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Hereditary folate malabsorption (HFM) is an inherited disorder of folate transport characterized by a systemic and central nervous system (CNS) folate deficiency manifesting as megaloblastic anemia, failure to thrive, diarrhea and/or oral mucositis, immunologic dysfunction and neurological disorders. ## Epidemiology The prevalence is unknown. Approximately 30 cases have been reported to date. ## Clinical description Disease onset usually occurs a few months after birth. Manifestations include failure to thrive, diarrhea and/or mouth ulcers, various neurological manifestations (motor impairment, seizures, developmental delay, cognitive and behavioral disorders), megaloblastic anemia and hypoimmunoglobulinemia. Megaloblastic anemia is the primary manifestation of HFM and can be very severe if untreated. Hypoimmunoglobulinemia results in unusual infections with Pneumocystis jiroveccii, C. difficile and cytomegalovirus (CMV) which can be recurrent and life-threatening in undiagnosed infants. Neurological manifestations may be the presenting symptoms in some but are absent in others. Seizures, if present, begin in infancy or later in childhood. Intracranial calcifications have been observed in some. ## Etiology HFM is caused by mutations in the SLC46A1 gene found on chromosome 17q11.2 which encodes the proton-coupled folate transporter (PCFT). PCFT is essential for intestinal folate absorption and transport of folates across the blood-cerebrospinal fluid (CSF) barrier. A defect in this protein leads to a systemic folate and CNS folate deficiency. Infants cannot absorb adequate folate from breast milk/formula and become deficient once their stores accumulated during gestation are exhausted. ## Diagnostic methods Diagnosis is based on clinical and laboratory findings. It is confirmed by findings of an impaired absorption of an oral folate load (even after correction of serum folate concentration) and a low CSF folate concentration (0-1.5nM). Bone marrow biopsy confirms the presence of megaloblastic anemia. Sequence analysis of the SLC46A1 coding region can identify any mutations present in the gene, also confirming diagnosis of HFM. ## Differential diagnosis The immunodeficiency seen in HFM may resemble severe combined immune deficiency (SCID; see this term). Other differential diagnoses include methionine synthase deficiency with megaloblastic anemia and developmental delay, formiminoglutamic aciduria, tyrosinemia type 1, methylenetetrahydrofolate reductase deficiency and erythroleukemia (see these terms). ## Antenatal diagnosis Antenatal diagnosis is possible via prenatal testing. Screening of newborns with a family history of HFM allows for early diagnosis and treatment with folate immediately after birth, before symptoms occur. ## Genetic counseling HFM is inherited autosomal recessively. Genetic counseling is possible. ## Management and treatment High dose oral or parenteral 5-formyltetrahydrofolate (5-formylTHF) and oral L-5-methyltetrahydrofolate (L-5-methylTHF) are the two types of reduced folates used to treat HFM. Dosage is monitored and adjusted (individualized for each patient) so that the CSF folate levels remain within the normal range (around 100nM in infants-2 year olds). Folic acid should not be used as it binds to folate receptors and blocks folate transport. If anemia is severe, a transfusion may be necessary. Early treatment with reduced folates before the appearance of symptoms can prevent the metabolic consequences of HFM. Patients should have regular blood tests to monitor complete blood count, serum and CSF folate and homocysteine concentrations and serum immunoglobulin concentrations. ## Prognosis With proper treatment the prognosis is good and reversal of most of the systemic consequences of the disease is usually achieved. Only when untreated is the prognosis poor. [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	Hereditary folate malabsorption	c0342705	2,800	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90045	2021-01-23T17:57:50	{"gard": ["12983"], "mesh": ["C562799"], "omim": ["229050"], "umls": ["C0342705"], "icd-10": ["D52.8"], "synonyms": ["Congenital folate malabsorption"]}
A number sign (#) is used with this entry because of evidence that familial Behcet-like autoinflammatory syndrome (AISBL) is caused by heterozygous mutation in the TNFAIP3 gene (191163) on chromosome 6q23. Description Familial Behcet-like autoinflammatory syndrome is an autosomal dominant disorder characterized by ulceration of mucosal surfaces, particularly in the oral and genital areas. Additional more variable features include skin rash, uveitis, and polyarthritis. Symptoms become apparent in the first or second decades. The disorder results from inappropriate activation of inflammatory cytokines; treatment with tumor necrosis factor (TNF; 191160) inhibitors may be beneficial (summary by Zhou et al., 2016). Clinical Features Zhou et al. (2016) reported 14 patients, 12 females and 2 males, from 6 unrelated families with an autosomal dominant autoinflammatory disorder. The age at onset ranged from 2 to 16 years in all but 1 patient who had onset at age 29. Patients had oral and genital ulcers reminiscent of Behcet disease (see 109650). Additional features found in some patients included polyarthritis, skin rash, uveitis (3 patients), and inflammation or ulceration in the gastrointestinal tract (4 patients). Two patients had periodic fevers, 1 had hemolytic anemia, and 1 had idiopathic thrombocytopenia. Three patients from 1 family had lupus anticoagulant and other autoantibodies, and 3 additional unrelated patients had antinuclear autoantibodies. Some patients responded to treatment with TNF inhibitors or colchicine. Inheritance The transmission pattern of Behcet-like autoinflammatory syndrome in the families reported by Zhou et al. (2016) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of 6 unrelated families with AISBL, Zhou et al. (2016) identified 6 different heterozygous truncating mutations in the TNFAIP3 gene (191163.0001-191163.0006). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; 3 subsequent mutations were found in 3 of 150 probands with a similar disorder who were directly screened for TNFAIP3 mutations. The sixth mutation was found in 1 of 768 individuals diagnosed with Behcet disease (109650) who underwent targeted sequencing. In vitro functional cellular expression studies showed that all mutations failed to suppress TNF-induced NFKB (see 164011) activity, although not in a dominant-negative fashion, which suggested haploinsufficiency as a disease mechanism. Patient cells showed reduced recruitment of TNFAIP3 to the TNFR complex (see 191190) compared to control cells. Patient-derived cells showed increased phosphorylation of IKKA (600664) and IKKB (603258) and subsequent degradation of I-kappa-B-alpha (NFKBIA; 164008), with nuclear translocation of the NFKB p65 subunit (RELA; 164014) together with increased expression of NFKB-mediated proinflammatory cytokines, consistent with activation of the NFKB pathway. Cells expressing the mutant proteins showed defective removal of lys63-linked ubiquitin from TRAF6 (602355), NEMO (IKBKG; 300248), and RIP1 (603453) after stimulation with TNF, indicating inefficient deubiquitination. Levels of proinflammatory cytokines were substantially higher in patient serum compared to controls, and showed evidence of increased IL1B (147720) signaling. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Uveitis (in some patients) \- Chorioretinal scarring (in some patients) Mouth \- Oral ulcers ABDOMEN Gastrointestinal \- Gastrointestinal inflammation (in some patients) \- Gastrointestinal ulcers (in some patients) GENITOURINARY External Genitalia (Male) \- Genital ulcers External Genitalia (Female) \- Genital ulcers Internal Genitalia (Female) \- Genital ulcers SKELETAL \- Polyarthritis (in some patients) SKIN, NAILS, & HAIR Skin \- Rash (in some patients) HEMATOLOGY \- Hemolytic anemia (1 patient) \- Thrombocytopenia (1 patient) IMMUNOLOGY \- Autoinflammation \- Autoantibodies (in some patients) \- Periodic fevers (in some patients) LABORATORY ABNORMALITIES \- Increased circulating proinflammatory cytokines MISCELLANEOUS \- Onset in first or second decades \- Variable manifestations \- Treatment with TNF inhibitors may be beneficial MOLECULAR BASIS \- Caused by mutation in the tumor necrosis factor-alpha-induced protein 3 gene (TNFAIP3, 191163.0001 ) ▲ 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	AUTOINFLAMMATORY SYNDROME, FAMILIAL, BEHCET-LIKE	c4225218	2,801	omim	https://www.omim.org/entry/616744	2019-09-22T15:48:03	{"omim": ["616744"], "orphanet": ["476102"], "synonyms": ["Behçet-like disease due to HA20", "Behçet-like disease due to haploinsufficiency of A20"]}
Type of trauma experienced in World War One For other uses, see Shellshock. Shell shock Other namesBullet wind, soldier's heart, battle fatigue, operational exhaustion[1] This particular soldier is one example of shell shock, of which a dazed expression and a steady stare are two common manifestations. SpecialtyPsychiatry Shell shock is a term coined in World War I by British psychologist Charles Samuel Myers[2] to describe the type of post traumatic stress disorder many soldiers were afflicted with during the war (before PTSD was termed).[3] It is a reaction to the intensity of the bombardment and fighting that produced a helplessness appearing variously as panic and being scared, flight, or an inability to reason, sleep, walk or talk.[4] During the War, the concept of shell shock was ill-defined. Cases of "shell shock" could be interpreted as either a physical or psychological injury, or simply as a lack of moral fibre. The term shell shock is still used by the Veterans Administration to describe certain parts of PTSD, but mostly it has entered into memory, and it is often identified as the signature injury of the War. In World War II and thereafter, diagnosis of "shell shock" was replaced by that of combat stress reaction, a similar but not identical response to the trauma of warfare and bombardment. ## Contents * 1 Origin * 2 Management * 2.1 Acute * 2.2 Chronic treatment * 3 Physical causes * 4 Cowardice * 5 Commission of enquiry * 6 Development of psychiatry * 7 Society and culture * 8 Modern cases of shell shock * 9 See also * 10 References * 11 Sources * 12 External links ## Origin[edit] During the early stages of World War I in 1914, soldiers from the British Expeditionary Force began to report medical symptoms after combat, including tinnitus, amnesia, headaches, dizziness, tremors, and hypersensitivity to noise. While these symptoms resembled those that would be expected after a physical wound to the brain, many of those reporting sick showed no signs of head wounds.[5] By December 1914 as many as 10% of British officers and 4% of enlisted men were suffering from "nervous and mental shock".[6] The term "shell shock" came into use to reflect an assumed link between the symptoms and the effects of explosions from artillery shells. The term was first published in 1915 in an article in The Lancet by Charles Myers. Some 60–80% of shell shock cases displayed acute neurasthenia, while 10% displayed what would now be termed symptoms of conversion disorder, including mutism and fugue.[6] The number of shell shock cases grew during 1915 and 1916 but it remained poorly understood medically and psychologically. Some doctors held the view that it was a result of hidden physical damage to the brain, with the shock waves from bursting shells creating a cerebral lesion that caused the symptoms and could potentially prove fatal. Another explanation was that shell shock resulted from poisoning by the carbon monoxide formed by explosions.[7] At the same time an alternative view developed describing shell shock as an emotional, rather than a physical, injury. Evidence for this point of view was provided by the fact that an increasing proportion of men suffering shell shock symptoms had not been exposed to artillery fire. Since the symptoms appeared in men who had no proximity to an exploding shell, the physical explanation was clearly unsatisfactory.[7] In spite of this evidence, the British Army continued to try to differentiate those whose symptoms followed explosive exposure from others. In 1915 the British Army in France was instructed that: > Shell-shock and shell concussion cases should have the letter 'W' prefixed to the report of the casualty, if it was due to the enemy; in that case the patient would be entitled to rank as 'wounded' and to wear on his arm a 'wound stripe'. If, however, the man’s breakdown did not follow a shell explosion, it was not thought to be 'due to the enemy', and he was to [be] labelled 'Shell-shock' or 'S' (for sickness) and was not entitled to a wound stripe or a pension.[8] However, it often proved difficult to identify which cases were which, as the information on whether a casualty had been close to a shell explosion or not was rarely provided.[7] ## Management[edit] ### Acute[edit] At first, shell-shock casualties were rapidly evacuated from the front line – in part because of fear of their unpredictable behaviour.[9] As the size of the British Expeditionary Force increased, and manpower became in shorter supply, the number of shell shock cases became a growing problem for the military authorities. At the Battle of the Somme in 1916, as many as 40% of casualties were shell-shocked, resulting in concern about an epidemic of psychiatric casualties, which could not be afforded in either military or financial terms.[9] Among the consequences of this were an increasing official preference for the psychological interpretation of shell shock, and a deliberate attempt to avoid the medicalisation of shell shock. If men were 'uninjured' it was easier to return them to the front to continue fighting.[7] Another consequence was an increasing amount of time and effort devoted to understanding and treating shell shock symptoms. Soldiers who returned with shell shock generally couldn't remember much because their brain would shut out all the traumatic memories. By the Battle of Passchendaele in 1917, the British Army had developed methods to reduce shell shock. A man who began to show shell-shock symptoms was best given a few days' rest by his local medical officer.[6] Col. Rogers, Regimental Medical Officer, 4th Battalion Black Watch wrote: > You must send your commotional cases down the line. But when you get these emotional cases, unless they are very bad, if you have a hold of the men and they know you and you know them (and there is a good deal more in the man knowing you than in you knowing the man) … you are able to explain to him that there is really nothing wrong with him, give him a rest at the aid post if necessary and a day or two’s sleep, go up with him to the front line, and, when there, see him often, sit down beside him and talk to him about the war and look through his periscope and let the man see you are taking an interest in him.[8] If symptoms persisted after a few weeks at a local Casualty Clearing Station, which would normally be close enough to the front line to hear artillery fire, a casualty might be evacuated to one of four dedicated psychiatric centres which had been set up further behind the lines, and were labelled as "NYDN – Not Yet Diagnosed Nervous" pending further investigation by medical specialists. Although the Battle of Passchendaele generally became a byword for horror, the number of cases of shell shock were relatively few. 5,346 shell shock cases reached the Casualty Clearing Station, or roughly 1% of the British forces engaged. 3,963 (or just under 75%) of these men returned to active service without being referred to a hospital for specialist treatment. The number of shell shock cases reduced throughout the battle, and the epidemic of illness was ended.[10] During 1917, "shell shock" was entirely banned as a diagnosis in the British Army,[11] and mentions of it were censored, even in medical journals.[12] ### Chronic treatment[edit] The treatment of chronic shell shock varied widely according to the details of the symptoms, the views of the doctors involved, and other factors including the rank and class of the patient. There were so many officers and men suffering from shell shock that 19 British military hospitals were wholly devoted to the treatment of cases. Ten years after the war, 65,000 veterans of the war were still receiving treatment for it in Britain. In France it was possible to visit aged shell shock victims in hospital in 1960.[4] ## Physical causes[edit] Recent research by Johns Hopkins University has found that the brain tissue of combat veterans who have been exposed to improvised explosive devices (IEDs) exhibit a pattern of injury in the areas responsible for decision making, memory and reasoning. This evidence has led the researchers to conclude that shell shock may not only be a psychological disorder, since the symptoms exhibited by sufferers from the First World War are very similar to these injuries.[13] Immense pressure changes are involved in shell shock. Even mild changes in air pressure from weather have been linked to changes in behavior.[14] There is also evidence to suggest that the type of warfare faced by soldiers would affect the probability of shell shock symptoms developing. First hand reports from medical doctors at the time note that rates of such afflictions decreased once the war was mobilized again during the 1918 German offensive, following the 1916-1917 period where the highest rates of shell shock can be found. This could suggest that it was trench warfare, and the experience of siege warfare specifically, that led to the development of these symptoms.[15] ## Cowardice[edit] See also: British Army during World War I Some men suffering from shell shock were put on trial, and even executed, for military crimes including desertion and cowardice.[16] While it was recognised that the stresses of war could cause men to break down, a lasting episode was likely to be seen as symptomatic of an underlying lack of character.[17] For instance, in his testimony to the post-war Royal Commission examining shell shock, Lord Gort said that shell shock was a weakness and was not found in "good" units.[17] The continued pressure to avoid medical recognition of shell shock meant that it was not, in itself, considered an admissible defence. Although some doctors or medics did take procedure to try to cure soldiers' shell shock, it was first done in a brutal way. Doctors would provide electric shock to soldiers in hopes that it would shock them back to their normal, heroic, pre-war self. After almost a year of giving one of his patients electric shocks, putting cigarettes on his tongue, hot plates at the back of his throat, etc., a British clinician, Lewis Yealland, said to his patient, "You will not leave this room until you are talking as well as you ever did... You must behave as the hero I expected you to be."[18] Executions of soldiers in the British Army were not commonplace. While there were 240,000 Courts Martial and 3080 death sentences handed down, in only 346 cases was the sentence carried out.[19] 266 British soldiers were executed for "Desertion", 18 for "Cowardice", 7 for "Quitting a post without authority", 5 for "Disobedience to a lawful command" and 2 for "Casting away arms".[20] On 7 November 2006, the government of the United Kingdom gave them all a posthumous conditional pardon.[21] ## Commission of enquiry[edit] The British government produced a Report of the War Office Committee of Enquiry into "Shell-Shock" which was published in 1922.[22] Recommendations from this included: > In forward areas > No soldier should be allowed to think that loss of nervous or mental control provides an honourable avenue of escape from the battlefield, and every endeavour should be made to prevent slight cases leaving the battalion or divisional area, where treatment should be confined to provision of rest and comfort for those who need it and to heartening them for return to the front line. > In neurological centres > When cases are sufficiently severe to necessitate more scientific and elaborate treatment they should be sent to special Neurological Centres as near the front as possible, to be under the care of an expert in nervous disorders. No such case should, however, be so labelled on evacuation as to fix the idea of nervous breakdown in the patient’s mind. > In base hospitals > When evacuation to the base hospital is necessary, cases should be treated in a separate hospital or separate sections of a hospital, and not with the ordinary sick and wounded patients. Only in exceptional circumstances should cases be sent to the United Kingdom, as, for instance, men likely to be unfit for further service of any kind with the forces in the field. This policy should be widely known throughout the Force. > Forms of treatment > The establishment of an atmosphere of cure is the basis of all successful treatment, the personality of the physician is, therefore, of the greatest importance. While recognising that each individual case of war neurosis must be treated on its merits, the Committee are of opinion that good results will be obtained in the majority by the simplest forms of psycho-therapy, i.e., explanation, persuasion and suggestion, aided by such physical methods as baths, electricity and massage. Rest of mind and body is essential in all cases. > > The committee are of opinion that the production of hypnoidal state and deep hypnotic sleep, while beneficial as a means of conveying suggestions or eliciting forgotten experiences are useful in selected cases, but in the majority they are unnecessary and may even aggravate the symptoms for a time. > They do not recommend psycho-analysis in the Freudian sense. > > In the state of convalescence, re-education and suitable occupation of an interesting nature are of great importance. If the patient is unfit for further military service, it is considered that every endeavour should be made to obtain for him suitable employment on his return to active life. > Return to the fighting line > Soldiers should not be returned to the fighting line under the following conditions:- > (1) If the symptoms of neurosis are of such a character that the soldier cannot be treated overseas with a view to subsequent useful employment. > (2) If the breakdown is of such severity as to necessitate a long period of rest and treatment in the United Kingdom. > (3) If the disability is anxiety neurosis of a severe type. > (4) If the disability is a mental breakdown or psychosis requiring treatment in a mental hospital. > It is, however, considered that many of such cases could, after recovery, be usefully employed in some form of auxiliary military duty. Part of the concern was that many British veterans were receiving pensions and had long-term disabilities. > By 1939, some 120,000 British ex-servicemen had received final awards for primary psychiatric disability or were still drawing pensions – about 15% of all pensioned disabilities – and another 44,000 or so … were getting pensions for ‘soldier’s heart’ or Effort Syndrome. There is, though, much that statistics do not show, because in terms of psychiatric effects, pensioners were just the tip of a huge iceberg.[8] War correspondent Philip Gibbs wrote: > Something was wrong. They put on civilian clothes again and looked to their mothers and wives very much like the young men who had gone to business in the peaceful days before August 1914. But they had not come back the same men. Something had altered in them. They were subject to sudden moods, and queer tempers, fits of profound depression alternating with a restless desire for pleasure. Many were easily moved to passion where they lost control of themselves, many were bitter in their speech, violent in opinion, frightening.[8] One British writer between the wars wrote: > There should be no excuse given for the establishment of a belief that a functional nervous disability constitutes a right to compensation. This is hard saying. It may seem cruel that those whose sufferings are real, whose illness has been brought on by enemy action and very likely in the course of patriotic service, should be treated with such apparent callousness. But there can be no doubt that in an overwhelming proportion of cases, these patients succumb to ‘shock’ because they get something out of it. To give them this reward is not ultimately a benefit to them because it encourages the weaker tendencies in their character. The nation cannot call on its citizens for courage and sacrifice and, at the same time, state by implication that an unconscious cowardice or an unconscious dishonesty will be rewarded.[8] ## Development of psychiatry[edit] At the beginning of World War II, the term "shell shock" was banned by the British Army, though the phrase "postconcussional syndrome" was used to describe similar traumatic responses.[12] ## Society and culture[edit] Shell shock has had a profound impact in British culture and the popular memory of World War I. At the time, war writers like the poets Siegfried Sassoon and Wilfred Owen dealt with shell shock in their work. Sassoon and Owen spent time at Craiglockhart War Hospital, which treated shell shock casualties.[23] Author Pat Barker explored the causes and effects of shell shock in her Regeneration Trilogy, basing many of her characters on real historical figures and drawing on the writings of the first world war poets and the army doctor W. H. R. Rivers. ## Modern cases of shell shock[edit] Although the term "shell shocked" is typically used in discussion of WWI to describe early forms of PTSD, its high-impact explosives-related nature provides modern applications as well. During their deployment in Iraq and Afghanistan, approximately 380,000 U.S. troops, about 19% of those deployed, were estimated to have sustained brain injuries from explosive weapons and devices.[24] This prompted the U.S. Defense Advanced Research Projects Agency (DARPA) to open up a $10 million study of the blast effects on the human brain. The study revealed that, while the brain remains initially intact immediately after low level blast effects, the chronic inflammation afterwards is what ultimately leads to many cases of shell shock and PTSD.[25] ## See also[edit] * Combat stress reaction ## References[edit] 1. ^ "Post-traumatic stress disorder (PTSD) - Doctors Lounge(TM)". www.doctorslounge.com. 2. ^ "A Short History of The British Psychological Society" (PDF). British Psychological Society. British Psychological Society. Retrieved 9 November 2019. "Although he later came to regret it, it was Myers who coined the term ‘shell shock’" 3. ^ "Is Shell Shock the Same as PTSD?". Psychology Today. 4. ^ a b Hochschild, Adam (2012). To End All Wars - a story of loyalty and rebellion, 1914-1918. Boston, New York: Mariner Books, Houghton, Mifflin Harcourt. pp. xv, 242, 348. ISBN 978-0-547-75031-6. 5. ^ Jones, Fear and Wessely 2007, p.1641 6. ^ a b c McLeod, 2004 7. ^ a b c d Jones, Fear and Wessely 2007, p.1642 8. ^ a b c d e Shephard, Ben. A War of Nerves: Soldiers and Psychiatrists, 1914-1994. London, Jonathan Cape, 2000. 9. ^ a b Mcleod, 2004 10. ^ McLeod 2004 11. ^ Wessely 2006, p443 12. ^ a b Jones, Fear and Wessely 2007, p.1643 13. ^ "Combat Veterans' Brains Reveal Hidden Damage from IED Blasts - 01/14/2015". Retrieved 12 August 2016. 14. ^ Dabb, C (May 1997). The relationship between weather and children's behavior: a study of teacher perceptions. USU Thesis. 15. ^ van der Hart, Onno (2001). "Somatoform Dissociation in Traumatized World War I Combat Soldiers: A Neglected Clinical Heritage". Journal of Trauma & Dissociation. 1: 38. 16. ^ "BBC Inside Out Extra - Shell Shock - March 3, 2004". Retrieved 24 August 2020. 17. ^ a b Wessely 2006, p442 18. ^ "From shell-shock to PTSD, a century of invisible war trauma". PBS NewsHour. 11 November 2018. Retrieved 4 October 2019. 19. ^ Wessely 2006, p440 20. ^ Taylor-Whiffen, Peter (1 March 2002). "Shot at Dawn: Cowards, Traitors or Victims?". 21. ^ "War Pardons receives Royal Assent". ShotAtDawn.org.uk. Archived from the original on 6 December 2006. 22. ^ "Report of the War Office Committee of Enquiry into "Shell-Shock"". Wellcome Library. HMSO. Retrieved 13 August 2020. 23. ^ While Sassoon did not in fact suffer from shell shock, he was declared insane at the instigation of his friend Robert Graves in order to avoid prosecution for his anti-war publications. 24. ^ "The Shock of War". Smithsonian. Retrieved 13 February 2019. 25. ^ "Preventing Violent Explosive Neurologic Trauma (PREVENT)". www.darpa.mil. Retrieved 13 February 2019. ## Sources[edit] * Coulthart, Ross. The Lost Diggers, Sydney: HarperCollins Publishers, 2012. ISBN 9780732294618 * Jones, E, Fear, N and Wessely, S. "Shell Shock and Mild Traumatic Brain Injury: A Historical Review". Am J Psychiatry 2007; 164:1641–1645 * Hochschild, Adam. To End all Wars - a story of loyalty and rebellion, 1914-1918 Mariner Books, Houghton, Mifflin Harcourt, Boston, New York, 2011. ISBN 978-0-547-75031-6 * Leese, Peter. Shell Shock. Traumatic Neurosis and the British Soldiers of the First World War, Palgrave Macmillan, 2014. ISBN 978-1-137-45337-2. * Mcleod, A.D. "Shell shock, Gordon Holmes and the Great War" J R Soc Med. 2004 February; 97(2): 86–89. * Myers, C.S. "A contribution to the study of shell shock". Lancet, 1', 1915, pp. 316–320 * Shephard, Ben. A War of Nerves: Soldiers and Psychiatrists, 1914-1994. London, Jonathan Cape, 2000. * Wessely, S. The Life and Death of Private Harry Farr Journal of the Royal Society of Medicine, Vol 99, September 2006 ## External links[edit] Classification D * Shell Shock during World War I, by Professor Joanna Bourke - BBC * An Address on the Repression of War Experience, by W.H. Rivers, 4 December 1917 * Our Present Needs a Past: A Historical Look at Shell Shock Tedx Talk by Annessa Stagner on YouTube [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	Shell shock	c2930747	2,802	wikipedia	https://en.wikipedia.org/wiki/Shell_shock	2021-01-18T18:50:32	{"mesh": ["D003130"], "umls": ["C2930747"], "icd-9": ["308.9"], "icd-10": ["F43.0"], "wikidata": ["Q15061465"]}
Retroperitoneal fibrosis is a slowly progressive disorder in which the tubes that carry urine from the kidneys to the bladder (ureters) and other abdominal organs or vessels become blocked by a fibrous mass and inflammation in the back of the abdomen. The disorder may cause pain in the abdomen that worsens with time, pain or swelling of the legs, decreased urine output, and swelling of the scrotum in men. Risk factors for retroperitoneal fibrosis include asbestos exposure, smoking, tumor, infection, trauma, radiotherapy, surgery, and use of certain drugs.Treatment may include corticosteroids, tamoxifen, stents or surgery. [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	Retroperitoneal fibrosis	c0035357	2,803	gard	https://rarediseases.info.nih.gov/diseases/9568/retroperitoneal-fibrosis	2021-01-18T17:57:55	{"mesh": ["D012185"], "umls": ["C0035357"], "orphanet": ["49041"], "synonyms": ["Idiopathic retroperitoneal fibrosis", "Ormond's disease", "IgG4-related retroperitoneal fibrosis", "Ormond disease"]}
A rare mitochondrial oxidative phosphorylation disorder characterized by a highly variable clinical phenotype, including a benign infantile mitochondrial type affecting mainly the skeletal muscle, a lethal infantile mitochondrial myopathy linked to severe metabolic acidosis and mitochondrial dysfunction in skeletal muscle and often also in heart, Leigh syndrome, which causes severe, early-onset, progressive, and fatal encephalopathy, and French-Canadian type Leigh syndrome, which affects mostly the skeletal muscle, but also brain and liver. [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	Isolated cytochrome C oxidase deficiency	c0268237	2,804	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254905	2021-01-23T17:24:29	{"gard": ["48"], "mesh": ["D030401"], "omim": ["220110"], "umls": ["C0268237"], "icd-10": ["E88.8"], "synonyms": ["Isolated COX deficiency", "Isolated mitochondrial respiratory chain complex IV deficiency"]}
X-linked spastic paraplegia type 34 is a pure form of hereditary spastic paraplegia characterized by late childhood- to early adulthood-onset of slowly progressive spastic paraplegia with spastic gait and lower limb hyperreflexia, brisk tendon reflexes and ankle clonus. Lower limb pain and reduced lower limb vibratory sense is also reported in some older adult patients. [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	X-linked spastic paraplegia type 34	c2677897	2,805	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171607	2021-01-23T17:01:57	{"mesh": ["C567465"], "omim": ["300750"], "umls": ["C2677897"], "icd-10": ["G11.4"], "synonyms": ["SPG34"]}
Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement (FHHNCOI) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities. ## Epidemiology To date, approximately 72 cases have been described in the literature. ## Clinical description FHHNCOI has a childhood onset. The initial symptoms may include recurrent urinary tract infections, polyuria and polydipsia. Additional features include nephrocalcinosis, nephrolithiasis, enuresis, abdominal pain, muscular twitches and failure to thrive. The clinical hallmark of this disorder is an ocular abnormality involving severe bilateral myopia with divergent squint, nystagmus, keratoconus, corneal calcifications, cataract, chorioretinitis, pigmentary retinitis, pigmentary maculopathy, macular coloboma, strabismus or visual loss. Renal function generally declines progressively in most patients and patients may reach end stage renal disease in their adolescence or young adulthood. 50% of patients require renal replacement therapy in the second decade of life. ## Etiology FHHNCOI is caused by mutations in CLDN19 (1p34.2) which encodes claudin-19, a protein member of the claudin family which is highly expressed in the tight junctions of the thick ascending limb of Henle's loop, as well as in the retinal epithelium. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child. [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	Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis with severe ocular involvement	c1855466	2,806	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2196	2021-01-23T18:42:53	{"gard": ["3451"], "mesh": ["C565423"], "omim": ["248190"], "umls": ["C1855466", "C2931121"], "icd-10": ["E83.4"], "synonyms": ["FHHNC with severe ocular involvement", "Hypercalciuria-bilateral macular coloboma syndrome", "Meier-Blumberg-Imahorn syndrome"]}
