 cases of GCM have been described in the world literature and all patients are female with no known parental consanguinity.
## Clinical description
GCM is a congenital disorder in which patients present with a stocky body build, normal intelligence, coronal craniosynostosis, facial dysmorphism (brachy/turricephaly, low anterior and posterior hairline, coarse hair, synophrys, depressed supraorbital ridges, short and downslanted or upslanted palpebral fissures, ectropion of lower eyelid, underdeveloped ala nasi, prominent columella, midface hypoplasia, and underdeveloped small ears with increased posterior angulation), conductive hearing loss, ocular (coloboma of the eyelid (see this term), hyperopia, microphthalmia) and oro-dental (microdontia, irregularly shaped widely spaced teeth, oligodontia (see this term), narrow, and high arched narrow palate with medial cleft) anomalies and generalized hypertrichosis. Anomalies of the extremities (hypoplastic distal phalanges, small/aplastic nails, cutaneous syndactyly, absent flexion crease of the thumbs, single transverse palmar creases), umbilical hernia, and hypoplasia of labia majora are also observed. Other additional features that may be observed include congenital laryngomalacia and heart disease (patent arterial duct) (see these terms). Progeroid syndrome, Petty type and Saethre-Chotzen syndrome (see these terms) have overlapping features with GCM syndrome and should be considered in the differential diagnosis.
## Etiology
The etiology is still unknown and, to date, no causative gene has been implicated in the physiopathology of GCM.
## Genetic counseling
GCM is considered to be inherited in an autosomal recessive manner. However, the lack of consanguinity combined with the fact that all affected patients are female could suggest a de novo X-linked dominant disorder with male lethality.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Gorlin-Chaudhry-Moss syndrome | c0345382 | 4,970 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2095 | 2021-01-23T18:58:22 | {"gard": ["66"], "mesh": ["C537290"], "omim": ["612289"], "umls": ["C0345382"], "icd-10": ["Q87.0"], "synonyms": ["Craniofacial dysostosis-genital, dental, cardiac anomalies syndrome", "Cranofacial dysostosis-hypertrichosis-hypoplasia of labia majora syndrome", "Dental and eye anomalies-patent ductus arteriosus-normal intelligence syndrome", "GCM syndrome"]} |
A number sign (#) is used with this entry because CD59-mediated hemolytic anemia with or without immune-mediated polyneuropathy (HACD59) is caused by homozygous mutation in the CD59 gene (107271) on chromosome 11p13.
Description
CD59-mediated hemolytic anemia with immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (summary by Nevo et al., 2013).
Clinical Features
Yamashina et al. (1990) found that the erythrocytes from a patient thought to have paroxysmal nocturnal hemoglobinuria (PNH; 300818) were devoid of HRF20 (CD59) and that those of his parents were deficient in the protein, compatible with the heterozygous state. The patient, previously described by Ono et al. (1990), was a 22-year-old man with intermittent pallor and hematuria of 9 years' duration. Paroxysmal nocturnal hemoglobinuria had been diagnosed at the age of 13 years when he had an episode of hemolytic anemia and hemoglobinuria. During the subsequent 9 years, Ham and sucrose hemolysis tests were consistently positive, and 9 episodes of hemolysis occurred, with a cerebral infarction during the third and ninth episodes. His father and mother were cousins, but neither had a history of hemolytic anemia or hemoglobinuria. Rosse (1993) pointed out that although the patient had hemolytic anemia and thrombosis typical of PNH, he did not have other features of PNH, which is due to deficiency of PIGA (311770), the molecule that anchors CD59 and several other molecules to the cell surface. Nevo et al. (2013) noted that the patient reported by Yamashina et al. (1990) was not reported to have evidence of polyneuropathy.
Nevo et al. (2013) reported 5 children from 4 unrelated families of North African Jewish descent who presented with infantile onset of relapsing immune-mediated polyneuropathy and chronic hemolysis. One of the families was consanguineous. Disease onset was between age 3 and 7 months and was usually preceded by a minor viral illness. Symptoms included symmetric muscle weakness, hypotonia, and hyporeflexia affecting the lower limbs more than the upper limbs. The first episode lasted from days to weeks and treatment with IV immunoglobulins and corticosteroids resulted in restoration of muscle strength in the upper extremities. However, the disease course was relapsing-remitting in the following months, with exacerbations after infections. There was progressive muscle atrophy of the hands and feet, and persistent paralysis of the lower limbs associated with areflexia. A few of the exacerbations were accompanied by respiratory insufficiency requiring artificial ventilation, and 1 patient developed an acute episode of hemolytic-uremic syndrome during plasmapheresis that resolved. Cognitive development was normal. Laboratory studies during episodes showed acute hemolysis with decreased hemoglobin, increased C-reactive protein, and increased CSF protein levels. Nerve conduction studies showed demyelination with axonal damage in 2 of 3 patients, and spinal MRI showed root enhancement in 2 of 3 patients. Magnetic resonance imaging of the spine performed in 3 patients revealed root enhancement in 2 patients. Immunosuppressive treatment improved the time between relapses and reduced severity, but did not prevent recurrence. One patient died of acute respiratory failure at age 3.5 years.
Inheritance
The transmission pattern of chronic hemolysis and immune-mediated polyneuropathy in the family reported by Nevo et al. (2013) was consistent with autosomal recessive inheritance.
Clinical Management
Hochsmann et al. (2014) reported a female infant with CD59 deficiency who presented at age 7 months with bulbar symptoms, severe hypotonia, and areflexia. During later febrile illnesses, the patient developed acute hemolytic anemia with progressive neurologic deterioration, including T2-weighted hyperintense lesions on brain MRI, seizures, and visual impairment. Flow cytometric analysis of patient peripheral blood cells showed isolated CD59 deficiency. Treatment with eculizumab, an inhibitor of the complement membrane-attack complex, resulted in neurologic improvement about 6 months later. At age 5.5 years, the patient could eat and swallow normally, could walk short distances with support, and had improved cognitive and speech production.
Mapping
CD59 deficiency is caused by mutation in the CD59 gene, which maps to chromosome 11p13 (Heckl-Ostreicher et al., 1993).
Molecular Genetics
Motoyama et al. (1992) identified a homozygous single-nucleotide deletion in the CD59 gene (107271.0001) in the patient with CD59 deficiency and hemolytic anemia reported by Yamashina et al. (1990) and Ono et al. (1990).
In 5 patients from 4 unrelated families of North African Jewish descent with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy, Nevo et al. (2013) identified a homozygous mutation in the CD59 gene (C89Y; 107271.0002). The mutation was initially found by whole-exome sequencing in 2 affected sibs, segregated with the disorder in all families, and was not found in the dbSNP and the Exome Variant Server databases. Haplotype analysis indicated a founder effect. Nevo et al. (2013) suggested that improper activation of the complement system due to lack of CD59 expression may cause damage to red cell membranes and result in myelin and axonal damage.
In a girl with CD59 deficiency, Hochsmann et al. (2014) identified a homozygous truncating mutation in the CD59 gene (107271.0003).
Animal Model
To examine the role of CD59 in protecting host tissues in health and disease, Holt et al. (2001) generated Cd59-deficient (Cd59 -/-) mice by gene targeting in embryonic stem cells. Despite the complete absence of Cd59, mice were healthy and fertile. Red cells in vitro displayed increased susceptibility to complement and were positive in an acidified-serum lysis test. Despite this, Cd59 -/- mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from these mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation.
INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness, upper and lower limbs \- Muscle atrophy, progressive \- Hand and foot weakness NEUROLOGIC Peripheral Nervous System \- Chronic immune-mediated polyneuropathy \- Limb weakness \- Limb paralysis \- Areflexia \- Sensory and motor demyelination seen on sural nerve biopsy \- Secondary axonal damage HEMATOLOGY \- Hemolytic anemia LABORATORY ABNORMALITIES \- Increased CSF protein \- Absence of CD59 expression on red cells MISCELLANEOUS \- Onset in infancy (3 to 7 months) \- Exacerbations during infection \- Relapsing-remitting course \- Immunosuppressive therapy may be beneficial MOLECULAR BASIS \- Caused by mutation in the CD59 antigen gene (CD59, 107271.0001 ) ▲ Close
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| HEMOLYTIC ANEMIA, CD59-MEDIATED, WITH OR WITHOUT IMMUNE-MEDIATED POLYNEUROPATHY | c2676767 | 4,971 | omim | https://www.omim.org/entry/612300 | 2019-09-22T16:01:52 | {"mesh": ["C567355"], "omim": ["612300"], "orphanet": ["169464"], "synonyms": ["Alternative titles", "CD59 DEFICIENCY"]} |
BENTA disease (B cell Expansion with NF-κB and T cell Anergy) is a very rare congenital immune deficiency disorder. The main symptoms include spleen enlargement (splenomegalia) and frequent ear, sinus, and lung infections early in life. Some patients can present with molluscum contagiosum or chronic Epstein-Barr virus (EBV) infection. Blood exams show alterations of several immune cells with very high numbers of polyclonal B cell lymphocytos (above 2200/μl) and few memory B cells. Other findings are low levels of IgM in blood and poor antibody responses to specific vaccines. BENTA disease is caused by mutations in the CARD11 gene. There is no established treatment, but some patients have their spleen removed and there is one case of a hematopoietic stem cell transplantation with good results.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| BENTA disease | c4551967 | 4,972 | gard | https://rarediseases.info.nih.gov/diseases/13339/benta-disease | 2021-01-18T18:01:49 | {"synonyms": ["B-cell expansion with NF-kB and T-cell anergy disease", "B-cell expansion with NFKB and T-cell anergy"]} |
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical Features
Hameed et al. (2001) reported a 6-generation, consanguineous Pakistani family with autosomal recessive retinitis pigmentosa (arRP). All affected individuals had pigmentary retinopathy associated with symptoms of night blindness and the loss of peripheral visual fields by the age of 20 years, loss of central vision between the ages of 25 and 30 years, and complete blindness between the ages of 40 and 50 years.
Mapping
By linkage analysis in a Pakistani family with arRP, Hameed et al. (2001) mapped the disease locus to chromosome 4q32-q34, with a maximum lod score of 3.76 for marker D4S415, with no recombination. Further analyses gave a probable disease interval of 4.6 cM between markers D4S3035 and D4S2417. Mutation screening of 2 candidate genes, GPM6A (601275) and CLCN3 (600580), revealed no mutations.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Retinitis pigmentosa \- Constricted visual fields by age 20 years \- Night blindness by age 20 years \- Loss of central vision between ages 25-30 years \- Complete blindness between ages 40-50 years \- Fundus pigment lumps, bone-corpuscle/bone-spicule pattern \- Attenuation of retinal blood vessels \- Obliteration of peripheral retinal blood vessels (in some patients) \- Pallid optic disc MISCELLANEOUS \- One family reported (last curated July 2008) ▲ Close
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| RETINITIS PIGMENTOSA 29 | c0035334 | 4,973 | omim | https://www.omim.org/entry/612165 | 2019-09-22T16:02:16 | {"doid": ["0110378"], "mesh": ["D012174"], "omim": ["612165"], "orphanet": ["791"]} |
Renal disease occurs in 40 to 75% of systemic lupus erythematosus (SLE; 152700) patients and significantly contributes to morbidity and mortality (Garcia et al., 1996). Quintero-Del-Rio et al. (2002) explored the impact of the American College of Rheumatology's renal criterion for SLE classification on genetic linkage with SLE. They evaluated genome scan data in 75 pedigrees that had at least 1 SLE patient affected according to the SLE renal criterion. A multipoint sib-pair regression analysis produced evidence of linkage in African American pedigrees at a locus on 2q34-q35 (P = 0.000001), which Quintero-Del-Rio et al. (2002) designated SLEN2.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| SYSTEMIC LUPUS ERYTHEMATOSUS WITH NEPHRITIS, SUSCEPTIBILITY TO, 2 | c1842756 | 4,974 | omim | https://www.omim.org/entry/607966 | 2019-09-22T16:08:29 | {"omim": ["607966"]} |
Melanoma-associated retinopathy (MAR) is a rare autoimmune condition that occurs in some people with melanoma (a type of skin cancer) and can affect the vision. Signs and symptoms of MAR may include night blindness; photopsia (presence of perceived flashes of light); and progressive, painless vision loss. MAR occurs when the body's immune system, in response to melanoma, mistakenly attacks the cells of the retina; however, it is poorly understood why this autoimmune response occurs in some people but not others. There is, unfortunately, no established treatment for MAR. Proposed strategies for treatment include immunosuppressive medications and/or standard treatment of the melanoma (i.e. surgery, chemotherapy, and/or radiation therapy).
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Melanoma-associated retinopathy | c0730308 | 4,975 | gard | https://rarediseases.info.nih.gov/diseases/12041/melanoma-associated-retinopathy | 2021-01-18T17:59:10 | {"mesh": ["D059545"], "synonyms": []} |
Twelve cases of short, absent or partially fused radius and ulna and abnormalities of the digits were found in 3 generations by Stiles and Dougan (1940).
Limbs \- Short, absent or partially fused radius and ulna \- Abnormal digits Inheritance \- Autosomal dominant ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| ARMS, MALFORMATION OF | c1862534 | 4,976 | omim | https://www.omim.org/entry/107900 | 2019-09-22T16:44:46 | {"mesh": ["C566258"], "omim": ["107900"]} |
Brazilian purpuric fever
SpecialtyInfectious disease
Brazilian purpuric fever (BPF) is an illness of children caused by the bacterium Haemophilus influenzae biogroup aegyptius which is ultimately fatal due to sepsis. BPF was first recognized in the São Paulo state of Brazil in 1984. At this time, young children between the ages of 3 months and 10 years were contracting a strange illness which was characterized by high fever and purpuric lesions on the body. These cases were all fatal, and originally thought to be due to meningitis. It was not until the autopsies were conducted that the cause of these deaths was confirmed to be infection by H. influenzae aegyptius. Although BPF was thought to be confined to Brazil, other cases occurred in Australia and the United States during 1984–1990.
Haemophilus species are non-spore-forming gram-negative coccobacilli . They lack motility and are aerobic or facultatively anaerobic. They require preformed growth factors that are present in blood, specifically hemin (X factor) and NAD or NADP (V factor). The bacterium grows best at 35–37 °C and has an optimal pH of 7.6. Haemophilus species are obligate parasites and are part of the normal flora of the human upper respiratory tract.
## Contents
* 1 Presentation
* 2 Risk factors
* 3 Transmission
* 4 Pathogenesis
* 5 Diagnosis
* 6 Prevention
* 7 Treatment
* 8 References
* 9 External links
## Presentation[edit]
In documented BPF cases, the symptoms include high fever (101.3 °F/38,5 °C or higher), nausea, vomiting, severe abdominal pain, septic shock, and ultimately death. A history of conjunctivitis 30 days prior to the onset of fever was also present in the documented BPF cases. The physical presentation of children infected with BPF include purpuric skin lesions affecting mainly the face and extremities, cyanosis, rapid necrosis of soft tissue, particularly the hands, feet, nose, and ears. Analysis of the fatalities due to BPF showed hemorrhage in the skin, lungs, and adrenal glands. Histopathology showed hemorrhage, intravascular microthrombi and necrosis in the upper dermis, renal glomeruli, lungs, and hepatic sinusoids.
## Risk factors[edit]
The risk factors associated with BPF are not well known. However, it has been suggested that children under 5 years of age are more susceptible to BPF since they lack serum bactericidal activity against the infection. Older children and adults have much higher titers of bactericidal antibodies, which serve as a protective measure. Also children residing in warmer geographic areas have been associated with a higher risk of BPF infection.
## Transmission[edit]
The eye gnat (Liohippelates) was thought to be the cause of the conjunctivitis epidemic which occurred in Mato Grosso do Sul in 1991. These gnats were extracted from the conjunctival secretions of the children who were infected with conjunctivitis. 19 of those children developed BPF following the conjunctivitis. Other modes of transmission include contact with the conjunctival discharges of infected people, ophthalmic instruments which have not been properly sterilized, sharing eye makeup applicators or multiple-dose eye medications.
## Pathogenesis[edit]
The pathogenesis of BPF is not well established but it is thought that patients become pharyngeal or conjunctival carriers of H. aegyptius, which is followed by spreading to the bloodstream. This hypothesis is supported by the isolation of from both the conjunctiva and oropharynx of documented BPF cases with H. aegyptius bacteremia. Possible virulence factors of H. aegyptius include lipooligosaccharides (LOS), capsular polysaccharides, pilus proteins (mediates adhesion to mucosal membrane), immunoglobulin A1 (IgA1), membrane associated proteins, and extracellular proteins. In a study conducted by Barbosa et al., a 60 kilodalton hemagglutinating extracellular product was suggested to be the major pathogenic factor linked to the hemorrhagic manifestations of BPF. This molecule was found to be absorbable by human O-type erythrocytes. After the molecule had been injected into rabbits, they showed reactions similar to that of BPF patients. Further research is being conducted to determine the mechanisms involved with the other virulence factors of H. aegyptius. The overall pathogenesis of BPF probably involves multiple steps and a number of bacterial factors.