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) B (HPABH4B) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225). An autosomal recessive form of dopa-responsive dystonia with or without hyperphenylalaninemia is caused by mutation in the same gene. Dopa-responsive dystonia-5 (DYT5; 128230) is an allelic disorder resulting from heterozygous mutations in the GCH1 gene. For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640). Clinical Features Niederwieser et al. (1984) reported a 4-year-old girl with hyperphenylalaninemia, severe developmental retardation, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infection. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin were very low, although their relative proportions were normal. Spinal fluid showed low concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, neopterin, and biopterin. Oral administration of L-erythro-tetrahydrobiopterin (but not the dextroisomer) normalized the serum phenylalanine level within 4 hours. No defect of the immune system was found. The patient's parents were first cousins, suggesting autosomal recessive inheritance. Liver biopsy showed a deficiency of GTP cyclohydrolase I. Phytohemagglutinin-stimulated lymphocytes of the parents showed levels of enzyme activity intermediate between zero (in the child's lymphocytes) and normal. Naylor et al. (1987) made the diagnosis of GTP cyclohydrolase I deficiency in a 4-month-old infant in whom a positive Guthrie test for phenylketonuria (PKU; 261600) at birth led to institution of dietary therapy. Urinary pteridine screening for cofactor variants, however, revealed extremely low levels of both neopterin and biopterin. The diagnosis was confirmed by BH4-loading studies and assay of GTP cyclohydrolase I activity in the liver. Ichinose et al. (1995) reported a female infant with BH4-dependent hyperphenylalaninemia due to GTP1 deficiency. She developed feeding problems, poor sucking, and poor muscle tone in the first week of life, and later showed delayed development. By the age of 2 years, she was unable to walk and developed seizures and choreoathetosis. Urinary pterins showed a profound deficiency in neopterin and biopterin. She died at age 10 years. Blau et al. (1995) described a male infant in whom GCH1 deficiency was not detected in the newborn PKU screening program. The characteristic clinical phenotype developed at the age of 5 months: elevated plasma phenylalanine, undetectable urinary pterins, and absence of GCH1 enzyme activity in a liver biopsy. Developmental delay was first noted in the patient at 4 months of age. At that time, neurologic findings included generalized hypotonia and clonic movements. After 4.5 months, examination revealed developmental delay with generalized hypotonia and dystonic Parkinson-like movements with wide-ranging tremors, especially of the upper limbs and the head. When the patient was 9 months of age, BH4 and neurotransmitter replacement therapy was started, and the low-phenylalanine diet was stopped. One month later, a reduction in the intention tremors and dystonic movements was observed, but axial hypotonia persisted. When the patient was 15 months of age, after he had undergone therapy for 6 months, slight axial hypotonia persisted, but the intention tremors and the dystonic movements had completely disappeared. Administration of L-DOPA and 5-hydroxytryptophan was used to control the cerebrospinal fluid neurotransmitter levels. ### Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia Furukawa et al. (1998) described a phenotype, which they called 'dystonia with motor delay,' that showed a severity intermediate between the severe autosomal recessive hyperphenylalaninemia with neopterin deficiency and the milder Segawa dystonia-parkinsonism with diurnal fluctuation (DYT5; 128230). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia. Furukawa et al. (1998) reported a 6-year-old girl with dystonia with motor delay who was found to be compound heterozygous for 2 mutations in the GCH1 gene (600225.0010; 600225.0011). The maternal allele was also found in her mother, maternal grandmother, and great-grandmother, all of whom had progressive dystonia with diurnal variation. The second mutation was inherited from her asymptomatic father. The proband responded to treatment with tetrahydrobiopterin and levodopa. A second unrelated 17-year-old male with dystonia with motor delay was also found to be compound heterozygous for GCH1 mutations (600225.0012; 600225.0013). He could not walk until age 4, at which time language was normal except for mild dysarthria. Between the ages of 4 and 6 years, the patient's previously acquired motor and speech functions deteriorated, and he subsequently became wheelchair bound and mute. Hwu et al. (1999) described a girl with progressive dopa-responsive dystonia with diurnal fluctuation beginning at age 2 years and 8 months. Plasma phenylalanine was normal. Genetic analysis identified a homozygous mutation in the GCH1 gene (R249S; 600225.0016). Both unaffected parents were heterozygous for the mutation. The data suggested that patients with recessive GCH1 mutations do not necessarily have hyperphenylalaninemia, although they can develop a movement disorder. Nardocci et al. (2003) reported monozygotic twin girls who showed rigidity and tremors of the extremities, with diurnal fluctuation, from the first months of life associated with a homozygous mutation in the GCH1 gene (P199A; 600225.0022). One girl also had prolonged generalized dystonic spasms, with opisthotonus, hyperextension of lower limbs, and hyperpronation of the arms, also with diurnal fluctuation. Cognitive development was normal. At age 6 months, the girls showed delayed motor development with normal cognitive abilities, rigidity, irregular and arrhythmic hyperkinesias involving the limbs, and symmetric hyperreflexia without extensor plantar responses. Laboratory results were normal and neither had hyperphenylalaninemia. Treatment with L-DOPA resulted in marked clinical improvement, and both had almost normal neurologic examination at age 15, except for slight hyperreflexia and low-normal IQ. Neither parent had any signs or symptoms suggesting a GCH1 deficiency. Nardocci et al. (2003) interpreted the findings as expanding the clinical phenotype associated with recessive GCH1 mutations to include patients with neonatal onset of a movement disorder without hyperphenylalaninemia. Molecular Genetics ### BH4-deficient Hyperphenylalaninemia B In a male infant with HPA due to GCH1 deficiency, Blau et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0017). In a female infant with BH4-deficient HPA, Ichinose et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0020). ### Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia Furukawa et al. (1998), Hwu et al. (1999), and Nardocci et al. (2003) identified homozygous or compound heterozygous mutations in patients with dopa-responsive dystonia with or without hyperphenylalaninemia (see, e.g., 600225.0010, 600225.0016, and 600225.0022). Animal Model The hph1 mouse exhibits hyperphenylalaninemia and a reduction in GTP cyclohydrolase I activity (McDonald et al., 1988). Hyland et al. (2003) found that hph1 mice have low brain levels of BH4, catecholamines, serotonin, and their metabolites, together with low levels of tyrosine hydroxylase protein within the striatum. These findings are similar to the neurochemical findings in human patients with mutations in the GCH1 gene, suggesting that the hph1 mouse is a good model system of GCH1 deficiency. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor feeding in infancy HEAD & NECK Eyes \- Abnormal ocular movements Mouth \- Hypersalivation ABDOMEN Gastrointestinal \- Swallowing difficulties NEUROLOGIC Central Nervous System \- Delayed development \- Psychomotor retardation \- Mental retardation \- Hypotonia, truncal \- Hypertonia of the extremities \- Uncoordinated movements \- Tremor \- Dystonia \- Rigidity \- Hyperkinesia \- Seizures \- Choreoathetosis \- Lethargy Behavioral Psychiatric Manifestations \- Irritability METABOLIC FEATURES \- Hyperthermia, episodic LABORATORY ABNORMALITIES \- Hyperphenylalaninemia \- Decreased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) in CSF \- Decreased neopterin and biopterin in urine \- Decreased neopterin and biopterin in CSF \- Decreased or absent GCH1 activity MISCELLANEOUS \- Onset in infancy \- Variable severity \- Defect in tetrahydrobiopterin (BH4) synthesis \- Progressive neurologic deterioration if untreated \- Normal neonatal blood phenylalanine has been reported in rare patients \- Diurnal fluctuation of neurologic symptoms \- Treatment with BH4 is effective \- Neurotransmitter treatment with L-dopa and serotonin or precursors is effective \- Early treatment can reduce neurologic symptoms \- Autosomal dominant dopa-responsive dystonia (DYT5, 128230 ) is an allelic disorder with overlapping features MOLECULAR BASIS \- Caused by mutation in the GTP cyclohydrolase 1 gene (GCH1, 600225.0017 ) ▲ 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	HYPERPHENYLALANINEMIA, BH4-DEFICIENT, B	c0751436	2,807	omim	https://www.omim.org/entry/233910	2019-09-22T16:27:19	{"mesh": ["D010661"], "omim": ["233910"], "orphanet": ["238583", "2102"], "synonyms": ["Alternative titles", "HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO GTP CYCLOHYDROLASE I DEFICIENCY", "GTP CYCLOHYDROLASE I DEFICIENCY"]}
Donnai-Barrow syndrome is an inherited disorder that affects many parts of the body. This disorder is characterized by unusual facial features, including prominent, wide-set eyes with outer corners that point downward; a short bulbous nose with a flat nasal bridge; ears that are rotated backward; and a widow's peak hairline. Individuals with Donnai-Barrow syndrome have severe hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). In addition, they often experience vision problems, including extreme nearsightedness (high myopia), detachment or deterioration of the light-sensitive tissue in the back of the eye (the retina), and progressive vision loss. Some have a gap or split in the colored part of the eye (iris coloboma). In almost all people with Donnai-Barrow syndrome, the tissue connecting the left and right halves of the brain (corpus callosum) is underdeveloped or absent. Affected individuals may also have other structural abnormalities of the brain. They generally have mild to moderate intellectual disability and developmental delay. People with Donnai-Barrow syndrome may also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic hernia. This potentially serious birth defect allows the stomach and intestines to move into the chest and possibly crowd the developing heart and lungs. An opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel may also occur in affected individuals. Occasionally people with Donnai-Barrow syndrome have abnormalities of the intestine, heart, or other organs. ## Frequency Although its prevalence is unknown, Donnai-Barrow syndrome appears to be a rare disorder. A few dozen affected individuals have been reported in many regions of the world. ## Causes Mutations in the LRP2 gene cause Donnai-Barrow syndrome. The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream. Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis). It is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules). LRP2 gene mutations that cause Donnai-Barrow syndrome are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein. However, it is unclear how these abnormalities result in the specific signs and symptoms of the disorder. A condition previously classified as a separate disorder called facio-oculo-acoustico-renal (FOAR) syndrome has also been found to be caused by LRP2 mutations. FOAR syndrome is now considered to be the same disorder as Donnai-Barrow syndrome. ### Learn more about the gene associated with Donnai-Barrow syndrome * LRP2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. In almost all cases, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition. One individual with Donnai-Barrow syndrome was found to have inherited both copies of the mutated gene from his father as a result of a genetic change called uniparental disomy (UPD). UPD occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. [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	Donnai-Barrow syndrome	c1857277	2,808	medlineplus	https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/	2021-01-27T08:25:38	{"gard": ["1899"], "mesh": ["C536390"], "omim": ["222448"], "synonyms": []}
A number sign (#) is used with this entry because spinocerebellar ataxia-2 (SCA2) is caused by an expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517). Unaffected individuals have 13 to 31 CAG repeats, whereas affected individuals have 32 to 79 repeats, with some in the range of 500 repeats (summary by Almaguer-Mederos et al., 2010). There is also an association between 29 or more CAG repeats and the development of amyotrophic lateral sclerosis-13 (ALS13). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400). Description Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of disorders that were classified clinically by Harding (1983). Progressive cerebellar ataxia is the primary feature. In ADCA I, cerebellar ataxia of gait and limbs is invariably associated with supranuclear ophthalmoplegia, pyramidal or extrapyramidal signs, mild dementia, and peripheral neuropathy. In ADCA II, macular and retinal degeneration are added to the features. ADCA III is a pure form of late-onset cerebellar ataxia. ADCA I includes SCA1 (164400), SCA2, and SCA3, or Machado-Joseph disease (109150). These 3 are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Boller and Segarra (1969) reported the clinical and postmortem findings in a father (E.W.) and son (R.W.) with adult-onset ataxia. The pedigree of the 'W' family, extending through 5 generations, indicated autosomal dominant inheritance. Pogacar et al. (1978) reported 2 additional affected members of the family, R.W.'s daughter (S.W.), and a third cousin who was studied postmortem. Boller and Segarra (1969) had described the condition under the designation 'spinopontine degeneration.' When the family (of Anglo-Saxon extraction living in northern Rhode Island for over 300 years) was followed up by Pogacar et al. (1978), they questioned the separation from olivopontocerebellar ataxia (OPCA), because they found abolished tendon reflexes and flexion contractures of the legs in 1 patient, and onset at 18 years of age, palatal myoclonus, and optic atrophy in the second. Dementia developed in both. Pathologic findings, in contrast to earlier reports, showed involvement of the cerebellum and inferior olivary nuclei. Lazzarini et al. (1992) encountered a large, previously unreported branch of the 'W' family that shared a common ancestor 8 generations removed from the patients reported by Boller and Segarra (1969). Although phenotypically the disorder was similar to that in families with spinocerebellar ataxia-1, the disorder was not linked to HLA on chromosome 6p. Wadia and Swami (1971) reported the association of spinocerebellar degeneration and abnormal eye movements, specifically, absent rapid saccades and abnormally slow tracking. They described 37 patients in 12 families in India. Some of the patients were 'mentally backward.' Starkman et al. (1972) described the syndrome in a U.S. family. Whyte and Dekaban (1976) described a family with cerebellar degeneration and slow pursuit without nystagmus. Age at onset ranged from 10 to 31 years with earlier onset in successive generations, and a rapidly progressive course. Three individuals showed progressive mental deterioration. The proband had nevus of Ota, which was considered to be unrelated. Whyte and Dekaban (1976) suggested that the eye signs were due to a brainstem lesion of the paramedian pontine reticular formation. They noted that it may be the most frequent form of spinocerebellar degeneration in India. See 271322 for a possible recessive form of the Wadia-Swami syndrome. Wadia et al. (1998) reported reevaluation and genetic analysis of 6 Indian pedigrees with autosomal dominant spinocerebellar ataxia, some of whom had been reported by Wadia and Swami (1971). Genetic analysis confirmed SCA2. Saccadic velocity was reduced even in early stages of the disease, and the authors emphasized that it was an important diagnostic feature. Eto et al. (1990) described a family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset. The pedigree pattern in 4 generations was consistent with autosomal dominant inheritance. Eto et al. (1990) suggested that the form of spinopontine atrophy might be different from Machado-Joseph disease (SCA3): the eyes were not protuberant, extraocular movements were abnormal to a minor degree, and neuropathologically the substantia nigra and dentate nucleus were spared. Eto et al. (1990) considered their family to resemble most that reported by Boller and Segarra (1969). Bale et al. (1987) studied a 3-generation kindred in which several persons had dominantly inherited spinopontine atrophy. Linkage analysis gave negative lod scores with both HLA and GLO1. Bale et al. (1987) also reviewed 4 published kindreds with adequate clinical and neuropathologic descriptions in addition to HLA linkage studies. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with OPCA type 1. The conditions in the 2 'unlinked' families were phenotypically distinct with respect to extraocular movements and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes. Auburger et al. (1990) could find no evidence of linkage to HLA in over 100 affected members of a Cuban kindred of Spanish ancestry, first reported by Orozco et al. (1989). The diagnosis of spinocerebellar ataxia was confirmed at autopsy in 11 cases. Points of differentiation from Machado-Joseph disease (SCA3), including absence of the limitation of upward gaze, were outlined. The origins of the family group in Spain could not be traced. Age of onset varied from 2 to 65 years, with 40% of patients presenting before 25 years of age. Optic atrophy, retinopathy, dementia, spasticity, and rigidity were not part of the phenotype. Auburger et al. (1990) stated that 'the 300 patients already receiving medical attention constitute a severe problem for the regional health authorities in Holguin.' Spadaro et al. (1992) were unable to demonstrate linkage to HLA on chromosome 6 in 3 of 5 Italian families with late-onset autosomal dominant SCA. They reported clinical studies of 26 patients and neuropathologic study of 1. The disease was characterized by cerebellar and pyramidal involvement, variably associated with cranial nerve and peripheral nervous system disorders. MRI of a 53-year-old man with symptoms for 7 years showed marked atrophy of the cerebellar hemispheres and vermis as well as of the pons and medulla oblongata. Ueyama et al. (1998) studied 2 Japanese kindreds with spinocerebellar ataxia-2, for a total of 25 patients, 19 patients in 1 family and 6 patients in the other. Thirteen patients were fully evaluated, including a neurologic evaluation. The mean age of onset of symptoms was 43.5 years. The most common neurologic finding was cerebellar ataxia with deep sensory disturbance. Slow saccades were found only in patients younger than age 35 years. Brain MRI showed pontocerebellar atrophy, and PCR analysis showed that all patients had an expanded CAG allele in the ataxin-2 gene. Schols et al. (1997) compared clinical, electrophysiologic, and MRI findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 (183086) presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was broad, however. Giuffrida et al. (1999) performed brain MRI on 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects. The findings confirmed that olivopontocerebellar atrophy is a typical pattern in SCA2. No significant correlation was found between infratentorial atrophy, disease duration, or the number of CAG repeats, but there was a significant correlation between supratentorial atrophy, which was found in 12 patients, and disease duration. OPCA appeared to represent the 'core' abnormality of SCA2; however, central nervous system involvement was not limited to pontocerebellar structures. Giuffrida et al. (1999) concluded that central nervous system degeneration in SCA2 is a widespread atrophy. In 19 of 27 (70%) patients with confirmed SCA types 1, 2, 3, 6, or 7 (164500), van de Warrenburg et al. (2004) found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. All 3 patients with SCA2 had a neuronopathy. Velazquez-Perez et al. (2004) found that maximal horizontal saccade velocity (MSV) was significantly decreased in 82 SCA2 patients compared to controls (60-degree MSV range of 17 to 464 degrees per second and 277 to 678 degree per second, respectively). MSV was negatively correlated with polyglutamine expansion size and ataxia score; ataxia score was positively correlated with disease duration, and less so with polyglutamine expansion. Slowing of MSV was detected as early as 1 year after onset of ataxia. Velazquez-Perez et al. (2004) concluded that MSV is a sensitive and specific endophenotype useful for the identification of modifier genes in SCA2. Using high-resolution volumetric MRI to examine 8 SCA2 patients, Ying et al. (2006) found a significant correlation between region-specific cerebellar and pontine atrophy and a global measure of clinical dysfunction. Atrophy was also highly correlated with disease duration. ### Oculomotor Abnormalities Among 65 patients with SCA1, SCA2, or SCA3, Burk et al. (1996) found reduced saccade velocity in 56%, 100%, and 30% of patients, respectively. MRI showed severe olivopontocerebellar atrophy in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3. Careful examination of 3 major criteria of eye movements, saccade amplitude, saccade velocity, and presence of gaze-evoked nystagmus, permitted Rivaud-Pechoux et al. (1998) to assign over 90% of patients with SCA1, SCA2, or SCA3 to their genetically confirmed patient group. In SCA1, saccade amplitude was significantly increased, resulting in hypermetria. In SCA2, saccade velocity was markedly decreased. In SCA3, the most characteristic finding was the presence of gaze-evoked nystagmus. In an investigation of oculomotor function, Buttner et al. (1998) found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. Burk et al. (1999) found that gaze-evoked nystagmus was not associated with SCA2. However, severe saccade slowing was highly characteristic of SCA2. Saccade velocity in SCA3 was normal to mildly reduced. The gain in vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye movement disorders of SCA1 overlapped with both SCA2 and SCA3. The reticulotegmental nucleus of the pons (RTTG), also known as the nucleus of Bechterew, is a precerebellar nucleus important in the premotor oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuit. By postmortem examination, Rub et al. (2004) identified neuronal loss and astrogliosis in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4 SCA3 patients that correlated with clinical findings of hypometric saccades and slowed and saccadic smooth pursuits. The 3 patients without these specific oculomotor findings had intact RTTG regions. The authors concluded that the neurodegeneration associated with SCA1, SCA2, and SCA3 affects premotor networks in addition to motor nuclei in a subset of patients. ### Infantile Onset Babovic-Vuksanovic et al. (1998) reported an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa (RP) were noted at 10 months of age. Her father had mild SCA2 first noted at 22 years of age. Molecular studies showed that the father had a SCA2 CAG repeat expansion of 43 repeats, whereas the baby had an extreme expansion of more than 200 repeats. Babovic-Vuksanovic et al. (1998) noted the variable phenotype and genotype of SCA2. Moretti et al. (2004) reported a Mexican-American child who developed abnormal eye movements at 2 months of age. Motor and language development were delayed. At age 6 years, poor coordination, arm tremor, and cognitive deficits were noted. The clinical course slowly progressed, and he had difficulty walking, incontinence, drooling, and worsening tremor by age 9 years. MRI showed cerebellar atrophy and mild cerebral atrophy, and mutation analysis identified a 62 CAG repeat expansion of the ATXN2 gene. Moretti et al. (2004) emphasized that SCA2 can have rare infantile or childhood onset, that earlier onset is associated with a higher number of CAG repeats, and that the SCA2 phenotype is clinically heterogeneous. Vinther-Jensen et al. (2013) reported a family in which a father was diagnosed with SCA2 at age 49 years, after which it was discovered that his daughter, who had died 13 years earlier of multiorgan failure at age 19 months, had had infantile-onset SCA2. The father presented with classic adult-onset progressive SCA2, including gait ataxia, imbalance, dysarthria, fasciculations, abnormal saccades, and mild cognitive impairment. Brain MRI showed cerebellar atrophy. The daughter presented at age 3 months with delayed motor development, myoclonic jerks, and visual impairment. She later showed uncoordinated eye movements, pallor of the optic nerves, dystrophic retinas, poor head control, hypotonia, and dyskinetic movements. Molecular genetic analysis showed that the father carried an expanded ATXN2 allele of 45 CAG repeats, and the daughter carried an expanded allele of 124 repeats inherited from the father. Analysis of the father's spermatozoa showed that 4 (22%) had an expansion beyond the 45 CAG repeats detected in somatic cells, including 2 with repeat lengths of at least 92 and 116, respectively. Study of spermatozoa from another man with SCA2 showed similar meiotic instability of the expanded repeat allele. Vinther-Jensen et al. (2013) suggested that meiotic instability may be a general feature of SCA2, and noted that rare genetic disorders should be considered during diagnosis of infants and children even without a family history of a neurodegenerative disorder. ### Parkinsonian Phenotype Gwinn-Hardy et al. (2000) described 4 patients from a Chinese kindred with parkinsonian features and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype with decreased saccadic velocity, limb and truncal ataxia, and a subclinical sensory neuropathy, but also had parkinsonian features such as markedly reduced blink rate, bradykinesia, and asymmetry. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy, reminiscent of typical late-onset Parkinson disease (PD; 168600). The third patient, with a phenotype reminiscent of progressive supranuclear palsy, did not show a response to treatment. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations. Among 23 Chinese patients with familial parkinsonism, Shan et al. (2001) identified 2 patients who had expanded trinucleotide repeats (mildly elevated at 36 and 37 repeats) in the ATXN2 gene. Both patients had onset of leg tremor at age 50 years, followed by gait difficulty, rigidity, and slow, hypometric saccades. L-DOPA produced marked improvement in symptoms in both patients. In addition, PET scan showed reduced dopamine distribution in the caudate and putamen in both patients. Shan et al. (2001) noted that these 2 patients represented approximately one-tenth of their population with familial parkinsonism. In commenting on the paper by Shan et al. (2001), Kock et al. (2002) stated that in a study of 270 unrelated patients of mixed ethnic background with dopa-responsive parkinsonism, including 64 cases of early onset (age of onset less than 50 years) with a family history, 174 cases of early onset with no family history, and 32 cases of late onset with a family history, they found no expanded SCA2 alleles. Parkin (PARK2; 602544) mutations were found in 31 (18%) of 173 screened early-onset patients. In a reply, Shan and Soong (2002) suggested that SCA2-related parkinsonism is more likely to be found in late-onset cases, which tend to have lower numbers of repeats, and likely accounts for no more than one-tenth of familial parkinsonism. Furtado et al. (2002) reported a family in which 10 members over 5 generations were affected with dopa-responsive parkinsonism, without cerebellar abnormalities, transmitted in an autosomal dominant pattern. Average age of onset was 59 years (range, 31 to 86). Three patients exhibited dystonia. Genetic analysis showed identical expanded repeats for SCA2 in all affected individuals tested (22 and 39 repeats on each allele), which were stable between generations despite a clinical suggestion of anticipation. Furtado et al. (2002) emphasized that the genetic findings were unexpected because the family's presentation was consistent with typical cases of Parkinson disease (168600). Lu et al. (2004) stated that the normal range of SCA2 CAG repeats is 14 to 31, and that it ranges from 34 to more than 200 in affected patients. A range of 32 to 33 repeats is considered indeterminate. In 7 Taiwanese patients from 4 families with parkinsonism (representing approximately 10% of the initial group), Lu et al. (2004) found expanded CAG repeats in the ATXN2 gene. The phenotype was characterized by tremor, rigidity, and bradykinesia, and response to L-DOPA. A control group of 8 patients from 6 families had the ataxic SCA2 phenotype, characterized by cerebellar gait, slow saccades, ataxic dysarthria, hypotonia, and tendency to fall, without any parkinsonian features. Patients with the parkinsonism phenotype had an older mean age at onset (45.8 years) and shorter CAG repeats (36.2 repeats) compared to those with the ataxic phenotype (26.9 years) caused by SCA2 repeats (43.1 repeats). Lu et al. (2004) noted that there were a few overlapping features between the 2 groups, including dysarthria and postural instability, but emphasized the otherwise clear phenotypic distinction. Ragothaman et al. (2004) reported a consanguineous Indian family with SCA2 expansions and a complex phenotype comprising ataxia, parkinsonism, and retinitis pigmentosa, either in isolation or in combination. Two patients with homozygous SCA2 repeat expansions (35 to 39 repeats) presented with dopa-responsive parkinsonism, including tremor, rigidity, and bradykinesia. Age at onset was 15 and 22 years. Twelve other family members who were heterozygous for SCA2 repeat expansions had isolated late-onset parkinsonism (2 patients), late-onset parkinsonism and ataxia (1 patient), isolated ataxia (6 patients), ataxia and RP (2 patients), and isolated RP (1 patient). Approximately 38% of family members with expanded SCA2 repeats were asymptomatic. Charles et al. (2007) found that 3 (2%) of 164 French families with autosomal dominant parkinsonism had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (609007.0006) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability. Other Features By polysomnography of 8 patients from 5 families with SCA2, Tuin et al. (2006) observed evidence of REM sleep behavior disorder. Patient age ranged from 14 to 55 years; disease duration ranged from 3 to 31 years. Clinically, almost all patients reported good subjective sleep quality. Four patients with early disease stage showed REM without atonia accompanied by a consistent reduction of REM density. Three patients with later stage disease had undetectable REM sleep, whereas slow wave sleep was increased at the cost of light sleep. In addition, patients showed a progressive loss of dream recall that correlated with stages of REM and theoretically corresponded to progressive brain atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus. There is a wide range in the age at onset of SCA2, both between and within families, and several studies have shown a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms (Sanpei et al., 1996; Imbert et al., 1996). Almaguer-Mederos et al. (2010) analyzed a large group of 924 Cuban individuals, including 394 presymptomatic and 530 affected individuals with 32 to 79 CAG repeats. There was a highly significant negative linear relation between mean age at onset and CAG repeat number. There was a significant increase in the probability of manifesting disease for a given age as the CAG repeat number increased from 34 to 45 units. Cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34 to 45 unit range were significantly different for each studied CAG repeat number, stressing the importance of expanded allele CAG repeat number as the principal factor in determining age at onset in SCA2. Overall, the mean age at onset diminished by 4.15 +/- 3.45 years for each increase in the CAG repeat number. Inheritance SCA2 is most often transmitted in an autosomal dominant pattern of inheritance, and genetic anticipation is observed (Pulst et al., 1996). However, rare patients with homozygous ATXN2 repeat expansions have been reported (Ragothaman et al., 2004). Mapping In a Nebraska kindred with 33 affected members, of whom 12 were living, Ranum et al. (1992) excluded linkage to the highly informative GT-repeat marker D6S89, which had been located on 6p and found to be closely linked to the SCA1 locus in 5 other large kindreds. They excluded linkage to this marker for moderate to tight linkage, less than 11% recombination. The disorder was clinically indistinguishable from that in the linked kindreds. The clinical features were also identical to those in the Cuban family described by Orozco Diaz et al. (1990). Gispert et al. (1993) found that in the large Cuban (Holguin) kindred that failed to show linkage to chromosome 6 markers, the locus, designated SCA2, could be assigned to 12q23-q24.1 by linkage analysis. Probable flanking markers were D12S58 and phospholipase A2 (PLA2A; 172410). Hernandez et al. (1995) performed further studies on 11 large pedigrees from the Holguin SCA2 family collective. Three-point analysis localized the SCA2 mutation within the 6-cM interval between D12S84 and D12S79. The microsatellite D12S105 within that interval showed a peak 2-point lod score 16.14 at theta = 0.00, as well as complete linkage disequilibrium among affected individuals. A common disease haplotype was found in all family ancestors, supporting an SCA2 founder effect in Holguin. Investigation of linkage to the interval containing SCA2 in 7 French autosomal dominant SCA families, previously excluded from linkage to SCA1, provided preliminary data suggesting the existence of a third locus, SCA3 (607047). In 2 kindreds, 1 Austrian-Canadian and 1 French-Canadian, Lopes-Cendes et al. (1994) found that an autosomal dominant form of SCA could be mapped within a region of approximately 16 cM between the microsatellite markers D12S58 and D12S84/D12S105. Silveira et al. (1993) found that Machado-Joseph disease is not linked to the phenylalanine hydroxylase locus (PAH; 612349) on chromosome 12q; MJD was subsequently mapped to chromosome 14. Gispert et al. (1995) reported that complete allelic association was established with the microsatellite marker D12S105. The D12S105 sequence, including 342 basepairs representing the region of maximal allelic association in the Cuban SCA2 founder effect, was subjected to sequence homology analysis at the European Molecular Biology Laboratories database and yielded an almost perfect match (99.7% similarity) with intron 1 of the human D-amino acid oxidase gene (DAO; 124050), which had previously been shown to be linked to all SCA2 pedigrees worldwide with no recombination (Hernandez et al., 1995). The small sequence differences were the result of length variations in the 4 primitive repeat motifs contained in this intron. The authors stated that a mutation in the DAO gene could fit well with previous hypotheses on the pathologic mechanism of spinocerebellar degeneration, since oral loading tests with glutamate in such patients have demonstrated a decreased metabolism of glutamic acid and aspartic acid, and since accumulation of the excitotoxic neurotransmitter glutamate is known to lead to cerebellar Purkinje neuron death. However, Gispert et al. (1995) found recombinants between SCA2 and a second microsatellite marker within intron 1 of the DAO gene. These and other recombination data of Gispert et al. (1995) excluded the DAO gene from the SCA2 region. Belal et al. (1994) described an affected Tunisian family that showed linkage to the SCA2 locus. Multipoint linkage analysis, including markers D12S78, D12S79, and D12S105, generated a peak lod score of 3.46 at the D12S105 locus. By this analysis the SCA2 gene was localized to a 12.8-cM interval between D12S78 and D12S79. The members of the Tunisian pedigree exhibited progressive cerebellar ataxia and dysarthria with or without ophthalmoplegia, optic atrophy, pyramidal signs, sensory loss, dementia, or extrapyramidal features. Extrapyramidal signs were found in 23% of the Tunisians but in none of the Cubans. Ihara et al. (1994) identified Japanese families with OPCA showing linkage to a 6.2-cM interval between IGF1 (147440) and D12S84/D12S85 on chromosome 12. Pulst et al. (1993) identified a pedigree with linkage to 12q and established closer flanking markers for SCA2 than had been achieved in the Cuban pedigree. The second family was of southern Italian descent and showed segregation for SCA in 5 generations. All affected persons showed marked appendicular and gait ataxia as well as slow saccadic eye movements (Starkman et al., 1972). Mean age of onset in 19 affecteds was 26.9 +/- 12.5. Anticipation was demonstrated in this family; in 14 of 15 parent-child pairs, onset of the disease in the offspring occurred earlier than in the parent by 14.4 +/- 7.9 years. Pulst et al. (1993) suggested that this indicates that an expanded triplet repeat underlies SCA2 as it does in SCA1. Pathogenesis Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), mutant huntingtin (613004), mutant ataxin-1 (164400), and glutamine expanded proteins in patients with SCA3 (109150), Trottier et al. (1995) used Western blotting to detect a 150-kD protein in a patient with SCA2, but not his normal relative. By analogy to other disorders associated with anticipation in expanded triplet repeats, they suggested that this may be the protein encoded by the mutant gene responsible for this disorder. Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. In SCA2 brains, Huynh et al. (2000) found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 (58 CAG repeats) showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomic changes observed in ataxin-1(Q80) transgenic lines, ataxin-2(Q58) remained cytoplasmic without detectable ubiquitination. Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders. The ATXN2 promoter is located exon 1 of the ATXN2 gene in a typical CpG island devoid of a TATA box and is usually partially methylated. Using a methyl-specific PCR protocol, Laffita-Mesa et al. (2012) found differences in the methylation levels of the ATXN2 promoter in a family in which anticipation was observed without CAG repeat expansion. Specifically, the promoter was hypomethylated in an affected son with earlier onset of SCA2 compared to that of his affected mother with later onset of the disorder, even though both patients carried CAG expansions of 39 repeats on the pathogenic allele. In 9 SCA2 patients, quantitative analysis indicated that hypermethylation at the promoter, leading to partial or complete epigenetic silencing, was associated with longer expansions of the ATXN2 repeat and that alleles with pathogenic CAG expansions were preferentially hypermethylated. These findings may represent part of the cellular defense mechanism to reduce the burden of cytotoxic mutant ATXN2. Study of 2 patients with homozygous expansions of 43 and 39 CAG repeats, respectively, found an association between hypermethylation at the ATXN2 promoter and delayed age at onset. SCA3 (109150) is caused by a similar CAG repeat expansion in the ATXN3 gene (607047), which is closely connected to ATXN2. Laffita-Mesa et al. (2012) also found that hypermethylation at the ATXN2 promoter was associated with lower age of onset of SCA3, although methylation at the ATXN3 promoter had no effect on age at onset of SCA3. These findings suggested that the development of SCA3 may involve physiologic functions of ATXN2. Overall, the report of Laffita-Mesa et al. (2012) showed that methylation of the ATXN2 promoter can occur, consistent with epigenetic control of ATXN2 expression, and that differences in methylation may affect disease course. Molecular Genetics ### Spinocerebellar Ataxia 2 In patients with spinocerebellar ataxia-2, Pulst et al. (1996) identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene (601517.0001). They detected expansions of 36 to 52 repeats in affected individuals; the most common allele contained 37 repeats. They noted that the SCA2 repeat is unusual in that only 2 alleles were demonstrated in the normal population. A common allele with 22 repeats was found in people of European descent. Using RT-PCR, Pulst et al. (1996) determined that the SCA2 (CAG)n repeat is transcribed in lymphoblastoid cell lines and that the cells could be used to express the expanded repeat genes from patients with SCA2. Sanpei et al. (1996) analyzed 286 normal chromosomes and found that the (CAG)n repeats ranged in size from 15 to 24, with a unit of 22 repeats accounting for 94% of the alleles. In contrast, SCA2 patient chromosomes contained expanded repeats ranging in size from 35 to 59 units. Sanpei et al. (1996) reported that there was a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms. Imbert et al. (1996) reported that normal SCA2 alleles contained 17 to 29 (CAG)n repeats and 1 to 3 (CAA)n repeats (also glutamine-encoding). Mutated alleles contained 37 to 50 repeats and appeared to be particularly unstable in maternal and paternal transmissions. Sequence analysis of expanded repeats from 3 individuals revealed pure CAG stretches. Imbert et al. (1996) reported a steep inverse correlation between the age of onset of disease and (CAG)n repeat number. Riess et al. (1997) investigated the (CAG)n repeat length of the ATXN2 gene in 842 patients with sporadic ataxia and in 96 German patients with dominantly inherited SCA that did not harbor the SCA1 or MJD1/SCA3 mutation. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with respect to the age of onset in 41 patients revealed an inverse correlation. They found that 241 apparently healthy octogenarians carried alleles between 16 and 31 repeats. One 50-year-old healthy individual had 34 repeats; she had transmitted an expanded allele to her child. Riess et al. (1997) commented that the small difference between 'normal' and disease alleles makes it necessary to define the extreme values of their reaches. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany. Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases. Spadafora et al. (2007) reported 2 brothers and a nephew with SCA2. Molecular analysis identified CAG repeat numbers of 35/36, 22/35, and 22/42, respectively. The brother and nephew with the 35/36 and 22/42 repeat expansions showed earlier age at onset and a more severe progressive disorder compared to the brother with the 22/35 repeat expansions. The family was from Sicily and denied consanguinity, although both deceased parents of the brothers were reportedly affected late in life. Spadafora et al. (2007) concluded that SCA2 shows gene dosage effects on phenotype. ### Amyotrophic Lateral Sclerosis 13 Elden et al. (2010) demonstrated genetic, biochemical, and neuropathologic interactions between TDP43 (605078), a protein involved in amyotrophic lateral sclerosis (ALS10; 612069), and ATXN2, which raised the possibility that mutations in ATXN2 may have a causative role in ALS. The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS: Elden et al. (2010) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. They studied the frequency of intermediate-length ATXN2 polyglutamine repeat in ALS, comparing 915 subjects with ALS with 980 neurologically normal controls. Among those with ALS, 4.7% (43) had repeat lengths of 27 to 33, whereas only 1.4% (14) of neurologically normal subjects had glutamine expansions. The P value for this difference was 3.6 x 10(-5) with an odds ratio (OR) of 2.80. Elden et al. (2010) analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady-state levels of ATXN2 were comparable, cyclohexamide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. Elden et al. (2010) found that polyQ expansions in ATXN2 enhance its interaction with TDP43. Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. The authors proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress. In a case-control study of 556 ALS patients and 471 controls of French or French Canadian origin, Daoud et al. (2011) found that 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. However, receiver operating characteristic curve analysis yielded a significant association between ALS and high-length ATXN2 repeat alleles (29 or more repeats). CAG repeats of 29 or more were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). The association was even stronger for familial cases when stratified by familial versus sporadic cases (OR for familial cases, 9.29; p = 5.2 x 10(-5)). There was no correlation between size of repeat and age of onset. In addition, 2 familial and 9 sporadic ALS cases carried SCA2-sized pathogenic alleles (more than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. Among 1,845 sporadic and 103 familial ALS cases and 2,002 controls from Belgium and the Netherlands, Van Damme et al. (2011) found an association between ALS and an expanded repeat of 29 or more CAG repeats in the ATXN2 gene (OR, 1.92; p = 0.036). In controls, the repeat length ranged from 16 to 31, with 22 being the most abundant. Repeat sizes of 31 or less were not significantly different between patients and controls. However, receiver operating characteristic analysis showed that the greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036). There was no correlation between repeat length and disease parameters. When combined in a metaanalysis with the data of Elden et al. (2010), the association was highly significant (OR, 2.93; p less than 0.0001). Ten patients (0.05%) with sporadic ALS had 32 or more repeats, and none of these patients had signs of SCA2. Two of 91 families with ALS (2.2%) had expanded repeats: 1 with 31 repeats and the other with 33 repeats. In the 33-repeat family, which was consanguineous, 2 affected individuals had repeat expansions on both alleles, 33:33 and 33:31, respectively, although the phenotype was not significantly different from classic ALS, except for some sensory abnormalities. Two sibs from a third family with a heterozygous repeat length of 34 and 35, respectively, had classic SCA2 with no signs of upper motor neuron involvement. The findings indicated a genetic overlap between SCA2 and ALS13. Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP; 601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. Population Genetics In the vicinity of Holguin in northeastern Cuba (neighboring the Guantanamo Naval Base), Orozco et al. (1989) estimated a frequency of 41 per 100,000 for a form of dominantly inherited olivopontocerebellar atrophy occurring in persons of Spanish ancestry. The high prevalence was thought to be the result of founder effect. The clinical and biochemical features were described together with the neuropathologic findings in 7 autopsied patients. Geschwind et al. (1997) found that SCA2 accounts for 13% of patients with autosomal dominant cerebellar ataxia (without retinal degeneration), which is intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute more than 40% of the mutations leading to autosomal cerebellar ataxia type I. Geschwind et al. (1997) found that no patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, was observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, Schols et al. (1997) found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes, yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. SCA2 accounted for 5.9% of the cases. Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA2 was significantly higher in the Caucasian population (14%) compared to the Japanese population (5%). This corresponded to higher frequencies of large normal CACNA1A CAG repeat alleles (greater than 22 repeats) in Caucasian controls compared to Japanese controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA. Pareyson et al. (1999) evaluated 73 Italian families with type I ADCA. SCA1 was the most common genotype, accounting for 41% of cases (30 families); SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In an analysis of 42 Indian families, Saleem et al. (2000) found that SCA2 was the most frequent ataxia among those studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection in a pair of dizygotic twins of expanded alleles showing the same repeat number. Haplotype analysis indicated the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population. Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 (164500) in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin. Zhao et al. (2002) found that SCA2 is relatively common in the Malay population of Singapore. Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7. In a study of ATXN2 CAG repeat alleles in about 3,000 Cuban chromosomes, Laffita-Mesa et al. (2012) found that the range of repeats was distributed continuously from 13 to 31 repeats, with 22 repeats being the most frequent allele (76%). However, the distribution was skewed toward the large CAG range and was higher compared to Caucasian, Japanese, Indian, and Polish populations. Cuban chromosomes also had a high frequency of intermediate alleles (32 and 33 CAG repeats). Examination of 81 normal chromosomes showed high variance in the CAG with CAA interruption sequence, with many normal alleles lacking the stability-mediating CAA interruptions. Alleles with 27-31 repeats were somatically unstable, suggesting that they may give rise to de novo pathogenic expansions. Statistical analysis pointed to 27 CAG repeats as being the threshold for intermediate alleles. Animal Model ### Therapy Scoles et al. (2017) developed an antisense oligonucleotide, ASO7, that downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Slow saccades \- Ophthalmoplegia \- Gaze-evoked nystagmus \- Dysmetric saccades \- Impaired horizontal smooth pursuit \- Ocular motor apraxia \- Retinitis pigmentosa (rare) ABDOMEN Gastrointestinal \- Dysphagia GENITOURINARY Bladder \- Sphincter disturbances NEUROLOGIC Central Nervous System \- Cerebellar ataxia, progressive \- Hyporeflexia \- Dysarthria \- Dysmetria \- Dysdiadochokinesis \- Hypotonia \- Limb ataxia \- Action and postural tremor \- Fasciculation-like movements \- Myoclonus \- Dementia \- Dopamine-responsive parkinsonism \- Bradykinesia \- Rigidity \- Postural instability \- Spasticity \- Olivopontocerebellar atrophy \- Enlarged fourth ventricle \- Posterior column degeneration \- Spinocerebellar tract degeneration Peripheral Nervous System \- Peripheral neuropathy \- Decreased vibration sense \- Distal muscular atrophy MISCELLANEOUS \- Mean age of onset in third decade \- Rarely reported in infants \- Extreme phenotypic variability \- May manifest as 'ataxic' phenotype without parkinsonian features \- May manifest as late-onset 'parkinsonian' phenotype without severe ataxic features \- High prevalence in Holguin province of Cuba \- Genetic anticipation MOLECULAR BASIS \- Caused by expanded CAG trinucleotide repeats in the ataxin-2 gene (ATX2, 601517.0001 ). ▲ 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	SPINOCEREBELLAR ATAXIA 2	c0752121	2,809	omim	https://www.omim.org/entry/183090	2019-09-22T16:34:31	{"doid": ["0050955"], "mesh": ["D020754"], "omim": ["183090"], "orphanet": ["98756"], "synonyms": ["Alternative titles", "SPINOCEREBELLAR ATROPHY II", "OLIVOPONTOCEREBELLAR ATROPHY, HOLGUIN TYPE", "OLIVOPONTOCEREBELLAR ATROPHY II", "SPINOCEREBELLAR ATAXIA, CUBAN TYPE", "CEREBELLAR DEGENERATION WITH SLOW EYE MOVEMENTS", "WADIA-SWAMI SYNDROME", "SPINOCEREBELLAR DEGENERATION WITH SLOW EYE MOVEMENTS"], "genereviews": ["NBK1275"]}
De Yebenes et al. (1988) described a syndrome of branchial myoclonus, spastic paraparesis, and cerebellar ataxia in 6 members of 2 generations of a family that lived in the province of Toledo in Spain. Male-to-male transmission occurred. Rhythmic myoclonus involving the palate, pharynx, larynx, and face was followed by truncal ataxia and spastic paraparesis. Age of onset ranged from 40 to 50 years. Computerized tomography and magnetic resonance imaging showed mild atrophy of the cerebral and cerebellar cortex and severe atrophy of the medulla and spinal cord. The pons appeared normal, and the olives did not seem hypertrophic. Reduction of the serotonin metabolite 5-hydroxyindoleacetic acid was found in the cerebrospinal fluid. Treatment with 5-hydroxytryptophan and carbidopa at maximal tolerated doses improved ataxia mildly but did not modify the myoclonus. Treatment with other agents was unsuccessful. The clinical symptoms were progressive, leading to death or severe disability 5 to 10 years after onset of the disease. Branchial myoclonus is rare but has been observed with a variety of disorders including demyelinating disease, infarction, arteritis, neoplasm, and trauma involving the lower brainstem or the dentato-rubro-olivary pathways. Sperling and Hermann (1985), Leger et al. (1986), and Sasaki et al. (1987) described branchial myoclonus in patients with spinocerebellar degeneration and olivopontocerebellar atrophy, but de Yebenes et al. (1988) thought that the disorder in their family was different from that reported in any of these 3 publications. Howard et al. (1993) described a Kuwaiti family that came to attention because of 2 sisters and a brother, out of a sibship of 10, who presented with a progressive neurologic disorder beginning in the third decade of life and characterized by palatal myoclonus, nystagmus, bulbar weakness, and spastic tetraparesis. There was no evidence of intellectual deterioration or seizures. CT scan showed marked brainstem atrophy in 2 patients and basal ganglia calcification in 1. MRI scan in 1 showed high signal in the brainstem and periventricular region, and cerebral biopsy in this patient showed myelin loss and the presence of Rosenthal fibers, which are particularly characteristic of Alexander disease (203450). A similar disease affected the mother, who died at age 45, a maternal aunt, who died at age 50, and 2 daughters of the aunt who were still living. Howard et al. (1993) suggested autosomal dominant inheritance. It may be noteworthy that the parents of the 3 sibs were consanguineous, as were also the parents of the 'mother' and 'maternal aunt.' Palatal myoclonus, which also occurs in Machado-Joseph disease (109150) and in spinocerebellar ataxia type 2 (183090), is characterized by rhythmic oscillations of the soft palate. It is also called branchial myoclonus because it may be associated with synchronous contractions of muscles derived from the branchial arches, including the diaphragm, tongue, and sternomastoids. Misc \- Onset age 40 to 50 years \- Death or severe disability 5 to 10 years after onset Radiology \- CT and MRI show mild atrophy of the cerebral and cerebellar cortex and severe atrophy of the medulla and spinal cord, with normal pons and olives Neuro \- Rhythmic myoclonus of palate, pharynx, larynx, and face \- Truncal ataxia \- Spastic paraparesis \- Nystagmus 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	BRANCHIAL MYOCLONUS WITH SPASTIC PARAPARESIS AND CEREBELLAR ATAXIA	c1862071	2,810	omim	https://www.omim.org/entry/113610	2019-09-22T16:43:56	{"mesh": ["C566188"], "omim": ["113610"]}
Condition of possessing an extremely detailed autobiographical memory "HSAM" redirects here. For the Hierarchical Sequential Access Method, see HSAM (computing). Hyperthymesia Other nameshyperthymestic syndrome,[1] highly superior autobiographical memory[2] SpecialtyPsychology Psychiatry, neurology Hyperthymesia is a condition that leads people to be able to remember an abnormally large number of their life experiences in vivid detail. It is extraordinarily rare, with only about 60 people in the world having been diagnosed with the condition as of 2021.[3] American neurobiologists Elizabeth Parker, Larry Cahill, and James McGaugh (2006) identified two defining characteristics of hyperthymesia: spending an excessive amount of time thinking about one's past, and displaying an extraordinary ability to recall specific events from one's past.[1] The word "hyperthymesia" derives from Ancient Greek: hyper- ("excessive") and thymesis ("remembering"). ## Contents * 1 Signs and symptoms * 1.1 Difficulties * 2 Causes * 2.1 Psychological * 2.2 Biological * 3 Diagnosis * 4 Society and culture * 4.1 Notable cases * 4.2 Controversies * 4.3 Fiction * 4.3.1 Books * 4.3.2 Television * 4.3.3 Film * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Individuals with hyperthymesia can extensively recall the events of their lives, as well as public events that hold some personal significance to them. Those affected describe their memories as uncontrollable associations; when they encounter a date, they "see" a vivid depiction of that day in their heads without hesitation or conscious effort.[4] While memories are reported as vivid, they are not exact recordings of all experiences, as seen in the case of AJ:[1] > Although she describes her mind like having a movie running, she is not recording her world verbatim in its totality. One day after several hours together, she was asked to close her eyes and tell what her two interviewers were wearing. She was unable to do so. There is a distinction between those with hyperthymesia and those with other forms of exceptional memory, who generally use mnemonic or similar rehearsal strategies to memorize long strings of information. Memories recalled by hyperthymestic individuals tend to be personal, autobiographical accounts of both significant and mundane events in their lives. This extensive and highly unusual memory does not derive from the use of mnemonic strategies; it is encoded involuntarily and retrieved automatically.[5] Despite perhaps being able to remember the day of the week on which a particular date fell, hyperthymestics are not calendrical calculators, like some people with savant syndrome. Rather, hyperthymestic recall tends to be constrained to a person's lifetime and is believed to be a subconscious process. Although people showing a high level of hyperthymesia are not regarded as autistic, certain similarities exist between the two conditions. Like autistic savants, some individuals with hyperthymesia may also have an unusual and obsessive interest in dates. Russian psychologist Alexander Luria documented the famous case of mnemonist Solomon Shereshevsky,[6] who was quite different from the first documented hyperthymestic known as AJ (real name Jill Price) in that Shereshevsky could memorize virtually unlimited amounts of information deliberately, while AJ could not – she could only remember autobiographical information (and events she had personally seen on the news or read about). In fact, she was not very good at memorizing anything at all, according to the study published in Neurocase.[1] Hyperthymestic individuals appear to have poorer than average memory for arbitrary information. Another striking parallel drawn between the two cases was that Shereshevsky exemplified an interesting case of synesthesia[7] and it has been suggested that superior autobiographical memory is intimately tied to time-space synesthesia.[8] ### Difficulties[edit] Hyperthymestic abilities can have a detrimental effect. The constant, irrepressible stream of memories has caused significant disruption to AJ's life. She described her recollection as "non-stop, uncontrollable and totally exhausting" and as "a burden".[1] AJ is prone to getting lost in remembering. This can make it difficult to attend to the present or future, as she is permanently living in the past. Others who have hyperthymesia do not display any of these traits, however. AJ displays considerable difficulty in memorizing allocentric information. "Her autobiographical memory, while incredible, is also selective and even ordinary in some respects," – McGaugh.[1] This was demonstrated by AJ's poor performance on standardised memory tests. At school, AJ was an average student, unable to apply her exceptional memory to her studies. Deficits in executive functioning and anomalous lateralisation were also identified in AJ. These cognitive deficiencies are characteristic of frontostriatal disorders.[1] Even those with a high level of hyperthymesia do not remember exactly everything in their lives or have "perfect memory". Studies have shown that it is a selective ability, as shown by AJ's case, and they can have comparative difficulty with rote memorization and therefore cannot apply their ability to school and work. Their memorization of events tends to exceed their ability to memorize given facts; for example, if you told a hyperthymesiac a fact about the world, they may not remember what you said, but they will more likely remember what you wore and other details of the situation when you told them. ## Causes[edit] Due to the small number of people diagnosed with hyperthymesia, relatively little is known about the processes governing this superior memory ability. However, more is beginning to be understood about this condition. ### Psychological[edit] It has been proposed that the initial encoding of events by such people includes semantic processing, and therefore semantic cues are used in retrieval. Once cued, the memory is retrieved as episodic and follows a pattern similar to that of a spreading activation model. This is particularly evident in AJ's case. She describes how one memory triggers another, which in turn triggers another and how she is powerless to stop it: "It's like a split screen; I'll be talking to someone and seeing something else."[1] This theory serves to explain why hyperthymestics have both a sense of 'knowing' (semantic memory) and 'remembering' (episodic memory) during recollection. One writer claimed hyperthymesia may be a result of reviewing memories constantly to an obsessive-compulsive degree.[9] However AJ has completely dismissed this article as "a load of crap" and others with hyperthymesia claim to never revisit uneventful memories. Other findings have shown that the tendencies to absorb new information and fantasize are personality traits that are higher in hyperthymestics than the rest of the population. These traits, absorption and fantasizing, also correlated with one of the tests that measures superior autobiographical memory within the hyperthymestic sample.[10] ### Biological[edit] An MRI study conducted on AJ provides a plausible argument as to the neurological foundation of her superior memory.[11][12] Both the temporal lobe and the caudate nucleus were found to be enlarged. The hippocampus, located in the medial temporal lobe, is involved in the encoding of declarative memory (memory for facts and events), while the temporal cortex is involved in the storage of such memory.[13] The caudate nucleus is primarily associated with procedural memory, in particular habit formation, and is, therefore, intrinsically linked to obsessive-compulsive disorder. Parker and colleagues speculated that a defective frontostriatal circuit could be responsible for the observed executive function deficits in hyperthymesia. This circuit plays a crucial role in neurodevelopmental disorders. Given the parallels in some aspects of behavior, AJ's hyperthymestic abilities possibly stem from atypical neurodevelopment. Scientists now need to ascertain if and how these brain areas are connected to establish a coherent neurological model for superior autobiographical memory. ## Diagnosis[edit] Parker and colleagues used a variety of standardised neuropsychological tests in their diagnosis of AJ's hyperthymesia. These included tests of memory, lateralisation, executive functions, language, calculations, IQ, and visual-spatial and visual-motor functions.[1] They also devised novel tests to examine the extent of her memory abilities. These mostly consisted of questions pertaining to specific dates and events in history. Some of her personal recollections were verified with diary entries, as well as by her mother.[1] Neuroscientist David Eagleman at Stanford University developed a free on-line test for hyperthymesia (no longer available). Participants first give their year of birth, and then are challenged to match dates to 60 famous events that happened between the time they were five years old and the present day. To qualify as potentially hyperthymestic, participants must achieve a score at least three standard deviations above the average. To prevent people from searching for answers on-line during the test, reaction time for each question is measured; answers must be chosen within 11 seconds to qualify for consideration. However, many of the questions are sourced in American culture and test results could have a strong cultural bias against non-Americans. ## Society and culture[edit] ### Notable cases[edit] As of April 2016, six cases of hyperthymesia have been confirmed in peer-reviewed articles,[1][2][14][15] the first being that of "AJ" (real name Jill Price) in 2006. More cases have been identified that are yet to be published.[16][better source needed] AJ's case was originally reported by researchers from the University of California, Irvine, Elizabeth Parker, Larry Cahill, and James McGaugh, and is credited as being the first case of hyperthymesia. AJ can apparently recall every day of her life from when she was 14 years old: "Starting on February 5th, 1980, I remember everything. That was a Tuesday."[11] In March 2009, AJ was interviewed for an article in Wired magazine by Gary Marcus, a cognitive psychologist at New York University.[17] Price's brain had been subject to a brain scan and the hippocampus and prefrontal cortex had been reportedly normal. Marcus claimed, however, that her brain resembled "those of people with obsessive-compulsive disorder" and suggested that her remarkable memory might be "the byproduct of obsession", claiming also that "the memory woman clings tightly to her past". Price has since reacted angrily to such claims and McGaugh has also expressed skepticism about this explanation.[18] Price gave her first interview in over a year for the UK's Channel 4 documentary The Boy Who Can't Forget, and provided an insight into just how difficult life can be for people who have this ability.[18] As the condition has become better known, more people claiming to have hyperthymestic abilities have emerged. In the aftermath of the 2006 Neurocase publication alone, more than 200 people contacted McGaugh; however, only a handful of cases were determined to be actual cases of hyperthymesia. The second verified case was Brad Williams,[19][20][21][22] the third was Rick Baron,[23] and in 2009, Bob Petrella became the fourth person diagnosed with hyperthymestic syndrome.[24] On December 19, 2010, actress Marilu Henner was featured on the Australian television program 60 Minutes for her superior autobiographical memory ability. Henner claimed she could remember almost every day of her life since she was 11 years old.[25][26] The show was initially pitched as a story featuring hyperthymestic violinist Louise Owen, but the reporter Lesley Stahl volunteered her friend Henner as having a similar ability.[4] In June 2012, the case of HK Derryberry was reported, a blind 20-year-old man who could clearly recall every day of his life since the age of about 11.[15] Derryberry had been born at 27 weeks, weighing just over 2 pounds (0.91 kg) and was in neonatal intensive care for 96 days. A severe brain hemorrhage was the likely cause of cerebral palsy, and his prematurity resulted in congenital blindness.[27] He told researchers that his memories are rich in sensory and emotional details, regardless of whether they are from years ago or yesterday. About 90% of his memories are in the first person, compared with an average of 66% in the general population. Brandon Ally and his team, at Vanderbilt University, Nashville, Tennessee, conducted a series of tests with the subject, including a brain scan that was compared with 30 age-matched controls. His brain was smaller than average (probably a result of his premature birth at 27 weeks). His right amygdala, however, was 20% larger, with enhanced functional connectivity between the right amygdala and hippocampus and in other regions.[28] In 2016, HK's remarkable life story was published by HarperCollins Christian Publishing in a book entitled "The Awakening of HK Derryberry: My Unlikely Friendship with the Boy Who Remembers Everything". It was written by his mentor Jim Bradford with the help of Andy Hardin.[29] In September 2012, UK's Channel 4 screened the documentary The Boy Who Can't Forget, which examined the memory of 20-year-old Aurelien Hayman from Cardiff, a student at Durham University, who remembers practically every day of his life from the age of 10.[18] Hayman is the first British person to be identified as possessing this ability, and he views it positively.[30] When Hayman's brain was scanned by a team led by Professor Giuliana Mazzoni at the University of Hull, whilst he was prompted to remember a series of dates, a series of "visual areas" of the brain were activated, with much greater speed than would be expected in normal brain function. Potential problems with total recall were illustrated.[16][31] The documentary also featured 62-year-old TV producer Bob Petrella, whose memory has allowed him to catalogue the events from his "favorite days" over many years into an extensive scrapbook.[32] In March 2015, Markie Pasternak of Green Bay, Wisconsin was diagnosed as the youngest person to be living with HSAM. Born in 1994, Pasternak remembers every day of her life since February 2005. She was featured on 60 Minutes Australia in August 2016 with Rebecca Sharrock.[33] In January 2016, painter and polymath Nima Veiseh was featured by the BBC for his use of hyperthymesia to create paintings that could only be produced with his ability.[34] Veiseh claimed he could remember almost every day of his life since he was 15 years old, and that his ability to synthesize time and an "encyclopedic knowledge of the history of art" enabled him to create wholly unique visions on canvas. In March 2016 NPR examined further Veiseh's exploration of time and the human experience through art.[35] In April 2017, Rebecca Sharrock of Brisbane, Australia became known as a person who claims to recall even circumstantial details of every day of her life from her 12th day of life onward.[36] Discussing her hyperthymesia with BBC World Service, Sharrock revealed she was supporting two research projects – one with the University of Queensland and another with the University of California – to understand how a greater knowledge of hyperthymesia can support Alzheimer's disease research, particularly in repairing the degeneration of the Hippocampus.[37] Scans conducted during the studies showed that Sharrock's brain exhibited a heightened connection between the conscious and sub-conscious parts of her brain, which may aid easier memory recall – particular for events that took place earlier in life. In October 2018, it was reported that teenager Tyler Hickenbottom, who is an identical twin, had the condition, which allowed him to "remember every day of his life like it was yesterday".[38] ### Controversies[edit] The debate as to whether hyperthymestic syndrome can be considered a distinct form of memory is ongoing. It is also open to question how far it is an all-or-none condition, or whether people can have the condition to different degrees. K. Anders Ericsson of Florida State University does not believe that sufficient evidence exists to suggest that the skills of AJ and Williams need additional explanation: "Our work has pretty much concluded that differences in memory don't seem to be the result of innate differences, but more the kinds of skills that are developed."[39] McGaugh rejects the idea that hyperthymestic syndrome can be explained away so easily; he argues that nothing explains how subjects are able to memorize so much: "You'd have to assume that every day they rehearse it... The probability of these explanations dwindles as you look at the evidence."[39] Cases of hyperthymesia have forced many people to re-evaluate what is meant by "healthy" memory: "it isn't just about retaining the significant stuff. Far more important is being able to forget the rest."[39] Significant debate also exists over the limits of memory capacity. Some are of the view that the brain contains so many potential synaptic connections that, in theory at least, no practical limit exists to the number of long-term memories that the brain can store. In 1961, Wilder Penfield reported that specific stimulation of the temporal lobes resulted in vivid recollection of memories. He concluded that our brains were making "continuous, effortless, video-like recordings" of our experiences, but that these records are not consciously accessible to us.[40] However, a study published in the Proceedings of the National Academy of Sciences suggested that those with hyperthymesia may reconstruct memories from traces and incorporate post event information and associations—a finding at odds with Penfield's video-like recording analogy.[14] ### Fiction[edit] #### Books[edit] * In the 1942 short story "Funes the Memorious" by Jorge Luis Borges, the protagonist suffers a head injury after which he gains the ability to remember every detail of what he experiences, but comes to view this as a curse. The condition may not technically be an example of hyperthymesia, but shares some features. * In the 1980 series "The Book of the New Sun" by Gene Wolfe, the protagonist remembers everything he has ever seen starting from infancy. He describes his memories as being so vivid that he is capable of re-living anything he has experienced whenever he chooses to do so. * In a 2011 manga by Kohske called Gangsta, the main character, Worick Arcangelo, is said to have hyperthymesia, which he uses to help police identify murder victims.[41] * In the 2012 novel And She Was by Alison Gaylin, the protagonist, Brenna Spector, is a private detective with hyperthymesia. * In the 2014 novel The First Fifteen Lives of Harry August by Claire North, the protagonist Harry August displays signs of hyperthymesia. Although it is never explicitly stated in the novel that he has the condition, Harry, who continuously lives his life over and over in an endless cycle, is able to remember every detail of all fifteen of his previous lives. * In the 2015 novel Memory Man[42] by David Baldacci, the protagonist, Amos Decker, has hyperthymesia. In the book, a mystery-crime scene-thriller with graphic scenes, Decker uses his perfect memory brought on by a traumatic hit in football to solve the murder of his wife and child, and the school shooting connected to it. Decker recalls his memories as a "DVR", just playing when it wants to, or being rewound and played forward by conscious thought. #### Television[edit] * A 2011 episode of the TV series House entitled "You Must Remember This" is about a waitress with hyperthymesia. * The entire 2011 TV series Unforgettable is centered around a police detective with hyperthymesia. * A 2014 episode of The Blacklist features a character with hyperthymesia employed by a bank to avoid papertrails. * In the 2015–2016 Korean TV Thriller series Remember, the protagonist, Seo Jin-woo, has hyperthymesia.[citation needed] * On the American television series Superstore, the character Sandra Kaluiokalani has superior autobiographical memory. * In the 2017 episode of BBC TV series Doctors one of the characters has hyperthymesia.[43] * The 2020 South Korean television series Find Me in Your Memory is about a man with hyperthymesia. #### Film[edit] * In the 2014 film The Dark Place, the protagonist of the story, Keegan Dark, has hyperthymesia. Keegan uses it to solve the mystery at the heart of the story. His hyperthymesia memories are visually depicted in the movie as "screens" appearing to Keegan, often in an overwhelming and distressing manner.[44] ## See also[edit] * Daniel McCartney * Hypermnesia * Eidetic memory ## References[edit] 1. ^ a b c d e f g h i j k Parker ES, Cahill L, McGaugh JL (February 2006). "A case of unusual autobiographical remembering". Neurocase. 12 (1): 35–49. CiteSeerX 10.1.1.502.8669. doi:10.1080/13554790500473680. PMID 16517514. 2. ^ a b LePort, A.; Mattfeld, A.; Dickinson-Anson, H.; Fallon, J.; Stark, C.; Kruggel, F.; Cahill, L.; McGaugh, J. (2012). "Behavioral and neuroanatomical investigation of Highly Superior Autobiographical Memory (HSAM)" (PDF). Neurobiology of Learning and Memory. 98 (1): 78–92. doi:10.1016/j.nlm.2012.05.002. PMC 3764458. PMID 22652113. 3. ^ https://www.theguardian.com/news/audio/2021/jan/13/from-the-archives-total-recall-the-people-who-never-forget-podcast 4. ^ a b Finkelstein, Shari. "Understanding the gift of endless memory". 60 Minutes. CBS Interactive. Retrieved 2 December 2011. 5. ^ Treffert, Darold. "Hyperthymestic Syndrome: Extraordinary Memory for Daily Life Events. Do we all possess a continuous tape of our lives?". Wisconsin Medical Society. Archived from the original on November 27, 2011. Retrieved 2 December 2011. 6. ^ Luria, A R (1987). The mind of a mnemonist: a little book about a vast memory. Cambridge: Harvard University Press. ISBN 978-0-674-57622-3. 7. ^ Yaro, Caroline; Ward, J (17 April 2007). "Searching for Shereshevskii: What is superior about the memory of synaesthetes?". The Quarterly Journal of Experimental Psychology. 60 (5): 681–695. doi:10.1080/17470210600785208. PMID 17455076. 8. ^ Simner, Julia; Mayo, N; Spiller, M-J (21 July 2009). "A foundation for savantism? Visuo-spatial synaesthetes present with cognitive benefits" (PDF). Cortex. 45 (10): 1246–1260. doi:10.1016/j.cortex.2009.07.007. PMID 19665699. 9. ^ Marcus, Gary (2009-03-23). "Total Recall: The Woman Who Can't Forget". Wired. Archive.wired.com. Retrieved 2014-05-29. 10. ^ Patihis, Lawrence (2015-08-28). "Individual differences and correlates of highly superior autobiographical memory". Memory. 24 (7): 961–978. doi:10.1080/09658211.2015.1061011. ISSN 0965-8211. PMID 26314991. 11. ^ a b Shafy, Samiha (2008-11-21). "An Infinite Loop in the Brain". Spiegel Online. Retrieved 6 December 2011. 12. ^ Elias, Marilyn. "MRIs reveal possible source of woman's super-memory". USA Today. January 28, 2009 13. ^ Svoboda, Eva; McKinnon, MC; Levine, B (27 June 2006). "The functional neuroanatomy of autobiographical memory: A meta-analysis". Neuropsychologia. 44 (12): 2189–2208. doi:10.1016/j.neuropsychologia.2006.05.023. PMC 1995661. PMID 16806314. 14. ^ a b Patihis, L.; Frenda, S. J.; LePort, A. K. R.; Petersen, N.; Nichols, R. M.; Stark, C. E. L.; McGaugh, J. L.; Loftus, E. F. (2013). "False memories in highly superior autobiographical memory individuals". PNAS. 110 (52): 20947–20952. doi:10.1073/pnas.1314373110. PMC 3876244. PMID 24248358. 15. ^ a b Ally B.; Hussey E.; Donahue M. (2012). "A case of hyperthymesia: rethinking the role of the amygdala in autobiographical memory". Neurocase. 19 (2): 1–16. doi:10.1080/13554794.2011.654225. PMC 3432421. PMID 22519463. 16. ^ a b "BBC News - Memory man: Aurelien Hayman's hyperthymesia explained". 2012-09-25. 17. ^ Gary Marcus (23 March 2009). "Total Recall: The Woman Who Can't Forget". WIRED. 18. ^ a b c "The Boy Who Can't Forget". Channel 4. 25 September 2012. 19. ^ "Local "Memory Man" appears on Good Morning America". WXOW. January 15, 2008. Archived from the original on May 21, 2008. 20. ^ "Amazing memory man never forgets". CNN. Associated Press. Archived from the original on 2008-02-26. Retrieved 2008-02-23. 21. ^ David S. Martin (May 16, 2008). "Man's rare ability may unlock secret of memory". CNN. Retrieved 2008-05-16. 22. ^ Williams, Brad (2011-12-02). "Experience: I remember every day of my life". The Guardian. ISSN 0261-3077. Retrieved 2019-07-06. 23. ^ Elias, Marilyn. "Another person with super-memory skills comes forward". USA Today. May 13, 2008 24. ^ Thompson, Victoria (March 16, 2009). "He Never Forgets: Meet the Super-Memory Man". ABC News. Retrieved 8 December 2011. 25. ^ C., Tania. "Scientists Discover Hyperthymesia-The Perfect Memory". FinestDaily. 26. ^ Dionne, Zach. "'Taxi' Actress Marilu Henner Has Super-Rare Autobiographical Memory Ability". Popeater. December 20, 2010 27. ^ Photo by Daniel Dubois. "The Amazing Life and Memory of H.K. Derryberry (08/24/12)". Mc.vanderbilt.edu:8080. Retrieved 2014-05-29. 28. ^ Jarrett, Christian (2012-05-21). "Total recall: The man who can remember every day of his life in detail". British Psychological Society. Retrieved 28 June 2012. 29. ^ In 2016, HK's life story was published by HarperCollins Christian Publishing in "The Awakening of HK Derryberry: My Unlikely Friendship with the Boy Who Remembers Everything," which detailed his medical condition. [1] 30. ^ Audrey Ward (2012-09-23). "Total recall". The Sunday Times. Retrieved 2014-05-29. 31. ^ Sam Wollaston. "TV review: The Boy Who Can't Forget; The Paradise". the Guardian. 32. ^ "The Boy Who Can't Forget: Aurelien Heyman, Jill Price and Bob Petrella demonstrate their marvellous memories in this Channel 4 documentary - Unreality TV". Unreality TV. Archived from the original on 2014-10-23. 33. ^ "Rare detailed personal memory a burden, and ultimately a gift". 34. ^ David Robson (26 January 2016). "The blessing and the curse of the people who never forget". The British Broadcasting Corporation. Retrieved 24 April 2016. 35. ^ "Meet the Man Who Can Remember Everything". WNYC. 21 March 2016. Retrieved 24 April 2016. 36. ^ "I Can Remember Back to When I Was a Newborn Child". 17 April 2017. Retrieved 24 April 2017. 37. ^ "Outlook: I Can Remember When I Was a Newborn". The British Broadcasting Corporation. 30 August 2018. Retrieved 30 August 2018. 38. ^ "Total recall: Some people can remember every day like it was yesterday". 39. ^ a b c Marshall, Jessica. "Forgetfulness is Key to a Healthy Mind". New Scientist. Retrieved 6 December 2011. 40. ^ Penfield, Wilder (1952). "Memory Mechanisms". AMA Archives of Neurology and Psychiatry. 67 (2): 178–98. doi:10.1001/archneurpsyc.1952.02320140046005. PMID 14893992. 41. ^ Kohske (8 July 2011). Gangsta. Viz Media. 42. ^ Baldacci, David (April 21, 2015). Memory Man. Grand Central Publishing. pp. 416. ISBN 9781455559824. 43. ^ "BBC One – Doctors, Series 19, Episode 116, Forgive and Forget". BBC. Retrieved 6 December 2017. 44. ^ "Review:The Dark Place". 2014-12-12. ## External links[edit] Look up hyperthymesia in Wiktionary, the free dictionary. * Alix Spiegel (2013-12-27). "When Memories Never Fade, The Past Can Poison The Present". NPR. (featuring testimonials from persons with hyperthymesia) * People who remember every second of their life - Total recall \| 60 Minutes Australia * The Extraordinary Memory Test from David Eagleman's laboratory * Extraordinary Variations of the Human Mind: James McGaugh: Highly Superior Autobiographical Memory at photographicmemory.pro * Total Recall: NBC Indianapolis * Only 60 People in the World Live with Highly Superior Autobiographical Memory: Reader's Digest * v * t * e Human memory Basic concepts * Encoding * Storage * Recall * Attention * Consolidation * Neuroanatomy Types Sensory * Echoic * Eidetic * Eyewitness * Haptic * Iconic * Motor learning * Visual Short-term * "The Magical Number Seven, Plus or Minus Two" * Working memory Intermediate * Long-term * Active recall * Autobiographical * Explicit * Declarative * Episodic * Semantic * Flashbulb * Hyperthymesia * Implicit * Meaningful learning * Personal-event * Procedural * Rote learning * Selective retention * Tip of the tongue Forgetting * Amnesia * anterograde * childhood * post-traumatic * psychogenic * retrograde * transient global * Decay theory * Forgetting curve * Interference theory * Memory inhibition * Motivated forgetting * Repressed memory * Retrieval-induced forgetting * Selective amnesia * Weapon focus Memory errors * Confabulation * False memory * Hindsight bias * Imagination inflation * List of memory biases * Memory conformity * Mere-exposure effect * Misattribution of memory * Misinformation effect * Source-monitoring error * Wernicke–Korsakoff syndrome Research * Art of memory * Memory and aging * Deese–Roediger–McDermott paradigm * Exceptional memory * Indirect tests of memory * Lost in the mall technique * Memory disorder * Memory implantation * Methods used to study memory * The Seven Sins of Memory * Effects of exercise on memory In society * Collective memory * Cultural memory * False memory syndrome * Memory and social interactions * Memory sport * Politics of memory * Shas Pollak * World Memory Championships Related topics * Absent-mindedness * Atkinson–Shiffrin memory model * Context-dependent memory * Childhood memory * Cryptomnesia * Effects of alcohol * Emotion and memory * Exosomatic memory * Flashbacks * Free recall * Involuntary memory * Levels-of-processing effect * Memory and trauma * Memory improvement * Metamemory * Mnemonic * Muscle memory * Priming * Intertrial * Prospective memory * Recovered-memory therapy * Retrospective memory * Sleep and memory * State-dependent memory * Transactive memory People * Robert A. Bjork * Stephen J. Ceci * Susan Clancy * Hermann Ebbinghaus * Sigmund Freud * Patricia Goldman-Rakic * Jonathan Hancock * Judith Lewis Herman * HM (patient) * Ivan Izquierdo * Marcia K. Johnson * Eric Kandel * KC (patient) * Elizabeth Loftus * Geoffrey Loftus * Chris Marker * James McGaugh * Paul R. McHugh * Eleanor Maguire * George Armitage Miller * Brenda Milner * Lynn Nadel * Dominic O'Brien * Ben Pridmore * Henry L. Roediger III * Steven Rose * Cosmos Rossellius * Daniel Schacter * Richard Shiffrin * Arthur P. Shimamura * Andriy Slyusarchuk * Larry Squire * Susumu Tonegawa * Anne Treisman * Endel Tulving * Robert Stickgold * Clive Wearing * Psychology portal * Philosophy portal [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	Hyperthymesia	None	2,811	wikipedia	https://en.wikipedia.org/wiki/Hyperthymesia	2021-01-18T19:06:39	{"wikidata": ["Q45320"]}