## Diagnosis[edit]
A positive BPF diagnosis includes the clinical symptoms (mainly the fever, purpuric lesions, and rapid progression of the disease), isolation of Haemophilus Influenzae Biogroup aegyptius from blood, and negative laboratory tests for Neisseria meningitidis. The negative tests for Neisseria meningitidis rules out the possibility of the symptoms being caused by meningitis, since the clinical presentations of the two diseases are similar.
## Prevention[edit]
The basic method for control of the conjunctivitis includes proper hygiene and care for the affected eye. If the conjunctivitis is found to be caused by H. aegyptius Biogroup III then prompt antibiotic treatment preferably with rifampin has been shown to prevent progression to BPF. If the infected person resides in Brazil, it is mandatory that the infection is reported to the health authority so that a proper investigation of the contacts can be completed. This investigation will help to determine the probable source of the infection.
## Treatment[edit]
It is extremely difficult to successfully treat BPF, mainly because of the difficulty obtaining a proper diagnosis. Since the disease starts out with what seems to be a common case of conjunctivitis, H. aegyptius is not susceptible to the antibiotic eye drops that are being used to treat it. This treatment is ineffective because it treats only the local ocular infection, whereas if it progresses to BPF, systemic antibiotic treatment is required. Although BPF is susceptible to many commonly used antibiotics, including ampicillin, cefuroxime, cefotaxime, rifampin, and chloramphenicol, by the time it is diagnosed the disease has progressed too much to be effectively treated. However, with the fast rate of progression of BPF it is unlikely that it will be successfully treated. With antibiotic therapy, the mortality rate of BPF is around 70%.
## References[edit]
* Barbosa, S.F.C.; Hoshino-Shimizu, S.; das Gracas A. Alknin, M.; Goto, H. (2003). "Implications of Haemophilus influenzae Biogroup aegyptius Hemagglutinins in the Pathogenesis of Brazilian Purpuric Fever". Journal of Infectious Diseases. 188 (1): 74–80. doi:10.1086/375739. PMID 12825174.
* Harrison, L.H.; Da Silva, G.A.; Pittman, M.; Fleming, D.W.; Vranjac, A.; Broome, C.V. (1989). "Epidemiology and Clinical Spectrum of Brazilian Purpuric Fever". Journal of Clinical Microbiology. 27 (4): 599–604. doi:10.1128/JCM.27.4.599-604.1989. PMC 267380. PMID 2656737.
* Harrison, L.H.; Simonsen, V.; Waldman, E.A. (2008). "Emergence and Disappearance of a Virulent Clone of Haemophilus influenzae Biogroup aegyptius,cause of Brazilian Purpuric Fever". Clinical Microbiology Reviews. 21 (4): 599–605. doi:10.1128/CMR.00020-08. PMC 2570154. PMID 18854482.
* McGillivary, G.; Tomaras, A.P.; Rhodes, E.R.; Actis, L.A (2005). "Cloning and sequencing of a genomic island found in the Brazilian Purpuric Fever clone of Haemophilis influenzae Biogroup aegyptius". Infection and Immunity. 73 (4): 1927–1938. doi:10.1128/IAI.73.4.1927-1938.2005. PMC 1087403. PMID 15784532.
* Rubin, L.G.; St. Geme III, J.W. (1993). "Role of Lipooligosaccharide in Virulence of the Brazilian Purpuric Fever Clone of Haemophilus influenzaeBiogroup aegyptius for Infant Rats". Infection and Immunity. 61 (2): 650–655. doi:10.1128/IAI.61.2.650-655.1993. PMC 302776. PMID 8093694.
## External links[edit]
Classification
D
* ICD-10: A48.4
* DiseasesDB: 35123
* CDC
* v
* t
* e
Proteobacteria-associated Gram-negative bacterial infections
α
Rickettsiales
Rickettsiaceae/
(Rickettsioses)
Typhus
* Rickettsia typhi
* Murine typhus
* Rickettsia prowazekii
* Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus
Spotted
fever
Tick-borne
* Rickettsia rickettsii
* Rocky Mountain spotted fever
* Rickettsia conorii
* Boutonneuse fever
* Rickettsia japonica
* Japanese spotted fever
* Rickettsia sibirica
* North Asian tick typhus
* Rickettsia australis
* Queensland tick typhus
* Rickettsia honei
* Flinders Island spotted fever
* Rickettsia africae
* African tick bite fever
* Rickettsia parkeri
* American tick bite fever
* Rickettsia aeschlimannii
* Rickettsia aeschlimannii infection
Mite-borne
* Rickettsia akari
* Rickettsialpox
* Orientia tsutsugamushi
* Scrub typhus
Flea-borne
* Rickettsia felis
* Flea-borne spotted fever
Anaplasmataceae
* Ehrlichiosis: Anaplasma phagocytophilum
* Human granulocytic anaplasmosis, Anaplasmosis
* Ehrlichia chaffeensis
* Human monocytotropic ehrlichiosis
* Ehrlichia ewingii
* Ehrlichiosis ewingii infection
Rhizobiales
Brucellaceae
* Brucella abortus
* Brucellosis
Bartonellaceae
* Bartonellosis: Bartonella henselae
* Cat-scratch disease
* Bartonella quintana
* Trench fever
* Either B. henselae or B. quintana
* Bacillary angiomatosis
* Bartonella bacilliformis
* Carrion's disease, Verruga peruana
β
Neisseriales
M+
* Neisseria meningitidis/meningococcus
* Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia
M−
* Neisseria gonorrhoeae/gonococcus
* Gonorrhea
ungrouped:
* Eikenella corrodens/Kingella kingae
* HACEK
* Chromobacterium violaceum
* Chromobacteriosis infection
Burkholderiales
* Burkholderia pseudomallei
* Melioidosis
* Burkholderia mallei
* Glanders
* Burkholderia cepacia complex
* Bordetella pertussis/Bordetella parapertussis
* Pertussis
γ
Enterobacteriales
(OX−)
Lac+
* Klebsiella pneumoniae
* Rhinoscleroma, Pneumonia
* Klebsiella granulomatis
* Granuloma inguinale
* Klebsiella oxytoca
* Escherichia coli: Enterotoxigenic
* Enteroinvasive
* Enterohemorrhagic
* O157:H7
* O104:H4
* Hemolytic-uremic syndrome
* Enterobacter aerogenes/Enterobacter cloacae
Slow/weak
* Serratia marcescens
* Serratia infection
* Citrobacter koseri/Citrobacter freundii
Lac−
H2S+
* Salmonella enterica
* Typhoid fever, Paratyphoid fever, Salmonellosis
H2S−
* Shigella dysenteriae/sonnei/flexneri/boydii
* Shigellosis, Bacillary dysentery
* Proteus mirabilis/Proteus vulgaris
* Yersinia pestis
* Plague/Bubonic plague
* Yersinia enterocolitica
* Yersiniosis
* Yersinia pseudotuberculosis
* Far East scarlet-like fever
Pasteurellales
Haemophilus:
* H. influenzae
* Haemophilus meningitis
* Brazilian purpuric fever
* H. ducreyi
* Chancroid
* H. parainfluenzae
* HACEK
Pasteurella multocida
* Pasteurellosis
* Actinobacillus
* Actinobacillosis
Aggregatibacter actinomycetemcomitans
* HACEK
Legionellales
* Legionella pneumophila/Legionella longbeachae
* Legionnaires' disease
* Coxiella burnetii
* Q fever
Thiotrichales
* Francisella tularensis
* Tularemia
Vibrionaceae
* Vibrio cholerae
* Cholera
* Vibrio vulnificus
* Vibrio parahaemolyticus
* Vibrio alginolyticus
* Plesiomonas shigelloides
Pseudomonadales
* Pseudomonas aeruginosa
* Pseudomonas infection
* Moraxella catarrhalis
* Acinetobacter baumannii
Xanthomonadaceae
* Stenotrophomonas maltophilia
Cardiobacteriaceae
* Cardiobacterium hominis
* HACEK
Aeromonadales
* Aeromonas hydrophila/Aeromonas veronii
* Aeromonas infection
ε
Campylobacterales
* Campylobacter jejuni
* Campylobacteriosis, Guillain–Barré syndrome
* Helicobacter pylori
* Peptic ulcer, MALT lymphoma, Gastric cancer
* Helicobacter cinaedi
* Helicobacter cellulitis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Brazilian purpuric fever | c0275703 | 4,977 | wikipedia | https://en.wikipedia.org/wiki/Brazilian_purpuric_fever | 2021-01-18T18:52:09 | {"umls": ["C0275703"], "icd-10": ["A48.4"], "wikidata": ["Q4958908"]} |
A number sign (#) is used with this entry because nephronophthisis-14 (NPHP14) is caused by homozygous mutation in the ZNF423 gene (604557) on chromosome 16. Heterozygous mutation in the ZNF423 gene causes Joubert syndrome-19 (JBTS19).
For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).
For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
Clinical Features
Chaki et al. (2012) reported 2 Turkish sibs, born of consanguineous parents (family F824), with infantile-onset NPHP, cerebellar vermis hypoplasia, and situs inversus. Chaki et al. (2012) referred to these patients as having an NPHP-related ciliopathy, despite the presence of cerebellar vermis hypoplasia. Chaki et al. (2012) also reported 2 unrelated patients with Joubert syndrome. One patient had cerebellar vermis hypoplasia, Leber congenital amaurosis (see 204000), and polycystic kidney disease. The other patient had polycystic kidney disease, nephronophthisis, retinal degeneration, cerebellar vermis hypoplasia, and perinatal breathing abnormalities. Neither of the Joubert patients had a family history of a similar disorder.
Inheritance
The transmission pattern of NPHP14 in the family reported by Chaki et al. (2012) was consistent with autosomal recessive inheritance. Two patients with Joubert syndrome-19 were found to carry heterozygous ZNF423 mutations, suggesting autosomal dominant inheritance.
Molecular Genetics
By homozygosity mapping and whole-exome sequencing of 2 Turkish sibs with nephronophthisis, Chaki et al. (2012) identified a homozygous mutation in the ZNF423 gene (P913L; 604557.0001). The mutation was predicted to result in a loss of function. Two of 96 additional patients with Joubert syndrome were found to carry heterozygous ZNF423 mutations (604557.0002 and 604557.0003). The heterozygous mutations caused a dominant-negative effect on protein function in cellular studies.
INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Eyes \- Retinal degeneration (in some patients) \- Leber congenital amaurosis (in some patients) ABDOMEN \- Situs inversus (in 1 family) GENITOURINARY Kidneys \- Nephronophthisis \- Polycystic kidney disease NEUROLOGIC Central Nervous System \- Cerebellar vermis hypoplasia MISCELLANEOUS \- Four patients from 3 families have been reported (last curated February 2014) \- Variable phenotype \- NPHP shows autosomal recessive inheritance \- JBTS shows autosomal dominant inheritance MOLECULAR BASIS \- Caused by mutation in the zinc finger protein 423 gene (ZNF423, 604557.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| NEPHRONOPHTHISIS 14 | c1855675 | 4,978 | omim | https://www.omim.org/entry/614844 | 2019-09-22T15:54:03 | {"doid": ["0111122"], "mesh": ["C537430"], "omim": ["614844"], "orphanet": ["2318"], "genereviews": ["NBK368475", "NBK1325"]} |
A number sign (#) is used with this entry because of evidence that progressive familial heart block type IB (PFHB1B) is caused by heterozygous mutation in the TRPM4 gene (606936) on chromosome 19q13.
For a phenotypic description and a discussion of genetic heterogeneity of progressive familial heart block type I, see PFHB1A (113900).
Clinical Features
Brink and Torrington (1977) reported a 6-generation South African family of Portuguese and French ancestry with 261 known relatives, in which conduction defects segregated in an autosomal dominant pattern. Of 55 members in the last 3 generations who underwent electrocardiography, 31 had conduction abnormalities, including 16 with monofascicular right bundle branch block (RBBB), 3 with left anterior hemiblock, and 6 with complete heart block; another 6 individuals had a mildly prolonged QT interval or short PR interval without a Wolff-Parkinson-White (194200) pattern. The average age at which a pacemaker was implanted in the 3 successive generations decreased from 54.5 years in the fourth to 25 years in the fifth to 1 year of age in the sixth generation. Sudden cardiac death occurred in 22 individuals over the 3 generations, also at increasingly younger ages, dropping from an average of 50.7 years to 44.7 years to 12.3 years in the fourth, fifth, and sixth generations, respectively. Van der Merwe et al. (1986) and van der Merwe et al. (1988) provided follow-up information on the kindred reported by Brink and Torrington (1977) and documented the progressive nature of the disorder.
Stephan (1978) studied a Lebanese kindred with over 265 living descendants of a polygamous progenitor who was known to have had a slow pulse and syncope. Many examples of conduction defects, mainly right bundle branch block, left anterior hemiblock, bifascicular block and atrioventricular (AV) block, were found in his descendants. The abnormality was thought to be congenital, with a pedigree pattern consistent with autosomal dominant inheritance. However, 1 person presented with complete heart block at age 41.
Stephan et al. (1997) provided follow-up on the Lebanese kindred reported by Stephan (1978). They considered the most appropriate designation for this disorder to be 'hereditary bundle branch defect' (HBBD). Stephan et al. (1985) reported an autopsied case. There were over 400 descendants of the progenitor in 5 generations. Stephan et al. (1997) studied the evolution of the disorder in this kindred over a 2-decade period, described a variety of electrocardiographic abnormalities encountered in the family, and reassessed penetrance. A total of 396 persons had at least one clinical examination and electrocardiogram, of whom 47 were judged affected and 36 'indeterminate.' The conduction block may be overt in the first year of life, and among affected individuals there was a worsening of the conduction block in 5 to 15% of cases, leading to complete atrioventricular block and possibly to sudden death. A group of individuals had QRS anomalies in right precordial leads, possibly indicating partial right bundle branch block. A high proportion of these were identified as mutation carriers (the disorder in this family was shown to map to 19q) and about one-fifth of these patients evolved toward a complete fascicular block. By contrast, mutation carriers with a normal electrocardiogram remained normal. Mutation carriers demonstrated a conduction block significantly more often in males than females (75% and 50%, respectively). Brink et al. (1994, 1995) had found almost 100% penetrance in their South African family. Stephan et al. (1997) presented a table of penetrance values estimated from 9 other families as well as their own.
Liu et al. (2010) studied the large Lebanese kindred with autosomal dominant isolated cardiac conduction block, originally reported by Stephan (1978), as well as 2 French families with a variety of cardiac conduction blocks segregating in an autosomal dominant fashion. Altogether, there were 2 cases of isolated left axis deviation (LAD), 10 cases of complete right bundle branch block, 16 cases of incomplete RBBB, 15 cases of complete RBBB with LAD, 6 cases of complete RBBB with right axis deviation (RAD), and 7 cases of complete atrioventricular conduction block. Liu et al. (2010) observed 2 remarkable features in the 3 families: no family member had left bundle branch block (LBBB), complete or incomplete, and no other cardiac anomalies were found on repeated cardiac investigations, including echocardiogram, stress test, ambulatory electrocardiogram, and heart scintigraphy. The authors concluded that the 3 families shared an autosomal dominant disease resulting in any conduction block but LBBB, and no other cardiac anomalies.
Mapping
Brink et al. (1995) analyzed the large South African kindred reported by Brink and Torrington (1977) and demonstrated linkage to 19q13.2-q13.3. They pointed out that this kindred descended from an ancestor who emigrated from Portugal in 1696. It had been estimated that there may be between 1,000 and 9,000 gene carriers among his descendants. Maximum 2-point lod scores were 6.49 at theta = 0.0 for kallikrein (KLK1; 147910), 5.72 at theta = 0.01 for the myotonic dystrophy locus (DM; 160900), 3.44 at theta = 0.0 for the creatine kinase muscle-type locus (CKM; 123310), and 4.51 at theta = 0.10 for the apolipoprotein C2 locus (APOC2; 608083). Brink et al. (1995) noted that the gene for myotonin protein kinase, which is implicated as a cause of myotonic dystrophy, lies within this region and that myotonic dystrophy is a disease complicated by heart block and other conduction abnormalities; however, a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHB1B.
Using a genomewide screening approach with polymorphic (CA)n repeat markers in the Lebanese family originally described by Stephan (1978), de Meeus et al. (1995) obtained a maximum multipoint lod score of 7.18 at D19S604 on chromosome 19q13.3. Flanking loci D19S606 and D19S571 were excluded due to a recombination event in 3 affected individuals, narrowing the critical region to a 13-cM interval.
Using additional microsatellite markers in the Afrikaner kindred with progressive heart block originally reported by Brink and Torrington (1977), Kruse et al. (2009) narrowed the PFHB1B locus to a 0.5-Mb interval between markers D19S1059 and D19S604 on chromosome 19q13.33 containing approximately 25 genes.
Liu et al. (2010) analyzed polymorphic markers on chromosome 19q13 in 2 French families segregating autosomal dominant cardiac conduction defects as well as the large Lebanese kindred originally reported by Stephan (1978), and obtained a total multipoint lod score of 10.5, with a family-specific haplotype shared by all affected family members. The data narrowed the critical region to a 4-Mb interval flanked by CABP3 and D19S601.
Molecular Genetics
Kruse et al. (2009) analyzed the candidate gene TRPM4 in the Afrikaner kindred with progressive heart block originally reported by Brink and Torrington (1977) and identified a heterozygous missense mutation (E7K; 606936.0001) that segregated with the disease. Of 71 mutation carriers identified, 48 had pacemakers implanted. The mutation was not found in 230 ancestry-matched, unrelated Afrikaner controls or in 389 unrelated individuals of mixed European descent.
In the large Lebanese kindred originally reported by Stephan (1978) and 2 French families with autosomal dominant cardiac conduction defects mapping to chromosome 19q13, Liu et al. (2010) analyzed 12 candidate genes and identified 3 heterozygous missense mutations (606936.0002-606936.0004) in the TRPM4 gene that were found in all affected members of each family. The mutations were also detected in several family members with incomplete right bundle branch block or no block, consistent with incomplete penetrance; penetrance was calculated to be 75% for males and 54% for females. None of the variants was found in 300 ethnically matched chromosomes.
Stallmeyer et al. (2012) analyzed the TRPM4 gene in 160 unrelated patients with various types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients (see, e.g., 606936.0002 and 606936.0004-606936.0006), including 5 (26.3%) of 19 patients with RBBB and 3 (11.5%) of 26 patients with atrioventricular block. No mutations were identified in patients with other types of cardiac arrhythmias. Noting the phenotypic variability in the mutation-positive patients, Stallmeyer et al. (2012) suggested that additional factors might modulate the disease phenotype in some patients.
### Exclusion Studies
In selected affected members of the family originally reported by Brink and Torrington (1977), Bardien-Kruger et al. (2002) screened the coding region of the positional candidate gene KCNA7 by PCR-SSCP analysis and direct DNA sequencing and found no pathogenic sequence changes.
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Cardiac conduction defects \- Bradycardia \- Syncope \- Left axis deviation \- Right axis deviation \- Right bundle branch block, incomplete or complete \- Left anterior hemiblock \- Bifascicular block \- Atrioventricular block, incomplete or complete \- Prolonged QT interval \- Short PR interval MISCELLANEOUS \- Patients often require implantation of a pacemaker \- Conduction defect is progressive MOLECULAR BASIS \- Caused by mutation in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4, 606936.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB | c1879286 | 4,979 | omim | https://www.omim.org/entry/604559 | 2019-09-22T16:11:55 | {"doid": ["0111076"], "mesh": ["C566873"], "omim": ["604559"], "orphanet": ["871"], "synonyms": ["Alternative titles", "PFHBIB"]} |
Not to be confused with Daydream, Fantasy (psychology), or Maladaptive daydreaming.
A fixed fantasy – also known as a "dysfunctional schema" – is a belief or system of beliefs held by a single individual to be genuine, but that cannot be verified in reality. The term is typically applied to individuals suffering from some type of psychiatric dysregulation, most often a personality disorder.
The term is also used in the different context of psychoanalysis to distinguish between a normal transitory one and a fixed fantasy with respect to the fantasised fulfilment in conscious or unconscious thought of the sexualised wish.[1]
## Contents
* 1 Self-destruction
* 1.1 Basic beliefs and cognitive therapy
* 1.2 Religion
* 2 Psychosexual
* 3 See also
* 4 References
* 5 Further reading
## Self-destruction[edit]
Studies of borderline children often uncovered at the base of their self-destructive behaviour patterns "a "fixed fantasy" ... a rigid, nonreflective scenario of self-induced pain."[2] As part of a psychic defence mechanism, "the omnipotence betrayed by the "fixed fantasy" underlying self-victimization or other forms of self-defeating behaviour ... creates the illusory sense that they are actively producing the abandonment [and] pain",[3] rather than merely suffering it passively – "arranging deceits ... arrang[ing] for blows to fall."[4] Unfortunately "in the course of development, these patterns acquire multiple adaptive functions ... and serve as a key organizer of their sense of self."[5]
"In producing movement away from fixed fantasy systems, commonplace statements are often necessary because the more fixed and extensive the fantasy system, the fewer the transitional opportunities offered; there is little conflicting material to ride. Banalities may be the only resource",[6] as anything more complex may be used to feed back into the fantasy system itself.
### Basic beliefs and cognitive therapy[edit]
A fixed fantasy differs from a delusion or delusional system in that, superficially, a fixed fantasy tends to appear plausible, and the person expressing the fantasy is not suffering a break from reality, as occurs in a delusional state. For example, sufferers of obsessive-compulsive personality disorder would believe that "everything has to be perfect" while sufferers of avoidant personality disorder would believe that they are "not good enough". Challenging such "automatic thoughts ... attitudes and basic negative beliefs"[7] is an important part of cognitive therapy.
### Religion[edit]
A fixed fantasy also differs from religion or superstition in that these are culturally bound, whereas a fixed fantasy is specific to an individual. In and of themselves, fixed fantasies are not necessarily harmful, but they can interfere with an individual's ability to develop a coherent and integrated life experience.
## Psychosexual[edit]
In a disciplinary distinct usage (though one equally dependent upon emotional conditioning, upon how "emotions can become associated and linked together ... an automatic switch,")[8] the term fixed fantasy has also been used in respect of psychosexual phantasies – conscious and unconscious.
"In rare cases, a person can become so fixed on a particular fantasy that he or she cannot become aroused without it."[9] Such fantasies underpin much perversion, where "the perverse and fixed "scenario" ... is as much a defence against the anxieties associated with alternative fantasies as it is with the gaining of satisfaction."[10] Robert Stoller considered such fixed fantasies to structure "one's preferred erotic script ... at the centre of which is a remembered (not always consciously remembered, however) bad experience or relationship in early childhood."[11] The fixed fantasy is "a primal daydream that summarises the person's erotic preferences and mirrors that person's whole character structure."[12]
## See also[edit]
* Aaron Beck
* Albert Ellis
* Archetype
* Fixation
* Life Script
* Idée fixe (psychology)
* Psychological trauma
## References[edit]
1. ^ Eleanor Schuker/Nadine A Levinson, Female Psychology (1991) p. 479
2. ^ Efraim Bleiberg, Treating Personality Disorders in Children and Adolescents (2004) p. 144
3. ^ Bleiberg, p. 145
4. ^ Hannah Green, I Never Promised You a Rose Garden (London 1967) p. 65 and p. 38
5. ^ Bleiberg, p. 145
6. ^ L. Havens/L. L. Havens, Participant Observation (1993) p. 44
7. ^ Paul Gilbert, Overcoming Depression (1998) p. 68
8. ^ Paul Gilbert, The Compassionate Mind (London 2009) p. 464 and p. 127
9. ^ Miriam Stoppard, in Nancy Kalish, The Nice Girl's Guide to Sensational Sex (2003) p. 109
10. ^ Susan Long, The Perverse Organisation and its Deadly Sins (2008) p. 17
11. ^ Quoted in John Forrester, Dispatches from the Freud Wars (London 1997) p. 239
12. ^ Robert J. Stoller, Sweet Dreams: Erotic Plots (2009) p. 4
## Further reading[edit]
* I. V Halvorsen/S. N. Olsen eds., New Research on Personality Disorders (2008)
* Robert J. Stoller, Perversion: The Erotic Form of Hatred (1986)
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Fixed fantasy | None | 4,980 | wikipedia | https://en.wikipedia.org/wiki/Fixed_fantasy | 2021-01-18T18:28:34 | {"wikidata": ["Q5456364"]} |
Localized scleroderma is characterized by thickening of the skin from excessive collagen deposits. Collagen is a protein normally present in our skin that provides structural support. However, when too much collagen is made, the skin becomes stiff and hard. Localized types of scleroderma are those limited to the skin and related tissues and, in some cases, the muscle below. Internal organs are not affected by localized scleroderma, and localized scleroderma can never progress to the systemic form of the disease. Often, localized conditions improve or go away on their own over time, but the skin changes and damage that occur when the disease is active can be permanent. For some people, localized scleroderma is serious and disabling.
There are two generally recognized types of localized scleroderma: morphea and linear.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Localized scleroderma | c0036420 | 4,981 | gard | https://rarediseases.info.nih.gov/diseases/7058/localized-scleroderma | 2021-01-18T17:59:20 | {"mesh": ["D012594"], "umls": ["C0036420"], "orphanet": ["90289"], "synonyms": ["Scleroderma, localized", "Localized fibrosing scleroderma"]} |
Milk-alkali syndrome
Other namesCalcium-alkali syndrome[1]
In medicine, milk-alkali syndrome is characterized by high blood calcium and metabolic alkalosis caused by taking in too much calcium and absorbable alkali; common sources of calcium and alkali are dietary supplements taken to prevent osteoporosis and antacids. If untreated, milk-alkali syndrome may lead to kidney failure or death.[2]
It was most common in the early 20th century, but since the 1990s, there has been an increase in the number of cases reported, linked to the increased use of calcium supplements to address or prevent osteoporosis.[3][4]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment
* 6 Outcomes
* 7 Epidemiology
* 8 History
* 9 References
* 10 External links
## Signs and symptoms[edit]
The most common symptoms are poor appetite, dizziness, headache, confusion, psychosis, and dry mouth; laboratory tests may show that a person with milk-alkali syndrome has high blood calcium, kidney failure, and metabolic alkalosis.[5]
## Causes[edit]
Milk-alkali syndrome is caused by taking too much calcium (usually in the form of dietary supplements taken to prevent osteoporosis) and absorbable alkali (as are found in antacid drugs).[5][6]
## Mechanism[edit]
The mechanism by which ingesting too much calcium and alkali leads to milk-alkali syndrome is unclear, since the human body tightly regulates levels of calcium. Impaired kidney function is a risk factor but even people with healthy kidneys can develop the syndrome.[5]
## Diagnosis[edit]
To diagnose milk-alkali syndrome, primary hyperparathyroidism has to be excluded. Usually the PTH is suppressed. Phosphorus levels are usually decreased while creatinine and bicarbonate levels are elevated.
## Treatment[edit]
Treatment involves having the person stop taking any calcium supplements and any other alkali agents they have been taking, and hydration.[5][7]
In severe cases, hospitalization may be required, in which case saline may be administered intravenously.[7]
If kidney failure is advanced then treatment for that is required, namely chronic dialysis.[7]
## Outcomes[edit]
In mild cases, full recovery is expected. In severe cases, permanent kidney failure or death may result.[5]
## Epidemiology[edit]
Among people hospitalized with high blood calcium, milk-alkali syndrome is the third most common cause, after hyperparathyroidism and cancer.[5]
## History[edit]
The name "milk-alkali syndrome" derives from a reaction that arose to a treatment for gastric ulcers created in the early 1900s by Bertrand Sippy; Sippy prescribed his patients milk and alkali on the theory that ulcers were caused by excessive gastric acid.[5] However within a few decades, an acute hypercalcemia syndrome with a relative good outcome was identified by Cuthbert Cope in 1936 (now called Cope syndrome), and in 1949 Charles H. Burnett identified a similar but more severe syndrome, with chronically high blood calcium levels and poor outcomes.[5]
When the true cause of most gastric ulcers was identified and drugs other than antacids were developed to treat heartburn – namely acid-reducing drugs like H2-receptor antagonists or proton pump inhibitors – the incidence of milk-alkali syndrome greatly diminished. However, as a result of increased osteoporosis awareness and the routine use of calcium supplements to prevent it, the incidence has again increased.[5]
## References[edit]
1. ^ "Milk-alkali syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 16 April 2019.
2. ^ Irtiza-Ali, Ayesha; Waldek, Stephen; Lamerton, Elizabeth; Pennell, Ashley; Kalra, Philip A. (2008). "Milk Alkali Syndrome Associated with Excessive Ingestion of Rennie®: Case Reports". Journal of Renal Care. 34 (2): 64–67. doi:10.1111/j.1755-6686.2008.00018.x. ISSN 1755-6678. PMID 18498570.
3. ^ Caruso JB, Patel RM, Julka K, Parish DC (July 2007). "Health-behavior induced disease: return of the milk-alkali syndrome". J Gen Intern Med. 22 (7): 1053–5. doi:10.1007/s11606-007-0226-0. PMC 2219730. PMID 17483976.
4. ^ Beall DP, Henslee HB, Webb HR, Scofield RH (May 2006). "Milk-alkali syndrome: a historical review and description of the modern version of the syndrome". Am. J. Med. Sci. 331 (5): 233–42. doi:10.1097/00000441-200605000-00001. PMID 16702792.
5. ^ a b c d e f g h i Medarov BI (2009). "Milk-alkali syndrome". Mayo Clin Proc. 84 (3): 261–7. doi:10.1016/S0025-6196(11)61144-0. PMC 2664604. PMID 19252114.
6. ^ U.S. Department of Health and Human Services, National Institutes of Health, U.S. National Library of Medicine. Last updated Update Date: 7 November 2013 by:Brent Wisse. Medline Plus: Milk-alkali syndrome
7. ^ a b c Scofield RH et al. for eMedicine. Updated: 12 Aug, 2014 eMedicine: Milk-Alkali Syndrome
## External links[edit]
Classification
D
* ICD-9-CM: 275.42
* DiseasesDB: 8215
External resources
* MedlinePlus: 000332
* eMedicine: article/123324
* v
* t
* e
Metal deficiency and toxicity disorders
Iron
excess:
* Iron overload
* Hemochromatosis
* Hemochromatosis/HFE1
* Juvenile/HFE2
* HFE3
* African iron overload/HFE4
* Aceruloplasminemia
* Atransferrinemia
* Hemosiderosis
deficiency:
* Iron deficiency
Copper
excess:
* Copper toxicity
* Wilson's disease
deficiency:
* Copper deficiency
* Menkes disease/Occipital horn syndrome
Zinc
excess:
* Zinc toxicity
deficiency:
* Acrodermatitis enteropathica
Other
* Inborn errors of metabolism
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Milk-alkali syndrome | c0026141 | 4,982 | wikipedia | https://en.wikipedia.org/wiki/Milk-alkali_syndrome | 2021-01-18T18:31:47 | {"mesh": ["D006934"], "icd-9": ["275.42"], "wikidata": ["Q441094"]} |
A rare neuro-ophthalmological disease characterized by nonprogressive cerebellar ataxia, delayed motor and language development and intellectual disability, in addition to ophthalmological abnormalities (e.g. oculomotor apraxia, strabismus, amblyopia, retinal dystrophy and myopia). Cerebellar cysts, cerebellar dysplasia and cerebellar vermis hypoplasia, seen on magnetic resonance imaging, are also characteristic of the disease.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Ataxia-intellectual disability-oculomotor apraxia-cerebellar cysts syndrome | c4014821 | 4,983 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370022 | 2021-01-23T17:13:53 | {"omim": ["615960"], "icd-10": ["G11.1"], "synonyms": ["Poretti-Boltshauser syndrome"]} |
An inherited hemoglobinopathy characterized by impaired synthesis of alpha-globin chains leading to a variable clinical picture depending on the number of affected alleles.
## Epidemiology
Like other globin gene disorders, alpha-thalassemia is highly prevalent in all tropical and subtropical regions (around 1/10,000), particularly in the African equatorial belt. Intermediate and severe forms of alpha-thalassemia are very rare in North America and Northern Europe (about 1/1,000,000), and are predominantly seen in immigrant populations from South-East Asia or Mediterranean countries.