Chromosome 6p deletion is a chromosome abnormality that occurs when there is a missing copy of the genetic material located on the short arm (p) of chromosome 6. The severity of the condition and the signs and symptoms depend on the size and location of the deletion and which genes are involved. Features that often occur in people with chromosome 6p deletion include developmental delay, intellectual disability, behavioral problems, and distinctive facial features. Chromosome 6p deletion can be de novo or inherited from a parent with a chromosomal rearrangement such as a balanced translocation. Treatment is based on the signs and 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	Chromosome 6p deletion	None	2,812	gard	https://rarediseases.info.nih.gov/diseases/10843/chromosome-6p-deletion	2021-01-18T18:01:21	{"synonyms": ["Deletion 6p", "Monosomy 6p", "6p deletion", "6p monosomy", "Partial monosomy 6p"]}
Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions. ## Epidemiology PNS are rare, affecting less than 1/10,000 patients with cancer. ## Clinical description Only the Lambert-Eaton myasthenic syndrome is relatively frequent, occurring in about 1% of patients with small cell lung cancer. The other most common PNS are subacute cerebellar ataxia, limbic encephalitis (LE), opsoclonus-myoclonus (OM), retinopathies (cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), Stiff-Person syndrome (SPS), chronic gastrointestinal pseudoobstruction (CGP), sensory neuronopathy (SSN), encephalomyelitis (EM) and dermatomyositis (see these terms). PNS can affect any part of the central or peripheral nervous system, the neuromuscular junction, and muscle. They can be isolated or occur in association. PNS are usually severely disabling. ## Etiology They are caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system (onconeural antigens). ## Diagnostic methods In most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist for identification of the neurological disorder as paraneoplastic. Due to their high specificity, the best way to diagnose a neurological disorder as paraneoplastic is to identify one of the well-characterized anti-onconeural protein antibodies in the patient's serum. In addition, as these antibodies are associated with a restricted range of cancers, they can guide the search for the underlying tumor at a stage when it is frequently not clinically overt. ## Management and treatment This is a critical point as, to date, the best way to stabilize PNS is to treat the cancer as soon as possible. Unfortunately, about one-third of patients do not have detectable antibodies and 5% to 10% have an atypical antibody that is not well-characterized. As PNS are believed to be immune-mediated, suppression of the immune response represents another treatment approach. [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	Paraneoplastic neurologic syndrome	c0393534	2,813	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36388	2021-01-23T17:59:20	{"gard": ["7326"], "mesh": ["D020362"], "umls": ["C0393534", "C0751911", "C3267031"], "synonyms": ["PCD", "PNS", "Paraneoplastic cerebellar degeneration"]}
Renal segmental hypoplasia Other namesAsk-Upmark kidney SpecialtyNephrology Renal segmental hypoplasia is a kidney with a partially developed or atrophic renal cortex.[1] ## Contents * 1 Presentation * 2 Cause * 3 See also * 4 References * 5 External links ## Presentation[edit] Ask-Upmark kidneys are a cause of secondary hypertension that can be curable.[2] ## Cause[edit] It is thought to be congenital or the consequence of vesicoureteral reflux.[2] in IVU “Slit scar” is seen. ## See also[edit] * Hypertension ## References[edit] 1. ^ Sugimoto T, Tanaka Y, Nitta N, Uzu T, Nishio Y, Kashiwagi A (2006). "Renal segmental hypoplasia, Ask-Upmark kidney, in a patient with adult-onset hypertension". Intern. Med. 45 (19): 1101–2. doi:10.2169/internalmedicine.45.1858. PMID 17077574. Free Full Text. 2. ^ a b Babin J, Sackett M, Delage C, Lebel M (2005). "The Ask-Upmark kidney: a curable cause of hypertension in young patients". Journal of Human Hypertension. 19 (4): 315–6. doi:10.1038/sj.jhh.1001822. PMID 15647775. ## External links[edit] Classification D * Ask-Upmark kidney \- whonamedit.com * Gross image of Ask-Upmark kidney \- nature.com * Neuroretinitis, Ask-Upmark kidney and abnormal brain MRI \- Journal of Pediatric Neurosciences [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	Renal segmental hypoplasia	None	2,814	wikipedia	https://en.wikipedia.org/wiki/Renal_segmental_hypoplasia	2021-01-18T18:50:21	{"icd-9": ["15.1"], "icd-10": ["Q60.5"], "wikidata": ["Q3932946"]}
Moebius syndrome is a rare neurological condition that primarily affects the muscles that control facial expression and eye movement. Signs and symptoms of the condition may include weakness or paralysis of the facial muscles; feeding, swallowing, and choking problems; excessive drooling; crossed eyes; lack of facial expression; eye sensitivity; high or cleft palate; hearing problems; dental abnormalities; bone abnormalities in the hands and feet; and/or speech difficulties. Affected children often experience delayed development of motor skills (such as crawling and walking), although most eventually acquire these skills. Moebius syndrome is caused by the absence or underdevelopment of the 6th and 7th cranial nerves, which control eye movement and facial expression. Other cranial nerves may also be affected. There is no cure for Moebius syndrome, but proper care and treatment give many individuals a normal life expectancy. [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	Moebius syndrome	c0853240	2,815	gard	https://rarediseases.info.nih.gov/diseases/8549/moebius-syndrome	2021-01-18T17:59:01	{"mesh": ["C531747"], "omim": ["157900"], "orphanet": ["570"], "synonyms": ["Mobius syndrome", "Congenital facial diplegia", "Congenital facial diplegia syndrome", "Congenital oculofacial paralysis", "Moebius sequence", "MBS", "Absence or underdevelopment of the 6th and 7th cranial nerves"]}
Digestive disease caused by an inflammation of a herniating pouch (diverticulum) Diverticulitis Other namesColonic diverticulitis Section of the large bowel (sigmoid colon) showing multiple pouches (diverticula). The diverticula appear on either side of the longitudinal muscle bundle (taenium) which runs horizontally across the specimen in an arc. SpecialtyGeneral surgery SymptomsAbdominal pain, fever, nausea, diarrhea, constipation, blood in the stool[1] ComplicationsAbscess, fistula, bowel perforation[1] Usual onsetSudden, age > 50[1] CausesUncertain[1] Risk factorsObesity, lack of exercise, smoking, family history, nonsteroidal anti-inflammatory drugs[1][2] Diagnostic methodBlood tests, CT scan, colonoscopy, lower gastrointestinal series[1] Differential diagnosisIrritable bowel syndrome[2] PreventionMesalazine, rifaximin[2] TreatmentAntibiotics, liquid diet, hospital admission[1] Frequency3.3% (developed world)[1][3] Diverticulitis, specifically colonic diverticulitis, is a gastrointestinal disease characterized by inflammation of abnormal pouches—diverticula—which can develop in the wall of the large intestine.[1] Symptoms typically include lower abdominal pain of sudden onset, but the onset may also occur over a few days.[1] There may also be nausea; and diarrhea or constipation.[1] Fever or blood in the stool suggests a complication.[1] Repeated attacks may occur.[2] The causes of diverticulitis are uncertain.[1] Risk factors may include obesity, lack of exercise, smoking, a family history of the disease, and use of nonsteroidal anti-inflammatory drugs (NSAIDs).[1][2] The role of a low fiber diet as a risk factor is unclear.[2] Having pouches in the large intestine that are not inflamed is known as diverticulosis.[1] Inflammation occurs in between 10% and 25% at some point in time, and is due to a bacterial infection.[2][4] Diagnosis is typically by CT scan, though blood tests, colonoscopy, or a lower gastrointestinal series may also be supportive.[1] The differential diagnoses include irritable bowel syndrome.[2] Preventive measures include altering risk factors such as obesity, inactivity, and smoking.[2] Mesalazine and rifaximin appear useful for preventing attacks in those with diverticulosis.[2] Avoiding nuts and seeds as a preventive measure is no longer recommended since there is no evidence these play a role in initiating inflammation in diverticula.[1][5] For mild diverticulitis, antibiotics by mouth and a liquid diet are recommended.[1] For severe cases, intravenous antibiotics, hospital admission, and complete bowel rest may be recommended.[1] Probiotics are of unclear value.[2] Complications such as abscess formation, fistula formation, and perforation of the colon may require surgery.[1] The disease is common in the Western world and uncommon in Africa and Asia.[1] In the Western world about 35% of people have diverticulosis while it affects less than 1% of those in rural Africa,[4] and 4 to 15% of those may go on to develop diverticulitis.[3] In North America and Europe the abdominal pain is usually on the left lower side (sigmoid colon), while in Asia it is usually on the right (ascending colon).[2][6] The disease becomes more frequent with age, being particularly common in those over the age of 50.[1] It has also become more common in all parts of the world.[2] In 2003 in Europe, it resulted in approximately 13,000 deaths.[2] It is the most frequent anatomic disease of the colon.[2] Costs associated with diverticular disease were around US $2.4 billion a year in the United States in 2013.[2] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 2.1 Diet * 3 Pathology * 4 Diagnosis * 4.1 Classification by severity * 4.2 Differential diagnoses * 5 Treatment * 5.1 Diet * 5.2 Antibiotics * 5.3 Surgery * 5.3.1 Technique * 5.3.2 Approach * 5.3.3 Maneuvers * 5.3.4 Bowel resection with colostomy * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Diverticulitis typically presents with lower quadrant abdominal pain of a sudden onset.[1] In North America and Europe the abdominal pain is usually on the left lower side (sigmoid colon), while in Asia it is usually on the right (ascending colon).[2][6] There may also be fever, nausea, diarrhea or constipation, and blood in the stool.[1] ### Complications[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2017) (Learn how and when to remove this template message) In complicated diverticulitis, an inflamed diverticulum can rupture, allowing bacteria to subsequently infect externally from the colon. If the infection spreads to the lining of the abdominal cavity (the peritoneum), peritonitis results. Sometimes, inflamed diverticula can cause narrowing of the bowel, leading to an obstruction. In some cases, the affected part of the colon adheres to the bladder or other organs in the pelvic cavity, causing a fistula, or creating an abnormal connection between an organ and adjacent structure or other organ (in the case of diverticulitis, the colon and an adjacent organ). Related pathologies may include: * Bowel obstruction * Peritonitis * Abscess * Fistula * Bleeding * Strictures ## Causes[edit] The causes of diverticulitis are poorly understood, with approximately 40 percent due to genes and 60 percent due to environmental factors.[7] Conditions that increase the risk of developing diverticulitis include arterial hypertension and immunosuppression.[8] Obesity is another risk factor.[7] Low levels of vitamin D are associated with an increased risk of diverticulitis.[9] ### Diet[edit] It is unclear what role dietary fiber plays in diverticulitis.[7] It is often stated that a diet low in fiber is a risk factor; however, the evidence to support this is unclear.[7] There is no evidence to suggest that the avoidance of nuts and seeds prevents the progression of diverticulosis to an acute case of diverticulitis.[5][10] It appears in fact that a higher intake of nuts and corn could help to avoid diverticulitis in adult males.[10] ## Pathology[edit] Right-sided diverticula are micro-hernias of the colonic mucosa and submucosa through the colonic muscular layer where blood vessels penetrate it.[2] Left-sided diverticula are pseudodiverticula, since the herniation is not through all the layers of the colon.[2] Diverticulitis is postulated to develop because of changes inside the colon, including high pressures because of abnormally vigorous contractions.[11] ## Diagnosis[edit] Diverticulitis in the left lower quadrant as seen on axial view by a CT scan (the abnormality is within the circled area). Diverticulitis on a CT scan in a coronal view. Diverticulitis showing acute purulent inflammation extending into the subserosal adipose tissue. People with the above symptoms are commonly studied with computed tomography, or a CT scan.[12] The CT scan is very accurate (98%) in diagnosing diverticulitis. In order to extract the most information possible about the person's condition, thin section (5 mm) transverse images are obtained through the entire abdomen and pelvis after oral and intravascular contrast have been administered. Images reveal localized colon wall thickening, with inflammation extending into the fat surrounding the colon.[13] The diagnosis of acute diverticulitis is made confidently when the involved segment contains diverticula.[14] CT may also identify people with more complicated diverticulitis, such as those with an associated abscess. It may even allow for radiologically guided drainage of an associated abscess, sparing a person from immediate surgical intervention. Barium enema and colonoscopy are contraindicated in the acute phase of diverticulitis because of the risk of perforation.[15][16] ### Classification by severity[edit] Four classifications by severity have been published recently in the literature. The most recent and widely accepted is as follows:[17] * Stage 0 – asymptomatic diverticulosis * Stage 1a – uncomplicated diverticulitis * Stage 1b – diverticulitis with phlegmonous peridiverticulitis * Stage 2a – diverticulitis with concealed perforation, and abscess with a diameter of one centimeter or less * Stage 2b – diverticulitis with abscess greater than one centimeter * Stage 3a – diverticulitis with symptoms but without complications * Stage 3b – relapsing diverticulitis without complications * Stage 3c – relapsing diverticulitis with complications The severity of diverticulitis can be radiographically graded by the Hinchey Classification.[18] ### Differential diagnoses[edit] The differential diagnoses include colon cancer, inflammatory bowel disease, ischemic colitis, and irritable bowel syndrome, as well as a number of urological and gynecological processes. In those with uncomplicated diverticulitis, cancer is present in less than 1% of people.[19] ## Treatment[edit] Most cases of simple, uncomplicated diverticulitis respond to conservative therapy with bowel rest. ### Diet[edit] People may be placed on a low-fiber diet.[20] It was previously thought that a low-fiber diet gives the colon adequate time to heal. Evidence tends to run counter to this, with a 2011 review finding no evidence for the superiority of low fiber diets in treating diverticular disease, and that a high-fiber diet may prevent diverticular disease.[21] A systematic review published in 2012 found no high-quality studies, but found that some studies and guidelines favour a high-fiber diet for the treatment of symptomatic disease.[22] While it has been suggested that probiotics may be useful for treatment, the evidence currently neither supports nor refutes this claim.[23] ### Antibiotics[edit] The use of antibiotics in mild cases of uncomplicated diverticulitis is supported with only "sparse and of low-quality" evidence, with no evidence supporting their routine use.[17][24] In spite of this, antibiotics are recommended by several current guidelines.[which?] With CT scan evidence of abscess, fistula, or intestinal rupture with peritonitis, antibiotics are recommended and routinely used.[citation needed] Along with antibiotics, IV fluids and bowel rest are part of the treatment for acute diverticulitis. [25] ### Surgery[edit] Indications for surgery are abscess or fistula formation; and intestinal rupture with peritonitis.[11] These, however, rarely occur.[11] Surgery for abscess or fistula is indicated either urgently or electively. The timing of the elective surgery is determined by evaluating factors such as the stage of the disease, the age of the person, their general medical condition, the severity and frequency of the attacks, and whether symptoms persist after the first acute episode. In most cases, elective surgery is deemed to be indicated when the risks of the surgery are less than the risks of the complications of the diverticulitis. Elective surgery is not indicated until at least six weeks after recovery from the acute event.[26] Emergency surgery is indicated for intestinal rupture with peritonitis.[27] #### Technique[edit] The first surgical approach consists of resection and primary anastomosis. This first stage of surgery is performed on people if they have a well-vascularized, nonedematous and tension-free bowel. The proximal margin should be an area of pliable colon without hypertrophy or inflammation. The distal margin should extend to the upper third of the rectum where the taenia coalesces. Not all of the diverticula-bearing colon must be removed, since diverticula proximal to the descending or sigmoid colon are unlikely to result in further symptoms.[28] #### Approach[edit] Diverticulitis surgery consists of a bowel resection with or without colostomy. Either may be done by the traditional laparotomy or by laparoscopic surgery.[29] The traditional bowel resection is made using an open surgical approach, called colectomy. During a colectomy the person is placed under general anesthesia. A surgeon performing a colectomy will make a lower midline incision in the abdomen or a lateral lower transverse incision. The diseased section of the large intestine is removed, and then the two healthy ends are sewn or stapled back together. A colostomy may be performed when the bowel has to be relieved of its normal digestive work as it heals. A colostomy implies creating a temporary opening of the colon on the skin surface, and the end of the colon is passed through the abdominal wall with a removable bag attached to it. The waste is collected in the bag.[30] However, most surgeons prefer performing the bowel resection laparoscopically, mainly because postoperative pain is reduced with faster recovery. The laparoscopic surgery is a minimally invasive procedure in which three to four smaller incisions are made in the abdomen or navel. After incisions into the abdomen are done, placement of trocars occur which allow a camera and other equipment entry into the peritoneal cavity. The greater omentum is reflected and the affected section of bowel is mobilized. [31] Alternately, laparoscopic sigmoid resection (LSR) compared to open sigmoid resection (OSR) showed that LSR is not superior over OSR for acute symptomatic diverticulitis. Furthermore, laparoscopic lavage was as safe as resection for perforated diverticulitis with peritonitis.[32] #### Maneuvers[edit] All colon surgery involves only three maneuvers that may vary in complexity depending on the region of the bowel and the nature of the disease. The maneuvers are the retraction of the colon, the division of the attachments to the colon and the dissection of the mesentery.[33] After the resection of the colon, the surgeon normally divides the attachments to the liver and the small intestine. After the mesenteric vessels are dissected, the colon is divided with special surgical staplers that close off the bowel while cutting between the staple lines. After resection of the affected bowel segment, an anvil and spike are used to anastomose the remaining segments of bowel. Anastomosis is confirmed by filling the cavity with normal saline and checking for any air bubbles. [34] #### Bowel resection with colostomy[edit] When excessive inflammation of the colon renders primary bowel resection too risky, bowel resection with colostomy remains an option. Also known as the Hartmann's operation, this is a more complicated surgery typically reserved for life-threatening cases. The bowel resection with colostomy implies a temporary colostomy which is followed by a second operation to reverse the colostomy. The surgeon makes an opening in the abdominal wall (a colostomy) which helps clear the infection and inflammation. The colon is brought through the opening and all waste is collected in an external bag.[35] The colostomy is usually temporary, but it may be permanent, depending on the severity of the case.[36] In most cases several months later, after the inflammation has healed, the person undergoes another major surgery, during which the surgeon rejoins the colon and rectum and reverses the colostomy. ## Epidemiology[edit] Diverticulitis most often affects the elderly. In Western countries, diverticular disease most commonly involves the sigmoid colon (95 percent of people with diverticulitis).[citation needed] The number of people affected with diverticular disease increased from an estimated 10 percent in the 1920s to between 35 and 50 percent by the late 1960s. 65 percent of people over 85 can be expected to have some form of diverticular disease of the colon.[citation needed] Less than 5 percent of those aged 40 years and younger are affected by diverticular disease.[citation needed] Left-sided diverticular disease (involving the sigmoid colon) is most common in the West, while right-sided diverticular disease (involving the ascending colon) is more common in Asia and Africa.[6] Among people with diverticulosis, 4 to 15% may go on to develop diverticulitis.[3] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x "Diverticular Disease". www.niddk.nih.gov. September 2013. Archived from the original on 13 June 2016. Retrieved 12 June 2016. 2. ^ a b c d e f g h i j k l m n o p q r s Tursi, A (March 2016). "Diverticulosis today: unfashionable and still under-researched". Therapeutic Advances in Gastroenterology. 9 (2): 213–28. doi:10.1177/1756283x15621228. PMC 4749857. PMID 26929783. 3. ^ a b c Pemberton, John H (16 June 2016). "Colonic diverticulosis and diverticular disease: Epidemiology, risk factors, and pathogenesis". UpToDate. Archived from the original on 2017-03-14. Retrieved 13 March 2017. 4. ^ a b Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Churchill Livingstone. 2014. p. 986. ISBN 9781455748013. Archived from the original on 2016-08-08. 5. ^ a b Young-Fadok, TM (October 2018). "Diverticulitis". New England Journal of Medicine. 379 (17): 1635–42. doi:10.1056/NEJMcp1800468. PMID 30354951. 6. ^ a b c Feldman, Mark (2010). Sleisenger & Fordtran's Gastrointestinal and liver disease pathophysiology, diagnosis, management (9th ed.). [S.l.]: MD Consult. p. 2084. ISBN 9781437727678. Archived from the original on 2016-08-08. 7. ^ a b c d Templeton, AW; Strate, LL (August 2013). "Updates in diverticular disease". Current Gastroenterology Reports. 15 (8): 339. doi:10.1007/s11894-013-0339-z. PMC 3832741. PMID 24010157. 8. ^ Böhm, Stephan K. (29 April 2015). "Risk Factors for Diverticulosis, Diverticulitis, Diverticular Perforation, and Bleeding: A Plea for More Subtle History Taking". Viszeralmedizin. 31 (2): 84–94. doi:10.1159/000381867. PMC 4789955. PMID 26989377. 9. ^ Ferguson LR, Laing B, Marlow G, Bishop K (January 2016). "The role of vitamin D in reducing gastrointestinal disease risk and assessment of individual dietary intake needs: Focus on genetic and genomic technologies". Mol Nutr Food Res. 60 (1): 119–33. doi:10.1002/mnfr.201500243. PMID 26251177. 10. ^ a b Weisberger, L; Jamieson, B (July 2009). "Clinical inquiries: How can you help prevent a recurrence of diverticulitis?". Journal of Family Practice. 58 (7): 381–2. PMID 19607778. 11. ^ a b c Morris, AM; Regenbogen, SE; Hardiman, KM; Hendren, S (Jan 15, 2014). "Sigmoid diverticulitis: a systematic review". JAMA. 311 (3): 287–97. doi:10.1001/jama.2013.282025. PMID 24430321. 12. ^ Lee, Kyoung Ho; Lee, Hye Seung; Park, Seong Ho; Bajpai, Vasundhara; Choi, Yoo Shin; Kang, Sung-Bum; Kim, Kil Joong; Kim, Young Hoon (2007). "Appendiceal Diverticulitis". Journal of Computer Assisted Tomography. 31 (5): 763–9. doi:10.1097/RCT.0b013e3180340991. PMID 17895789. S2CID 1027938. 13. ^ "CT scan of diverticulitis". ClariPACS. 2017. Retrieved 19 June 2017. 14. ^ Horton, KM; Corl, FM; Fishman, EK (2000). "CT evaluation of the colon: inflammatory disease". Radiographics. 20 (2): 399–418. doi:10.1148/radiographics.20.2.g00mc15399. PMID 10715339. 15. ^ Sai, V. F.; Velayos, F; Neuhaus, J; Westphalen, A. C. (2012). "Colonoscopy after CT Diagnosis of Diverticulitis to Exclude Colon Cancer: A Systematic Literature Review". Radiology. 263 (2): 383–390. doi:10.1148/radiol.12111869. PMC 3329267. PMID 22517956. 16. ^ Tursi, A (2015). "The role of colonoscopy in managing diverticular disease of the colon" (PDF). Journal of Gastrointestinal and Liver Diseases. 24 (1): 85–93. doi:10.15403/jgld.2014.1121.tur. PMID 25822438. Archived (PDF) from the original on 2017-08-10. 17. ^ a b Kruse, E; Leifeld, L (April 2015). "Prevention and Conservative Therapy of Diverticular Disease". Viszeralmedizin. 31 (2): 103–6. doi:10.1159/000377651. PMC 4789966. PMID 26989379. 18. ^ Klarenbeek, B. R.; De Korte, N; Van Der Peet, D. L.; Cuesta, M. A. (2011). "Review of current classifications for diverticular disease and a translation into clinical practice". International Journal of Colorectal Disease. 27 (2): 207–214. doi:10.1007/s00384-011-1314-5. PMC 3267934. PMID 21928041. 19. ^ Rottier, SJ; van Dijk, ST; van Geloven, AAW; Schreurs, WH; Draaisma, WA; van Enst, WA; Puylaert, JBCM; de Boer, MGJ; Klarenbeek, BR; Otte, JA; Felt, RJF; Boermeester, MA (July 2019). "Meta-analysis of the role of colonoscopy after an episode of left-sided acute diverticulitis". The British Journal of Surgery. 106 (8): 988–997. doi:10.1002/bjs.11191. PMC 6618242. PMID 31260589. 20. ^ Spirt, Mitchell (2010). "Complicated Intra-abdominal Infections: A Focus on Appendicitis and Diverticulitis". Postgraduate Medicine. 122 (1): 39–51. doi:10.3810/pgm.2010.01.2098. PMID 20107288. S2CID 46716128. 21. ^ Tarleton, S; DiBaise, JK (April 2011). "Low-residue diet in diverticular disease: putting an end to a myth". Nutrition in Clinical Practice. 26 (2): 137–42. doi:10.1177/0884533611399774. PMID 21447765. 22. ^ Ünlü, C; Daniels, L; Vrouenraets, BC; Boermeester, MA (April 2012). "A systematic review of high-fiber dietary therapy in diverticular disease". International Journal of Colorectal Disease. 27 (4): 419–27. doi:10.1007/s00384-011-1308-3. PMC 3308000. PMID 21922199. 23. ^ Lahner, E; Bellisario, C; Hassan, C; Zullo, A; Esposito, G; Annibale, B (March 2016). "Probiotics in the Treatment of Diverticular Disease. A Systematic Review" (PDF). Journal of Gastrointestinal and Liver Diseases. 25 (1): 79–86. doi:10.15403/jgld.2014.1121.251.srw. hdl:11573/866049. PMID 27014757. S2CID 19519787. 24. ^ de Korte N, Unlü C, Boermeester MA, Cuesta MA, Vrouenreats BC, Stockmann HB (June 2011). "Use of antibiotics in uncomplicated diverticulitis". Br. J. Surg. 98 (6): 761–7. doi:10.1002/bjs.7376. PMID 21523694. S2CID 32230475. 25. ^ [1], Berger D, Erstad D J. Laparoscopic Low Anterior Resection for Diverticulitis. J Med Ins. 2015;2015(87) doi:https://jomi.com/article/87 26. ^ Merck, Sharpe & Dohme. "Diverticulitis treatments" Archived 2010-03-06 at the Wayback Machine 2010-02-23. 27. ^ What's the diverticulitis surgery? Archived 2010-02-27 at the Wayback Machine Digestive Disorders portal. Retrieved on 2010-02-23 28. ^ Diverticulitis: Treatment & Medication Archived 2010-03-16 at the Wayback Machine eMedicine. 2010-02-23 29. ^ Diverticulitis Surgery Archived 2010-02-12 at the Wayback Machine 2010-02-23 30. ^ Gupta, Aditya K.; Chaudhry, Maria; Elewski, Boni (2003). "Tinea corporis, tinea cruris, tinea nigra, and piedra". Dermatologic Clinics. 21 (3): 395–400, v. doi:10.1016/S0733-8635(03)00031-7. PMID 12956194. 31. ^ [2], Berger D, Erstad D J. Laparoscopic Low Anterior Resection for Diverticulitis. J Med Ins. 2015;2015(87) doi:https://jomi.com/article/87 32. ^ Ahmed, Ali Mahmoud; Mohammed, Abdelrahman Tarek; Mattar, Omar Mohamed; Mohamed, Esraa Mowafy; Faraag, Esraa Abdelmon'em; AlSafadi, Ammar Mohammed; Hirayama, Kenji; Huy, Nguyen Tien (1 July 2018). "Surgical treatment of diverticulitis and its complications: A systematic review and meta-analysis of randomized control trials". The Surgeon. 20 (6): 372–383. doi:10.1016/j.surge.2018.03.011. PMID 30033140. 33. ^ Bowel resection procedure Archived 2010-01-29 at the Wayback Machine Encyclopedia of surgery. Retrieved on 2010-02-23 34. ^ [3], Berger D, Erstad D J. Laparoscopic Low Anterior Resection for Diverticulitis. J Med Ins. 2015;2015(87) doi:https://jomi.com/article/87 35. ^ Diverticulitis treatments and drugs Archived 2010-02-12 at the Wayback Machine Mayo Clinic. 2010-02-23 36. ^ Vermeulen J, Coene PP, Van Hout NM, van der Harst E, Gosselink MP, Mannaerts GH, Weidema WF, Lange JF (July 2009). "Restoration of bowel continuity after surgery for acute perforated diverticulitis: should Hartmann's procedure be considered a one-stage procedure?". Colorectal Disease. 11 (6): 619–24. doi:10.1111/j.1463-1318.2008.01667.x. PMID 18727727. S2CID 20693528. ## External links[edit] Classification D * ICD-10: K57 * ICD-9-CM: 562 * MeSH: D004238 * DiseasesDB: 3876 External resources * MedlinePlus: 000257 * eMedicine: med/578 * Diverticulosis and diverticulitis at NIDDK * Diverticulitis at Mayo Clinic * Staging of Acute Diverticulitis online calc * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum [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	Diverticulitis	c0012813	2,816	wikipedia	https://en.wikipedia.org/wiki/Diverticulitis	2021-01-18T19:03:43	{"mesh": ["D004238"], "umls": ["C0012813"], "icd-9": ["562"], "icd-10": ["K57"], "wikidata": ["Q1066061"]}
A number sign (#) is used with this entry because of evidence that elliptocytosis-2 (EL2) is caused by heterozygous mutation in the alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23. For a general description and a discussion of genetic heterogeneity of elliptocytosis (HE), see EL1 (611804). Clinical Features In some families with HE, spectrin is abnormally heat-sensitive (Lux and Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of hereditary elliptocytosis and found an abnormality of tryptic digestion in 1. This patient was previously reported by Gomperts et al. (1973) as an instance of hemolytic anemia due to HE. Liu et al. (1982) examined erythrocytes from 18 patients with hereditary elliptocytosis. In 8 patients (referred to as type 1), spectrin was defective in dimer-dimer association as demonstrated in 2 ways. First, spectrin dimer was increased and tetramer decreased; spectrin dimer represented 15 to 33% of total spectrin compared with a normal range of 3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer association was decreased in both solution and in situ in red cell membranes. In the other 10 patients (referred to as type 2), dimer-dimer association was normal. Membrane skeletons, produced from both types of elliptocytosis by Triton X-100 extraction of the red cell ghosts, were unstable when mechanically shaken. Spectrin tetramers but not dimers can crosslink actin. Evans et al. (1983) studied a family in which 3 sibs had severe transfusion-dependent, presumably homozygous elliptocytosis and both parents had asymptomatic elliptocytosis. Red cell membranes of all 3 sibs showed an excess of spectrin dimers over tetramers in spectrin extracts. Both parents showed an intermediate increase in spectrin dimers. In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et al. (1985) found an abnormal thermal sensitivity and an important defect of spectrin dimer self-association. An excess of spectrin dimer and deficient dimer-to-tetramer conversion were demonstrated. Peptide patterns of crude spectrin showed a marked decrease in the 80-kD peptide (previously identified as the dimer-dimer interaction domain of the alpha chain) and a concomitant appearance of a novel 65-kD peptide. Anti-alpha-spectrin antibodies showed that the latter peptide was derived from the alpha chain. The patients were 3 unrelated adults, 2 children with hemolytic anemia, and the father of each child. Lawler et al. (1984, 1985) described a molecular defect in the alpha subunit of spectrin in a subset of patients with hereditary elliptocytosis; the self-association of alpha-beta heterodimers to form tetramers was defective. Abnormality of alpha spectrin was reported by Ravindranath and Johnson (1985) in a case of congenital hemolytic anemia. Lambert and Zail (1987) also found a variant of the alpha subunit. Two brothers with the poikilocytic variant of hereditary elliptocytosis were found to have a defect in spectrin dimer association and a decreased spectrin/band 3 ratio. The major abnormal tryptic peptides derived from the alpha-I domain had lower molecular weights and more basic isoelectric points than hitherto described. The propositus of Lambert and Zail (1987) was a black South African miner. In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic anemia with red cell fragmentation, poikilocytosis, and elliptocytosis. Both parents and a brother of the propositus had compensated mild hereditary elliptocytosis. Studies indicated that the proband was homozygous for an alpha-I/65 spectrin variant whereas both parents were heterozygous. In a family with hereditary elliptocytosis, Lane et al. (1987) found that alpha-spectrin subunits migrated anomalously in SDS-PAGE. The quantity of the alpha-spectrin mutant, expressed as a percentage of the total alpha spectrin, varied from 9.9 to 45.2% among 6 affected persons. Other findings suggested that this new alpha-spectrin mutant is responsible for decreased spectrin dimer-dimer association and for red cell instability. The propositus, a 23-month-old boy, exhibited anemia, hyperbilirubinemia requiring phototherapy, and striking red cell poikilocytosis at birth. His only sib, a 4-year-old who had hyperbilirubinemia at birth, exhibited elliptocytosis without poikilocytosis at the time of study. The mother, 2 of her sibs, and the maternal grandfather had elliptocytosis. Mapping Morton (1956) defined the existence of Rh-linked (611804) and Rh-unlinked forms of elliptocytosis and emphasized the usefulness of linkage studies in demonstration of genetic heterogeneity. Keats (1979) suggested that a second elliptocytosis locus unlinked to Rh is on chromosome 1. She found a lod score of 1.97 for theta of 0.0 for linkage with Duffy. Molecular Genetics By in situ hybridization, the SPTA1 gene was mapped to 1q22-1q25 (Huebner et al., 1985) in the region proposed by Keats (1979) for a non-Rh-linked form of elliptocytosis. In patients with elliptocytosis, Marchesi et al. (1987) identified heterozygous mutations in the SPTA1 gene (182860.0001-182860.0002). This is one of the first examples of positive results from the 'candidate gene' approach to elucidating etiopathogenesis. History From analysis of the data by a maximum likelihood method, Rao et al. (1979) concluded that there is 'nonsignificant evidence of linkage' of an Rh-unlinked form of elliptocytosis to chromosome 1 (lod score, 2.08). INHERITANCE \- Autosomal dominant HEMATOLOGY \- Elliptocytosis MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the spectrin, alpha, erythrocytic-1 gene (SPTA1, 182860.0001 ) ▲ 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	ELLIPTOCYTOSIS 2	c0013902	2,817	omim	https://www.omim.org/entry/130600	2019-09-22T16:41:45	{"doid": ["2373"], "mesh": ["D004612"], "omim": ["130600"], "orphanet": ["288"], "synonyms": ["Alternative titles", "ELLIPTOCYTOSIS, RHESUS-UNLINKED TYPE"]}