## Clinical description
The disease can be classified into clinical subtypes of increasing severity: silent alpha thalassemia, alpha thalassemia trait (or alpha thalassemia minor), hemoglobin H disease (HbH), and Hb Bart's hydrops fetalis. A rare form called alpha-thalassemia-intellectual deficit syndrome linked to chromosome 16 (16p13.3) has also been identified (see these terms). Alpha thalassemia trait causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. HbH patients develop moderate hemolytic anemia with variable amounts of HbH along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin with serious developmental implications. Alpha-thalassemia-intellectual deficit syndrome is characterized by very mild to severe anemia associated with developmental abnormalities.
## Etiology
Alpha globin synthesis is regulated by four alpha-globin genes, two on each copy of chromosome 16 (16p13.3). Alpha-thalassemia most frequently results from deletion of one or both alleles (HBA1 and HBA2). More rarely, point mutations in critical regions of these genes may cause non-deletional alpha-thalassemia. Deletions of regulatory elements located upstream of the alpha-globin genes have also been found. The severity of the clinical picture is correlated with the degree of alpha-globin chain deficiency. It has been found that interactions involving non-deletional forms lead to more severe manifestations than those involving deletional forms. Deletion of 1 allele results in the silent form, 2 alleles in alpha-thalassemia trait, and 3 alleles in HbH.
## Diagnostic methods
Diagnosis is based on hematologic testing of red blood cell (RBC) indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies, and qualitative and quantitative hemoglobin analysis. Confirmation of diagnosis is based on molecular genetic testing.
## Differential diagnosis
Differential diagnosis should include iron deficiency anemia and defects in heme synthesis. An acquired form known as alpha-thalassemia-myelodysplastic syndrome (ATMDS; see this term) has been described mainly in adult males and should also be considered. It is characterized by myelodysplasia (MD) associated with HbH.
## Antenatal diagnosis
Prenatal diagnosis should be made available for pregnancies at risk for Hb Bart's hydrops fetalis or severe forms of HbH disease.
## Genetic counseling
Alpha-thalassemia is transmitted in an autosomal recessive manner. Genetic counseling can be offered but may be complex due to the large number of alleles and mutations involved.
## Management and treatment
Patients with silent alpha-thalassemia or thalassemia trait do not require treatment. Specific treatment is however required for other forms of the disease and may include occasional red blood cell transfusions, iron chelation, and other supportive measures.
## Prognosis
The prognosis for carriers of silent alpha-thalassemia or alpha-thalassemia trait is very good. Neonates with Hb Bart's hydrops fetalis usually die in the perinatal period. In patients with hemoglobin H disease, the prognosis is usually good, but depends on complications and care.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Alpha-thalassemia | c0002312 | 4,984 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=846 | 2021-01-23T17:47:55 | {"gard": ["621"], "mesh": ["D017085"], "omim": ["604131"], "umls": ["C0002312", "C1456873"], "icd-10": ["D56.0"]} |
Heterotopic pregnancy
Play media
Ruptured heterotopic pregnancy on ultrasound[1]
SpecialtyObstetrics
A heterotopic pregnancy is a rare[2][3] complication of pregnancy in which both extra-uterine (ectopic pregnancy) and intrauterine pregnancy occur simultaneously.[4] It may also be referred to as a combined ectopic pregnancy, multiple‑sited pregnancy, or coincident pregnancy.
## Contents
* 1 Cause
* 2 Pathogenesis
* 3 Diagnosis
* 3.1 Differential diagnosis
* 4 Management
* 5 Prognosis
* 6 Epidemiology
* 7 References
* 8 External links
## Cause[edit]
In a heterotopic pregnancy there is one fertilized ovum which implants normally in the uterus, and one fertilized ovum which implants abnormally, outside of the uterus.[5]
## Pathogenesis[edit]
In the general population, the major risk factors for heterotopic pregnancy are the same as those for ectopic pregnancy. For women in an assisted reproductive program, there are additional factors: a higher incidence of multiple ovulation, a higher incidence of tubal malformation and/or tubal damage, and technical factors in embryo transfer which may increase the risk for ectopic and heterotopic pregnancy.
## Diagnosis[edit]
Free fluid (blood) see between the liver and kidney in a person with a ruptured heterotopic pregnancy[1]
### Differential diagnosis[edit]
A heterotopic pregnancy may have similar signs and symptoms as a normal intrauterine pregnancy, a normal intrauterine pregnancy and a ruptured ovarian cyst, a corpus luteum, or appendicitis. Blood tests and ultrasound can be used to differentiate these conditions.
Signs of ectopic pregnancy include abdominal pain, shoulder pain, vaginal bleeding, and a feeling of dizziness.[6]
## Management[edit]
Heterotopic pregnancy is treated with surgical removal of the ectopic gestation by salpingectomy or salpingostomy.[7] Expectant management of ectopic pregnancies has been successfully applied in select cases.[8] Treatment of heterotopic pregnancy will depend on the specific location of the ectopic pregnancy, as well as the pregnant person's clinical presentation and stability.[8]
## Prognosis[edit]
Extrauterine pregnancies are non-viable and can be fatal to the mother if left untreated.[8]
## Epidemiology[edit]
The prevalence of heterotopic pregnancy is estimated at 0.6‑2.5:10,000 pregnancies.[3] There is a significant increase in the incidence of heterotopic pregnancy in women undergoing ovulation induction. An even greater incidence of heterotopic pregnancy is reported in pregnancies following assisted reproduction techniques such as In vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT), with an estimated incidence at between 1 and 3 in 100 pregnancies.[9] If there is embryo transfer of more than 4 embryos, the risk has been quoted as 1 in 45.[9] In natural conceptions, the incidence of heterotopic pregnancy has been estimated to be 1 in 30 000 pregnancies.[9]
## References[edit]
1. ^ a b "UOTW #9 - Ultrasound of the Week". Ultrasound of the Week. 15 July 2014. Retrieved 27 May 2017.
2. ^ Richards, S. R.; Stempel, L. E.; Carlton, B. D. (1982). "Heterotopic pregnancy: Reappraisal of incidence". Am. J. Obstet. Gynecol. 142 (7): 928. PMID 7065071.
3. ^ a b Bello, G. V.; Schonolz, D.; Moshirpur, J.; et al. (1986). "Combined pregnancy: The Mount Sinai experience". Obstet. Gynecol. Surv. 41 (10): 603. PMID 3774265.
4. ^ "Archived copy". Archived from the original on 2006-09-27. Retrieved 2008-08-19.CS1 maint: archived copy as title (link)
5. ^ Hilbert, SueLin M.; Gunderson, Stephanie (2019). "Complications of Assisted Reproductive Technology". Emergency Medicine Clinics of North America. 37 (2): 239–249. doi:10.1016/j.emc.2019.01.005. ISSN 1558-0539. PMID 30940369.
6. ^ "Ectopic Pregnancy". medlineplus.gov. Retrieved 2020-10-22.
7. ^ Mummert, Tyler; Gnugnoli, David M. (2020), "Ectopic Pregnancy", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30969682, retrieved 2020-10-22
8. ^ a b c Panelli, Danielle M.; Phillips, Catherine H.; Brady, Paula C. (2015-10-15). "Incidence, diagnosis and management of tubal and nontubal ectopic pregnancies: a review". Fertility Research and Practice. 1. doi:10.1186/s40738-015-0008-z. ISSN 2054-7099. PMC 5424401. PMID 28620520.
9. ^ a b c Kirk, E.; Bottomley, C.; Bourne, T. (2013). "Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location". Human Reproduction Update. 20 (2): 250–61. doi:10.1093/humupd/dmt047. PMID 24101604.
## External links[edit]
Classification
D
* ICD-10: O00.8
* ICD-9-CM: 633.8
* MeSH: D011271
External resources
* eMedicine: med/3212 emerg/478 radio/231
* v
* t
* e
Pathology of pregnancy, childbirth and the puerperium
Pregnancy
Pregnancy with
abortive outcome
* Abortion
* Ectopic pregnancy
* Abdominal
* Cervical
* Interstitial
* Ovarian
* Heterotopic
* Embryo loss
* Fetal resorption
* Molar pregnancy
* Miscarriage
* Stillbirth
Oedema, proteinuria and
hypertensive disorders
* Gestational hypertension
* Pre-eclampsia
* HELLP syndrome
* Eclampsia
Other, predominantly
related to pregnancy
Digestive system
* Acute fatty liver of pregnancy
* Gestational diabetes
* Hepatitis E
* Hyperemesis gravidarum
* Intrahepatic cholestasis of pregnancy
Integumentary system /
dermatoses of pregnancy
* Gestational pemphigoid
* Impetigo herpetiformis
* Intrahepatic cholestasis of pregnancy
* Linea nigra
* Prurigo gestationis
* Pruritic folliculitis of pregnancy
* Pruritic urticarial papules and plaques of pregnancy (PUPPP)
* Striae gravidarum
Nervous system
* Chorea gravidarum
Blood
* Gestational thrombocytopenia
* Pregnancy-induced hypercoagulability
Maternal care related to the
fetus and amniotic cavity
* amniotic fluid
* Oligohydramnios
* Polyhydramnios
* Braxton Hicks contractions
* chorion / amnion
* Amniotic band syndrome
* Chorioamnionitis
* Chorionic hematoma
* Monoamniotic twins
* Premature rupture of membranes
* Obstetrical bleeding
* Antepartum
* placenta
* Circumvallate placenta
* Monochorionic twins
* Placenta accreta
* Placenta praevia
* Placental abruption
* Twin-to-twin transfusion syndrome
Labor
* Amniotic fluid embolism
* Cephalopelvic disproportion
* Dystocia
* Shoulder dystocia
* Fetal distress
* Locked twins
* Nuchal cord
* Obstetrical bleeding
* Postpartum
* Pain management during childbirth
* placenta
* Placenta accreta
* Preterm birth
* Postmature birth
* Umbilical cord prolapse
* Uterine inversion
* Uterine rupture
* Vasa praevia
Puerperal
* Breastfeeding difficulties
* Low milk supply
* Cracked nipples
* Breast engorgement
* Childbirth-related posttraumatic stress disorder
* Diastasis symphysis pubis
* Postpartum bleeding
* Peripartum cardiomyopathy
* Postpartum depression
* Postpartum psychosis
* Postpartum thyroiditis
* Puerperal fever
* Puerperal mastitis
Other
* Concomitant conditions
* Diabetes mellitus
* Systemic lupus erythematosus
* Thyroid disorders
* Maternal death
* Sexual activity during pregnancy
* Category
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Heterotopic pregnancy | c0269291 | 4,985 | wikipedia | https://en.wikipedia.org/wiki/Heterotopic_pregnancy | 2021-01-18T19:10:39 | {"mesh": ["D063192"], "icd-9": ["633.8"], "icd-10": ["O00.8"], "wikidata": ["Q3117073"]} |
Spina bifida is a type of neural tube defect in which the neural tube (the structure in an embryo that becomes the brain and spinal cord) does not completely close during development in the womb. This may result in part of the spinal cord sticking out through an opening in the spine, leading to permanent nerve damage. Babies born with spina bifida often have a fluid-filled sac, covered by skin, on their back. This is called a meningocele. If the sac contains part of the spinal cord and its protective covering, it is known as a myelomeningocele. The signs and symptoms of spina bifida can range from mild to severe, depending on the location and extent of spinal cord involvement. Possible symptoms include include a loss of feeling below the level of the opening, weakness or paralysis of the feet or legs, problems with bladder and bowel control, hydrocephalus, and learning problems.
The cause in most cases is multifactorial, which means that both genetic and environmental factors interact to cause spina bifida. Some cases may be due to the inheritance of specific gene mutations, chromosome abnormalities, or fetal exposure to teratogens. Maternal folate deficiency increases the risk to have a baby with spina bifida, and women who take folic acid supplements before and during early pregnancy are much less likely to have a baby with spina bifida.
Treatment typically involves antibiotics, sac closure, and ventriculoperitoneal shunting, usually shortly after birth. Long-term physical, occupational, and/or speech therapy may be needed. In some cases, the condition is life-threatening and is not treatable.
There is also a milder form of the condition called spina bifida occulta in which the nerves develop normally and health problems rarely occur.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Spina bifida | c0080178 | 4,986 | gard | https://rarediseases.info.nih.gov/diseases/7673/spina-bifida | 2021-01-18T17:57:38 | {"mesh": ["D016135"], "orphanet": ["823"], "synonyms": ["Spinal dysraphism", "Cleft spine", "Open spine", "Rachischisis", "Isolated spina bifida"]} |
A rare non-Langerhans cell histiocytosis characterized by the association of specific nodular skin lesions and destructive arthritis.
## Epidemiology
Prevalence is unknown but around 200 cases have been reported in the literature so far.
## Clinical description
Onset is insidious, usually occurring at around 50 years of age. Multicentric reticulohistiocytosis (MRH) is a progressive disease, articular inflammation becomes more severe and, after periods of worsening and improving symptoms, incapacitating arthritis is a frequent feature. Multiple joints may be involved (mainly of the hands, wrists, shoulders, knees, hips and ankles). Joint symptoms oscillate and severe deforming arthritis, known as mutilating arthritis, is a prominent manifestation in between 11 and 45% of the cases, depending on the patient series. Similarly, cutaneous nodules appear and regress, with new eruptions developing over periods of many months, as the old ones become inactive, stabilize or disappear. The cutaneous nodules are either skin-colored or have a red/brown appearance and are usually asymptomatic. They are more frequent on the upper body, particularly the hands, and may also appear on mucosal surfaces. Internal organ involvement has also been reported. After a period of many years (usually 6 to 8), in the majority of cases, arthritis becomes quiescent and the mucocutaneous nodules stabilize or become smaller.
## Etiology
The etiology is unknown. MRH is believed to reflect a peculiar type of reactive inflammatory response to unknown stimuli with involvement of macrophages and T lymphocytes. An underlying malignancy has been described in around a quarter of patients.
## Diagnostic methods
Histopathological and immunohistochemical studies (revealing the characteristic reticulohistiocytic granulomas mainly composed of CD68 positive cells) are diagnostic in most cases. Radiologic examinations should be performed in all patients.
## Differential diagnosis
The differential diagnosis should include leprosy, rheumatoid arthritis, xanthogranulomas, lymphomas, sarcoidosis, Urbach-Wiethe disease, Farber disease and dermatomyositis (see these terms).
## Management and treatment
At present, no satisfactory treatment is available. Some chemotherapeutical schemes, particularly those involving alkylating agents and specific therapies targeted towards the tumor necrosis factor (TNF) or its receptors may lead to some improvement. Systemic steroids are usually of only limited benefit.
## Prognosis
Patients with MRH usually undergo spontaneous remission within a variable period of 6 to 8 years, however, sequelae (esthetic sequelae associated with the skin lesions and deforming sequelae associated with the arthritis) are frequent after cure. Death can occur due to internal organ involvement or as a result of the underlying malignancy.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Multicentric reticulohistiocytosis | c0311284 | 4,987 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139436 | 2021-01-23T18:39:11 | {"gard": ["7103"], "umls": ["C0311284"], "icd-10": ["D76.3"], "synonyms": ["Giant cell histiocytomatosis", "Lipoid dermatoarthritis"]} |
Digitalis (digoxin) poisoning is a potentially life-threatening poisoning that provokes conduction disturbances, characterized by increased automaticity and decreased conduction. Acute poisoning presents with the common initial manifestations of nausea and vomiting, cardiovascular manifestations (bradycardia, heart block and a variety of dysrhythmias), central nervous system manifestations (lethargy, confusion and weakness) and hyperkalemia. Chronic poisoning is more insidious, manifesting with gastrointestinal symptoms, altered mental status, and visual disturbances.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Digitalis poisoning | c0274726 | 4,988 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=31828 | 2021-01-23T18:35:33 | {"icd-10": ["T46.0"]} |
A number sign (#) is used with this entry because of evidence that Carpenter syndrome-2 (CRPT2) is caused by homozygous or compound heterozygous mutation in the MEGF8 gene (604267) on chromosome 19q13.
Description
Carpenter syndrome-2 is an autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease (summary by Twigg et al., 2012).
For a discussion of genetic heterogeneity of Carpenter syndrome, see 201000.
Clinical Features
Altunhan et al. (2011) described a Turkish boy who was born with acrocephaly and a peculiar facies characterized by frontal bossing. Digital abnormalities included clinodactyly of the fifth fingers, membranous syndactyly of fingers 3 and 4, syndactyly of toes 1 and 2, and preaxial polydactyly of the big toes bilaterally. Other abnormalities included widely spaced nipples and bilateral cryptorchidism. On cardiac auscultation, heart sounds were best heard at the right intersternal border, and chest radiograph revealed dextrocardia; echocardiography did not demonstrate any other cardiac abnormalities. Abdominal ultrasound revealed that the liver was in the left upper quadrant and the spleen was in the right upper quadrant. No brain abnormalities were detected on MRI; skull x-rays and 3D CT showed metopic anterior and posterior sagittal synostosis. Altunhan et al. (2011) stated that this was the first report of Carpenter syndrome in association with situs inversus totalis.