A number sign (#) is used with this entry because X-linked ichthyosis (XLI), which results from steroid sulfatase deficiency, is caused by mutation or deletion of the STS gene (300747) on chromosome Xp22. Most patients (90%) have deletions of the STS gene. Some patients have larger deletions at Xp22.3 that encompass neighboring genes. These patients may present with mental retardation, Kallmann syndrome (KAL1; 308700), which comprises hypogonadotrophic hypogonadism and anosmia, features of X-linked chondrodysplasia punctata (CDPX1; 302950), short stature (SHOX; 312865), and/or ocular albinism (OA1; 300500) in addition to X-linked ichthyosis. These complicated forms of XLI thus represent contiguous gene deletion syndromes (Ballabio et al., 1989; Cuevas-Covarrubias and Gonzalez-Huerta, 2008). Description X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Cutaneous manifestations are present soon after birth and usually do not improve with age. The histopathology of XLI typically shows compact hyperkeratosis and slight acanthosis with a normal granular layer (summary by Takeichi and Akiyama, 2016). X-linked ichthyosis is fundamentally the same disorder as placental steroid sulfatase deficiency, which is often first noted in the pregnant mother of affected males by decreased estrogen or delayed progression of parturition (Alperin and Shapiro, 1997). This is thus an example of affinity ('lumping') of phenotypes thought previously to be separate, the opposite of genetic heterogeneity. Schnyder (1970) gave a useful classification of the inherited ichthyoses. Hernandez-Martin et al. (1999) provided a comprehensive review of X-linked ichthyosis. They pointed out that among all genetic disorders X-linked ichthyosis shows one of the highest ratios of chromosomal deletions; complete deletion has been found in up to 90% of patients. Takeichi and Akiyama (2016) reviewed inherited nonsyndromic forms of ichthyosis. Clinical Features Csorsz (1928) reported a Hungarian family with X-linked ichthyosis. There were 2 affected females who were presumed to be homozygous. Schlammadinger et al. (1987) restudied the Hungarian family reported by Csorsz (1928). A female member of the family who as a child was described as having ichthyosis was found on restudy to have no sign of the disorder and was determined to be heterozygous by enzyme studies. A second affected female, presumably homozygous, was apparently not investigated by enzyme levels. No pregnancy-related complications, hypogenitalism, cryptorchidism, or deep corneal opacities were found in the family. Orel (1929) found reports of 10 families with the X-linked form of ichthyosis in the literature. Wells and Jennings (1967) reported that onset of the X-linked form of ichthyosis was at birth, and that the scalp, ears, neck, and some of the flexures were involved. There was more striking scaling on the abdomen than on the back, as well as scaling down the front of the leg onto the dorsum of the foot. Sever et al. (1968) described deep corneal opacities in all of 17 males with X-linked ichthyosis. There were no overt symptoms. Jay et al. (1968) found ocular opacities as a late feature of X-linked ichthyosis including the carrier state; in their series, all patients over 25 years, but only 5 of 8 patients under 25, showed this abnormality. Went et al. (1969) reported a large Dutch kindred with X-linked ichthyosis spanning 7 generations. None of those affected had obvious symptoms at birth, but developed scaling of the skin soon after or during the first year of life. The lesions were symmetrical and affected anterior and posterior surfaces of the upper and lower extremities, scalp, and trunk. Almost all patients had no involvement of the flexure areas, palms, or soles. The scales were black or gray in about half of patients, and white in the other half. All affected individuals reported improvement of the lesions during the summer. Jobsis et al. (1976) was the first to publish the association between X-linked ichthyosis and steroid sulfatase deficiency. Koppe et al. (1977, 1978) reported 3 pregnant women with decreased urinary estrogen secretion who gave birth to 3 boys that later developed ichthyosis at ages 2 to 8 months. The placenta in each case had decreased steroid sulfatase activity, which was also demonstrated in the skin of all 3 affected boys. Two of the families had a history consistent with X-linked recessive inheritance. Koppe et al. (1977, 1978) concluded that the sulfatase deficiency was a factor in the skin disorder. France and Liggins (1969) reported a family from New Zealand in which several women had low estrogen production during pregnancy resulting from placental steroid sulfatase deficiency. The disorder was manifest clinically by delay in the onset of labor and relative refractoriness to oxytoxic agents. France and Downey (1974) showed that the deficiency was limited to the placenta; the mother did not show deficiency in her tissues. All affected pregnancies were males. Shapiro et al. (1978) reported that several male members of the family with placental steroid sulfatase deficiency reported by France and Liggins (1969) developed ichthyosis in the first months of life. Most had normal-appearing skin at birth. The trunk and extensor surfaces of the extremities were the most involved. One patient had deep corneal opacities found by slit-lamp examination. Noting that normal skin has sulfatase activity, Shapiro et al. (1978) postulated that the skin disorder in this family resulted from steroid-sulfatase deficiency. In a follow-up study, Shapiro et al. (1978) found decreased steroid sulfatase activity in fibroblasts isolated from 25 individuals with X-linked ichthyosis from 4 countries. Controls and patients with other forms of ichthyosis did not have decreased enzyme levels. Shapiro et al. (1978) stated that they knew of no patient with X-linked ichthyosis that did not have this specific enzyme defect, and concluded that the disorder results in the skin disease postnatally in affected males. The authors concluded that X-linked ichthyosis results from a common mutation affecting steroid sulfatase activity. Macsai and Doshi (1994) described a 73-year-old man with X-linked ichthyosis and steroid sulfatase deficiency in whom superficial corneal opacities were found. The opacities were granular in nature, involving the subepithelial and anterior stromal layers. ### Heterozygous Females Sever et al. (1968) described deep corneal opacities in 7 of 8 heterozygous females. There were no overt symptoms. Went et al. (1969) reported mild abnormalities of the skin in about one-fourth of obligate heterozygous females of a large Dutch kindred with X-linked ichthyosis. Solomon and Schoen (1971) reported a patient with XO Turner syndrome and ichthyosis, the latter of which was shown to be X-linked by pedigree and clinical features. Other Features Traupe and Happle (1983) found 7 instances of cryptorchidism in a series of 25 patients with STS deficiency and suggested a causal relationship. Lykkesfeldt et al. (1983) reported 2 men with STS deficiency and testicular cancer. One patient had the left testis removed for seminoma at age 21 and the right testis removed for embryonal cancer at age 26. The second had the left testis removed for seminoma at age 31. Both had normally descended testes, but a nephew of the second patient had STS deficiency, ichthyosis, and bilateral inguinal cryptorchidism. The authors noted that the testis has potent STS activity and may have a role in gonadal steroid regulation. Lykkesfeldt et al. (1985) studied 76 cases in 50 kindreds; 42 kindreds had multiple cases. Maldescent of the testes was noted in 9 patients. Testicular cancer occurred in 2 males with normally descended testes. Corneal opacities, not impairing visual acuity, were seen in 14 of 28 males by slit-lamp examination. Garcia Perez and Crespo (1981) and Stoll et al. (1983) reported 2 families containing 5 boys with the combination of hypertrophic pyloric stenosis and X-linked recessive ichthyosis. Biochemical Features Hameister et al. (1979) reported 3 independent pregnancies with partial deficiency of placental steroid sulfatase associated with low estriol excretion and failure of labor induction. In all 3 cases, a male was delivered and diagnosis was confirmed enzymatically in placenta homogenates. In 1 case, fibroblasts from the son showed steroid sulfatase that was 34% of normal, whereas the mother had normal values. None of the cases had developed ichthyosis by the age of 6 months. Epstein et al. (1981) found that low density lipoproteins from patients with X-linked ichthyosis have abnormally rapid anodic electrophoretic mobility. The finding was explained by increased plasma cholesterol sulfate concentration, which is found predominantly in the low density lipoprotein fraction of plasma. Diagnosis Shapiro et al. (1978) identified placental steroid sulfatase deficiency by measuring estriol in the urine of pregnant women as an indication of a gestational abnormality. Lake et al. (1991) developed a histochemical method for demonstration of hexanol dehydrogenase activity by use of a simple staining method on cryostat sections of skin biopsies as an adjunct to the biochemical assay in the differentiation of the various forms of ichthyosis. Shapiro (1997) noted that the detection of STS deficiency, which may have a frequency of 1 in 3,000 males, has increased greatly by routine use of screening of estrogen metabolism in pregnancy. Clinical Management In a prospective half-side trial, Lykkesfeldt and Hoyer (1983) found that a topical cream containing 10% cholesterol effected considerable improvement, suggesting that reduction in the cholesterol content of the stratum corneum may be responsible for abnormal cornification in this disorder. ### Gene Therapy Freiberg et al. (1997) used X-linked ichthyosis to develop a model of corrective gene therapy to human skin in vivo. They produced a retroviral expression vector and used it for STS gene transfer to primary keratinocytes in patients with this disorder. Transduction was associated with restoration of full-length STS protein expression as well as steroid sulfatase activity in proportion to the number of proviral integrations in XLI cells. Transduced and uncorrected XLI keratinocytes, along with normal controls, were then grafted onto immunodeficient mice to regenerate full thickness human epidermis. Unmodified XLI keratinocytes regenerated a hyperkeratotic epidermis lacking STS expression with defective skin barrier function, effectively recapitulating the human disease in vivo. Transduced XLI keratinocytes from the same patients, however, regenerated epidermis histologically indistinguishable from that formed by keratinocytes from patients with normal skin. Transduced XLI epidermis demonstrated STS expression in vivo by immunostaining, as well as a normalization of histologic appearance at 5 weeks post-grafting. In addition, transduced XLI epidermis demonstrated a return of barrier function parameters to normal. Pathogenesis Elias et al. (1984) concluded that accumulation of undegraded cholesterol sulfate is responsible for scale-formation in steroid sulfatase deficiency. Shapiro (1997) noted that ichthyosis with STS deficiency is related to increased water loss in the skin with resulting desiccation. Ichthyosis occurs with other disorders of lipid metabolism in the skin, including Refsum disease (266500) and Sjogren-Larsson syndrome (270200). Zettersten et al. (1998) investigated the significance of the fact that patients with X-linked ichthyosis display a 10-fold increase in cholesterol sulfate in squamous keratinizing epithelia, as well as a 50% reduction in cholesterol. They found that patients with this disorder displayed both an abnormal barrier under basal conditions and a delay in barrier recovery after acute perturbation. Moreover, both the functional and the structural abnormalities were corrected by topical cholesterol. However, topical cholesterol sulfate produced both a barrier abnormality in intact skin and extracellular abnormalities in isolated stratum corneum, effects largely reversed by coapplications of cholesterol. These results suggested that cholesterol sulfate accumulation rather than cholesterol deficiency is responsible for the barrier abnormality. Mapping Kerr et al. (1964) presented evidence suggesting that the X-linked ichthyosis locus may be within 'mappable' distance of the Xg locus (314700). Closer situation of the Xg and ichthyosis loci was indicated by studies of Adam et al. (1969) who estimated the recombination fraction as 0.105 and of Went et al. (1969) who found a value of 0.115. Close linkage with the deutan colorblindness (303800), protan colorblindness (303900) and G6PD (305900) loci was excluded (Filippi and Meera Khan, 1968; Adam et al., 1969). Tiepolo et al. (1980) found steroid sulfatase to be severely deficient in a boy with ichthyosis and nullisomy for the distal portion of Xp; the mother, who was monosomic for this segment, had steroid sulfatase levels in the heterozygous range. Muller et al. (1981) used deletion mapping to assign the steroid sulfatase locus to Xp22.3; they found almost undetectable levels of the enzyme in 2 brothers with the same defect as in the patient of Tiepolo et al. (1980) and levels like those of heterozygotes in the mother. Wieacker et al. (1983) studied the linkage between RC8 (DXS9) on Xp22.3-p21 and X-linked ichthyosis. At least 2 crossovers were found among 9 meioses in an informative family, suggesting that the 2 loci were about 25 cM apart. Since STS is 15 cM proximal to the Xg locus and since the RC8 and Duchenne muscular dystrophy loci (DMD; 310200) are closely linked, DMD may be 50 cM or more from Xg. Ballabio et al. (1986) reported an Italian family in which 5 males had X-linked ichthyosis associated with STS deficiency as well as hypogonadotropic hypogonadism and anosmia, consistent with Kallmann syndrome. Linkage analysis suggested linkage between STS deficiency and X-linked Kallmann syndrome. Shapiro (1987) suggested that the STS locus must be very close to the pseudoautosomal segment of Xp. The STS locus was usually deleted in XX males in whom TDF (480000) was presumably translocated to the end of Xp. Shapiro (1987) suggested that anomalous exchange between the X and Y chromosomes may account for a high frequency of X-linked ichthyosis, about 1 in 5,000 in many populations. Gillard et al. (1987) used a RFLP closely linked to STS to demonstrate deletion of the STS locus at Xpter-p22.3 in 8 of 9 families with X-linked ichthyosis. In an extension of these studies, Gillard et al. (1987) found deletion of a DNA marker tightly linked to STS in affected males in 12 of 15 families with X-linked ichthyosis. The findings suggested that a high proportion of the mutations at the STS locus leading to enzyme deficiency are deletions, presumably generated by unequal crossover events in female meiosis or by illegitimate X-Y interchange in male meiosis. Wirth et al. (1988) used polymorphic DNA markers from distal Xp to examine 9 unrelated families with X-linked ichthyosis. Close linkage was found between the disease locus and the markers DXS16, DXS89, and DXS143. In 8 families, Southern hybridization with the human steroid sulfatase cDNA and GMGX9 probes showed a deletion of corresponding loci in affected males. Three patients in the ninth family had no evident deletion when studied with 2 probes. Cytogenetics ### Complicated X-Linked Ichthyosis Due to Contiguous Gene Deletion Syndrome Metaxotou et al. (1983) described a 14-year-old boy with X-linked ichthyosis associated with nullisomy for the Xpter-p22 segment and a translocation t(X;Y)(p22;q11). The boy also had mental retardation and hypogonadism. The mother was monosomic for the deleted segment of Xp and had the same X;Y translocation. Traupe et al. (1984) described a typical instance of X-linked ichthyosis in which the patient also had severe hypogenitalism and hypogonadism. Delivery was protracted. The patient had an affected maternal first cousin, and the maternal grandfather of the 2 affected males was affected. Curry et al. (1984) reported 2 families in which affected males had X-linked chondrodysplasia punctata, nasal hypoplasia, ichthyosis, and mental retardation associated with an inherited deletion of Xp22.32. Biochemical studies suggested a deletion of the STS gene, Xg, and the M1C2X locus. The women carrying the Xp deletion had normal gonadal function and fertility, but were shorter than the noncarriers in their families (P less than 0.00001). These findings indicated that small cytogenetic abnormalities may account for the cosegregation of several disorders with mendelian patterns of inheritance. Ross et al. (1985) described a family in which 4 brothers had X-linked ichthyosis, mental retardation, and short stature associated with nullisomy for Xpter-p22.3 resulting from an Xp to Yq translocation with the entire Y short arm and deletion of Xpter-p22.3: 46,Y,t(x;y)(Xqter-p22.3::Yq11-qter). Cultured cells were completely deficient in steroid sulfatase. Sunohara et al. (1986) described a family in which 3 men had ichthyosis, anosmia, hypogonadotropic hypogonadism, nystagmus with decreased visual acuity, strabismus, hypopigmentation of the iris, and mirror movements of the hands and feet. Two of them had limitation of ocular movement and unilateral renal agenesis or hypoplasia. Inheritance appeared to be X-linked recessive. Steroid sulfatase and arylsulfatase C activities in leukocytes and fibroblasts were markedly diminished. Karyotype was normal. Ballabio et al. (1986) reported an Italian family in which 5 males had X-linked ichthyosis associated with STS deficiency and hypogonadotropic hypogonadism. The pregnancies were complicated by prolonged labor, necessitating C-section in 3 patients. All had the classic skin lesions, as well as variable features including micropenis, small testes, and cryptorchidism. All also had some form of anosmia, consistent with Kallmann syndrome. These families and the family reported by Andria et al. (1984) were postulated to have a microdeletion of Xp chromosome involving both the STS gene and the gene responsible for X-linked Kallmann syndrome. Linkage studies in 1 of their families showed no crossing over with a probe that maps to Xpter-p22, suggesting that the disease locus was indeed in that area. Ballabio et al. (1986) noted that the patients described by Sunohara et al. (1986) showed peculiar manifestations that have been reported in patients with Kallmann syndrome, including renal agenesis and neurologic disorders such as mirror movements. Shapiro and Yen (1987) responded to the suggestion that the condition in these patients may represent a microcytogenetic disorder (Schmickel, 1986). They stated that homologous but nonfunctional sequences of STS were found on the long arm of the Y chromosome in the patients of Sunohara et al. (1986). Indeed, they found a complete deletion of the STS gene with continued presence of MIC2 (313470) sequences, which are located more distally on the X chromosome, in both the X and Y chromosomes. In studies of 9 unrelated patients with simple X-linked ichthyosis, they found 7 with complete deletion of the STS gene and 1 with a partial 5-prime deletion. Only 1 subject had an intact STS gene. Ballabio et al. (1988) described a family in which an X/Y translocation t(X;Y)(p22;q11) was transmitted through females in at least 3 generations. Two male first-cousins who had the translocation had X-linked ichthyosis as well as mental retardation. Both deliveries were protracted. One of the boys had features of X-linked chondrodysplasia punctata. STS activity in fibroblasts was profoundly decreased. Ballabio et al. (1988) demonstrated that the translocated region of the Y chromosome included STS; the X/Y translocation may have thus been derived from a recombination event between homologous regions located on the Xp chromosome and the long arm of the Y chromosome. They pointed out that all cases of X/Y translocation involving the STS gene showed mental retardation, whereas patients without mental retardation with X/Y translocation did not have involvement of the STS gene. Their review of families with X/Y translocations, including the family reported by them, showed 24 affected persons in 30 informative meioses. This suggested preferential fertilization of the oocyte carrying the aberrant X chromosome. Pike et al. (1989) described X-linked ichthyosis and hypogonadism in males in 3 separate sibships connected through females. Endocrinologic testing suggested hypogonadotropic hypogonadism with deficiency of luteinizing hormone. Gohlke et al. (2000) reported monozygotic male twins with an interstitial deletion of Xp22.3, including the STS gene. The twins had ichthyosis, mental retardation, and epilepsy. Analysis of flanking STS markers narrowed the locus for this phenotype to a region bounded by markers DXS6837 and GS1. In 4 XLI patients with mental retardation, Van Esch et al. (2005) detected a 1.5-Mb interstitial microdeletion that deleted the VCX3A (300533) and VCX (300229) genes. Array CGH with DNA of an XLI patient with mental retardation and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all 4 VCX genes and duplication of both VCY (400012) homologs. These data supported the role of VCX3A in the occurrence of mental retardation in XLI patients. Van Esch et al. (2005) proposed a VCX/VCY teamwork-dependent mechanism for the incidence of mental impairment in XLI patients. Lesca et al. (2005) reported a family in which 7 males had X-linked recessive ichthyosis caused by deletion of Xp22.3, including the VCX3A and VCX genes. Only 1 of the 7 patients had mental retardation. Detailed molecular analysis detected no differences in the deleted chromosomal region between the 1 patient with mental retardation and another with ichthyosis but no mental retardation. Lesca et al. (2005) concluded that VCX3A is not specifically involved in mental retardation. Among 80 Mexican patients with isolated XLI and normal intelligence, Cuevas-Covarrubias and Gonzalez-Huerta (2008) detected 2 different deletion patterns at the STS locus. One included 62 patients with deletion of STS, VCX3A, and VCX, whereas the other included 18 patients with breakpoints on either side of STS and not including the VCX3A gene. The authors concluded that deletion of VCX3A is not sufficient to result in mental retardation in XLI patients. Heterogeneity Munke et al. (1983) documented heterogeneity in the syndrome of ichthyosis and hypogonadism, with STS deficiency in some cases and not in others. See 308200 for a discussion of Rud syndrome, in which ichthyosis and hypogonadism are combined with neurologic abnormality. Traupe et al. (1984) described a presumably isolated case of ichthyosis associated with hypogenitalism and hypogonadism in a Pakistani male. However, STS activity and serum lipoprotein electrophoresis were normal. The disorder was clinically indistinguishable from that of another patient with STS deficiency and hypogonadism. Robledo et al. (1995) described a Sardinian kindred in which congenital ichthyosis was associated with normal levels of steroid sulfatase and a normal pattern on Southern blot analysis suggesting the presence of an intact STS gene. Although the pedigree pattern was entirely consistent with X-linked recessive inheritance, the ichthyosis was found to segregate independently of genetic polymorphisms detected by probes mapping to Xp22.3, where the STS locus maps. The search for linkage to markers elsewhere on the X chromosome had not been successful. Robledo et al. (1995) concluded that there may be a form of X-linked ichthyosis due to some mechanism other than STS deficiency (see 300001). Molecular Genetics In 12 steroid sulfatase-deficient patients, including 8 cases of classic ichthyosis, Ballabio et al. (1987) found deletion of the STS gene using a specific probe. One of the patients had been reported by Ballabio et al. (1986) as having X-linked ichthyosis and Kallmann syndrome. In all cases, karyotype analysis was normal. Bonifas et al. (1987) found gross deletions of genomic DNA containing the STS gene in 14 of 15 probands with X-linked ichthyosis. Yen et al. (1987) identified complete STS gene deletions in 8 of 10 patients with inherited STS deficiency. Shapiro et al. (1987) reviewed 4 studies with a total of 45 unrelated cases of X-linked ichthyosis; 41 were found to have a deletion. In 16 men from 10 unrelated Italian families affected with STS deficiency, Ballabio et al. (1987) found no hybridization signal when Southern blotting was done with an STS cDNA probe. The sample included 2 families with a total of 7 cases combining X-linked ichthyosis and Kallmann syndrome. Basler et al. (1990, 1992) identified 3 different point mutations in the STS gene (300747.0001-300747.0003) in 3 unrelated patients with X-linked ichthyosis. Alperin and Shapiro (1997) identified 3 additional point mutations in the STS gene (300747.0004-300747.0006) in patients with X-linked ichthyosis and reviewed the point mutations reported by Basler et al. (1990, 1992). All 6 mutations were located in a 105-amino acid region of the C-terminal half of the polypeptide. Five of the 6 mutations were missense, whereas 1 resulted in a frameshift and premature protein termination. In vitro functional expression studies showed that all 6 mutants lacked STS enzymatic activity. Cuevas-Covarrubias et al. (1995) investigated 5 apparently sporadic cases of X-linked recessive ichthyosis and their mothers. None of the XLI patients showed STS activity; 4 mothers had an activity level compatible with the carrier state and only 1 showed a normal level, indicating that her son had a de novo mutation. Valdes-Flores et al. (2000) reported a patient with X-linked ichthyosis and a partial STS deletion. The deletion included exons 2 through 10 and included 3-prime flanking sequences extending through DXS1131 and DXS1133. Valdes-Flores et al. (2000) noted that this was the fourth patient with partial deletion of the STS gene to be described, and that Nomura et al. (1995) had reported the third patient. Valdes-Flores et al. (2001) evaluated 12 apparently sporadic cases of males with X-linked ichthyosis and their mothers. All affected males had undetectable levels of STS activity and complete deletion of the STS gene. Evaluation of their mothers showed 9 of 12 with STS activity compatible with that expected for X-linked carriers. These results were corroborated by FISH. One mother who was shown to be a carrier by FISH had STS activity that was classified as normal. The authors recommended including FISH analysis in mothers of apparently sporadic cases, even when they have normal STS activity, to diagnose the carrier state correctly. Since FISH will not detect partial deletions or point mutations, the authors emphasized the importance of confirming the nature of the mutation in the affected individual before testing the mother. Population Genetics X-linked recessive ichthyosis occurs in about 1 in 6,000 males studied in various populations (Shapiro et al., 1978). Animal Model Eicher (1974) speculated that the 'scurfy' (sf) mutation in the mouse may be homologous to X-linked ichthyosis of man. Buckle et al. (1985) alluded to ichthyosis with male hypogonadism (see 308200) as an entity separate from ichthyosis with steroid sulfatase deficiency and homologous to 'scurfy' in the mouse. From comparative mapping of the X chromosomes of mouse and man, they predicted that this possibly separate human condition may be determined by a mutation on Xp near OTC (300461). History For a biographical account of Karoly Csorsz, see Czeizel (1979). INHERITANCE \- X-linked recessive HEAD & NECK Eyes \- Corneal opacities on slit-lamp examination \- Vision is usually not affected GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKIN, NAILS, & HAIR Skin \- Ichthyosis \- Skin lesions are usually symmetrical \- Lesions occur mainly on extremities, scalp, neck, and trunk \- Sparing of flexure areas, palms, and soles \- Lesions are often brownish colored NEOPLASIA \- Increased risk of testicular cancer PRENATAL MANIFESTATIONS Delivery \- Protracted delivery LABORATORY ABNORMALITIES \- Pregnant mothers of affected children have decreased plasma and urinary estrogen \- Decreased or absent steroid sulfatase activity MISCELLANEOUS \- Onset soon after birth or within the first year of life \- Symptoms improve during the summer \- Most (80 to 90%) of cases result from deletions of the STS gene \- Incidence of 1 in 6,000 males \- A subset of patients have additional features, including mental retardation and hypogonadism associated with larger deletions at Xp22.3 MOLECULAR BASIS \- Caused by mutation in the steroid sulfatase gene (STS, 300747.0001 ) ▲ 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	ICHTHYOSIS, X-LINKED	c2720163	2,818	omim	https://www.omim.org/entry/308100	2019-09-22T16:18:09	{"doid": ["1700"], "mesh": ["D016114"], "omim": ["308100"], "icd-10": ["Q80.1"], "orphanet": ["461", "281090"], "synonyms": ["Alternative titles", "STEROID SULFATASE DEFICIENCY", "STS DEFICIENCY", "PLACENTAL STEROID SULFATASE DEFICIENCY", "STEROID SULFATASE DEFICIENCY DISEASE"]}
A number sign (#) is used with this entry because of evidence that male-limited precocious puberty can be caused by constitutively activating mutations in the luteinizing hormone receptor gene (LHCGR; 152790). See 139320.0019 for testotoxicosis in paradoxical combination with pseudohypoparathyroidism type Ia, due to a specific mutation in the GNAS1 gene. Description Familial male precocious puberty is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4 years (Shenker et al., 1993). Nomenclature Rosenthal et al. (1983) suggested the term 'familial testotoxicosis' for this disorder, in analogy to thyrotoxicosis. Clinical Features Schedewie et al. (1981) and Rosenthal et al. (1983) described a syndrome of sexual precocity in boys, characterized by a sex-limited autosomal dominant inheritance pattern and extremely rapid virilization. In this syndrome, in contrast to 'true' precocious puberty, increased gonadal testosterone secretion appears to be gonadotropin-independent because both basal and gonadotropin-releasing hormone-induced secretion of luteinizing hormone (LH; 152780) is low whether measured by radioimmunoassay or bioassay and there are no suppressive effects of potent gonadotropin-releasing hormone analogs. Schedewie et al. (1981) studied 2 brothers; one, aged 3 years, showed advanced spermatogenesis on testis biopsy. Of the 4 patients described by Rosenthal et al. (1983), 3 were adopted and 1 had a history of sexual precocity in the maternal grandfather. One was born of a pregnancy complicated by hyperthyroidism treated with prophylthiouracil. They mentioned preliminary studies of a family with 24 affected males over 6 generations. Reiter et al. (1984) had an opportunity to define the natural history of the disorder on the basis of affected males in 3 consecutive generations. The grandfather, aged 59, began precocious sexual development at about 1 year of age, was 165 cm tall, had 4 brothers and 4 sisters who were all normal, and had had 3 children of whom the oldest was affected (the father of the proband grandson). The proband's father, aged 28, had onset of sexual precocity at age 1 year, prompting adrenal exploration (with normal findings) at age 18 months. He was 154.4 cm tall, well muscled and well virilized, had normal-sized penis and very small, soft testes, and showed reduced sperm count but had fathered 3 children in less than 5 years. The proband presented at 12 months of age with a 2-month history of accelerated growth velocity, deepening voice, pubic hair, axillary odor, and striking enlargement of the penis. Bone age was 2 and 2/3 years. Testosterone levels in all 3 subjects were very high. (In this family, the grandfather's condition may have been the result of new mutation. Since his 2 normal children were girls and the 2 normal children of his affected son were girls, a Y-linked mutation cannot be excluded.) Gondos et al. (1985) reviewed the testicular changes found in biopsy specimens. In all cases, Leydig cells showed nuclear and cytoplasmic features characteristic of fully differentiated steroidogenic cells. Manasco et al. (1991) found that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production. They demonstrated the testis-stimulating factor by a bioassay using adult male cynomolgus monkeys. The factor was inactive in a rodent system. Lim and Low (1994) reported testotoxicosis in a Chinese father and son. Both had early sexual development. In both, testicular volume was only 6 ml despite fully developed secondary sexual characteristics. Both had adult testosterone concentrations but a suppressed gonadotropin response to gonadotropin-releasing hormone. Clinical Management Laue et al. (1989) reasoned that because the pubertal growth spread in boys appears to be mediated by both androgens and estrogens, blockade of both androgen action and estrogen synthesis would normalize the growth of boys with this disorder. In studies of 9 boys from 8 families they found that neither spironolactone, an antiandrogen, nor testolactone, an inhibitor of androgen-to-estrogen conversion, had any effect when given alone. However, a combination of the 2, given for at least 6 months, restored both the growth rate and the rate of bone maturation to normal prepubertal levels and controlled acne, spontaneous erections, and aggressive behavior. Molecular Genetics Shenker et al. (1993) noted that testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone. Since the LH receptor is a member of the family of G protein-coupled receptors, they hypothesized that male-limited precocious puberty might be due to a mutant receptor that is activated in the presence of little or no agonist. In testing their hypothesis, they identified a mutation in the LHCGR gene (D578G; 152790.0001) in affected individuals from 8 different families. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in this disorder is caused by a constitutively activated LH receptor. This is an example of constitutive activation of a stimulatory G protein comparable to that in the McCune-Albright syndrome (174800) and in hyperfunctioning thyroid adenoma (152790.0002). Martin et al. (1998) reported a 35-year-old man, previously diagnosed with familial male-limited precocious puberty (FMPP) and in whom heterozygosity for the dominant gain-of-function D578G mutation in the LHCGR gene was identified, who was subsequently found to have a testicular seminoma. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient, raising the possibility of a potentially harmful effect of prolonged increased concentrations of sex hormones, with onset early in life, upon the cellular components of the testes. Liu et al. (1999) described 3 unrelated boys with precocious puberty and Leydig cell adenomas containing a somatic activating mutation of the LHCGR gene (D578H; 152790.0019). Canto et al. (2002) reported 2 additional unrelated boys with gonadotropin-independent hypersecretion of testosterone due to Leydig cell adenomas; the same heterozygous D578H mutation was found in DNA from the tumors from both patients, but not from the adjacent normal tissue or blood leukocytes. Leschek et al. (2001) reported a boy diagnosed with gonadotropin-independent precocious puberty at 4 years of age, in whom they identified a constitutively activating missense mutation in the LHCGR gene (D564G; 152790.0029) in peripheral blood leukocytes. At 10.8 years of age, ultrasound examination to quantitate testicular volume revealed a right testicular mass, and at the time of surgery for excisional biopsy, 2 masses were found and removed. Histologic examination of the masses showed nodular Leydig cell hyperplasia surrounded by normal-appearing seminiferous tubules with spermatogenesis; DNA from tumor tissue revealed the same D564G mutation that was present in peripheral blood leukocytes. Leschek et al. (2001) noted that in another FMPP family known to carry the D564G mutation (Wu et al., 2000), none of the members had Leydig cell nodules to date. Leschek et al. (2001) stated that the only previously reported testicular mass in FMPP was a seminoma (Martin et al., 1998), and suggested that LH receptor activation may be a predisposing factor in the development of testicular tumors. History This disorder was reported by Stone (1852) in a 4-year-old boy named Theodore. It was noted that 'the father presented extreme precocity, having experienced his first sexual indulgence at the age of 8 years. He informed us that between the ages of 10 and 13 years he was a 'better man' than he had ever been since. Delicacy forbids my detailing his prowess at that early age.' Endocrine \- Male-limited sexual precocity \- Extremely rapid virilization GU \- Small testes Lab \- Increased gonadotropin-independent gonadal testosterone secretion \- Low basal and gonadotropin-releasing hormone-induced secretion of luteinizing hormone (LH) \- Advanced spermatogenesis on testis biopsy \- Novel plasma stimulator of testicular testosterone Inheritance \- Sex-limited 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	PRECOCIOUS PUBERTY, MALE-LIMITED	c0342549	2,819	omim	https://www.omim.org/entry/176410	2019-09-22T16:35:44	{"mesh": ["C536961"], "omim": ["176410"], "orphanet": ["3000"], "synonyms": ["Alternative titles", "SEXUAL PRECOCITY, FAMILIAL, GONADOTROPIN-INDEPENDENT", "TESTOTOXICOSIS, FAMILIAL"]}