Twigg et al. (2012) studied 5 patients with mutation in the MEGF8 gene and a phenotype closely resembling classic Carpenter syndrome (CRPT1; 201000). One of the patients was the Turkish boy previously described by Altunhan et al. (2011). In both phenotypes, the spectrum of limb anomalies was similar and consisted of brachydactyly, syndactyly, and preaxial polydactyly. Other common features included a tendency toward high birth weight and childhood obesity and the occurrence of cryptorchidism or undescended testes in males. However, craniosynostosis tended to be less severe in the CRPT2 patients and usually involved only the metopic suture; this was frequently accompanied by a paradoxical hypertelorism, associated with a distinctive dysmorphic facies comprising a broad depressed nasal bridge, epicanthus, upslanted palpebral fissures, highly arched eyebrows, and low-set poorly angulated ears. Defects of lateralization were present in at least 3 of the patients and ranged from transposition of the great arteries to dextrocardia to complete situs inversus. The remaining 2 patients were Saudi Arabian brothers who were both diagnosed with diaphragmatic eventration and central position of the liver, but their clinical information was incomplete. Wide-spaced, hypoplastic, and/or supernumerary nipples and thoracic skeletal abnormalities appeared to be more characteristic in CRPT2 patients, whereas umbilical hernia and genu valgum, prominent features in CRPT1, were less characteristic in CRPT2.
Molecular Genetics
In a consanguineous Turkish family in which the proband was a 9-year-old boy with the cardinal features of Carpenter syndrome and dextrocardia, who was negative for mutation in the RAB3 (602536) and GLI3 (165240) genes, Twigg et al. (2012) performed homozygosity mapping followed by exome sequencing and identified a homozygous missense mutation in the MEGF8 gene (604267.0001) that segregated with disease in the family. Analysis of MEGF8 in 22 additional individuals with a suspected diagnosis of Carpenter syndrome but who were negative for mutation in RAB3 revealed 3 more patients who were homozygous or compound heterozygous for mutations in MEGF8, 1 of whom was the boy previously described by Altunhan et al. (2011) (see, e.g., 604267.0002-604267.0004). No mutations were found in the MEGF3 gene in 15 patients with heterotaxy but no craniosynostosis or limb anomalies. Noting that 3 of the mutation-positive patients also had complete situs inversus, dextrocardia, or transposition of the great arteries, respectively, Twigg et al. (2012) concluded that mutation in MEGF8 causes a Carpenter syndrome subtype frequently associated with defective left-right patterning.
INHERITANCE \- Autosomal recessive GROWTH Weight \- Increased birth weight \- Obesity HEAD & NECK Head \- Acrocephaly (rare) \- Trigonocephaly (rare) \- Brachycephaly (rare) Face \- Frontal bossing (rare) \- Midface retrusion \- Retrognathia (rare) Ears \- Low-set ears \- Increased posterior angulation \- Protruding ears (rare) \- Hearing loss, sensorineural, mild (rare) Eyes \- Hypertelorism \- Epicanthal folds \- Upslanting palpebral fissures \- Nasolacrimal duct obstruction due to ectropion of lower eyelids (rare) \- High-arched eyebrows \- Sparse eyebrows (rare) Nose \- Depressed nasal bridge \- Wide nasal bridge \- Anteverted nares \- Narrow nares (rare) Mouth \- Narrow palate \- High-arched palate Teeth \- Multiple dental caries Neck \- Short neck \- Webbed neck (rare) CARDIOVASCULAR Heart \- Dextrocardia \- Atrial septal defect (rare) \- Tricuspid valve insufficiency (rare) Vascular \- Transposition of great vessels (rare) \- Patent ductus arteriosus CHEST Ribs Sternum Clavicles & Scapulae \- Pectus carinatum \- Pectus excavatum Breasts \- Widely spaced nipples \- Hypoplastic nipples \- Accessory nipples Diaphragm \- Eventration of diaphragm \- Elevated right hemidiaphragm ABDOMEN \- Situs inversus totalis (rare) External Features \- Umbilical hernia (rare) Liver \- Left-sided liver (rare) \- Central position of liver Spleen \- Right-sided spleen (rare) GENITOURINARY External Genitalia (Male) \- Small penis (rare) \- Shawl scrotum (rare) Internal Genitalia (Male) \- Cryptorchidism SKELETAL Skull \- Craniosynostosis (primarily metopic, but may also involve coronal or sagittal sutures) Pelvis \- Coxa vara (rare) Hands \- Brachydactyly \- Syndactyly, cutaneous \- Camptodactyly \- Broad thumbs \- Radially deviated thumbs \- Absent middle phalanges \- Postaxial polydactyly (rare) \- Preaxial polydactyly, partial (rare) \- Clinodactyly, 5th finger (rare) Feet \- Brachydactyly \- Syndactyly, cutaneous \- Preaxial polydactyly \- Absent middle phalanges \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Loose skin Hair \- Sparse eyebrows NEUROLOGIC Central Nervous System \- Developmental delay, variable severity MISCELLANEOUS \- Variable features present MOLECULAR BASIS \- Caused by mutation in the multiple epidermal growth factor-like domains-8 gene (MEGF8, 604267.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| CARPENTER SYNDROME 2 | c1275078 | 4,989 | omim | https://www.omim.org/entry/614976 | 2019-09-22T15:53:42 | {"doid": ["0060234"], "mesh": ["C563187"], "omim": ["614976"], "orphanet": ["65759"]} |
A number sign (#) is used with this entry because choreoacanthocytosis can be caused by homozygous or compound heterozygous mutation in the VPS13A gene (605978), which encodes chorein, on chromosome 9q21.
Description
Choreoacanthocytosis (CHAC) is a rare disorder characterized by progressive neurodegeneration and red cell acanthocytosis, with onset in the third to fifth decade of life (Rubio et al., 1997).
See also McLeod syndrome (300842) for a phenotypically similar disorder.
Clinical Features
Critchley et al. (1967, 1968) described an adult form of acanthocytosis associated with neurologic abnormalities and apparently normal serum lipoproteins. The proband had onset in his mid-twenties of generalized weakness and involuntary movements, including grimacing, dystonia, and chorea. Orofacial movements were especially dramatic, and the patient had multiple bite lesions on his lips, tongue, and cheeks. The neurologic manifestations resembled those of the Gilles de la Tourette syndrome (137580) or Huntington disease (143100). Four of the proband's sibs had neurologic manifestations. A niece had acanthocytes and a neurologic disorder suggesting Friedreich ataxia (229300).
Estes et al. (1967) and Levine et al. (1968) reported a family in which 19 persons in 4 generations had some degree of neurologic abnormalities, 15 with, and 4 without, acanthocytosis. Acanthocytes averaged from 1 to 20% of the total erythrocyte count, and there was no obvious association between the degree of acanthocytosis and the severity of the neurologic disability. There were no demonstrable quantitative defects of low density (beta) or high density (alpha) lipoproteins. Major neurologic symptoms included muscle weakness and atrophy, leg cramps, disturbances of coordination, hyporeflexia, chorea, and seizures. Inheritance was consistent with autosomal dominance. Levine et al. (1968) concluded that the disorder was neuronal.
Critchley et al. (1970) reported a single case from England, a woman who showed self-mutilation of the tongue, lips, and cheeks. Another family was reported by Aminoff (1972). Wasting of girdle and proximal limb muscles, absent tendon reflexes, and disturbance of bladder function were other features.
Cederbaum et al. (1971) and Bird et al. (1978) observed a consanguineous family in which 3 adult sibs developed progressive chorea and dementia similar to Huntington disease (143100), but with acanthocytes in the peripheral blood. No malabsorption or abnormalities of serum beta-lipoprotein were found. The proband was a 41-year-old male, and an affected brother and sister had died at ages 32 and 39 years. Postmortem examination showed marked neuronal loss and gliosis of the caudate and putamen. Two children of the proband were healthy. The authors suggested that the same disorder may have been present in the family of Critchley et al. (1967), although the pattern of inheritance in that family appeared to be autosomal dominant. In a patient with acanthocytosis and degeneration of the basal ganglia, Copeland et al. (1982) found an abnormally high level of a protein in the 100,000 MW range on 2-D O'Farrell gel electrophoresis of red cell membranes. This patient was from the family reported by Bird et al. (1978) (Motulsky, 1982).
Yamamoto et al. (1982) reported 2 sibs with neuroacanthocytosis with normal serum lipoprotein levels. Features included orolingual tic-like movements associated with vocalization, biting of the lip and tongue, dysphagia, subtle parkinsonism, and chorea.
Gross et al. (1985) reported a 46-year-old man of Hispanic Puerto Rican ancestry who had familial amyotrophic chorea with acanthocytosis (FACWA). At age 36 years, he developed progressive orofacial dyskinesia, dysarthria, dysphagia, and chorea of the trunk and limbs. Generalized tonic-clonic seizures appeared at age 40. Examination at age 46 showed the abnormal movements, as well as atrophy and weakness of the limb muscles and areflexia. Laboratory studies showed acanthocytosis on peripheral blood smear and increased serum creatine kinase. Family history revealed a brother who was less severely affected. The index patient also had increased free sialic acid, which the authors attributed to tissue destruction; the brother did not have this finding. Gross et al. (1985) noted the phenotypic similarity to the family reported by Estes et al. (1967).
Hardie et al. (1991) reviewed neuroacanthocytosis on the basis of 19 cases, 12 familial and 7 nonfamilial. The mean age at onset was 32 years (range, 8-62) and the clinical course was usually progressive with cognitive impairment, psychiatric features, and organic personality changes in over half the cases. More than one-third of the cases had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria. Chorea was seen in almost all cases, and dystonia, tics, and akinetic-rigid features also occurred. CT imaging showed cerebral atrophy, but caudate atrophy was seen less commonly. Postmortem examination in 1 case revealed extensive neuronal loss and gliosis affecting the striatum, pallidum, and substantia nigra. Kartsounis and Hardie (1996) reviewed the clinical features of 19 reported cases of neuroacanthocytosis and found that the most consistent neurologic findings were impairment of frontal lobe function and psychiatric morbidity, in a pattern suggesting subcortical dementia.
See Kay (1991) for a discussion of band 3 protein (109270) abnormalities in autosomal recessive choreoacanthocytosis.
In 3 patients with neuroacanthocytosis, Rinne et al. (1994) demonstrated reduced neuronal density in the substantia nigra. As in Parkinson disease, the ventral lateral region was most severely affected, but with a slightly more diffuse distribution.
Sorrentino et al. (1999) described late appearance of acanthocytes in the course of chorea-acanthocytosis. The patient was a 37-year-old man whose parents were second cousins. Onset was reported to be at the age of 20 years with personality changes, sexual disinhibition, aggressiveness, and sporadic orofaciolingual dyskinesias. Persistent choreic movements of the head, shoulders, trunk, and limbs appeared later. At 28 years, he developed sporadic, generalized tonic-clonic seizures which disappeared after the age of 33 years. At that time, neurologic examination showed self mutilation of tongue and lip, dysarthria, mild diffuse muscle atrophy, and lack of deep tendon reflexes. Blood smears failed to show acanthocytes. Three years later when he was restudied for progression of neurologic manifestations, a fresh Wright stain revealed 51% acanthocytes.
Requena Caballero et al. (2000) described a 34-year-old male, son of consanguineous parents, who had a progressive neurologic illness characterized by seizures, tics, choreic movements, and mood changes. Acanthocytosis was present in the blood, and serum beta-lipoprotein was normal. No KX (314850) changes of McLeod syndrome were found. Serial neuroimaging studies demonstrated progressive caudate atrophy. Elevated creatine kinase and muscle biopsy showed a nonspecific myopathy. Genetic study demonstrated linkage of the disorder to the 9q21 region.
Lossos et al. (2005) reported 3 unrelated Jewish patients with choreoacanthocytosis confirmed by genetic analysis (605978.0006; 605978.0007). One of the patients had trichotillomania beginning in adolescence, 2 decades before diagnosis of CHAC. She also experienced postpartum exacerbation of CHAC. Another patient showed increased serum creatine kinase and hepatosplenomegaly approximately 10 years before other symptoms of CHAC developed.
Gradstein et al. (2005) described the eye movement abnormalities in 3 patients with CHAC. All had degeneration of the basal ganglia on MRI typical of CHAC. Their eye movement findings suggested brainstem involvement as an additional site of neurodegeneration outside the basal ganglia in CHAC. All 3 patients were later reported by Dobson-Stone et al. (2002) to have mutations in the VPS13A gene.
Ruiz-Sandoval et al. (2007) reported 2 Mexican mestizo sisters, born of consanguineous parents, with choreoacanthocytosis associated with a homozygous VPS13A mutation (605978.0009). The proband had onset at age 32 years and showed severe progression of the disorder; at age 42, she was emaciated, anarthric, and reactive only to simple commands. In contrast, her sister had onset at age 45 years and primarily showed motor and verbal tics, paranoid behavior, and depression. Ruiz-Sandoval et al. (2007) noted the clinical heterogeneity of the disorder in this family despite the patients having the same mutation.
Inheritance
Spitz et al. (1985) reported 2 brothers from a consanguineous family with motor and vocal tics, parkinsonism, distal muscular atrophy, and acanthocytosis. The neurologic features became most apparent in their thirties. Villegas et al. (1987) reported 2 affected sibs whose parents were normal. The patients did not have anemia or signs of hemolysis.
Vance et al. (1987) reported 4 affected patients from 3 families, and concluded that the inheritance was most likely autosomal recessive. Two of the 3 propositi were initially diagnosed as having Huntington disease. MRI showed atrophy of the caudate and putamen. Obligate heterozygotes did not show acanthocytosis. The authors noted that the disorder may be more frequent in Japan than elsewhere (Kito et al., 1980; Nagashima et al., 1979; Yamamoto et al., 1982). Vance et al. (1987) reviewed the literature and concluded that of 9 families in which there were 2 or more affected members, 2 were probably autosomal dominant and 7 were autosomal recessive.
Diagnosis
### Differential Diagnosis
Walker et al. (2002) reported a family in which 3 members were affected with what the authors thought was autosomal dominant choreoacanthocytosis. The 56-year-old proband had initially been diagnosed with Huntington disease (143100). All 3 patients had 30 to 35% acanthocytosis on peripheral blood smear. However, in affected members of this family, Walker et al. (2003) identified trinucleotide repeat expansions in the junctophilin-3 gene (605268.0001), confirming a diagnosis of Huntington disease-like-2 (HDL2; 606438). Walker et al. (2003) suggested that HDL2 should be considered in the differential diagnosis of choreoacanthocytosis.
Mapping
Rubio et al. (1997) performed linkage studies of 11 families segregating for CHAC that were of diverse geographic origin. They found linkage in all families to a 6-cM region of 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum 2-point lod score of 7.1 at theta = 0.0 was achieved for D9S1867. The results of these studies were confirmed by homozygosity-by-descent analysis in offspring from consanguineous marriages. Together, these data provided strong evidence for the involvement of a single locus for CHAC.
Molecular Genetics
In the 11 CHAC families reported by Rubio et al. (1997), Rampoldi et al. (2001) identified 16 different mutations in the gene encoding chorein (see, e.g., 605978.0001).
In 4 affected patients from 3 Japanese kindreds with CHAC, Ueno et al. (2001) identified homozygosity for a deletion in the VPS13A gene (605978.0003). The unaffected parents were heterozygous for the deletion. Haplotype analysis indicated a founder effect.
Among 43 patients with choreoacanthocytosis, Dobson-Stone et al. (2002) identified 57 different mutations distributed throughout the CHAC gene (see, e.g., 605978.0004). In 7 patients, only 1 heterozygous mutation was found; in 4 patients, no disease mutations were found. The authors noted that small gene deletions or rearrangements may not have been detected in these patients.
In 2 affected sibs from a Japanese family with choreoacanthocytosis with apparent autosomal dominant inheritance, Saiki et al. (2003) identified heterozygosity for mutation in the CHAC gene (605978.0005). In an erratum, the authors stated that an error in sequencing had occurred and the inheritance pattern should have been reported as autosomal recessive (pseudodominant).
Dobson-Stone et al. (2005) identified a homozygous 37-kb deletion in the VPS13A gene (605978.0008) in affected members of 3 French Canadian families with choreoacanthocytosis. Haplotype analysis indicated a founder effect.