Prolactinoma is a tumor of the pituitary gland that causes increased levels of the hormone prolactin. This hormone normally stimulates breast development and milk production in women. Prolactinoma can affect men or women. In women, the symptoms may include unusual milk production (galactorrhea) when not pregnant or nursing and having no menstrual cycles (amenorrhea). In men, the most common symptoms are decreased sex drive and infertility. Most prolactinomas occur by chance (sporadically) in people with no family history. In a small number of cases, prolactinoma may be caused by a genetic condition such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma. Treatment for prolactinoma usually involves taking oral medications known as dopamine agonists. These medications can reduce prolactin levels and shrink the tumor. In more severe cases, radiation therapy or surgery may be needed. [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	Prolactinoma	c0033375	2,820	gard	https://rarediseases.info.nih.gov/diseases/4508/prolactinoma	2021-01-18T17:58:08	{"mesh": ["D015175"], "omim": ["600634"], "umls": ["C0033375"], "orphanet": ["2965"], "synonyms": ["Lactotroph adenoma", "Pituitary lactotrophic adenoma", "PRL-secreting pituitary adenoma", "PRLoma", "Prolactin-secreting pituitary adenoma", "Forbes-Albright syndrome (formerly)", "Prolactin-Producing Pituitary Gland Adenoma"]}
Futcher line is a linear discontinuity in intensity of pigmentation on the upper arm and deltoid area of blacks. It is located on the lateral aspect of the arm and marks the junction between the dorsal and ventral parts of the extremity. Futcher (1938, 1940) found it bilaterally in 17.5% of blacks regardless of age, sex and intensity of overall pigmentation. Another 2% had a line on one side only. Apparently no family studies have been done. This and other forms of pigmentary demarcation lines were discussed by Selmanowitz and Krivo (1975). Inheritance \- Autosomal dominant Skin \- Pigment demarcation of upper arm and deltoid area of blacks ▲ 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	FUTCHER LINE	c1850937	2,821	omim	https://www.omim.org/entry/137000	2019-09-22T16:40:53	{"omim": ["137000"]}
A number sign (#) is used with this entry because of evidence that this form of type A1 brachydactyly (BDA1D) is caused by heterozygous mutation in the BMPR1B gene (603248) on chromosome 4q22. Mutation in the BMPR1B gene has also been reported to cause type A2 brachydactyly (BDA2; 112600). For a general phenotypic description and discussion of genetic heterogeneity of type A1 brachydactyly, see 112500. Clinical Features Racacho et al. (2015) reported 2 unrelated patients with 'BDA1-like' brachydactyly. The first proband, a 16-month-old Caucasian girl born to healthy unrelated parents, was of normal stature but had very short index fingers and ulnar curvature of the fifth digits, with reduced digital creases at the distal interphalangeal joints. She also had shortened big toes and very long second toes, with moderate syndactyly between toes 2 and 3. Hand x-rays showed absence of the middle phalanges of the index fingers, with very small middle phalanges of the fifth digits, as well as slightly reduced size of the terminal phalanges of the thumbs. The metacarpophalangeal pattern profile (MCPP) revealed short proximal and distal phalanges of both thumbs, severe shortening of the middle phalanx of digit 2, shortening of the middle and distal phalanges of digit 3, and slight shortening of the middle phalanx of digit 5. The bones of digit 4 appeared to be normal. The second proband, a 9-year-old boy of African descent who was born to healthy unrelated parents, presented at 11 months of age with brachydactyly and clinodactyly of both fifth digits and the right thumb. Hand x-rays showed a small cube-shaped middle phalanx of digit 2, with a socket-like groove for the epiphysis of the proximal phalanx, as well as a small trapezoid-shaped middle phalanx of digit 5 in both hands. MCPP from both hands revealed a shortened proximal phalanx of digit 1, moderate shortening of the distal phalanges of digits 1 and 2, and severe shortening of the middle phalanges of digits 2 and 5. The feet of this patient were not described. Noting the disproportionate lengthening of digits 3 and 4 in the hands, Racacho et al. (2015) designated his condition as mixed BDA1-arachnodactyly. Molecular Genetics In 2 unrelated children with BDA1-like brachydactyly, who were negative for mutation in the IHH (600726) and GDF5 (601146) genes, Racacho et al. (2015) sequenced the candidate gene BMPR1B and identified a heterozygous missense mutation (K325N; 603248.0008) in 1 patient and a heterozygous splice site mutation (603248.0009) in the other patient as well as in his unaffected mother. Neither mutation was found in 100 controls or in public variant databases. Racacho et al. (2015) noted the remarkable similarity in the MCPPs of both probands, as well as phenotypic similarities between these patients and those described with BDA2-causing mutations in BMPR1B. However, unlike the reported BDA2 patients, both probands displayed shortening of the proximal and distal phalanges of the thumb, which the authors noted was also distinct from BDC (113100). Racacho et al. (2015) stated that their findings illustrated the continuum of phenotypes between BDA1 and BDA2. INHERITANCE \- Autosomal dominant SKELETAL Hands \- Short proximal phalanges of thumbs \- Short distal phalanges of thumbs \- Short to absent middle phalanges of index fingers \- Short distal phalanges of index fingers \- Short middle phalanges of third digits (1 patient) \- Short distal phalanges of third digits (1 patient) \- Short middle phalanges of fifth digits \- Fifth-finger clinodactyly (1 patient) \- Fifth-finger ulnar curvature (1 patient) \- Disproportionate lengthening of third and fourth digits (1 patient) Feet \- Short great toes (1 patient) \- Very long second toes (1 patient) SKIN, NAILS, & HAIR Skin \- Reduced distal interphalangeal creases MISCELLANEOUS \- Based on report of 2 unrelated patients MOLECULAR BASIS \- Caused by mutation in the type 1B bone morphogenetic protein receptor gene (BMPR1B, 603248.0008 ) ▲ 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	BRACHYDACTYLY, TYPE A1, D	c1862151	2,822	omim	https://www.omim.org/entry/616849	2019-09-22T15:47:44	{"doid": ["0110978"], "mesh": ["C537088"], "omim": ["616849"], "orphanet": ["93388"]}
## Summary ### Clinical characteristics. Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control. ### Diagnosis/testing. The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing. ### Management. Treatment of manifestations: Multidisciplinary care involves supportive treatment of: neurologic manifestations – physical and occupational therapy to help maintain mobility and function, and pharmacologic treatment to reduce symptoms; dysarthria – speech and language therapy and alternative communication methods; dysphagia – feeding therapy to improve nutrition and reduce the risk of aspiration; and reduced vision – use of low vision aids and consultation with agencies for the visually impaired. Surveillance: Routine follow up with multidisciplinary care providers. Agents/circumstances to avoid: Avoid: alcohol intake (especially if excessive) as it can further impair cerebellar function; foods identified by a registered dietitian as possible causes of dizziness or disorientation. Therapies under investigation: Several ongoing clinical trials for medications used as treatment for ataxia. ### Genetic counseling. SCA7 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG repeat expansion in ATXN7. Once an ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA7 are possible. ## Diagnosis ### Suggestive Findings Spinocerebellar ataxia type 7 (SCA7) should be suspected in individuals with the following clinical findings (by age) and family history. #### Clinical Findings Adult onset * Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia. * Cone-rod retinal dystrophy with the following: * Loss of central vision * A tritan-axis (blue/yellow) defect on detailed color vision testing * Macular changes on fundoscopic examination * Paracentral scotoma on visual field testing * On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function Infantile or early-childhood onset * Failure to thrive and loss of motor milestones (may be the earliest findings) * Rapid deterioration with early death * Ataxia and visual loss not obvious #### Family History Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Note that in this nucleotide repeat disorder, anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with a CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004]. ### Establishing the Diagnosis The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing (see Table 1). Note: Pathogenic (CAG)n repeat expansions in ATXN7 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing. Repeat sizes * Normal. 7-27 CAG repeats * Mutable normal. 28-33 CAG repeats [Lebre et al 2003]. Repeats in this range are meiotically unstable, but not associated with an abnormal phenotype. A mutable normal repeat may expand to the pathogenic range in one generation [Mittal et al 2005]. * Pathogenic. The distinction between reduced-penetrance CAG repeat size and full-penetrance CAG repeat size is likely to remain unclear until more families are reported; nonetheless, regardless of the "descriptor" used for these CAG repeats, they should be considered unstable and pathogenic: * Pathogenic reduced penetrance. 34-36 CAG repeats. When manifestations occur, they are more likely to be later onset and milder than average. (See case reports in Genotype-Phenotype Correlations.) * Pathogenic full penetrance. 37-460 CAG repeats [Nardacchione et al 1999, van de Warrenburg et al 2001, Michalik et al 2004]. Molecular genetic testing relies on targeted analysis to characterize the number of ATXN7 CAG repeats (see Table 8). ### Table 1. Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 7 View in own window Gene 1Method 2, 3Proportion of Probands with a Pathogenic Variant Detectable by Method ATXN7Targeted analysis for CAG trinucleotide expansions~100% 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Table 8 for specific methods to characterize the number of CAG repeats in ATXN7. 3\. Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. ## Clinical Characteristics ### Clinical Description Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy with progressive central visual loss to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death [Giunti et al 1999]. One important aspect of SCA7 clinical manifestations is their extreme variability with respect to age of onset and rate of progression. Affected individuals may present in infancy, childhood, adolescence, young adulthood, middle age, or old age. When onset is at or before adolescence, initial manifestations are typically impaired vision, ultimately progressing to blindness from retinal degeneration. Individuals with manifestations in their teens may be blind within a decade or less. In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) usually precedes the onset of visual manifestations. The age of onset inversely correlates with rate of progression and extent of symptomatology, as onset in or after the fifth decade of life gives a predominant cerebellar ataxia without progression to significant visual impairment, whereas onset prior to middle age often features progression to vision loss. Progression to severe disability resulting in death varies based on age of onset, ranging from months in infants to fewer than ten years in older children to two to three decades in adolescents and adults. While the rate of progression varies, the eventual result for almost all affected individuals is severe dysarthria, dysphagia, and a bedridden state with loss of motor control. To date, more than 1,000 individuals with SCA7 have been identified worldwide. Frequency of select features in adolescent- or adult-onset disease are summarized in Table 2. #### Adolescent- or Adult-Onset SCA7 ### Table 2. Select Features of Adolescent- or Adult-Onset SCA7 View in own window Feature% of Persons w/FeatureComment Cerebellar ataxia100%Unsteady gait; finger-to-nose dysmetria Dysarthria100%Garbled or slurred speech Dysphagia40%Difficulty swallowing Oculomotor abnormalities80% * Slowed ocular saccades * Ophthalmoplegia Motor neuron degeneration100% * Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia. * Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss) Sensory loss40%↓ sensation to light touch, pinprick, &/or joint position Restless leg syndrome35%Discomfort in legs resulting in uncontrollable urge to move one’s legs, typically worse in evening or nighttime Cognitive decline20%Impaired executive function Behavior disorder/ Psychosis10% * Altered mentation * Impaired reality testing Cone-rod dystrophy70% * Loss of central vision & color vision * Abnormal fundoscopic exam Neurologic findings. In adult-onset disease (age >30 years), cerebellar ataxia (manifesting as difficulty with walking, manual dexterity, and speech) is the most common clinical feature and is often the first reported manifestation (see Genotype-Phenotype Correlations). Affected individuals often then develop more extensive neurologic deficits, dysarthria, dysphagia, hypoacusis (hearing loss), and eye movement abnormalities (slow ocular saccades, staring). Slowing of ocular saccades may progress to frank ophthalmoplegia. Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses. Cognitive decline and psychosis have been reported [Benton et al 1998]. Neuropsychiatric testing of some individuals has revealed selective deficits in social cognition [Sokolovsky et al 2010]. Retinal degeneration. The retinal degeneration is a progressive cone-rod dystrophy that may result in total blindness [To et al 1993, Aleman et al 2002, Ahn et al 2005, Hugosson et al 2009]. In adolescent- or young adult-onset disease (age <30 years), profound visual loss can be accompanied by minimal ophthalmoscopic findings and minimal ataxia [Thurtell et al 2009] (see Genotype-Phenotype Correlations). The onset of cone-rod dystrophy is often characterized by hemeralopia (inability to see clearly in bright light), photophobia (extreme sensitivity to light), decreased central visual acuity, and abnormalities in the tritan (blue-yellow) axis on detailed color vision testing [Miller et al 2009]. As cone function decreases over time, central visual acuity decreases to 20/200 (legally blind) and central scotomas develop; more prominent macular changes appear (see Figure 1), and all color discrimination is lost. Eventually all vision is lost. #### Figure 1. Funduscopic photo shows extreme macular degeneration of late-stage SCA7. Early signs of cone-rod dystrophy are subtle granular changes in the macula. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [Miller et al 2009]. In classic adult-onset disease (age >40 years), vision loss from retinal degeneration typically follows the onset of ataxia (sometimes many years to decades later) and gradually declines, seldom progressing to total blindness [Miller et al 2009]. #### Infantile- or Early Childhood-Onset SCA7 In infancy or early childhood disease, progression is always more rapid and aggressive than in adults. In infants, the clinical diagnosis may be elusive because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings. Other findings include progressive hypotonia, poor feeding, dysphagia, and congestive heart failure [Babovic-Vuksanovic et al 1998, Benton et al 1998]. Indeed, with rapid multisystem failure (including cerebellar and brain stem degeneration and other organ systems including lungs, heart, and kidneys), retinal degeneration and related vision loss may not be evident. Affected infants usually die within months of initial presentation and never survive into early childhood [Ansorge et al 2004], a distinctly different clinical course from adult-onset SCA7, in which other organ system involvement does not occur (see Genotype-Phenotype Correlations). Pathology. Neuronal loss, loss of myelinated fibers, and gliosis are observed in the cerebellum (especially Purkinje cells); the inferior olivary, dentate, and pontine nuclei; and to a lesser extent in the cerebral cortex, basal ganglia, thalamus, and midbrain [Rüb et al 2008, Seidel et al 2012]. ### Genotype-Phenotype Correlations A correlation between CAG repeat sizes and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease. * Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the ATXN7CAG repeat region that often underestimate the repeat expansion size may report a CAG repeat size of fewer than 150. * Childhood onset is usually associated with CAG repeat sizes greater than 100. * Juvenile onset is often associated with CAG repeat sizes 60-100. A correlation between CAG repeat size and initial clinical manifestation exists [Johansson et al 1998]: * CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation. * CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation. Despite observations correlating CAG repeat length with age of onset, disease severity, and course, CAG repeat size cannot provide sufficient predictive value for clinical prognosis within the classic adult-onset CAG repeat size range of 38 to 50 repeats [Andrew et al 1997]. Reports of pathogenic (age-related reduced-penetrance) repeats include the following: * A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [Nardacchione et al 1999]. * An individual with 35 CAG repeats was symptomatic [Koob et al 1998], in contrast to asymptomatic adults with 35 CAG repeats described by David et al [1998] and Stevanin et al [1998]. * An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [Nardacchione et al 1999]. ### Penetrance See Genotype-Phenotype Correlations for CAG repeat sizes associated with age-related reduced penetrance. ### Anticipation In families with a pathogenic (full-penetrance) CAG repeat expansion, the repeat size tends to expand with transmission to successive generations, with more marked expansions seen in affected offspring of affected males [Gouw et al 1998]. This explains, at the genetic level, the marked anticipation seen in families with SCA7, now regarded as the most unstable of all CAG repeat disorders. Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004]. Repeat contraction has not been reported. ### Nomenclature Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and ADCA type II. ### Prevalence The prevalence is fewer than 1:300,000. In several studies, SCA7 represented 2% of all SCAs [Filla et al 2000, Storey et al 2000]. SCA7 occurs predominantly in two racial population groups: northern Europeans and Africans. Indeed, SCA7 is the only repeat expansion disease, with the exception of Huntington disease-like 2 (HDL2), with a large number of affected individuals of African racial ancestry. For this reason, a substantial fraction of individuals with SCA7 in the United States are of African racial ancestry. Worldwide, SCA7 is seen in North America, Europe, Eurasia, Australia, South Africa, and South America. Due to a founder effect in Mexico dating back to the colonial era, a very large concentration of individuals with SCA7 have been ascertained in the state of Veracruz in Mexico, with well over 150 documented affected individuals. ## Differential Diagnosis While many of the neurologic and pathologic findings of the other spinocerebellar ataxias (SCAs) overlap with SCA7, retinal degeneration is the distinguishing feature of SCA7 (see Hereditary Ataxia Overview). ### Table 3. Disorders with Retinal Degeneration in the Differential Diagnosis of Spinocerebellar Ataxia Type 7 View in own window Gene(s)DisorderMOIEye FindingsNeurologic & Pathologic FindingsDistinguishing Features CRXCone-rod dystrophy 2 (OMIM 120970)ADImpaired color vision; central scotomaNo neurologic findingsNo neurologic findings MT-ND1 MT-ND4 MT-ND6 1Leber hereditary optic neuropathyMatImpaired color vision; central scotomaNo neurologic findingsUsually midlife presentation OPA3Costeff syndrome (3-methylglutaconic aciduria type 3)ARBilateral optic atrophyChorea, spastic paraparesis, mild ataxia * Optic atrophy in childhood (age <10 yrs) * Common in persons of Iraqi Jewish origin due to founder variant WFS1 CISD2Wolfram syndrome (See WFS1 Wolfram Syndrome Spectrum Disorder.)ARBilateral optic trophyAtaxia, diabetes mellitus/insipidus, hearing lossChildhood-onset diabetes mellitus & optic atrophy AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance 1\. Three common mtDNA pathogenic variants in the listed genes account for 90%-95% of Leber hereditary optic neuropathy (LHON). Pathogenic variants in other mitochondrial genes (MT-ND2, MT-ND4L, and MT-ND5) are also known to be associated with LHON. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7) of adolescent or adult onset, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis of SCA7: Adolescent or Adult Onset View in own window System/ConcernEvaluationComment NeurologicNeurologist assessment for cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS). 1 UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations)Since most exhibit some corticospinal tract involvement, comprehensive assessment of motor & sensory function recommended for all affected persons Refer to neuromuscular clinic (OT/PT / rehab specialist).Assess gross motor & fine motor skills, gait, ambulation, need for adaptive devices, PT, &OT. Ophthalmologic involvementComplete eye examIncl: * BCVA * Extraocular movement * Refractive error * Color vision testing * Full-field ERG * Spectral-domain OCT SpeechFor those w/dysarthria: speech/language evalConsider involving certified practitioner of speech/language pathology. FeedingFor those w/frequent choking or severe dysphagia, assess: * Nutritional status; * Aspiration risk. Consider involving gastroenterology/nutrition/feeding team. RespiratoryFor those w/respiratory symptoms or muscular involvement: obtain pulmonary function tests.Consider involving pulmonary specialist / respiratory therapist. Bladder functionHistory of spastic bladder symptoms: urgency, frequency, difficulty voiding * Referral to urologist * Consider urodynamic eval. Restless legs syndromeObtain comprehensive history w/emphasis on triggering & relieving factors.Consider referral to specialist w/experience in caring for individuals w/SCA7. Chronic painA comprehensive history & physical & neurologic exam must be performed.Consider referral to specialist (e.g., pain clinic or pain service). Cognitive/ PsychiatricAssess for cognitive dysfunction assoc w/cerebellar cognitive & affective syndrome (executive function, language processing, visuospatial / visuoconstructional skills, emotion regulation)Consider use of: * CCAS scale 2 to evaluate cognitive & emotional involvement; * Psychiatrist, psychologist, neuropsychologist if needed. Family support/ resourcesConsider individual’s disease severity & ability to receive regular care & support from his/her family.Assess: * Use of community or online resources; * Need for social work involvement for caregiver support; * Need for home nursing referral. Genetic counselingBy genetics professionals 3To inform affected persons & their families re nature, MOI, & implications of SCA7 to facilitate medical & personal decision making BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; CCAS = cerebellar cognitive affective syndrome; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron 1\. Bürk & Sival [2018] 2\. Hoche et al [2018] 3\. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ### Treatment of Manifestations Management of affected individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists. ### Table 5. Treatment of Manifestations of SCA 7: Adolescent or Adult Onset View in own window Manifestation/ ConcernTreatmentConsiderations/Other Cerebellar ataxiaPT/OT * PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function 1 * OT to optimize ADLs (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks) * Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). * In-patient rehab w/OT/PT may improve ataxia & functional abilities. 2, 3 * Weight control to avoid obesity * Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Pharmacologic treatment * Therapies intended to ↓ symptoms work variably well in different individuals. * Most commonly used drugs: amantadine, buspirone, riluzole TMSThis treatment modality is still being evaluated, w/most promising initial results obtained w/cerebellar repetitive TMS. UMN involvement (spasticity)Pharmacologic treatmentConsider pharmacologic treatment of generalized spasticity w/oral medications (usually in this order due to the profile of side effects & better tolerance): baclofen, tizanidine, gabapentin, clonazepam, dantrolene sodium, diazepam LMN involvement (weakness)Mainly supportiveBraces, orthotics, PT Ophthalmologic involvementUse of low vision aidsConsultation w/agencies for visually impaired DysarthriaSpeech/language therapyConsider alternative communication methods as needed (e.g., writing pads & digital devices). DysphagiaFeeding therapy programs to improve nutrition & dysphagia, & ↓ risk of aspirationVideo esophagram may help define best food consistency. WeightNutrition assessment * Consider nutritional & vitamin supplementation to meet dietary needs. * Avoid obesity (which can exacerbate difficulties with ambulation & mobility). Bladder dysfunctionPharmacologic treatment * If physical rehab or biofeedback do not remedy problem, consider anticholinergic drugs for overactive bladder. * Anticholinergic agents are also indicated for neurogenic bladder. * Botulinum toxin injections should be reserved for severe or unresponsive bladder dysfunction. Restless legs syndromePharmacologic treatmentLevodopa or dopamine agonist Chronic painRequires specialist eval & managementRefer to pain clinic or pain specialist. Cognitive/ PsychiatricPharmacologic treatmentStandard treatment for psychiatric manifestations (e.g., depression, anxiety, & psychosis) Psychotherapy / neuropsychological rehabConsider cognitive & behavioral therapy, incl goal management training. ADLs = activities of daily living; LMN = lower motor neuron; OT = occupational therapy/therapist; PT = physical therapy/therapist; TMS = transcranial magnetic stimulation; UMN = upper motor neuron 1\. Martineau et al [2014] 2\. Zesiewicz et al [2018] 3\. van de Warrenburg et al [2014] ### Surveillance ### Table 6. Recommended Surveillance for Individuals with SCA7 View in own window System/ConcernEvaluationFrequency Neurologic * Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction * Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS). 1 Annually; more often for an acute exacerbation Physiatry; OT/PT assessment of mobility; self-help skills as they relate to ataxia, spasticity, weakness DysarthriaAssess need for alternative communication method or speech therapy.Per symptom progression DysphagiaAssess aspiration risk & feeding methods. RetinopathyExam by ophthalmologist for evidence of cone-rod dystrophy: BCVA, color vision testing, visual field testing, ERGEvery 3-5 yrs or as needed based on concerns re visual acuity, visual field deficits, &/or color vision (as an indicator of cone function) Cognitive/ PsychiatricEvaluate mood, signs of psychosis, cognitive complaints to identify need for pharmacologic & psychotherapeutic interventions.Per symptom progression & development of psychiatric symptoms Family support/ resourcesProvide various options for affected persons & their families, ranging from joining patient support groups (e.g., National Ataxia Foundation, which has local chapters throughout the US) to social work consultation.Per symptom progression BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron 1\. Bürk & Sival [2018] ### Agents/Circumstances to Avoid Avoid drinking alcoholic beverages, as alcohol intake can further impair cerebellar function, especially if excessive. Avoid foods identified by a registered dietician as potentially causing dizziness or disorientation. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Ongoing clinical trials for SCA7 include a study of: * Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov: NCT03701399); * Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov: NCT03660917). Ionis Pharmaceuticals™ is developing an antisense oligonucleotide for dosage reduction of ataxin-7 in the retina and brain, as a preclinical trial of this strategy was found to be an effective treatment for retinal degeneration in an SCA7 mouse model [Niu et al 2018]. 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. [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	Spinocerebellar Ataxia Type 7	c0752125	2,823	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1256/	2021-01-18T20:54:55	{"mesh": ["D020754"], "synonyms": ["SCA7"]}
Mixed autoimmune hemolytic anemia is a type of autoimmune hemolytic anemia (AIHA; see this term) defined by the presence of both warm and cold autoantibodies, which have a deleterious effect on red blood cells at either body temperature or at lower temperatures. ## Epidemiology Mixed AIHA occurs in less than 10% of cases of AIHA, whose annual incidence is between 1/35,000-1/80,000 in North America and Western Europe. ## Clinical description Mixed AIHA can occur at any age but is rare in children. Patients with mixed AIHA usually present with abrupt onset severe hemolysis and anemia. ## Etiology Mixed AIHA can be idiopathic or secondary, mainly associated with systemic lupus erythematosus (SLE) and lymphoma. ## Diagnostic methods Diagnosis is based on clinical or laboratory evidence of hemolytic anemia and the detection of autoantibodies, usually both IgG and IgM, with the direct anti-globulin test (DAT) showing a pattern of IgG with complement C3, and the presence of cold agglutinins (IgM) in the serum at a significant titer. ## Differential diagnosis Erroneous diagnosis of mixed AIHA is sometimes made on the basis of inadequate serologic studies as a large proportion of patients with warm AIHA also have cold autoantibodies that are measured but are clinically insignificant. Unless a cold autoantibody with a high thermal amplitude (>30 degrees C) is observed in association with a warm autoantibody, a diagnosis of mixed AIHA is not warranted. ## Management and treatment The principles of management are comparable to that of warm AIHA (see this term), including corticosteroids and, if these are ineffective, splenectomy, but avoidance of cold must also be considered. Cautious transfusion is possible in cases with severe anemia. However, the best compatible or ``least incompatible'' packed red blood cell units must be identified by the blood centre to avoid post-transfusional hemolysis. ## Prognosis The disease responds to corticosteroids, and may be followed by remission, but usually runs a chronic course with intermittent exacerbations. [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	Mixed-type autoimmune hemolytic anemia	None	2,824	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90036	2021-01-23T17:17:16	{"icd-10": ["D59.1"], "synonyms": ["Mixed AIHA"]}
Mantle cell lymphoma Micrograph showing mantle cell lymphoma (bottom of image) in a biopsy of the terminal ileum. H&E stain. SpecialtyHematology and oncology Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases.[1][2] There are only about 15,000 patients presently[when?] in the United States with mantle cell lymphoma. MCL is a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal germinal center follicles. MCL cells generally over-express cyclin D1 due to a t(11:14)[3] chromosomal translocation in the DNA. Specifically, the translocation is at t(11;14)(q13;q32).[4][5] Lymph nodes of the head and neck, from Gray's Anatomy (click image to enlarge) ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 4 Treatments * 4.1 Chemotherapy * 4.2 Immunotherapy * 4.3 Targeted therapy * 4.4 Gene therapy * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] At diagnosis, patients typically are in their 60s and present to their physician with advanced disease. About half have B symptoms such as fever, night sweats, or unexplained weight loss (over 10% of body weight). Enlarged lymph nodes (for example, a "bump" on the neck, armpits or groin) or enlargement of the spleen are usually present. Bone marrow, liver and gastrointestinal tract involvement occurs relatively early in the course of the disease.[6] Mantle cell lymphoma has been reported in rare cases to be associated with severe allergic reactions to mosquito bites. These reactions involve extensive allergic reactions to mosquito bites which range from greatly enlarged bite sites that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening anaphylaxis. In several of these cases, the mosquito bite allergy reaction occurred prior to the diagnosis of MCL suggesting that MBA can be a manifestation of early developing, and therefore a harbinger of mantle cell lymphoma.[7][8] ## Pathogenesis[edit] MCL, like most cancers, results from the acquisition of a combination of (non-inherited) genetic mutations in somatic cells. This leads to a clonal expansion of malignant B lymphocytes. The factors that initiate the genetic alterations are typically not identifiable, and usually occur in people with no particular risk factors for lymphoma development. Because it is an acquired genetic disorder, MCL is neither communicable nor inheritable. A defining characteristic of MCL is mutation and overexpression of cyclin D1, a cell cycle gene, that contributes to the abnormal proliferation of the malignant cells. MCL cells may also be resistant to drug-induced apoptosis, making them harder to cure with chemotherapy or radiation. Cells affected by MCL proliferate in a nodular or diffuse pattern with two main cytologic variants, typical or blastic. Typical cases are small to intermediate-sized cells with irregular nuclei. Blastic (aka blastoid) variants have intermediate to large-sized cells with finely dispersed chromatin, and are more aggressive in nature.[9] The tumor cells accumulate in the lymphoid system, including lymph nodes and the spleen, with non-useful cells eventually rendering the system dysfunctional. MCL may also replace normal cells in the bone marrow, which impairs normal blood cell production. ## Diagnosis[edit] Lymph node with mantle cell lymphoma (low power view, H&E) Mantle cell lymphoma. Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry the lymphoma cells expressed CD20, CD5 and Cyclin D1 (high power view, H&E) Micrograph of terminal ileum with mantle cell lymphoma (bottom of image). H&E stain. Micrograph of terminal ileum with mantle cell lymphoma (bottom of image - brown colour). Cyclin D1 immunostain. Diagnosis generally requires stained slides of a surgically removed part of a lymph node. Other methods are also commonly used, including cytogenetics and fluorescence in situ hybridization (FISH). Polymerase chain reaction (PCR) and CER3 clonotypic primers are additional methods, but are less often used.[medical citation needed] The immunophenotype profile consists of CD5+ (in about 80%),[10] CD10-/+, and it is usually CD5\+ and CD10-.[11] CD20+, CD23-/+ (though plus in rare cases). Generally, cyclin D1 is expressed but it may not be required. Cyclin D1 negative mantle cell lymphoma can be diagnosed by detecting SOX11 marker. The workup for Mantle cell lymphoma is similar to the workup for many indolent lymphomas and certain aggressive lymphomas. Mantle cell lymphoma is a systemic disease with frequent involvement of the bone marrow and gastrointestinal tract (generally showing polyposis in the lining). There is also a not-uncommon leukemic phase, marked by presence in the blood. For this reason, both the peripheral blood and bone marrow are evaluated for the presence of malignant cells. Chest, abdominal, and pelvic CT scans are routinely performed.[medical citation needed] Since mantle cell lymphoma may present a lymphomatous polyposis coli and colon involvement is common, colonoscopy is now[when?] considered a routine part of the evaluation. Upper endoscopy and neck CT scan may be helpful in selected cases. In some patients with the blastic variant, lumbar puncture is done to evaluate the spinal fluid for involvement.[medical citation needed] CT scan \- Computerized tomography scan yields images of part or whole body. Gives a large number of slices on X-ray image.[medical citation needed] PET scan \- Generally of the whole body, shows a three-dimensional image of where previously injected radioactive glucose is metabolized at a rapid rate. Faster-than-average metabolism indicates that cancer is likely present. Metabolism of radioactive glucose may give a false positive, particularly if the patient has exercised before the test.[medical citation needed] PET scans are much more effective when the information from them is integrated with that from a CT scan to show more precisely where the cancer activity is located and to more accurately measure the size of tumors.[medical citation needed] ## Treatments[edit] There are no proven standards of treatment for MCL, and there is no consensus among specialists on how to treat it optimally.[12] Many regimens are available and often get good response rates, but patients almost always get disease progression after chemotherapy. Each relapse is typically more difficult to treat, and relapse is generally faster. Regimens are available that treat relapses, and new approaches are under test. Because of the aforementioned factors, many MCL patients enroll in clinical trials to get the latest treatments.[medical citation needed] There are four classes of treatments currently[when?] in general use: chemotherapy, immune based therapy, radioimmunotherapy and new biologic agents. The phases of treatment are generally: frontline, following diagnosis, consolidation, after frontline response (to prolong remissions), and relapse. Relapse is usually experienced multiple times.[medical citation needed] On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Tecartus, intended for the treatment of relapsed or refractory mantle cell lymphoma (MCL).[13] The applicant for this medicinal product is Kite Pharma EU B.V.[13] Tecartus is an autologous T‑cell immunotherapy which will be available as a dispersion for infusion (0.4–2.0 x 108 cells).