Nomenclature
Sakai et al. (1985) suggested the term 'Levine-Critchley syndrome' as the best designation for this disorder. They considered the term choreoacanthocytosis inappropriate because tics, dystonia, or parkinsonism may dominate the clinical picture (Spitz et al., 1985). 'Neuroacanthocytosis' was also considered inappropriate because it might include the Bassen-Kornzweig syndrome (200100). Jankovic et al. (1985) noted that there are 2 other neuroacanthocytoses: one associated with hypobetalipoproteinemia (615558) and another that is part of the McLeod syndrome.
INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Orofacial dyskinesia Neck \- Neck flexion, intermittent ABDOMEN Gastrointestinal \- Dysphagia \- Drooling SKELETAL Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Limb muscular atrophy \- Limb muscle weakness NEUROLOGIC Central Nervous System \- Progressive choreoathetosis \- Orofacial dyskinesia \- Hyporeflexia \- Dysarthria \- Seizures \- Tics \- Dystonia \- Parkinsonism \- Caudate atrophy \- Putamen atrophy \- Dementia (in some patients) Peripheral Nervous System \- Hyporeflexia \- Areflexia Behavioral Psychiatric Manifestations \- Personality changes \- Mood changes \- Anxiety \- Disinhibition \- Psychosis \- Aggressiveness \- Self-mutilation of tongue and lips due to involuntary movements HEMATOLOGY \- Acanthocytes LABORATORY ABNORMALITIES \- Increased creatine kinase \- Normal serum lipoprotein levels MISCELLANEOUS \- Age of onset 23-59 years \- Clinical variability \- Progressive disorder \- Neurologic findings closely resemble those of Huntington disease (HD, 143100 ) MOLECULAR BASIS \- Caused by mutation in the vacuolar protein sorting 13A gene (VPS13A, 605978.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
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*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
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*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
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*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| CHOREOACANTHOCYTOSIS | c0393576 | 4,990 | omim | https://www.omim.org/entry/200150 | 2019-09-22T16:31:42 | {"doid": ["0050766"], "mesh": ["D054546"], "omim": ["200150"], "orphanet": ["2388"], "synonyms": ["Alternative titles", "LEVINE-CRITCHLEY SYNDROME", "ACANTHOCYTOSIS WITH NEUROLOGIC DISORDER", "NEUROACANTHOCYTOSIS", "CHOREA-ACANTHOCYTOSIS"], "genereviews": ["NBK1387"]} |
Pericardial cyst is an abnormal dilatation of pericardium of the heart.
## Contents
* 1 Types
* 2 Clinical features
* 3 Diagnosis
* 4 References
## Types[edit]
Pericardial cyst can be simple or complex. Simple pericardial cyst are usually more prevalent with water, blood, or necrotic content. Complex cyst contains solid elements with septations. Sizes varies from 2 to 28 cm but they are usually less than 5 cm. Cyst wall is usually lined by mesothelial cells and located at the right pericardiophrenic angle.[1]
Pericardial cysts can also be divided into congenital and acquired. In congenital cyst, lacunaes failed to merged embryologically. For acquired cysts, it could be due to inflammation, pseudocysts, trauma, post myocardial infection, or viral infection.[1]
## Clinical features[edit]
Clinical features include: pleuritic chest pain, dyspnea, palpitations, cough, pain on swallowing, fever, weight loss, and paroxysmal tachycardia.[1]
## Diagnosis[edit]
On chest x-ray, there will be abnormal tissue density or an isolated cystic shadow over the cardiophrenic angle. On transthoracic echocardiogram, there is lack of flow on the affected area on colour Doppler. On cardiac CT scan, there is non-enhancing, homogenous attenuation of the affected area. Cardiac CT is good for precise localisation of percardial anatomy. On cardiac magnetic resonance imaging, there is non-enhancing thin wall mass with low T1 signal and high T2 signal. Late gadolinium enhancement is negative.[1]
## References[edit]
1. ^ a b c d Khayata, Mohamed; Alkharabsheh, Saqer; Shah, Nishant P.; Klein, Allan L. (July 2019). "Pericardial Cysts: a Contemporary Comprehensive Review". Current Cardiology Reports. 21 (7): 64. doi:10.1007/s11886-019-1153-5. ISSN 1523-3782.
This article related to pathology is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Pericardial cyst | c0031038 | 4,991 | wikipedia | https://en.wikipedia.org/wiki/Pericardial_cyst | 2021-01-18T19:05:25 | {"mesh": ["D008476"], "umls": ["C0031038"], "wikidata": ["Q9360143"]} |
A number sign (#) is used with this entry because methylmalonic aciduria (MMA) of the complementation group 'mut' is caused by mutation in the gene encoding methylmalonyl-CoA mutase (MUT; 609058).
Description
Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism. Isolated methylmalonic aciduria is found in patients with mutations in the MUT gene causing partial, mut(-), or complete, mut(0), enzyme deficiency. This form is unresponsive to B12 therapy. Various forms of isolated methylmalonic aciduria also occur in a subset of patients with defects in the synthesis of the MUT coenzyme adenosylcobalamin (AdoCbl) and are classified according to complementation group: cblA (251100), caused by mutation in the MMAA gene (607481) on chromosome 4q31, and cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24.
Combined methylmalonic aciduria and homocystinuria may be seen in complementation groups cblC (277400), cblD (277410), and cblF (277380).
See the comprehensive review of Ledley (1990).
Clinical Features
The clinical spectrum of methylmalonic aciduria is wide, ranging from a benign condition (Ledley et al., 1984) to fatal neonatal disease (Matsui et al., 1983).
Oberholzer et al. (1967) reported an inborn error of metabolism characterized by methylmalonic aciduria associated with developmental retardation and chronic metabolic acidosis. Treatment with cobalamin was ineffective. Barness and Morrow (1968) noted that some cases of methylmalonic aciduria responded to vitamin B12. Of those not responsive to B12, only a subset had hyperglycinemia. Morrow et al. (1969) provided enzymatic proof of 2 forms of the disease with regard to response to cobalamin treatment: methylmalonyl-CoA mutase activity was essentially absent from the liver in a vitamin B12-unresponsive case, whereas residual enzyme activity increased to normal with added coenzyme in a vitamin B12-responsive case. The latter case was interpreted as having a defect in AdoCbl synthesis.
Gravel et al. (1975) confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls.
Willard and Rosenberg (1977) found that the mutase enzyme in cells from some MMA patients showed decreased affinity for AdoCbl with abnormally high Km for the coenzyme. These cases were considered to represent a structurally abnormal enzyme and were characteristic of the mut(-) phenotype. By immunohistochemical analysis of the mutase enzyme, Kolhouse et al. (1981) found that cell lines from mut(-) patients had detectable crossreacting material (CRM) ranging from 20 to 100% of control, whereas cells from mut(0) patients had CRM ranging from no detectable protein to 40% of controls.
Matsui et al. (1983) collected detailed information on 45 patients with MMA: 15 with mut(0) type, 5 with mut(-), 14 with cblA, and 11 with cblB. The most common presenting symptoms at onset were lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia. Other common features included hepatomegaly, developmental delay, and coma. Mut(0) patients presented earlier in infancy than the 3 other groups. All patients had methylmalonic acidemia and normal serum cobalamin, and most had metabolic acidosis, ketonuria, hyperammonemia, and hyperglycinemia. Approximately half of all the patients had pancytopenia. Most cblA and nearly half of cblB patients showed a decrease in urine and blood concentrations of methylmalonic acid in response to vitamin B12 supplementation, whereas none of the mut(0) or mut(-) responded. Most cblA, cblB, and mut(-) patients were still living at the time of the report; most mut(0) patients died during the first few months of life.
Shevell et al. (1993) compared the clinical features in 11 mut(0) patients with those in 9 mut(-) patients. All 11 mut(0) patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurologic outcome as evidenced by severe developmental delay or spastic quadriparesis with dystonia. The 2 other survivors included a 27-month-old child with mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut(-) patients, 7 became symptomatic in late infancy or childhood and 2 were found on screening. No episode of metabolic decompensation had occurred in 2 of the 9, yet both were neurologically compromised, one being severely retarded and autistic and the other mildly delayed. Four mut(-) patients had had episodic acidosis and were neurologically moderately affected, while 3 had had episodic acidosis but were neurologically intact. Although a broad correlation was found between mutase class and phenotype, survival with good outcome was possible among mut(0) patients and, conversely, significant morbidity occurred among mut(-) patients. Acidosis and metabolic imbalance were not necessary preconditions for significant morbidity. van den Bergh et al. (1992) reported sudden death in a child with MMA.
Giorgio et al. (1976) reported 2 French-Canadian brothers, aged 62 and 70 years, who had a benign form of MMA due to methylmalonyl-CoA mutase deficiency. Neither had anemia or hepatic dysfunction. Serum vitamin B12 was normal and the methylmalonic aciduria was unaffected by administration of vitamin B12 in large dosage. The brothers had presented with adult-onset diabetes mellitus. Ledley et al. (1984) reported a benign form of MMA due to deficiency of methylmalonyl-CoA mutase in 8 children identified through routine neonatal screening or screening of infants with affected sibs. Despite lack of dietary or vitamin therapy, the children had normal growth and development (age range, 18 months to 13 years) and performed as well as their unaffected sibs on psychometric tests. None responded to vitamin B12 treatment and there was no other evidence of a cofactor defect. In 2 sibs, complementation studies showed a defect in the mutase apoenzyme.
Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidemia. Van Calcar et al. (1998) reported a patient with mut(-) MMA who developed chronic tubulointerstitial nephropathy during adolescence. After 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.
In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria (606054), and methylmalonic aciduria can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation.
Kruszka et al. (2013) studied renal growth in isolated MMA. Fifty patients with MMA (35 mut subtype, 9 cblA subtype, and 6 cblB subtype), followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple regression analyses. Comparisons with age-matched controls showed that renal length in subjects with MMA was significantly decreased (p less than 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C (604312), and serum methylmalonic acid concentrations best predicted kidney size. Kruszka et al. (2013) concluded that renal length, reflective of kidney growth, significantly decreased in patients with MMA over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.
Clinical Management
Kaplan et al. (2006) reported the long-term (9 years) outcome for the first patient with severe methylmalonic acidopathy transplanted in the United States and provided new biochemical data that indicated why transplanted patients remain susceptible to 'metabolic strokes.' In their 10-year-old male patient, there was clear evidence that the de novo synthesis of propionyl-CoA within the central nervous system led to brain methylmalonate accumulation that was largely unaffected by transplantation. Kaplan et al. (2006) concluded that liver transplantation is not a cure for methylmalonic acidopathy.
Pathogenesis
Using 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut -/- mouse, Remacle et al. (2018) investigated mechanisms leading to brain damage in methylmalonic aciduria. The in vitro model was challenged with the catabolic stress of temperature shift. Remacle et al. (2018) found typical metabolites for methylmalonic aciduria as well as a massive ammonia increase in the media of mutant mouse brain cultures. Investigation of pathways involved in intracerebral ammonia production revealed increased expression of glutaminase-2 (GLS2; 606365) and diminished expression of glutamate dehydrogenase-1 (GLUD1; 138130) in Mut -/- aggregates. Astrocytes showed swollen fibers and cell bodies, and oligodendrocytes showed inhibited axonal elongation and delayed myelination. Most effects were even more pronounced after 48 hours at 39 degrees C. Microglia activation and an increased apoptosis rate suggested degeneration of Mut -/- brain cells.
Other Features
Because of improvements in therapy, many patients with MMA reach childbearing age. Wasserstein et al. (1999) reported a successful pregnancy and delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidemia complicated by moderate renal insufficiency, chronic pancreatitis, anemia, and optic atrophy. Strict metabolic control was maintained throughout her pregnancy. The patient remained clinically asymptomatic during and after delivery, and her metabolic condition remained stable after discharge except for a slight decline in her renal function.
Diagnosis
Wilkemeyer et al. (1991) showed that the mut and cbl forms of MMA can be differentiated not only by somatic cell complementation but also by DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone. Transfer of the MUT clone into mut fibroblasts reconstituted holoenzyme activity, whereas the same process had no effect on cbl fibroblasts.
Cytogenetics
Abramowicz et al. (1994) studied a newborn female with a mut(0) form of MMA and complete absence of insulin-producing beta cells in otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus (IDDM; 222100). The patient died 2 weeks after birth. Serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, study of polymorphic DNA markers of chromosome 6, and cytogenetic analysis demonstrated paternal uniparental isodisomy, involving at least a 25-cM portion of chromosome 6 that encompasses the major histocompatibility complex. Duplication of the mutated allele on chromosome 6 inherited from the father was thought to be responsible for methylmalonic acidemia. It was also considered likely that isodisomy was etiologically related to the agenesis of beta cells, and the authors postulated the existence of a gene on chromosome 6 involved in beta-cell differentiation.
Molecular Genetics
In a patient with MMA mut(0), defined as having no residual enzyme activity, Jansen and Ledley (1990) identified compound heterozygosity for 2 mutations in the MUT gene (609058.0001 and 609058.0002).
In a patient with MMA mut(-), defined as having some residual enzyme activity, who had been reported by Ledley et al. (1990), Crane et al. (1992) identified a homozygous mutation in the MUT gene (609058.0005).
Acquaviva et al. (2001) reported a novel MUT missense mutation (609058.0010) in 5 unrelated families of French and Turkish descent from a population of 19 patients with MCM apoenzyme deficiency. All the patients exhibited a severe mut(0) methylmalonic acidemia phenotype, and 3 of them were homozygous for the mutation. The findings represented the first frequent MUT mutation reported in the Caucasian population.
Champattanachai et al. (2003) reported 2 novel mutations in a Thai patient with mut(0) methylmalonic acidemia.
History
Hoffman (1991) recounted the story of Patricia Stallings who was sentenced to life in prison for the presumed murder of her infant son with ethylene glycol, an ingredient of antifreeze. While in prison, the woman gave birth to a second son, who was found to have methylmalonic acidemia. William Sly and James Shoemaker at St. Louis University performed analyses of the first son's blood and did not detect ethylene glycol; Piero Rinaldo at Yale University demonstrated the biochemical features of methylmalonic acidemia and found no evidence of ethylene glycol in the body fluids. All charges against Patricia Stallings were dropped. Shoemaker et al. (1992) determined that the gas chromatographic peak that had been identified as ethylene glycol by a clinical laboratory was actually due to propionic acid. Woolf et al. (1992) noted that the opposite situation could occur: intentional infantile ethylene glycol poisoning being misinterpreted as an inborn error of metabolism leading to recurrent infantile metabolic acidosis.
INHERITANCE \- Autosomal recessive GROWTH Weight \- Failure to thrive CARDIOVASCULAR Heart \- Cardiomyopathy ABDOMEN Liver \- Hepatomegaly Pancreas \- Pancreatitis Gastrointestinal \- Recurrent episodes of vomiting GENITOURINARY Kidneys \- Interstitial nephritis \- Chronic renal failure NEUROLOGIC Central Nervous System \- Lethargy \- Hypotonia \- Developmental delay \- Coma \- Severe involvement of globus pallidus \- Delay in myelination \- Cerebellar hemorrhage (rare) \- Ischemic stroke in the basal ganglia (rare) METABOLIC FEATURES \- Dehydration \- Neonatal or infantile metabolic ketoacidosis HEMATOLOGY \- Leukopenia \- Thrombocytopenia LABORATORY ABNORMALITIES \- Normal serum cobalamin \- Metabolic ketoacidosis \- Hyperammonemia \- Hyperglycinemia \- Methymalonicaciduria \- Methylmalonyl-CoA mutase deficiency \- Low plasma free and total carnitine MISCELLANEOUS \- mut-0 denotes individuals with cultured fibroblast mutase activity that is undetectable secondary to no functional mutase \- mut- denotes individuals with structurally altered mutase with reduced affinity for adenosylcobalamin (AdoCbl) \- Incidence of 1/50,000 births MOLECULAR BASIS \- Caused by mutation in the methylmalonyl-CoA mutase gene (MUT, 251000.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY | c1855114 | 4,992 | omim | https://www.omim.org/entry/251000 | 2019-09-22T16:25:15 | {"doid": ["0060740"], "mesh": ["C565390"], "omim": ["251000"], "orphanet": ["79312", "289916", "27"], "synonyms": ["Vitamin B12-unresponsive methylmalonic aciduria type mut-", "Alternative titles", "METHYLMALONIC ACIDEMIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY MMA DUE TO MCM DEFICIENCY", "METHYLMALONIC ACIDURIA, mut TYPE", "Partial deficiency of methylmalonyl-CoA mutase"], "genereviews": ["NBK1231"]} |
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Atypical trigeminal neuralgia
Other namesType 2 trigeminal neuralgia,
Detailed view of trigeminal nerve, shown in yellow.
SpecialtyNeurology
Atypical trigeminal neuralgia (ATN), or type 2 trigeminal neuralgia, is a form of trigeminal neuralgia, a disorder of the fifth cranial nerve. This form of nerve pain is difficult to diagnose, as it is rare and the symptoms overlap with several other disorders.[1] The symptoms can occur in addition to having migraine headache, or can be mistaken for migraine alone, or dental problems such as temporomandibular joint disorder or musculoskeletal issues. ATN can have a wide range of symptoms and the pain can fluctuate in intensity from mild aching to a crushing or burning sensation, and also to the extreme pain experienced with the more common trigeminal neuralgia.
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Risk factors
* 4 Diagnosis
* 5 Treatment
* 5.1 Medication
* 5.2 Surgery
* 6 References
* 7 External links
## Signs and symptoms[edit]
ATN pain can be described as heavy, aching, stabbing, and burning. Some sufferers have a constant migraine-like headache. Others may experience intense pain in one or in all three trigeminal nerve branches, affecting teeth, ears, sinuses, cheeks, forehead, upper and lower jaws, behind the eyes, and scalp. In addition, those with ATN may also experience the shocks or stabs found in type 1 TN.
Many TN and ATN patients have pain that is "triggered" by light touch on shifting trigger zones. ATN pain tends to worsen with talking, smiling, chewing, or in response to sensations such as a cool breeze. The pain from ATN is often continuous, and periods of remission are rare. Both TN and ATN can be bilateral, though the character of pain is usually different on the two sides at any one time.[2]
ATN pain is aching and burning like a constant tension headache or the start of a migraine like headache everyday. If you rate the pain on a 1-10 scale with 1 associated with the least amount of pain and 10 excruciating pain, an easy day with ATN would rank at a 3 to 5 depending on the affected nerve branches. The pain experience on this day would feel like a dull constant headache or tension headache and may make you wonder if you have an upper respiratory infection due to the pain in the cheek area of the face. ATN pain might also rank between 6-8. During these times you experience something much like the pain of a migraine or, perhaps, an upper respiratory infection with possible earache and pain in your teeth and jaw. Full blown episodes of pain are far from unusual, and rate 9-10. This pain is described as akin to a terrible migraine, with pain behind the eye, along with a sinus/upper respiratory infection, ear infection, abscessed molar(s) and a pinched nerve in the neck or shoulders. Days without pain are rare.
## Causes[edit]
The trigeminal nerve.
ATN is usually attributed to inflammation or demyelination, with increased sensitivity of the trigeminal nerve. These effects are believed to be caused by infection, demyelinating diseases, or compression of the trigeminal nerve (by an impinging vein or artery, a tumor, or arteriovenous malformation) and are often confused with dental problems. An interesting aspect is that this form affects both men and women equally and can occur at any age, unlike typical trigeminal neuralgia, which is seen most commonly in women. Though TN and ATN most often present in the fifth decade, cases have been documented as early as infancy.
## Risk factors[edit]
Both forms of facial neuralgia are relatively rare, with an incidence recently estimated between 12 and 24 new cases per hundred thousand population per year.[3][4]
ATN often goes undiagnosed or misdiagnosed for extended periods, leading to a great deal of unexplained pain and anxiety. A National Patient Survey conducted by the US Trigeminal Neuralgia Association in the late 1990s indicated that the average facial neuralgia patient may see six different physicians before receiving a first definitive diagnosis. The first practitioner to see facial neuralgia patients is often a dentist who may lack deep training in facial neurology. Thus ATN may be misdiagnosed as Tempormandibular Joint Disorder.[5]
This disorder is regarded by many medical professionals to comprise the most severe form of chronic pain known in medical practice. In some patients, pain may be unresponsive even to opioid drugs at any dose level that leaves the patient conscious. The disorder has thus acquired the unfortunate and possibly inflammatory nickname, "the suicide disease".[6]
Symptoms of ATN may overlap with a pain disorder occurring in teeth called atypical odontalgia (literal meaning "unusual tooth pain"), with aching, burning, or stabs of pain localized to one or more teeth and adjacent jaw. The pain may seem to shift from one tooth to the next, after root canals or extractions. In desperate efforts to alleviate pain, some patients undergo multiple (but unneeded) root canals or extractions, even in the absence of suggestive X-ray evidence of dental abscess.
ATN symptoms may also be similar to those of post-herpetic neuralgia, which causes nerve inflammation when the latent herpes zoster virus of a previous case of chicken pox re-emerges in shingles. Fortunately, post-herpetic neuralgia is generally treated with medications that are also the first medications tried for ATN, which reduces the negative impact of misdiagnosis.
The subject of atypical trigeminal neuralgia is considered problematic even among experts. The term atypical TN is broad and due to the complexity of the condition, there are considerable issues with defining the condition further. Some medical practitioners no longer make a distinction between facial neuralgia (a nominal condition of inflammation) versus facial neuropathy (direct physical damage to a nerve).
Due to the variability and imprecision of their pain symptoms, ATN or atypical odontalgia patients may be misdiagnosed with atypical facial pain (AFP) or "hypochondriasis", both of which are considered problematic by many practitioners.[7] The term "atypical facial pain" is sometimes assigned to pain which crosses the mid-line of the face or otherwise does not conform to expected boundaries of nerve distributions or characteristics of validated medical entities. As such, AFP is seen to comprise a diagnosis by reduction.
As noted in material published by the [US] National Pain Foundation: "atypical facial pain is a confusing term and should never be used to describe patients with trigeminal neuralgia or trigeminal neuropathic pain. Strictly speaking, AFP is classified as a "somatiform pain disorder"; this is a psychological diagnosis that should be confirmed by a skilled pain psychologist. Patients with the diagnosis of AFP have no identifiable underlying physical cause for the pain. The pain is usually constant, described as aching or burning, and often affects both sides of the face (this is almost never the case in patients with trigeminal neuralgia). The pain frequently involves areas of the head, face, and neck that are outside the sensory territories that are supplied by the trigeminal nerve. It is important to correctly identify patients with AFP since the treatment for this is strictly medical. Surgical procedures are not indicated for atypical facial pain."[8]
The term "hypochondriasis" is closely related to "somatoform pain disorder" and "conversion disorder" in the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association. As of July 2011, this axis of the DSM-IV is undergoing major revision for the DSM-V, with introduction of a new designation "Complex Somatic Symptom Disorder". However, it remains to be demonstrated that any of these "disorders" can reliably be diagnosed as a medical entity with a discrete and reliable course of therapy.[9][10][11][12]
It is possible that there are triggers or aggravating factors that patients need to learn to recognize to help manage their health. Bright lights, sounds, stress, and poor diet are examples of additional stimuli that can contribute to the condition. The pain can cause nausea, so beyond the obvious need to treat the pain, it is important to be sure to try to get adequate rest and nutrition.
Depression is frequently co-morbid with neuralgia and neuropathic pain of all sorts, as a result of the negative effects that pain has on one's life. Depression and chronic pain may interact, with chronic pain often predisposing patients to depression, and depression operating to sap energy, disrupt sleep and heighten sensitivity and the sense of suffering. Dealing with depression should thus be considered equally important as finding direct relief from the pain.[13]
## Diagnosis[edit]
This section is empty. You can help by adding to it. (March 2018)
## Treatment[edit]
### Medication[edit]
Treatment of people believed to have ATN or TN is usually begun with medication. The long-time first drug of choice for facial neuralgia has been carbamazepine, an anti-seizure agent. Due to the significant side-effects and hazards of this drug, others have recently come into common use as alternatives. These include oxcarbazepine, lamotrigine, and gabapentin. A positive patient response to one of these medications might be considered as supporting evidence for the diagnosis, which is otherwise made from medical history and pain presentation. There are no present medical tests to conclusively confirm TN or ATN.
If the anti-seizure drugs are found ineffective, one of the tricyclic antidepressant medications such as amitriptyline or nortriptyline, may be used. The tricyclic antidepressants are known to have dual action against both depression and neuropathic pain. Other drugs which may also be tried, either individually or in combination with an anti-seizure agent, include baclofen, pregabalin, anti-seizure drugs (to calm nerve endings), muscle relaxants, and opioid drugs such as oxycodone or an oxycodone/paracetamol combination.
For some people with ATN opioids may represent the only viable medical option which preserves quality of life and personal functioning. Although there is considerable controversy in public policy and practice in this branch of medicine, practice guidelines have long been available and published.[14][15][16]
### Surgery[edit]
If drug treatment is found to be ineffective or causes disabling side effects, one of several neurosurgical procedures may be considered. The available procedures are believed to be less effective with type II (atypical) trigeminal neuralgia than with type I (typical or "classic") TN. Among present procedures, the most effective and long lasting has been found to be microvascular decompression (MVD), which seeks to relieve direct compression of the trigeminal nerve by separating and padding blood vessels in the vicinity of the emergence of this nerve from the brain stem, below the cranium.[17]
Choice of a surgical procedure is made by the doctor and patient in consultation, based on the patient's pain presentation and health and the doctor's medical experience. Some neurosurgeons resist the application of MVD or other surgeries to atypical trigeminal neuralgia, in light of a widespread perception that ATN pain is less responsive to these procedures. However, recent papers suggest that in cases where pain initially presents as type I TN, surgery may be effective even after the pain has evolved into type II.[18]
## References[edit]
1. ^ Quail G (August 2005). "Atypical facial pain--a diagnostic challenge". Aust Fam Physician. 34 (8): 641–5. PMID 16113700.
2. ^ R.A. Lawhern, Ph.D., "Classification and Treatment of Chronic Face Pain"
3. ^ Koopman JS, Dieleman JP, Huygen FJ, de Mos M, Martin CG, Sturkenboom MC (December 2009). "Incidence of facial pain in the general population". Pain. 147 (1–3): 122–7. doi:10.1016/j.pain.2009.08.023. PMID 19783099. S2CID 35327709.
4. ^ Hall GC, Carroll D, Parry D, McQuay HJ (May 2006). "Epidemiology and treatment of neuropathic pain: the UK primary care perspective". Pain. 122 (1–2): 156–62. doi:10.1016/j.pain.2006.01.030. PMID 16545908. S2CID 6844949.
5. ^ Drangsholt M, Truelove EL (July 2001). "Trigeminal Neuralgia Mistaken as Temporomandibular Disorder". J Evid Base Dent Pract. 1 (1): 41–50. doi:10.1067/med.2001.116846.
6. ^ TN "Trigeminal Neuralgia) Description / Definition", [US] Facial Pain Association, "Archived copy". Archived from the original on 2011-10-04. Retrieved 2011-08-01.CS1 maint: archived copy as title (link)
7. ^ Graff-Radford SB, Solberg WK (May 1993). "Is atypical odontalgia a psychological problem?". Oral Surg. Oral Med. Oral Pathol. 75 (5): 579–82. doi:10.1016/0030-4220(93)90228-v. PMID 8155097.
8. ^ National Pain Foundation, "Trigeminal Neuralgia — Definitions"
9. ^ Rief W, Isaac M (March 2007). "Are somatoform disorders 'mental disorders'? A contribution to the current debate". Curr Opin Psychiatry. 20 (2): 143–6. doi:10.1097/YCO.0b013e3280346999. PMID 17278912. S2CID 23584862.
10. ^ Voigt K, Nagel A, Meyer B, Langs G, Braukhaus C, Löwe B (May 2010). "Towards positive diagnostic criteria: a systematic review of somatoform disorder diagnoses and suggestions for future classification". J Psychosom Res. 68 (5): 403–14. doi:10.1016/j.jpsychores.2010.01.015. PMID 20403499.
11. ^ Kroenke K, Sharpe M, Sykes R (2007). "Revising the classification of somatoform disorders: key questions and preliminary recommendations". Psychosomatics. 48 (4): 277–85. CiteSeerX 10.1.1.631.4736. doi:10.1176/appi.psy.48.4.277. PMID 17600162. Archived from the original on 2012-07-30.
12. ^ Dimsdale J, Sharma N, Sharpe M (2011). "What do physicians think of somatoform disorders?". Psychosomatics. 52 (2): 154–9. doi:10.1016/j.psym.2010.12.011. PMID 21397108.[dead link]
13. ^ Daniel K. Hall-Flavin, MD, "Depression (Major Depression)", Mayo Clinic Expert Answers
14. ^ O'Connor AB, Dworkin RH (October 2009). "Treatment of neuropathic pain: an overview of recent guidelines". Am. J. Med. 122 (10 Suppl): S22–32. doi:10.1016/j.amjmed.2009.04.007. PMID 19801049.
15. ^ Dworkin RH, O'Connor AB, Audette J, et al. (March 2010). "Recommendations for the pharmacological management of neuropathic pain: an overview and literature update". Mayo Clin. Proc. 85 (3 Suppl): S3–14. doi:10.4065/mcp.2009.0649. PMC 2844007. PMID 20194146. Archived from the original on 2013-01-28.
16. ^ Vadalouca A, Siafaka I, Argyra E, Vrachnou E, Moka E (November 2006). "Therapeutic management of chronic neuropathic pain: an examination of pharmacologic treatment". Ann. N. Y. Acad. Sci. 1088 (1): 164–86. Bibcode:2006NYASA1088..164V. doi:10.1196/annals.1366.016. PMID 17192564.
17. ^ Sindou M, Leston J, Decullier E, Chapuis F (December 2007). "Microvascular decompression for primary trigeminal neuralgia: long-term effectiveness and prognostic factors in a series of 362 consecutive patients with clear-cut neurovascular conflicts who underwent pure decompression". J. Neurosurg. 107 (6): 1144–53. doi:10.3171/JNS-07/12/1144. PMID 18077952.
18. ^ Tiril Sandell, M.D, Per Kristian Eide, M.D., Ph.D. "Effect of Microvascular Decompression in Trigeminal Neuralgia Patients with or without Constant Pain". Archived from the original on 2011-07-13. Retrieved 2011-08-04.CS1 maint: multiple names: authors list (link) Note: registration with the Facial Pain Association is required for access to this article.
## External links[edit]
* Trigeminal Neuralgia Fact Sheet National Institute of Neurological Disorders and Stroke
Classification
D
* ICD-10: G50.0
* ICD-9-CM: 350.1
* MeSH: D014277
* DiseasesDB: 13363
External resources
* eMedicine: emerg/617
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Atypical trigeminal neuralgia | None | 4,993 | wikipedia | https://en.wikipedia.org/wiki/Atypical_trigeminal_neuralgia | 2021-01-18T18:49:50 | {"icd-9": ["350.1"], "icd-10": ["G50.0"], "wikidata": ["Q758292"]} |
Self-healing papular mucinosis is a rare form of localized lichen myxedematosus (see this term) occurring primarily in children and characterized by the development of mucinous papules on various parts of the body (face, neck, trunk, and limbs) that resolve spontaneously within some weeks to months. Systemic symptoms can be observed such as fever, arthralgias and weakness.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Self-healing papular mucinosis | None | 4,994 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90397 | 2021-01-23T17:14:45 | {"icd-10": ["L98.5"]} |
## Clinical Features
Okamoto et al. (1997) reported what they believed to be a new MCA/MR syndrome in a 2-year-old Japanese girl and an unrelated 15-month-old Japanese boy. Manifestations included congenital hydronephrosis, severe mental retardation, growth failure, generalized floppiness, and cleft palate. The facies showed midface hypoplasia, hypertrichosis, long eyelashes, prominent eyes, epicanthus, low-set ears, long ear lobe, flat nasal bridge, short upturned nose, long philtrum, and webbed neck. The girl had mild aortic stenosis and regurgitation; ventricular septal defect, atrial septal defect, and patent ductus arteriosus (see 607411) had closed. The boy had endocardial cushion defect. In both patients, the karyotype was normal, the parents were nonconsanguineous and healthy, and sibs were normal.
Wallerstein et al. (2005) reported a 6-month-old Chinese American boy with congenital hydronephrosis, cleft palate, severe hypotonia, congenital heart defect, developmental delay, and characteristic facial features with an open-mouthed appearance and full lower lip. The authors considered this to be the third reported case of Okamoto syndrome. The infant also had idiopathic splenomegaly and nonspecific MRI changes in the brain, which had not been reported in the first 2 cases. Wallerstein and Rhoads (2013) provided a follow-up of this patient. At age 8 years, he had significant developmental disabilities, with a motor level of approximately 6 to 8 months and a language age of about 24 months. Conteh et al. (2017) noted that the patient was diagnosed with a tethered spinal cord at age 8 years 7 months. At age 11 years and 3 months, he presented with back and leg pain with severe gait difficulty, lower extremity paresthesia, numbness, and weakness, with worsening bladder dysfunction. Following filum terminale sectioning with neuromonitoring for release of his cord, his symptoms improved and he was able to ambulate independently.
Markouri et al. (2008) reported a 2-year-old Greek female with Okamoto syndrome, born to healthy, nonconsanguineous parents. The child had multiple congenital anomalies including cleft palate, stenosis of the ureteropelvic junction with hydronephrosis, and cardiac anomalies, along with generalized hypotonia, severe developmental delay, and growth failure. The distinctive facial appearance included microcephaly, midface hypoplasia, prominent eyes, epicanthal folds, long eyelashes, synophrys, low-set ears with long earlobe, flat nasal bridge with short upturned nose, open mouth appearance, full lower lip, and downturned mouth. Unlike previously reported patients, she had severe anal stenosis.
Taylor and Aftimos (2010) reported what they believed to be the fifth reported case of Okamoto syndrome. The female offspring of nonconsanguineous parents of mixed ethnic background had multiple congenital anomalies and characteristic facial features. Echocardiogram showed severe aortic stenosis with mildly hypoplastic left ventricle, mild mitral valve hypoplasia, and 2 small atrial septal defects. She was profoundly hypotonic and made little spontaneous movement. In the facies, she had mild supraorbital ridging and hypertrichosis of the forehead, temple, and cheeks, prominent eyes with large palpebral fissures and hypertelorism, depressed nasal bridge and infraorbital grooves, short upturned nose, tented upper lip, cleft palate, large and low-set ears, and redundancy of skin of the posterior neck. A brain MRI showed thinning of the corpus callosum and presence of germinolytic cysts within the lateral ventricles. She also had intestinal malrotation and uterine didelphyis, features not reported previously. She died at age 12 days after the withdrawal of supportive medical care.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| HYDRONEPHROSIS, CONGENITAL, WITH CLEFT PALATE, CHARACTERISTIC FACIES, HYPOTONIA, AND MENTAL RETARDATION | c1858043 | 4,995 | omim | https://www.omim.org/entry/604916 | 2019-09-22T16:11:41 | {"mesh": ["C565736"], "omim": ["604916"], "orphanet": ["2729"], "synonyms": ["OKAMOTO SYNDROME", "Alternative titles"]} |
Marinesco-Sjögren syndrome is a condition that has a variety of signs and symptoms affecting many tissues. People with Marinesco-Sjögren syndrome have clouding of the lens of the eyes (cataracts) that usually develops soon after birth or in early childhood. Affected individuals also have muscle weakness (myopathy) and difficulty coordinating movements (ataxia), which may impair their ability to walk. People with Marinesco-Sjögren syndrome may experience further decline in muscle function later in life.
Most people with Marinesco-Sjögren syndrome have mild to moderate intellectual disability. They also have skeletal abnormalities including short stature and a spine that curves to the side (scoliosis). Other features of Marinesco-Sjögren syndrome include eyes that do not look in the same direction (strabismus), involuntary eye movements (nystagmus), and impaired speech (dysarthria).
Affected individuals may have hypergonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, puberty is either delayed or absent.
## Frequency
Marinesco-Sjögren syndrome appears to be a rare condition. More than 100 cases have been reported worldwide.
## Causes
Mutations in the SIL1 gene cause Marinesco-Sjögren syndrome. The SIL1 gene provides instructions for producing a protein located in a cell structure called the endoplasmic reticulum. Among its many functions, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape. The SIL1 protein plays a role in the process of protein folding.
SIL1 gene mutations result in the production of a protein that has little or no activity. A lack of SIL1 protein is thought to impair protein folding, which could disrupt protein transport and cause proteins to accumulate in the endoplasmic reticulum. This accumulation likely damages and destroys cells in many different tissues, leading to ataxia, myopathy, and the other features of Marinesco-Sjögren syndrome.
Approximately one-third of people with Marinesco-Sjögren syndrome do not have identified mutations in the SIL1 gene. In these cases, the cause of the condition is unknown.
### Learn more about the gene associated with Marinesco-Sjögren syndrome
* SIL1
## Inheritance Pattern
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Marinesco-Sjögren syndrome | c0024814 | 4,996 | medlineplus | https://medlineplus.gov/genetics/condition/marinesco-sjogren-syndrome/ | 2021-01-27T08:25:45 | {"gard": ["8341"], "mesh": ["D013132"], "omim": ["248800"], "synonyms": []} |
Turner syndrome is a sporadic disorder of females in which all or part of one X chromosome is deleted. Characteristic features include short stature with somatic features such as broad, 'shield-like' chest, webbed neck, low-set ears, and gonadal dysgenesis. The cytogenetically full-blown form is characterized by 45 chromosomes with only one X chromosome. Intelligence is usually normal, but social adjustment problems are common. Skuse et al. (1997) considered that it should be possible to identify the effects of an X-linked imprinted locus by comparing classes of females with Turner syndrome. In 70% of monosomic (45,X) Turner syndrome females, the single X chromosome is maternal in origin; in the remainder it is paternal. Normal 46,XX females possess both a maternally derived X chromosome, X(m), and a paternally derived chromosome, X(p), 1 of which is randomly inactivated in any given somatic cell. In monosomic X (Turner syndrome), the single chromosome is never inactivated. Skuse et al. (1997) suggested that differences in physical or behavioral phenotypes between the 2 classes of Turner syndrome subjects might indicate the existence of an imprinted genetic locus. In a study of 80 females with Turner syndrome and a 45,X karyotype, they found that 55 had their X chromosome from the mother and 25 from the father. Members of the 45,X(p) group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. The observations suggested the existence of a genetic locus for social cognition that is imprinted and is not expressed from the maternally-derived X chromosome. Neurophysiologic and molecular investigations of 8 females with partial deletions of the short arm of the X chromosome indicated that the putative imprinted locus escapes X inactivation and probably lies on Xq or close to the centromere on Xp. Skuse et al. (1997) speculated that, if expressed only from the paternal X chromosome, such a locus could explain why 46,XY males, whose single X chromosome is maternal, are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females. They stated that an alternative explanation might be the presence of a greater degree of cryptic mosaicism (with a normal 46,XX cell line) than among those who were 45,X(m). Some degree of mosaicism in apparently monosomic females may be essential for the fetus to avoid spontaneous abortion. However, in studies of both blood and skin fibroblast cells (tissues of mesodermal and ectodermal origin, respectively), Skuse et al. (1997) found 2 cryptic mosaics, but both were from the 45,X(m) group. In general, males are substantially more vulnerable to a variety of developmental disorders of speech, language impairment, and reading disability, as well as more severe conditions such as autism. The findings of Skuse et al. (1997) are consistent with the hypothesis that the locus they described, which they proposed is silent both in normal males and 45,X(m) females, acts synergistically with susceptibility loci elsewhere in the genome to increase the male-to-female prevalence ratio of such disorders. Their data on normally developing children suggested that the locus may also exert an effect on social and cognitive abilities in the normal range. The findings provided evidence for the evolution of an imprinted X-linked locus that contributes to the development of sexual dimorphism in social behavior.
Naumova et al. (1998) proposed that the association of transmission-ratio distortion with only 1 sex of offspring may be a hallmark of defective imprinting (or defective imprint 'erasure'). In 47 normal, genetic disease-free families, they analyzed the transmission of maternal alleles at loci spanning the length of the X chromosome and found significant deviation from the expected 1:1 ratio of grandparental:grandmaternal alleles at loci in Xp21.1-p11.4. The distortion in inheritance ratio was found only among male offspring and was manifested as a strong bias in favor of the inheritance of the alleles of the maternal grandfather. An analysis of recombinant chromosomes inherited by male offspring indicated that an 11.6-cM on the short arm of the X chromosome, bounded by DXS538 and DXS7, contains an imprinted gene that affects the survival of male embryos. Naumova et al. (1998) called the region of maximum distortion DMS1, for 'distorter male-specific-1.' They commented that the DMS1 region is in an area that contains a number of genes that escape X inactivation (Disteche, 1995; Miller et al., 1995; Jones et al., 1996).
The study of Turner syndrome subjects by Skuse et al. (1997) suggested the existence of a gene on the X chromosome for aptitude for spatial visualization (313000).
Donnelly et al. (2000) described a single case of autistic disorder (209850) in association with monosomy X (Turner syndrome). They found that the patient's X chromosome was of maternal origin, providing further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition. Theirs was the fourth documented case of maternal inheritance of the syndrome and autistic disorder.
Individuals with Turner syndrome have a spectrum of anatomic, physiologic, and behavioral phenotypes with expressivity dependent on the extent of monosomy and the parental origin of the single X chromosome (Ranke and Saenger, 2001). As noted, parent-of-origin influences on social cognition in Turner syndrome may be due to the presence of imprinted genes on the X chromosome (Skuse et al., 1997). Imprinting of X-linked genes has also been implicated in the male prevalence of autistic spectrum disorders, in male sexual orientation, and in the developmental delay of XO mouse embryos (Thornhill and Burgoyne, 1993 and Jamieson et al., 1998). Using a mouse model for Turner syndrome, Raefski and O'Neill (2005) searched for locus-specific imprinting of X-linked genes in developing brain. They identified a cluster of X-linked genes containing at least 3 genes that show transcriptional repression of paternal alleles. Imprinting of these 3 genes, Xlr3b, Xlr4b, and Xlr4c, was independent of X-chromosome inactivation and had a dynamic and complex pattern of tissue and stage specificity.
Davies et al. (2005) used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Their findings confirmed the existence of X-linked imprinted effects on cognitive processes and identified a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.
By bioinformatic analysis of the homologous region of the human X chromosome (Xq28), Davies et al. (2005) identified an apparent pseudogene with homology to the Xlr3 gene family of the mouse. The pseudogene was most closely related to FAM9B (300478), a gene located at Xp22.3.
Neuro \- Social adjustment \- Verbal and higher-order executive function skills \- Development of sexual dimorphism in social behavior Inheritance \- X-linked imprinting ▲ Close
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| COGNITIVE FUNCTION 1, SOCIAL | c1848140 | 4,997 | omim | https://www.omim.org/entry/300082 | 2019-09-22T16:20:54 | {"omim": ["300082"], "synonyms": ["Alternative titles", "SOCIAL COGNITION"]} |
A complex form of hereditary spastic paraplegia characterized by spastic paraplegia, demyelinating peripheral sensorimotor neuropathy, poikiloderma (manifesting with loss of eyebrows and eyelashes in childhood in addition to delicate, smooth, and wasted skin) and distal amyotrophy (presenting after puberty). There have been no further descriptions in the literature since 1992.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| Spastic paraplegia-neuropathy-poikiloderma syndrome | c1866851 | 4,998 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2821 | 2021-01-23T17:29:36 | {"gard": ["4921"], "mesh": ["C536870"], "omim": ["182815"], "umls": ["C1866851"], "synonyms": ["Antinolo-Nieto-Borrego syndrome"]} |
A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-8 (CSS8) is caused by heterozygous mutation in the SMARCC2 gene (601734) on chromosome 12q13.
Description
Coffin-Siris syndrome-8 is characterized by variable degrees of impaired intellectual development including speech impairment, hypotonia, feeding difficulties, and behavioral abnormalities. Dysmorphic features may or may not be present and include hypertrichosis or thin scalp hair, thick eyebrows, thin upper vermilion, and upturned nose (Machol et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Clinical Features
As part of a study of 119 patients with undiagnosed genetic disorders analyzed by whole-exome sequencing, Zhu et al. (2015) identified a 7-year-old boy with failure to thrive, benign hydrocephalus, speech delay, hypotonia, elevated lactate and ammonia, vitiligo, and developmental delay. Seizures and regression were absent.
Martinez et al. (2017) identified a girl with impaired intellectual development, delayed speech and language development, hypotonia, short stature, abnormalities of the mouth and nose, skeletal abnormalities, hypertrichosis and synophrys, sleep disturbances, and seizures.
Machol et al. (2019) studied 15 unrelated individuals with impaired intellectual development with speech and behavioral abnormalities, hypotonia, and varying dysmorphism. Two of these individuals had been reported by Zhu et al. (2015) and Martinez et al. (2017), respectively. Eight individuals had absent speech, and a total of 13 of the 15 had some speech abnormalities. Ten had behavioral problems including aggression, self-injurious behavior, hyperactivity, hypersensitivity to touch, sleep disturbances, and obsessive or rigid behavior. Six of the 15 had failure to thrive, and 8 had sucking or feeding difficulties. Thirteen had hypotonia, 2 manifested spasticity, 4 had seizures, and 2 had a movement disorder. Six of the 12 patients who had brain MRIs had abnormalities which included white matter lesions, white matter loss, thinning of the corpus callosum, generalized cerebral atrophy, and hypomyelination. Four had fifth finger or toenail anomalies. Five had scoliosis, with 1 of those manifesting as kyphosis. Only 2 had cardiovascular abnormalities. While a typical facial gestalt was not observed, 11 of the 15 were reported to have dysmorphic craniofacial features, the most pronounced of which were hypertrichosis, thick eyebrows/prominent supraorbital ridges, thin upper or thick lower lip vermilion, and upturned nose/anteverted nostrils.
Molecular Genetics
In 15 patients with Coffin-Siris syndrome, Machol et al. (2019) detected 13 heterozygous mutations in the SMARCC2 gene, 12 of which were shown to have occurred de novo. Three mutations affected splicing, 1 resulted in frameshift, 1 caused a premature termination codon, 7 were missense, and 1 was an in-frame single amino acid deletion. Two mutations were recurrent. All 7 missense mutations occurred in highly conserved amino acids and were predicted to be deleterious by various in silico tools. The mutations clustered in the SWIRM and SANT domains of the protein, and the majority of missense and splice site mutations suggested a dominant-negative mechanism.
INHERITANCE \- Autosomal dominant GROWTH Other \- Failure to thrive HEAD & NECK Eyes \- Thick eyebrows \- Long eyelashes \- Ptosis Nose \- Upturned nose \- Anteverted nares Mouth \- Thick lower lip vermilion \- Thin upper lip vermilion ABDOMEN Gastrointestinal \- Poor suck \- Feeding difficulties SKELETAL Spine \- Scoliosis (in some patients) SKIN, NAILS, & HAIR Skin \- Pigmentation abnormalities (in some patients) \- Eczema (in some patients) Hair \- Thick scalp hair \- Thin scalp hair \- Thick eyebrows NEUROLOGIC Central Nervous System \- Impaired intellectual development, mild to severe \- Speech delay (in some patients) \- Absence of language \- Seizures (uncommon) \- Hypotonia Behavioral Psychiatric Manifestations \- Behavioral abnormalities \- Aggression \- Self-injurious behavior \- Hyperactivity \- Hypersensitivity to touch \- Sleep disturbances \- Obsessive and rigid behavior MISCELLANEOUS \- De novo mutation (in most patients) \- Variable dysmorphic features may be present MOLECULAR BASIS \- Caused by mutation in the SW1/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily c, member 2 gene (SMARCC2, 601734.0001 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
*[NC]: neurogenic claudication
*[LSS]: lumbar spinal stenosis
*[DDD]: degenerative disc disease
*[CI]: confidence interval
*[E2]: estradiol
*[CEEs]: conjugated estrogens
*[Diff]: Difference
*[7d avg]: Average of the last 7 days
*[per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population
*[Cases per 100k]: Cases per 100,000 county population
*[Deaths per 100k]: Deaths per 100,000 county population
*[Percent]: Percent of total in category
*[Rate]: ICU-care cases per confirmed cases in each category
*[GER]: Germany
*[FRA]: France
*[ITA]: Italy
*[ESP]: Spain
*[DEN]: Denmark
*[SUI]: Switzerland
*[USA]: United States
*[COL]: Colombia
*[KAZ]: Kazakhstan
*[NED]: Netherlands
*[LIT]: Lithuania
*[POR]: Portugal
*[AUT]: Austria
*[AUS]: Australia
*[RUS]: Russia
*[LUX]: Luxembourg
*[UKR]: Ukraine
*[SLO]: Slovenia
*[GBR]: Great Britain
*[CZE]: Czech Republic
*[BEL]: Belgium
*[CAN]: Canada
| COFFIN-SIRIS SYNDROME 8 | c0265338 | 4,999 | omim | https://www.omim.org/entry/618362 | 2019-09-22T15:42:18 | {"mesh": ["C536436"], "omim": ["618362"], "orphanet": ["1465"]} |
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