[13] The active substance in Tecartus is genetically modified autologous anti-CD19-transduced CD3+ cells.[13] By binding to CD19-expressing cancer cells and normal B cells, the medicine starts T‑cell activation and secretion of inflammatory cytokines and chemokines.[13] This sequence of events leads to killing of CD19-expressing cells.[13] The benefit of Tecartus is the tumor shrinkage (response) of mantle cell lymphoma which had relapsed or was refractory to other treatment.[13] ### Chemotherapy[edit] Chemotherapy is widely used as frontline treatment, and often is not repeated in relapse due to side effects. Alternate chemotherapy is sometimes used at first relapse. For frontline treatment, CHOP with rituximab is the most common chemotherapy, and often given as outpatient by IV. A stronger chemotherapy with greater side effects (mostly hematologic) is HyperCVAD, often given in the hospital setting, with rituximab and generally to fitter patients (some of which are over 65). HyperCVAD is becoming popular and showing promising results, especially with rituximab. It can be used on some elderly (over 65) patients, but seems only beneficial when the baseline Beta-2-MG blood test was normal. It is showing better complete remissions (CR) and progression-free survival (PFS) than CHOP regimens. A less intensive option is bendamustine with rituximab.[14] Second line treatment may include fludarabine, combined with cyclophosphamide and/or mitoxantrone, usually with rituximab. Cladribine and clofarabine are two other medications being investigated in MCL. A relatively new regimen that uses old medications is PEP-C, which includes relatively small, daily doses of prednisone, etoposide, procarbazine, and cyclophosphamide, taken orally, has proven effective for relapsed patients. According to John Leonard, PEP-C may have anti-angiogenetic properties,[15][16] something that he and his colleagues are testing through an ongoing drug trial.[17] Another approach involves using very high doses of chemotherapy, sometimes combined with total body irradiation (TBI), in an attempt to destroy all evidence of the disease. The downside to this is the destruction of the patient's entire immune system as well, requiring rescue by transplantation of a new immune system (hematopoietic stem cell transplantation), using either autologous stem cell transplantation, or those from a matched donor (an allogeneic stem cell transplant). A presentation at the December 2007 American Society of Hematology (ASH) conference by Christian Geisler, chairman of the Nordic Lymphoma Group[18] claimed that according to trial results, mantle cell lymphoma is potentially curable with very intensive chemo-immunotherapy followed by a stem cell transplant, when treated upon first presentation of the disease.[19][20] These results seem to be confirmed by a large trial of the European Mantle Cell Lymphoma Network indicating that induction regimens containing monoclonal antibodies and high dose ARA-C (Cytarabine) followed by ASCT should become the new standard of care of MCL patients up to approximately 65 years.[21][22] A study released in April 2013 showed that patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.[23] ### Immunotherapy[edit] Immune-based therapy is dominated by the use of the rituximab monoclonal antibody, sold under the trade name Rituxan (or as Mabthera in Europe and Australia). Rituximab may have good activity against MCL as a single agent, but it is typically given in combination with chemotherapies, which prolongs response duration. There are newer[when?] variations on monoclonal antibodies combined with radioactive molecules known as radioimmunotherapy (RIT). These include Zevalin and Bexxar. Rituximab has also been used in small numbers of patients in combination with thalidomide with some effect.[24] In contrast to these antibody-based 'passive' immunotherapies, the field of 'active' immunotherapy tries to activate a patient's immune system to specifically eliminate their own tumor cells. Examples of active immunotherapy include cancer vaccines, adoptive cell transfer, and immunotransplant, which combines vaccination and autologous stem cell transplant. Though no active immunotherapies are currently[when?] a standard of care, numerous clinical trials are ongoing.[25][26][27] ### Targeted therapy[edit] Two Bruton tyrosine kinase inhibitors (BTKi), one In November 2013, ibrutinib (trade name Imbruvica, Pharmacyclics LLC) and in October 2017, acalabrutinib (trade name Calquence, AstraZeneca Pharmaceuticals LP) were approved in the United States for treating MCL.[28] Other targeted agents include the proteasome inhibitor bortezomib, mTOR inhibitors such as temsirolimus, and the P110δ inhibitor GS-1101.[citation needed] In November 2019, zanubrutinib (Brukinsa) was approved in the United States with an indication for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy.[29] ### Gene therapy[edit] Brexucabtagene autoleucel (Tecartus) was approved for medical use in the United States in July 2020, with an indication for the treatment of adults with relapsed or refractory mantle cell lymphoma.[30][31][32] Each dose of brexucabtagene autoleucel is a customized treatment created using the recipient's own immune system to help fight the lymphoma.[30] The recipient's T cells, a type of white blood cell, are collected and genetically modified to include a new gene that facilitates the targeting and killing of the lymphoma cells.[30] These modified T cells are then infused back into the recipient.[30] ## Prognosis[edit] Recent[when?] clinical advances in mantle cell lymphoma (MCL) have seen standard‐of‐care treatment algorithms transformed. Frontline rituximab combination therapy, high dose cytarabine‐based induction in younger patients and, more recently,[when?] Bruton Tyrosine Kinase (BTK) inhibitors in the relapse setting have all demonstrated survival advantage in clinical trials (Wang et al, 2013; Eskelund et al, 2016; Rule et al, 2016). Over the last[when?] 15 years these practices have gradually become embedded in clinical practice and real‐world data has observed corresponding improvements in patient survival (Abrahamsson et al, 2014; Leux et al, 2014).[33] The overall 5-year survival rate for MCL is generally 50%[34] (advanced stage MCL) to 70%[35] (for limited-stage MCL). Prognosis for individuals with MCL is problematic and indexes do not work as well due to patients presenting with advanced stage disease. Staging is used but is not very informative, since the malignant B-cells can travel freely though the lymphatic system and therefore most patients are at stage III or IV at diagnosis. Prognosis is not strongly affected by staging in MCL and the concept of metastasis does not really apply.[medical citation needed] The Mantle Cell Lymphoma International Prognostic Index (MIPI) was derived from a data set of 455 advanced stage MCL patients treated in series of clinical trials in Germany/Europe. Of the evaluable population, approximately 18% were treated with high-dose therapy and stem cell transplantation in first remission. The MIPI is able to classify patients into three risk groups: low risk (median survival not reached after median 32 months follow-up and 5-year OS rate of 60%), intermediate risk (median survival 51 months) and high risk (median survival 29 months). In addition to the 4 independent prognostic factors included in the model, the cell proliferation index (Ki-67) was also shown to have additional prognostic relevance. When the Ki67 is available, a biologic MIPI can be calculated.[36] MCL is one of the few NHLs that can cross the boundary into the brain, yet it can be treated in that event.[medical citation needed] There are a number of prognostic indicators that have been studied. There is not universal agreement on their importance or usefulness in prognosis.[medical citation needed] Ki-67 is an indicator of how fast cells mature and is expressed in a range from about 10% to 90%. The lower the percentage, the lower the speed of maturity, and the more indolent the disease. Katzenberger et al. Blood 2006;107:3407 graphs survival versus time for subsets of patients with varying Ki-67 indices. He shows median survival times of about one year for 61-90% Ki-67 and nearly 4 years for 5-20% Ki-67 index. MCL cell types can aid in prognosis in a subjective way. Blastic is a larger cell type. Diffuse is spread through the node. Nodular are small groups of collected cells spread through the node. Diffuse and nodular are similar in behavior. Blastic is faster growing and it is harder to get long remissions. Some thought is that given a long time, some non-blastic MCL transforms to blastic. Although survival of most blastic patients is shorter, some data shows that 25% of blastic MCL patients survive to 5 years. That is longer than diffuse type and almost as long as nodular (almost 7 yrs).[medical citation needed] Beta-2 microglobulin is another risk factor in MCL used primarily for transplant patients. Values less than three have yielded 95% overall survival to six years for auto SCT where over three yields a median of 44 most overall survival for auto SCT (Khouri 03). This is not yet[when?] fully validated.[medical citation needed] Testing for high levels of Lactate dehydrogenase (LDH) in NHL patients is useful because LDH is released when body tissues break down for any reason. While it cannot be used as a sole means of diagnosing NHL, it is a surrogate for tracking tumor burden in those diagnosed by other means. The normal range is approximately 100-190.[medical citation needed] ## Epidemiology[edit] 6% of non-Hodgkin lymphoma cases are mantle cell lymphoma.[2] As of 2015[update], the ratio of males to females affected is about 4:1.[2] ## See also[edit] * In situ mantle cell lymphoma * List of hematologic conditions ## References[edit] 1. ^ "Mantle Cell Lymphoma Facts" (PDF). lls.org. Retrieved 10 April 2018. 2. ^ a b c Skarbnik AP, Goy AH (January 2015). "Mantle cell lymphoma: state of the art". Clin Adv Hematol Oncol. 13 (1): 44–55. PMID 25679973. 3. ^ "t(11;14)(q13;q32) IGH/CCND1". atlasgeneticsoncology.org. Retrieved 10 April 2018. 4. ^ Li JY, Gaillard F, Moreau A, et al. (May 1999). "Detection of translocation t(11;14)(q13;q32) in mantle cell lymphoma by fluorescence in situ hybridization". Am. J. Pathol. 154 (5): 1449–52. doi:10.1016/S0002-9440(10)65399-0. PMC 1866594. PMID 10329598. 5. ^ Barouk-Simonet E, Andrieux J, Copin MC, et al. (2002). "TPA stimulation culture for improved detection of t(11;14)(q13;q32) in mantle cell lymphoma". Ann. Genet. 45 (3): 165–8. doi:10.1016/S0003-3995(02)01122-X. PMID 12381451. 6. ^ Leukemia&Lymphoma Society (2014). "Mantle Cell Lymphoma Facts" (PDF). www.LLS.org. 7. ^ Tatsuno K, Fujiyama T, Matsuoka H, Shimauchi T, Ito T, Tokura Y (June 2016). "Clinical categories of exaggerated skin reactions to mosquito bites and their pathophysiology". Journal of Dermatological Science. 82 (3): 145–52. doi:10.1016/j.jdermsci.2016.04.010. PMID 27177994. 8. ^ Kyriakidis I, Vasileiou E, Karastrati S, Tragiannidis A, Gompakis N, Hatzistilianou M (December 2016). "Primary EBV infection and hypersensitivity to mosquito bites: a case report". Virologica Sinica. 31 (6): 517–520. doi:10.1007/s12250-016-3868-4. PMID 27900557. S2CID 7996104. 9. ^ Goy, Andre. "Mantle Cell Lymphoma: An Update for Clinicians". Medscape. Retrieved 18 October 2007. 10. ^ Stanford School of Medicine: "Mantle Cell Lymphoma, Differential Diagnosis" [1] 11. ^ Barekman CL, Aguilera NS, Abbondanzo SL (July 2001). "Low-grade B-cell lymphoma with coexpression of both CD5 and CD10. A report of 3 cases". Arch. Pathol. Lab. Med. 125 (7): 951–3. doi:10.1043/0003-9985(2001)125<0951:LGBCLW>2.0.CO;2 (inactive 14 January 2021). PMID 11419985.CS1 maint: DOI inactive as of January 2021 (link) 12. ^ Rajabi B, Sweetenham JW (2015). "Mantle cell lymphoma: observation to transplantation". Ther Adv Hematol. 6 (1): 37–48. doi:10.1177/2040620714561579. PMC 4298490. PMID 25642314. 13. ^ a b c d e f g "Tecartus: Pending EC decision". European Medicines Agency (EMA). 16 October 2020. Retrieved 16 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 14. ^ "Archived copy" (PDF). Archived from the original (PDF) on 23 June 2017. Retrieved 18 March 2015.CS1 maint: archived copy as title (link) 15. ^ http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=23&abstractID=104642[full citation needed] 16. ^ "Archived copy". Archived from the original on 17 April 2008. Retrieved 24 February 2008.CS1 maint: archived copy as title (link)[full citation needed] 17. ^ http://clinicaltrials.gov/ct2/show/NCT00151281?cond=%22Lymphoma%2C+Mantle-Cell%22&rank=55[full citation needed] 18. ^ "Archived copy". Archived from the original on 16 April 2008. Retrieved 15 February 2008.CS1 maint: archived copy as title (link) 19. ^ "Mantle Cell Lymphoma is Curable with Intensive Immunochemotherapy". DocGuide. 20. ^ http://www.abstracts2view.com/hem07/view.php?nu=HEM07L1_6026&terms=[permanent dead link][full citation needed] 21. ^ Ye H, Desai A, Huang S, et al. (July 2018). "Paramount therapy for young and fit patients with mantle cell lymphoma: strategies for front-line therapy". J. Exp. Clin. Cancer Res. 37 (1): 150. doi:10.1186/s13046-018-0800-9. PMC 6044039. PMID 30005678. 22. ^ Ye H, Desai A, Zeng D, et al. (November 2018). "Frontline Treatment for Older Patients with Mantle Cell Lymphoma". Oncologist. 23 (11): 1337–1348. doi:10.1634/theoncologist.2017-0470. PMC 6291324. PMID 29895632. 23. ^ Rummel MJ, Niederle N, Maschmeyer G, et al. (April 2013). "Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial". Lancet. 381 (9873): 1203–10. doi:10.1016/S0140-6736(12)61763-2. PMID 23433739. S2CID 27886488. 24. ^ Kaufmann H, Raderer M, Wöhrer S, et al. (October 2004). "Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma". Blood. 104 (8): 2269–71. doi:10.1182/blood-2004-03-1091. PMID 15166030. 25. ^ "Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00101101". ClinicalTrials.gov. Retrieved 28 February 2016. 26. ^ "Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00005780". ClinicalTrials.gov. Retrieved 28 February 2016. 27. ^ "Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00490529". ClinicalTrials.gov. Retrieved 28 February 2016. 28. ^ "FDA approves Imbruvica for rare blood cancers". U.S. Food and Drug Administration (FDA) (Press release). 13 November 2013. "FDA approves Calquence, on October 31, 2017, the Food and Drug Administration granted accelerated approval to acalabrutinib, (AstraZeneca Pharmaceuticals Inc. under license of Acerta Pharma BV) with an indication for the treatment of adults with mantle cell lymphoma (MCL) who have received at least one prior round of therapy" (Press release). Archived from the original on 16 February 2017. Retrieved 15 November 2019. 29. ^ "FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage". U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019. This article incorporates text from this source, which is in the public domain. 30. ^ a b c d "FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL". U.S. Food and Drug Administration (FDA). 24 July 2020. Retrieved 24 July 2020. This article incorporates text from this source, which is in the public domain. 31. ^ "Tecartus". U.S. Food and Drug Administration (FDA). 24 July 2020. STN: BL 125703. Retrieved 24 July 2020. 32. ^ "U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma" (Press release). Kite Pharma. 24 July 2020. Retrieved 24 July 2020 – via Business Wire. 33. ^ British Journal of Haematology 20 November 2018 34. ^ Most recent values in:Herrmann A, Hoster E, Zwingers T, et al. (February 2009). "Improvement of overall survival in advanced stage mantle cell lymphoma". J. Clin. Oncol. 27 (4): 511–8. doi:10.1200/JCO.2008.16.8435. PMID 19075279. 35. ^ Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R, Connors JM (October 2003). "Limited-stage mantle-cell lymphoma". Ann. Oncol. 14 (10): 1555–61. doi:10.1093/annonc/mdg414. PMID 14504058. 36. ^ Hoster E, Dreyling M, Klapper W, et al. (January 2008). "A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma". Blood. 111 (2): 558–65. doi:10.1182/blood-2007-06-095331. PMID 17962512. ## Further reading[edit] * Cohen JB, Zain JM, Kahl BS (2017). "Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and Therapies". Am Soc Clin Oncol Educ Book. 37 (37): 512–25. doi:10.1200/EDBK_175448. PMID 28561694. * Dreyling M, Ferrero S, Hermine O (November 2014). "How to manage mantle cell lymphoma". Leukemia. 28 (11): 2117–30. doi:10.1038/leu.2014.171. PMID 24854989. S2CID 22105743. * Schieber M, Gordon LI, Karmali R (2018). "Current overview and treatment of mantle cell lymphoma". F1000Res. 7: 1136. doi:10.12688/f1000research.14122.1. PMC 6069726. PMID 30109020. ## External links[edit] Classification D * ICD-10: C83.1 * ICD-9-CM: 200.4 * ICD-O: M9673/3 * MeSH: D020522 External resources * eMedicine: med/1361 * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 * Medicine portal [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	Mantle cell lymphoma	c0334634	2,825	wikipedia	https://en.wikipedia.org/wiki/Mantle_cell_lymphoma	2021-01-18T18:45:01	{"gard": ["6969"], "mesh": ["D020522"], "umls": ["C0334634", "C0555202"], "icd-9": ["200.4"], "icd-10": ["C85.7"], "orphanet": ["52416"], "wikidata": ["Q268713"]}
Schwartz Jampel syndrome (SJS) is a genetic disorder that affects bone and muscle development. Signs and symptoms may include muscle stiffness and weakness; joint deformities that affect mobility (contractures); short stature; small "fixed" facial features; and eye abnormalities. Previously, SJS was divided into types 1 and 2. SJS type 2 (also refereed to as neonatal SJS) is now considered a distinct, more severe condition called Stuve-Wiedemann syndrome, which is caused by mutations in the LIFR gene. SJS is subdivided into types 1A and 1B, differentiated by severity and age of onset. Type 1A, considered classic SJS, is the most commonly recognized type. People with type 1A typically develop more mild symptoms later in childhood, while individuals with type 1B have symptoms that are more severe and are apparent immediately after birth. SJS is caused by mutations in the HSPG2 gene. SJS is thought to be inherited in an autosomal recessive manner; however, some cases reported in the medical literature suggest an autosomal dominant inheritance pattern. Treatment for type 1A and 1B aims to normalize muscle activity through various methods including massage and stretching, medications such as botulinum toxin (Botox), and surgery. [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	Schwartz Jampel syndrome	c0036391	2,826	gard	https://rarediseases.info.nih.gov/diseases/250/schwartz-jampel-syndrome	2021-01-18T17:57:49	{"mesh": ["D010009"], "omim": ["255800"], "umls": ["C0036391"], "orphanet": ["800"], "synonyms": ["Aberfeld syndrome", "Burton skeletal dysplasia", "Burton syndrome", "Catel-Hempel syndrome", "Dysostosis enchondralis metaepiphysaria, Catel-Hempel type", "Osteochondromuscular dystrophy", "Schwartz-Jampel syndrome", "Schwartz-Jampel-Aberfeld syndrome", "SJS", "SJS1", "Schwartz Jampel Aberfeld syndrome", "Myotonic myopathy dwarfism chondrodystrophy and ocular and facial abnormalities", "SJA syndrome", "Chondrodystrophic myotonia", "Myotonic chondrodystrophy", "Myotonic myopathy, dwarfism, chondrodystrophy, ocular and facial anomalies"]}
Heart defect – round face – congenital developmental delay is very rare syndrome described in three sibs of one Japanese family and characterized by congenital heart disease, round face with depressed nasal bridge, small mouth, short stature, and relatively dark skin and typical dermatoglyphic anomalies, and intellectual deficit. [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	Congenital heart defect-round face-developmental delay syndrome	c0796162	2,827	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1355	2021-01-23T17:05:26	{"gard": ["4905"], "mesh": ["C536680"], "omim": ["270460"], "umls": ["C0796162"], "icd-10": ["Q87.8"], "synonyms": ["Sonoda syndrome"]}
## Summary ### Clinical characteristics. Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in non-scarring blisters and erosions caused by minor mechanical trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 17 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview: * EBS, localized (EBS-loc; previously known as Weber-Cockayne type) * EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type) * EBS-with mottled pigmentation (EBS-MP) * EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type) The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. * In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant. * In EBS, gen intermed, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev. * In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur. * In EBS-gen sev, onset is usually at birth; severity varies greatly, both among and within families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding, especially in neonates and infants. Blistering can be severe enough to result in neonatal or infant death. ### Diagnosis/testing. The diagnosis of epidermolysis bullosa simplex (EBS) is established in a proband by the identification of biallelic pathogenic variants in EXPH5 or TGM5 or heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14 by molecular genetic testing; examination of a skin biopsy using immunofluorescence microscopy and transmission electron microscopy may be considered but can have limitations in the diagnosis of EBS. ### Management. Treatment of manifestations: Supportive care to protect the skin from blistering; use of dressings that will not further damage the skin and will promote healing of open wounds. Lance and drain new blisters. Dressings involve three layers: a primary nonadherent contact layer; a secondary layer providing stability, adding padding, and absorbing drainage; and a tertiary layer with elastic properties. Prevention of primary manifestations: Aluminum chloride (20%) applied to palms and soles can reduce blister formation in some individuals with EBS. Cyproheptadine (Periactin®), tetracycline, erythromycin, or botulimun toxin can reduce blistering in some individuals. Keratolytics and softening agents for palmar plantar hyperkeratosis may prevent tissue thickening and cracking. Prevention of secondary complications: Monitor for wound infection; treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Nutritional support and feeding therapy may be necessary for infants and children with oral manifestations of EBS. Management of fluid and electrolyte problems in severely affected infants. Appropriate footwear and physical therapy may preserve ambulation in children who have difficulty walking because of blistering and hyperkeratosis. Surveillance: For infection and proper wound healing. Agents/circumstances to avoid: Excessive heat may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin. Avoid ordinary medical tape or Band-Aids®. ### Genetic counseling. EBS caused by pathogenic variants in EXPH5 or TGM5 is inherited in an autosomal recessive manner. EBS caused by pathogenic variants in KRT5 or KRT14 is usually inherited in an autosomal dominant manner, but in rare families (especially those with consanguinity) it can be inherited in an autosomal recessive manner. * In families with autosomal recessive inheritance, the parents of an affected child are obligate heterozygotes; at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a heterozygote. * In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and having EBS. Molecular genetic testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known. ## Diagnosis ### Suggestive Findings The diagnosis of epidermolysis bullosa simplex (EBS) should be suspected in individuals with the following clinical findings: * Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring * Blistering that: * May be present in the neonatal period * Primarily affects the hands and feet but can affect the whole body * Occurs in annular or curvilinear groups or clusters * Can lead to progressive brown pigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life * Is associated with palmar and plantar hyperkeratosis that may be severe * Nail dystrophy * Milia * Family history that is consistent with either an autosomal recessive or autosomal dominant inheritance pattern Note: Absence of a known family history of EBS does not preclude the diagnosis. ### Establishing the Diagnosis The diagnosis of epidermolysis bullosa simplex (EBS) is best established in a proband by the identification of biallelic pathogenic variants in EXPH5 or TGM5 or heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14 by molecular genetic testing (see Table 1). Examination of a skin biopsy using immunofluorescence microscopy and transmission electron microscopy (see Skin biopsy below) may be considered but can have limitations in the diagnosis of EBS. Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing. Serial single-gene testing * Sequence analysis of KRT5 and KRT14 is performed first. * If no pathogenic variants are found in KRT5 or KRT14 by sequence analysis, sequence analysis of EXPH5 and TGM5 should be considered next. * If sequence analysis of EXPH5 and TGM5 reveals no or only one pathogenic variant, gene-targeted deletion/duplication analysis of EXPH5, KRT5, KRT14, and/or TGM5 may be considered. Note, however: * The majority of pathogenic variants in KRT5 and KRT14 are dominant-negative missense variants inherited in an autosomal dominant manner. * Loss-of-function variants in EXPH5, KRT5, KRT14, and TGM5 occur rarely and cause recessive disease. * No large deletion or duplication in EXPH5, KRT5, KRT14, or TGM5 has been reported. Therefore, a multigene panel or genomic testing may be higher yield than deletion/duplication analysis. A multigene panel that includes EXPH5, KRT5, KRT14, TGM5 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 is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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. More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes EXPH5, KRT5, KRT14, and TGM5) fails to confirm a diagnosis in an individual with features of EBS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex (EBS) View in own window Gene 1Proportion of EBS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detected by Method 3 Sequence analysis 4Gene-targeted deletion/duplication analysis 5 EXPH5Estimated at 1%-2%>90%Unknown 6 KRT5~37% 7~99% 8, 9Unknown 6 KRT14~37% 7~99% 8, 10Unknown 6 TGM5Estimated at 5%>90% 11Unknown 6 Other or unknown 12~19%NA 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\. In individuals with biopsy-diagnosed EBS 4\. 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. 5\. 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. 6\. No data on detection rate of gene-targeted deletion/duplication analysis are available. However, deletion/duplication analysis is likely to have a low yield for these genes (see Establishing the Diagnosis). 7\. For further information on the proportion of each EBS subtype caused by pathogenic variants in KRT5 and KRT14, see Table 3. 8\. Yasukawa et al [2006], Rugg et al [2007], Bolling et al [2011] 9\. Approximately 90%-95% of individuals with EBS-MP will have the p.Pro25Leu pathogenic variant in KRT5 [Pascucci et al 2006, Shurman et al 2006]. Horiguchi et al [2005] describe a second pathogenic variant associated with EBS-MP. 10\. Approximately 2%-5% of individuals with EMB-MP have a p.Met119Thr pathogenic variant in KRT14 [Harel et al 2006]. 11\. A common founder variant in the catalytic domain, p.Gly113Cys, has been found in the European population. 12\. Because only approximately 75% of individuals with biopsy-proven EBS have identifiable heterozygous (or rarely biallelic) pathogenic variants in KRT5 or KRT14, it is possible that pathogenic variants in another as-yet unidentified gene are also causative [Yasukawa et al 2006, Rugg et al 2007, Bolling et al 2011]. Note: Two individuals with features of EBS caused by biallelic pathogenic variants in DST, encoding dystonin, have been reported [Groves et al 2010, Liu et al 2012]. More recent studies from the Netherlands identified a heterozygous pathogenic variant in PLEC in six of 16 individuals with biopsy-proven EBS who did not have a pathogenic variant detected in KRT5 or KRT14 [Bolling et al 2014]. Skin biopsy. Immunofluorescence antigenic mapping has been the sine qua non for the diagnosis of EBS because of its rapid turnaround time and high sensitivity and specificity [Yiasemides et al 2006]. However, advances in molecular genetic testing have lead clinicians to use genetic testing for diagnosis, as opposed to skin biopsy. Skin biopsy should still be considered in the evaluation of newborns with extensive blistering and erosions, in cases where the EB phenotype is not clear and a prompt diagnosis is needed, and when genetic testing is not available. * Biopsy technique * To insure the most accurate diagnosis, the leading edge of a fresh blister induced by mechanical friction should be biopsied. The healing in non-induced intact blisters may obscure the morphology. * Induced blisters are typically analyzed by light microscopy, immunofluorescent microscopy, and transmission electron microscopy. * Histology (light microscopy) * In all cases of EBS, splitting is observed within or above the basal cell layer of the skin. Routine histology suggests the diagnosis of EB but is an inadequate and unacceptable test for accurately diagnosing the EB type and subtype. It is most valuable to rule out other causes of blistering when the differential diagnosis is broad. * Transmission electron microscopy * In cases of EBS caused by biallelic pathogenic variants in EXPH5, widened space between keratinocytes, aggregation of keratin filaments, and vesicles near the plasma membrane and nucleus have been reported [McGrath et al 2012]. * In EBS-gen sev, the keratin intermediate filaments (also called tonofilaments) are clumped, a finding that serves as a distinguishing feature [Bergman et al 2007]. This finding is only seen using electron microscopy, making this study useful when the diagnosis of EBS-gen sev is suspected. The absence of keratin intermediate filaments is a distinguishing feature of autosomal recessive EBS caused by biallelic pathogenic variants in KRT14 (EBS-AR K14). * Immunofluorescence microscopy * In most cases of EBS, diagnosis using immunofluorescent microscopy is made by mapping the blister. Antibodies to keratin 5 or keratin 14 and other dermal-epidermal junction antigens (typically laminin 332 and type VII collagen) show localization of stained epitopes to the blister floor. This mapping pattern is specific to EBS but does not further delineate the EBS subtype. It also relies on the formation of a blister in the biopsy specimen. Thus, there is a risk in affected individuals with less severe disease that a blister may not be induced and the biopsy may be non-diagnostic. * Immunofluorescent microscopy can be helpful in the diagnosis of autosomal recessive forms of EBS, as the affected protein will be substantially reduced or absent. However, antibodies to exophilin 5 and transglutaminase 5 are not widely available, limiting the clinical utility of this study to the exceedingly rare forms of EBS-AR caused by biallelic pathogenic variants in KRT14. ## Clinical Characteristics ### Clinical Description The most common forms of epidermolysis bullosa simplex (EBS) are subdivided into clinical phenotypes — EBS, localized (EBS-loc) (previously known as EBS, Weber-Cockayne type); EBS, generalized intermediate (EBS-gen intermed) (previously known as EBS, Koebner type); EBS-with mottled pigmentation (EBS-MP); and EBS, generalized severe (EBS-gen sev, previously known as EBS, Dowling-Meara) — based primarily on dermatologic and histopathologic findings. Although it is now recognized that these phenotypes are part of a continuum with overlapping features, it is reasonable to continue to think of EBS in terms of the phenotypes in order to provide affected individuals with information about the expected clinical course. The clinical features of these disorders are summarized in Table 2. ### Table 2. Diagnostic Clinical Features of the Four Most Common Subtypes of EBS View in own window EBS SubtypeLocalizedGeneralized IntermediateMottled PigmentationGeneralized Severe Age of onsetInfancy, usually by 12-18 mosBirth/infancyBirth/infancyBirth Clinical featureBlistersDistributionUsually limited to hands, feet; can occur at sites of repeated trauma (e.g., belt line)GeneralizedGeneralizedGeneralized Grouped (herpetiform)NoNoSometimesYes MucosalRareOccasionallyOccasionallyOften Hyperkeratosis of palms & soles (keratoderma)OccasionallyOccasionallyCommon, focalCommon, progressive Nail involvementOccasionallyOccasionallyOccasionallyCommon MiliaRareOccasionallyUnknownCommon Hyper/ hypopigmentationNoCan occurAlwaysCommon #### EBS, Localized (EBS-loc) Blisters begin in infancy and can present at birth; severity is usually mild. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 12-18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life. Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; for example, blisters can develop on the buttocks after horseback riding and around the waist after wearing a tight belt. The palms and soles are usually more involved than the backs of the hands and the tops of the feet. Symptoms are worse in warm weather and worsen with sweating. Hyperkeratosis of the palms and soles can develop in later childhood and adult life. Occasionally, a large blister in a nail bed may result in shedding of the nail. #### EBS, Generalized Intermediate (EBS-gen intermed) Blisters may be present at birth or develop within the first few months of life. EBS-gen intermed is distinguished from EBS-loc by its more widespread involvement and from EBS-sev gen by absence of clumped keratin intermediate filaments in basal keratinocytes on electron microscopy (see Establishing the Diagnosis, Skin biopsy). In general, EBS-gen intermed is milder than EBS-sev gen, but clinical overlap is high. Similarly, mild EBS-gen intermed can be indistinguishable from EBS-loc. Branches of one large pedigree were reported separately as EBS-Koebner (now EBS-gen intermed) and EBS-Weber Cockayne (now EBS-loc), reflecting the variability in severity even within families. #### EBS with Mottled Pigmentation (EBS-MP) Skin fragility in EBS-MP is evident at birth and is clinically indistinguishable from generalized forms of EBS. Small hyperpigmented macules begin to appear in early childhood, progress over time, and coalesce to a reticulate pattern. Hypopigmented macules may be interspersed. These changes tend to develop on the trunk (particularly in large skin folds such as the neck, groin, and axillae) and then on the extremities. The pigmentation does not occur in areas of blistering (a factor distinguishing it from post-inflammatory hyperpigmentation and hypopigmentation) and often disappears in adult life. Focal palmar and plantar hyperkeratoses may occur. #### EBS, Generalized Severe (EBS-gen sev) Onset is usually at birth and severity varies greatly both within and between families. Blistering can be severe enough to result in neonatal or infant death. Widespread and severe blistering and/or multiple grouped clumps of small blisters (whose resemblance to the blisters of herpetic infection gave the disorder one of its names) are typical. Hemorrhagic blisters are common. The mucosa can be involved; this usually improves with age. Decreased frequency of blistering occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life. Progressive hyperkeratosis (punctate or diffuse) of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy (thickened, deformed nails) is common. Both hyper- and hypopigmentation can occur, typically in areas of blistering. Mucosal involvement in EBS-gen sev may interfere with feeding. Laryngeal involvement, manifesting as a hoarseness, can also occur, but is not life threatening. #### Cancer Risk Squamous cell carcinoma is not usually associated with EBS. ### Phenotype Correlations by Gene The proportion of EXPH5, KRT5, KRT14, and TGM5 pathogenic variants responsible for each phenotype is shown in Table 3. Clinical overlap between EBS-gen intermed and EBS-gen sev is substantial; thus, much of the molecular genetic data have been lumped in the literature and the proportions presented in the table are necessarily imprecise. In addition, predominance of pathogenic variants in KRT5 or KRT14 may be population specific [Abu Sa'd et al 2006, Yasukawa et al 2006, Rugg et al 2007]. ### Table 3. Molecular Basis of EBS Types Caused by EXPH5, KRT5, KRT14, and TGM5 Pathogenic Variants View in own window Phenotype% of all EBSInheritanceSeverityProportion of Pathogenic Variants EXPH5KRT5KRT14TGM5 EBS-loc60%ADMild1%-2%<47%>47%5% <1%AR EBS-gen intermed15%ADModerate-severeNI<50%>50%NI EBS-gen sev25%NI<50%>50%NI EBS-MP<1%<1% 194% 25%NI All EBS100%1%-2%47%47%5% In 25% of biopsy proven EBS, no pathogenic variant in KRT5 or KRT14 could be identified [Bolling et al 2010]; molecular genetic testing of EXPH5 and TGM5 was not performed in this study. Further studies from the Netherlands identified a heterozygous pathogenic variant in PLEC in six of 16 individuals with biopsy-proven EBS who did not have a pathogenic variant detected in KRT5 or KRT14 [Bolling et al 2014]. NI = no information 1\. Turcan et al [2016] 2\. Hamada et al [2004], Horiguchi et al [2005] ### Genotype-Phenotype Correlations EXPH5. Pathogenic variants in EXPH5 are rare, with only seven cases reported to date. All reported pathogenic variants resulting in EXPH5-related EBS are loss-of-function variants that can be located anywhere in the gene. KRT5 and KRT14. A moderate correlation exists between the EBS phenotypes and the functional domain of either KRT5 or KRT14 in which the pathogenic variant is located [reviewed in Irvine & McLean 2003, Müller et al 2006]: * Pathogenic variants in the nonhelical linker segments (L1 and L2) and in the 1A segment of the rod domain are associated with EBS-loc. * Pathogenic variants in the 1A or 2B segments of the rod domain of KRT5 and KRT14 are common for EBS-gen intermed. * Pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of KRT5 and beginning of the 1A or 2B segments of the rod domain of KRT5 and KRT14 are typical in EBS-gen sev. * The p.Pro25Leu and c.1649delG pathogenic variants in KRT5 are associated with EBS-MP. Two pathogenic variants are described in KRT14 [see Harel et al 2006, Arin et al 2010]. ### Penetrance Penetrance is 100% for known heterozygous (autosomal dominant) and biallelic (autosomal recessive) KRT5 and KRT14 pathogenic variants. Penetrance is also 100% for known biallelic pathogenic variants in EXPH5 and TGM5. Disease severity may be influenced by other factors and may show intrafamilial variation [Indelman et al 2005]. ### Nomenclature In 1886, Koebner coined the term epidermolysis bullosa hereditaria. In the late nineteenth and early twentieth centuries, Brocq and Hallopeau coined the terms traumatic pemphigus, congenital traumatic blistering, and acantholysis bullosa; these terms are no longer in use [Fine et al 1999]. The nomenclature for EBS has changed four times in the last fifteen years. The eponyms EBS-Weber-Cockayne and EBS-Koebner were changed to EBS, localized and EBS-other generalized in the 2008 classification system [Fine et al 2008]. The most recent classification system, referred to as the "onion skin" terminology, arose from the most recent international consensus meeting, the recommendations of which were published in June 2014 [Fine et al 2014]. This classification system expands on the histologic description and specific pathogenic variants found in affected individuals (see Table 4). ### Table 4. Comparison of 2008 Nomenclature with Proposed "Onion Skin" Terminology: Representative Examples View in own window Old Name (per 2008 recommendations)2014 Nomenclature EBS, localizedEBS localized, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type) EBS, Dowling-MearaEBS generalized severe, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type) EBS, generalized otherEBS generalized intermediate, normal keratin 5 and 14 staining, KRT5 or KRT14 pathogenic variant (specify type) EBM-MPEBS-MP, normal keratin 5 staining, KRT5 pathogenic variant (specify type) EBS = epidermolysis bullosa simplex; MP = mottled pigmentation ### Prevalence The prevalence of EBS is uncertain; estimates range from 1:30,000 to 1:50,000. EBS-loc is most prevalent as it does not result in neonatal death and interferes least with fitness. EBS-gen sev and EBS-gen intermed are rare, and EBS-MP is even rarer. The experience of the National Epidermolysis Bullosa Registry (NEBR) suggests that ascertainment is highly biased and incomplete. Horn and colleagues estimate a prevalence of 28.6 per million in Scotland, and prevalence estimates from other countries range from one to 28 per million [Horn et al 1997]. ## Differential Diagnosis According to the 2014 classification system, the four major types of epidermolysis bullosa (EB), caused by pathogenic variants in 18 different genes, are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome [Fine et al 2014]. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features and supported by molecular diagnosis. The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring — especially in young children and neonates — may not be established or significant enough to allow identification of EB type; thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators. Post-inflammatory changes, such as those seen in EBS-sev gen, are often mistaken for scarring or mottled pigmentation. Scarring can occur in simplex and junctional EB as a result of infection of erosions or scratching, which further damages the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature. Corneal erosions, esophageal strictures, and nail and tooth enamel involvement may indicate either DEB or JEB. In milder cases, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB. Other subtypes of EB simplex (EBS). The 2014 classification system divides EBS into two subtypes based on the location of blistering in the epidermis. In the suprabasal forms of EBS, blistering occurs above the basal keratinocytes. The suprabasal forms of EBS include: EBS superficialis; EBS acantholytic; and skin fragility syndromes resulting from deficiencies of desmoplakin, plakoglobin, or plakophilin. * Acantholytic EBS is caused by biallelic pathogenic variants in the tail region of DSP, which encodes desmoplakin [Jonkman et al 2005, Bolling et al 2010, Hobbs et al 2010]. Affected neonates present with progressive erosions without blistering, alopecia, or loss of nails. Death within the first days after birth secondary to profound fluid and electrolyte imbalance is common. * EBS-plakophilin (skin fragility-ectodermal dysplasia syndrome) is characterized by mild skin fragility associated with perioral cracking and cheilitis, hypotrichosis or alopecia, and a painful and fissured palmoplantar keratoderma; it is caused by biallelic loss-of-function variants in PKP1 (for review, see McGrath & Mellerio [2010]). In the basal forms of EBS, blistering occurs within the basal keratinocytes. The most common subtypes of basal EBS are the subject of this GeneReview. Other rare forms of basal EBS in the 2014 classification are: EBS, migratory circinate (EBS-migr); EBS with muscular dystrophy (EBS-MD); EBS with pyloric atresia (EBS-PA); EBS-Ogna (EBS-Og); and EBS, autosomal recessive-BP230 deficiency (EBS-AR BP230). EB caused by pathogenic variants in PLEC. Biallelic and heterozygous pathogenic variants in PLEC, the gene encoding plectin, which is located in the hemidesmosomes of the basement membrane zone of skin and muscle cells, cause cleavage in the basal keratinocyte layer. Hence, these disorders are classified as EBS in the 2014 classification system. In most cases, the associated phenotypes (i.e., EB with muscular dystrophy, EB with pyloric atresia) are more complex: * EB with muscular dystrophy (OMIM 226670). Some individuals with EB resulting from biallelic pathogenic variants in PLEC1 develop muscular dystrophy either in childhood or later in life [Smith et al 1996, Shimizu et al 1999, Charlesworth et al 2003, Koss-Harnes et al 2004, Schara et al 2004, Pfendner et al 2005a]. Within basal keratinocytes, plectin is localized to the inner plaques of the hemidesmosomes, which are hypoplastic and show poor association with keratin filaments. Electron microscopy of skin biopsies reveals a plane of cleavage (level of separation) within the bottom layer of the basal keratinocytes, just above the hemidesmosomes. Inheritance is autosomal recessive. * EB with pyloric atresia is associated with biallelic premature termination pathogenic variants in PLEC. An identical phenotype is seen in JEB with pyloric atresia caused by the genes encoding alpha 6 integrin (ITGA6) or beta 4 integrin (ITGB4) [Nakamura et al 2005, Pfendner & Uitto 2005]. Disease course is severe and usually lethal in the neonatal period. Inheritance is autosomal recessive. * EB-Ogna (OMIM 131950) was originally described in one Norwegian and one German family and is caused by a heterozygous site-specific pathogenic missense variant within the rod domain of PLEC [Koss-Harnes et al 2002]. In these cases, transmission electron microscopy of a skin biopsy identified the cleavage plane to be just above the inner plates of the hemidesmosomes in the deep basal cell cytoplasm. Immunofluorescence staining of a skin biopsy showed reduced and/or patchy plectin staining. Inheritance is autosomal dominant. More recent work by Bolling and colleagues [2014] in the Netherlands demonstrated that approximately 40% of individuals with biopsy-proven EBS who lack identifiable pathogenic variants in KRT5 or KRT14 have a heterozygous pathogenic variant in PLEC. This work suggests that mutation of PLEC1 may be more common than previously realized. Junctional EB (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers, and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. The broad classification of JEB is divided into generalized and localized major subtypes with subordinate phenotypic subtypes. JEB, generalized includes: JEB, generalized severe (JEN-gen sev, formerly Herlitz JEB); JEN, generalized intermediate (JEB-gen intermed); JEN with pyloric atresia (JEB-PA); JEB-late onset (JEB-LO); and JEB with respiratory and renal involvement (JEB-RR). In JEB-gen sev, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB-gen intermed, the phenotype may be milder with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, and joint contractures. Biallelic pathogenic variants in one of the following four genes are known to cause JEB: LAMB3 (70% of all JEB), COL17A1 (12%), LAMC2 (9%), and LAMA3 (9%). JEB with pyloric atresia has been associated with biallelic pathogenic variants in either α6β4 integrin or plectin (see EBS with pyloric atresia); inheritance is autosomal recessive. Dystrophic EB (DEB). The blister forms below the basement membrane, in the superficial dermis. The basement membrane is attached to the blister roof, resulting in scarring when blisters heal. Both heterozygous and biallelic pathogenic variants in COL7A1, the gene encoding type VII collagen, have been associated with DEB. The designation Bart syndrome (OMIM 132000) is not used in the current classification of EB. Bart characterized a kindred with congenital absence of the skin on the lower legs and feet, non-scarring blistering of the skin and oral mucosa, and nail abnormalities. Genetic studies of the original kindred identified heterozygous pathogenic variants in COL7A1 [Christiano et al 1996], and some consider Bart syndrome to be most often, but not exclusively, a manifestation of dominant DEB. However, congenital absence of skin can be seen in all forms in EB and may not be a distinguishing feature of any particular form of EB. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the following evaluations are recommended: * Consultation with a dermatologist to evaluate the sites of blister formation, including oral mucosa * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing of open wounds, and prevention and treatment of secondary infection are the mainstays of EB treatment. Encourage children to tailor their activities to minimize trauma to the skin while participating as much as possible in age-appropriate play. Lance and drain new blisters to prevent further spread from fluid pressure. Dressings usually involve three layers: * A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary bandages. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline® Gauze, Adaptic®, Xeroform). Nonstick products (e.g., Telfa or N-Terface®) or silicone-based products without adhesive (e.g., Mepitel® or Mepilex®) are also popular. * A secondary layer absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or rolls of gauze (e.g., Kerlix®) are commonly used. * A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters, such as BandNet®). Note: Many individuals with EBS, in contrast to those with junctional EB and dystrophic EB, find that excessive bandaging may actually lead to more blistering, presumably as a result of increased heat and sweating. Such individuals may benefit from dusting the affected areas with corn starch to help absorb moisture and reduce friction on the skin, followed by a simple (i.e., one-layer) dressing. ### Prevention of Primary Manifestations In the following studies, small sample sizes limit the statistical validity and generalizability of the results; however, given the lack of effective treatments for EBS, these potentially helpful treatments should be considered on a case-by-case basis: * 20% aluminum chloride applied to palms and soles can reduce blister formation in some individuals with EBS, presumably by decreasing sweating. * A case report [Abitbol & Zhou 2009] and small study [Swartling et al 2010] suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin. * In one study of a limited number of individuals with EBS-gen sev, cyproheptadine (Periactin®) reduced blistering. This may result from the anti-pruritic effect of the medication, but the true mechanism is not clear [Neufeld-Kaiser & Sybert 1997]. * In another study, tetracycline reduced blister counts in two thirds of persons with EBS-loc [Weiner et al 2004]. A recent study evaluated three months of oral erythromycin therapy in six children ages one to eight years with EBS-gen sev, and showed the medication was well tolerated and improved blistering in three children [Chiaverini et al 2015]. An anti-inflammatory mechanism, rather an anti-microbial mechanism, is proposed for the effect of antibiotics in the treatment of EBS. Other. Use of keratolytics and softening agents such as urea for palmar plantar hyperkeratosis has some benefit in preventing tissue thickening and cracking. In addition, soaking the hands and feet in salt water helps soften hyperkeratosis and ease debridement of the thick skin. ### Prevention of Secondary Complications Infection is the most common secondary complication. Surveillance for wound infection is important and treatment with topical and/or systemic antibiotics or silver-impregnated dressings or gels can be helpful. Additional nutritional support may be required for failure to thrive in infants and children with EBS-gen sev or EBS-gen intermed who have more severe involvement. Infants with significant oral disease may develop an aversion to eating by mouth, even after oral disease improves. The involvement of a feeding therapist in these cases is suggested. Management of fluid and electrolyte problems is critical, as they can be significant and even life-threatening in the neonatal period and in infants with widespread disease. Some children have delays or difficulty walking because of blistering and hyperkeratosis, especially in EBS-gen sev. Appropriate footwear and physical therapy are essential to preserve ambulation. ### Surveillance Surveillance for infection and proper wound healing is indicated. ### Agents/Circumstances to Avoid Excessive heat may exacerbate blistering and infection in EBS. Poorly fitting or coarse-textured clothing and footwear can cause trauma and should be avoided. Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage, but affected individuals who are determined to find ways to participate in these endeavors should be encouraged. Many individuals with EBS cannot use ordinary medical tape or Band-Aids®. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management If a fetus is known to be affected with any form of EB, caesarean delivery may reduce the trauma to the skin during delivery. ### Therapies Under Investigation Proposed approaches to gene therapy for EBS include use of ribozymes, addition of other functional proteins [D'Alessandro et al 2004], induction of a compensating pathogenic variant [Smith et al 2004a], and use of pathogenic variant-specific siRNAs [Atkinson et al 2011]; no clinical trials have been carried out. The inducible mouse model for EBS should facilitate the development of these therapeutic approaches [Arin & Roop 2004]. 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. ### Other The use of corticosteroids and vitamin E in treating EBS has been reported anecdotally; no rigorous clinical trials have been undertaken. [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	Epidermolysis Bullosa Simplex	c0079298	2,828	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1369/	2021-01-18T21:28:35	{"mesh": ["D016110"], "synonyms": []}
Beta-mannosidosis Other namesBeta-mannosidase deficiency, MANSB This condition is autosomal recessive in inheritance SpecialtyMedical genetics SymptomsRespiratory infections, Hearing loss and Intellectual disability.[1] CausesMutations in the MANBA gene[2] Diagnostic methodUrine test[3] TreatmentBased on symptoms[4] Beta-mannosidosis, also called lysosomal beta-mannosidase deficiency,[5] is a disorder of oligosaccharide metabolism caused by decreased activity of the enzyme beta-mannosidase. This enzyme is coded for by the gene MANBA, located at 4q22-25. Beta-mannosidosis is inherited in an autosomal recessive manner.[5] Affected individuals appear normal at birth, and can have a variable clinical presentation. Infantile onset forms show severe neurodegeneration, while some children have intellectual disability. Hearing loss and angiokeratomas are common features of the disease.[3][2] ## Contents * 1 Symptoms and signs * 2 Cause * 3 Mechanism * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 See also * 7 References * 8 Further reading * 9 External links ## Symptoms and signs[edit] Angiokreatoma The initial affected individual described in 1986 had a complex phenotype, and was later found to have both beta-mannosidosis and Sanfilippo syndrome.[5] People have been described with a wide spectrum of clinical presentations from infants and children with intellectual disability to adults who present with isolated skin findings (angiokeratomas).[5] Most cases are identified in the first year of life with respiratory infections, hearing loss and intellectual disability. Because of its rarity, and non-specific clinical findings, beta-mannosidosis can go undiagnosed until adulthood, where it can present with intellectual disability and behavioral problems, including aggression.[6][1] ## Cause[edit] In terms of causation several mutations in the MANBA gene is the cause of beta-mannosidosis. The cytogenetic location of the gene is 4q24, furthermore the condition is inherited in an autosomal recessive manner[7][2] ## Mechanism[edit] Mannose The pathophysiology of this condition, is better comprehended, if one first looks at the normal function of beta-mannosidase such as its function of breaking down disaccharides[medical citation needed] Beta-mannosidase function is consistent with, it being a lysosomal enzyme catalyzing and thus involved in degradation route for N-linked oligosaccharide moieties(glycoproteins)[8] ## Diagnosis[edit] Urine test A diagnosis of beta-mannosidosis is suspected based on the persons clinical presentation. Urine testing to identify abnormal oligosaccharides is a useful screening test, and enzymatic analysis or molecular testing can be used for confirmation.[3] ### Differential diagnosis[edit] Diagnostic techniques for this condition can be done to offer a DDx, via lectin histochemistry to distinguish between α-mannosidosis and beta-mannosidosis.[9] ## Treatment[edit] In terms of beta-mannosidosis treatment there is none currently, individuals that exhibit muscle weakness or seizures are treated based on the symptoms (since there's no cure)[4] ## See also[edit] * Beta-mannosidase * Alpha-mannosidosis ## References[edit] 1. ^ a b "Mannosidosis, beta A, lysosomal \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-07-13. 2. ^ a b c Reference, Genetics Home. "beta-mannosidosis". Genetics Home Reference. Retrieved 2017-07-13. 3. ^ a b c Enns, Gregory M.; Steiner, Robert D.; Cowan, Tina M. (2009). "Lysosomal Disorders". In Sarafoglou, Kiriakie; Hoffmann, Georg F.; Roth, Karl S. (eds.). Pediatric Endocrinology and Inborn Errors of Metabolism (1st ed.). New York: McGraw-Hill Medical. pp. 721–755. ISBN 978-0-07-143915-2. 4. ^ a b Kelly, Evelyn B. (2013). Encyclopedia of Human Genetics and Disease. ABC-CLIO. p. 514. ISBN 9780313387135. Retrieved 10 December 2017. 5. ^ a b c d Online Mendelian Inheritance in Man (OMIM): 248510 6. ^ Sedel, F.; Baumann, N.; Turpin, J. -C.; Lyon-Caen, O.; Saudubray, J. -M.; Cohen, D. (2007). "Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults". Journal of Inherited Metabolic Disease. 30 (5): 631–641. doi:10.1007/s10545-007-0661-4. PMID 17694356. S2CID 8419283.subscription required 7. ^ Reference, Genetics Home. "MANBA gene". Genetics Home Reference. Retrieved 2017-10-25. 8. ^ "OMIM Entry - * 609489 - MANNOSIDASE, BETA A, LYSOSOMAL; MANBA". www.omim.org. Retrieved 9 May 2018. 9. ^ Johnson, William (2015). Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth ed.). Academic Press. pp. 369–383. ISBN 978-0-12-410529-4. ## Further reading[edit] * Molho-Pessach, Vered; Bargal, Ruth; Abramowitz, Yigal; Doviner, Victoria; Ingber, Arieh; Raas-Rothschild, Annick; Ne'eman, Zvi; Zeigler, Marsha; Zlotogorski, Abraham (2007). "Angiokeratoma corporis diffusum in human beta-mannosidosis: Report of a new case and a novel mutation". Journal of the American Academy of Dermatology. 57 (3): 407–412. doi:10.1016/j.jaad.2007.01.037. ISSN 1097-6787. PMID 17420068. * Huynh, T; Khan, JM; Ranganathan, S (30 November 2011). "A comparative structural bioinformatics analysis of inherited mutations in β-D-Mannosidase across multiple species reveals a genotype-phenotype correlation". BMC Genomics. 12 Suppl 3: S22. doi:10.1186/1471-2164-12-S3-S22. ISSN 1471-2164. PMC 3333182. PMID 22369051. ## External links[edit] Classification D * ICD-10: E77.1 * OMIM: 248510 * MeSH: D044905 * DiseasesDB: 34529 External resources * Orphanet: 118 Scholia has a topic profile for Beta-mannosidosis. * v * t * e Lysosomal storage diseases: Inborn errors of carbohydrate metabolism (Glycoproteinoses) Anabolism * Dolichol kinase deficiency * Congenital disorder of glycosylation Post-translational modification of lysosomal enzymes * Mucolipidosis: I-cell disease (ML II) * Pseudo-Hurler polydystrophy (ML III) Catabolism * Aspartylglucosaminuria * Fucosidosis * mannosidosis * Alpha-mannosidosis * Beta-mannosidosis * Sialidosis * Schindler disease Other * solute carrier family (Salla disease) * Galactosialidosis * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [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	Beta-mannosidosis	c2931893	2,829	wikipedia	https://en.wikipedia.org/wiki/Beta-mannosidosis	2021-01-18T18:54:53	{"mesh": ["D044905"], "umls": ["C0342849"], "icd-10": ["Q77.1"], "orphanet": ["118"], "wikidata": ["Q291617"]}
Premature closure of the arterial duct is a rare arterial duct anomaly, defined as a significant constriction or closure of the fetal arterial duct in the absence of structural heart defects with pathognomonic features of increased right ventricular afterload, tricuspid regurgitation and, consequently, right atrial dilation and right ventricular hypertrophy. The severity of symptoms is related to the degree and rate of ductal constriction and ranges from mild postnatal respiratory distress to development of ventricular failure with fetal hydrops and intrauterine death or severe cardiopulmonary compromise in the postnatal period. It may be associated with a prenatal exposure to cyclooxygenase inhibitors or corticosteroids. [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	Premature closure of the arterial duct	None	2,830	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=95486	2021-01-23T17:00:09	{"icd-10": ["Q25.8"], "synonyms": ["Premature closure of the patent ductus arteriosus"]}
LAMA2-related muscular dystrophy is a disorder that causes weakness and wasting (atrophy) of muscles used for movement (skeletal muscles). This condition varies in severity, from a severe, early-onset type to a milder, late-onset form. Early-onset LAMA2-related muscular dystrophy is apparent at birth or within the first few months of life. It is considered part of a class of muscle disorders called congenital muscular dystrophies and is sometimes called congenital muscular dystrophy type 1A. Affected infants may have severe muscle weakness, lack of muscle tone (hypotonia), little spontaneous movement, and joint deformities (contractures). Weakness of the muscles in the face and throat can result in feeding difficulties and an inability to grow and gain weight at the expected rate. Respiratory insufficiency, which occurs when muscles in the chest are weakened, causes a weak cry and breathing problems that can lead to frequent, potentially life-threatening lung infections. As affected children grow, they often develop an abnormal, gradually worsening side-to-side curvature of the spine (scoliosis) and inward curvature of the back (lordosis). Children with early-onset LAMA2-related muscular dystrophy often do not develop the ability to walk. Difficulty with speech may result from weakness of the facial muscles and an enlarged tongue. Seizures occur in about a third of individuals with early-onset LAMA2-related muscular dystrophy; rarely, heart complications occur in this form of the disorder. Symptoms of late-onset LAMA2-related muscular dystrophy become evident later in childhood or adulthood, and are similar to those of a group of muscle disorders classified as limb-girdle muscular dystrophies. In late-onset LAMA2-related muscular dystrophy, the muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs. Children with late-onset LAMA2-related muscular dystrophy sometimes have delayed development of motor skills such as walking, but generally achieve the ability to walk without assistance. Over time, they may develop rigidity of the back, joint contractures, scoliosis, and breathing problems. However, most affected individuals retain the ability to walk and climb stairs. ## Frequency The prevalence of LAMA2-related muscular dystrophy is estimated at between 1 in 50,000 and 1 in 400,000 individuals worldwide. This condition is thought to be the most common type of congenital muscular dystrophy, accounting for between 30 and 40 percent of total cases. ## Causes As its name suggests, LAMA2-related muscular dystrophy is caused by mutations in the LAMA2 gene. This gene provides instructions for making a part (subunit) of certain members of a protein family called laminins. Laminin proteins are made of three different subunits called alpha, beta, and gamma. There are several forms of each subunit, and each form is produced from instructions carried by a different gene. The LAMA2 gene provides instructions for the alpha-2 subunit. This subunit is found in the laminin 2 protein, also known as merosin; it is also part of another laminin protein called laminin 4. Laminins are found in an intricate lattice of proteins and other molecules that forms in the spaces between cells (the extracellular matrix). Laminin 2 and laminin 4 play a particularly important role in the skeletal muscles. The laminins attach (bind) to other proteins in the extracellular matrix and in the membrane of muscle cells, which helps maintain the stability of muscle fibers. Most LAMA2 gene mutations that cause the severe, early-onset form of LAMA2-related muscular dystrophy result in the absence of functional laminin alpha-2 subunit. Mutations that cause the milder, later-onset form usually result in a reduction (deficiency) of functional laminin alpha-2 subunit. Deficiency or absence of the laminin alpha-2 subunit results in a corresponding lack of laminin 2 and laminin 4, reducing the strength and stability of muscle tissue and leading to the signs and symptoms of LAMA2-related muscular dystrophy. ### Learn more about the gene associated with LAMA2-related muscular dystrophy * LAMA2 ## 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 [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	LAMA2-related muscular dystrophy	c1263858	2,831	medlineplus	https://medlineplus.gov/genetics/condition/lama2-related-muscular-dystrophy/	2021-01-27T08:25:08	{"gard": ["3843"], "mesh": ["C537384"], "omim": ["607855"], "synonyms": []}
Not to be confused with Ectromelia virus. Ectromelia SpecialtyOrthopedic Ectromelia is a congenital condition where long bones are missing or underdeveloped.[1]Examples include: * Amelia * Hemimelia * Phocomelia * Sirenomelia ## References[edit] 1. ^ "ectromelia" at Dorland's Medical Dictionary ## External links[edit] Classification D * ICD-10: Q73.8 * ICD-9-CM: 755.20, 755.30, 755.4 * MeSH: D004480 * SNOMED CT: 43036001 * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome This article about a disease of musculoskeletal and connective tissue 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	Ectromelia	c0013589	2,832	wikipedia	https://en.wikipedia.org/wiki/Ectromelia	2021-01-18T18:45:47	{"mesh": ["D004480"], "icd-9": ["755.30", "755.4", "755.20"], "icd-10": ["Q73.8"], "wikidata": ["Q1323724"]}
For a general phenotypic description and a discussion of genetic heterogeneity of hot water epilepsy, see HWE1 (613339). Clinical Features Ratnapriya et al. (2009) reported a 4-generation family from southern India in which 10 individuals had hot water epilepsy. All had complex partial seizures precipitated by a hot water head bath. The proband also developed secondary generalized tonic-clonic seizures. Two other affected individuals had a history of febrile seizures (121210). Inheritance The inheritance pattern of hot water epilepsy in the family reported by Ratnapriya et al. (2009) was autosomal dominant with reduced penetrance. Mapping By genomewide analysis of a large 4-generation family from southern India with hot water epilepsy, Ratnapriya et al. (2009) found linkage to chromosome 4q24-q28 (maximum 2-point lod score of 3.50 at D4S402). Haplotype analysis identified a 24.0-Mb (22.5-cM) region on chromosome 4q24-q28 between markers D4S1572 and D4S2277. [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	EPILEPSY, HOT WATER, 2	c3150536	2,833	omim	https://www.omim.org/entry/613340	2019-09-22T15:59:04	{"omim": ["613340", "613339"], "orphanet": ["166412"], "synonyms": []}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Premature heart beat" – news · newspapers · books · scholar · JSTOR (March 2015) (Learn how and when to remove this template message) Premature heart beat A premature ventricular contraction marked by the arrow. SpecialtyCardiology A premature heart beat is a heart rhythm disorder corresponding to a premature contraction of one of the chambers of the heart. Premature heart beats come in two different types, premature atrial contractions and premature ventricular contractions. Often they cause no symptoms but may present with fluttering in the chest or a skipped beat. Typically have no long term complications. They most often happen naturally but may be associated with caffeine, nicotine, or stress. Usually no treatment is needed. They are the most common arrhythmia.[1] ## Contents * 1 Physiopathology * 2 Diagnosis * 3 References * 4 External links ## Physiopathology[edit] The normal heart contraction comes from a cyclic membrane depolarization (reversal of the electrical polarity of the cell membrane) of a group of cells located on the upper part of the right atrium, the sinoatrial node. This depolarization spreads to the whole heart and causes muscle cells to contract. It is followed by a "refractory period", a short time when the cells are no longer stimulable. The heart rate is controlled by this node. ## Diagnosis[edit] Premature heart beat revealed by laser Doppler imaging by digital holography of the eye fundus Premature heart beat revealed by blood flow pulse wave in the central retinal artery (red) and vein (blue) by laser Doppler imaging. Premature heart beats can be asymptomatic (the patient does not complain about anything). The subject may experience palpitations, a feeling of cardiac "pause". Taking (prolonged) pulse may result in a rhythm that seems irregular. Electrocardiography and laser Doppler imaging[2] allow to visualize Premature heart beats. From their appearance, their location can be assessed. The Holter monitor allows to quantify them, to specify their characteristics and their repetition. ## References[edit] 1. ^ "Types of Arrhythmia". nhlbi.nih.gov. July 1, 2011. Archived from the original on June 7, 2015. Retrieved March 7, 2015. 2. ^ Puyo L, Paques M, Fink M, Sahel JA, Atlan M (October 2019). "Waveform analysis of human retinal and choroidal blood flow with laser Doppler holography". Biomedical Optics Express. 10 (10): 4942–4963. doi:10.1364/BOE.10.004942. PMC 6788604. PMID 31646021. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx * MeSH: D005117 [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	Premature heart beat	c0340464	2,834	wikipedia	https://en.wikipedia.org/wiki/Premature_heart_beat	2021-01-18T18:51:55	{"mesh": ["D005117"], "umls": ["C0340464"], "icd-9": ["427.6"], "wikidata": ["Q840646"]}
Autosomal recessive spastic paraplegia type 61 (SPG61) is a rare, complex form of hereditary spastic paraplegia characterized by an onset in infancy of spastic paraplegia (presenting with the inability to walk unsupported and a scissors gait) associated with a motor and sensory polyneuropathy with loss of terminal digits and acropathy. SPG61 is due to a mutation in the ARL6IP1 gene (16p12-p11.2) encoding the ADP-ribosylation factor-like protein 6-interacting protein 1. [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	Autosomal recessive spastic paraplegia type 61	c3810294	2,835	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=401780	2021-01-23T17:00:55	{"omim": ["615685"], "icd-10": ["G11.4"], "synonyms": ["SPG61"]}
Familial aortic dissection Other namesCystic medial necrosis of aorta, Annuloaortic ectasia Aorta Familial aortic dissection or FAD refers to the splitting of the wall of the aorta in either the arch, ascending or descending portions. FAD is thought to be passed down as an autosomal dominant disease and once inherited will result in dissection of the aorta, and dissecting aneurysm of the aorta, or rarely aortic or arterial dilation at a young age. Dissection refers to the actual tearing open of the aorta. However, the exact gene(s) involved has not yet been identified.[1] It can occur in the absence of clinical features of Marfan syndrome and of systemic hypertension.[2][3][4][5][6] Over time this weakness, along with systolic pressure, results in a tear in the aortic intima layer thus allowing blood to enter between the layers of tissue and cause further tearing. Eventually complete rupture of the aorta occurs and the pleural cavity fills with blood. Warning signs include chest pain, ischemia, and hemorrhaging in the chest cavity. This condition, unless found and treated early, usually results in death. Immediate surgery is the best treatment in most cases.[7] FAD is not to be confused with PAU (penetrating atherosclerotic ulcers) and IMH (intramural hematoma), both of which present in ways similar to that of familial aortic dissection.[8] ## Contents * 1 Causes * 2 Physiology * 3 Diagnosis * 4 Treatment * 5 Research directions * 6 References * 7 External links ## Causes[edit] Inheritance is thought to be rather complex. There is a good amount of evidence that shows the disease is autosomal dominant, with some penetrance. There is also the possibility of age related dependence. It is known that Marfan’s Syndrome and Ehler-Danlos Syndrome lead to an increased risk for development of FAD. Marfan’s Syndrome is not required to have an aortic dissection.[9] One study suggests that the chromosomal locus for the gene is 5q13-14. The same study found that other genes may be linked, and include loci for Marfan and Ehler-Danlos Syndromes, genes for metalloproteinase 3 and 9, and tissue inhibitor of malloproteinase 2 as well as two loci on chromosomes 5q13-14 and lq23.2-24.[2][3] Still other studies show that mutations in smooth muscle cell-specific isoforms of alpha actin and beta myosin heavy chain may cause FAD.[10] Mutations in the genes TGFBR 1 and 2 are known to cause dissections in aortas with normal diameter size (>4.3 cm) and gene FPN1 mutations typically affect aortas with larger diameters (<4.4 cm).[11] There are several hypotheses which attempt to explain how the dissection physically occurs. The first states that a tear develops in the intima layer of the aorta which allows blood to flow from the lumen of the aorta into the intima. This event creates a dissection and essentially two lumens. The second hypothesis suggests that the vasa vasorum ruptures and causes a hemorrhage in the wall of the aorta. The hemorrhaging promotes tearing of the intima and eventually aortic dissection.[12] The major risk factors for FAD include high blood pressure, old age, haematoma, genetic weakening of aortic wall, cocaine use, pregnancy and diseases causing abnormal connective tissue.[7][12] One study found that the average age(s) for the occurrence of dissection caused by degenerative aneurysm is 65 years and up. Dissections thought to be the result of genetic mutations appear to be more likely to occur between the ages of 40 and 60. Another study found that 20% of patients with FAD have a close relative with a history of thoracic aortic aneurysm or dissection which suggests yet another major risk factor.[13] ## Physiology[edit] FAD is normally associated with Marfan syndrome, Ehlers–Danlos syndrome, and various other genetic disorders which affect the connective tissues of the cardiovascular system. There are various mechanisms by which the medial layers of the lumen are stressed and eventually torn.[14] Once torn these areas begin to fill with blood and become susceptible to aneurysm formation. Depending on the location of the tear, FAD normally affects the ascending or descending aorta, where the primary characteristic of a bulge can be seen. This bulge is the result of the creation of a false lumen due to the vast amount of blood seepage from the aortas and surrounding veins.[15] In some cases it is not uncommon to see degeneration in the ascending and descending aorta and the atrioventricular and semilunar valves due to elastolysis or breakdown and loss of elastic fibers. These connective tissue malfunctions are traceable to mutations, and lack of genes encoding for important components such as collagens, and micro-fibril-associated glycoproteins. Breakdown among these connective layers eventually compromises the integrity of the aortic lumen.[14] Depending on the extent of pooling and damage to the blood vessel, the Svensson system was created to diagnose and describe the five classes of pathological processes that may be visible due to the dissection. Class 1 refers to any dissection with a true and false lumen. Class 2 specifically depends on the presence of hematoma or hemorrhaging at the site of the dissection. Class 3 is a dissection without hematoma. Class 4 is recognized by the presence of an ulcer among the lumen. Class 5 has to do with any sort of traumatic hemorrhaging in the dissection.[16] Class 5, in the most case, is the most severe and life-threatening due to large amounts of rapid blood loss. Those experiencing aortic dissection typically will complain of agonizing pains described with a ripping feeling in the chest that for some may migrate to their backs.[8] Anything that compromises or obstructs the amount of blood flow and the delivery of nutrients and oxygen to the walls of the ascending and descending aorta has a large impact on the viability of the layers of the surrounding lumen. Chronic hypertension, Inflammatory disease, excessive plaque build-up among coronary walls, intimal thickening, and arteriosclerosis are all believed[by whom?] to increase the likelihood of FAD occurring in an individual. ## Diagnosis[edit] Since the cause of FAD has not been genetically pinpointed, the only way to diagnose FAD is through the examination of phenotypic variations in the aorta. Usually echocardiography is used to take measurements of the aortic root[17] as well as transesophageal echocardiography.[8] Biomarkers lend a quick way to diagnose dissection when time is of the essence. These have the ability to relay the levels of smooth muscle mysosin heavy chain protein present, which is released from damaged aortic tissue.[18] There are two types of FAD; groups A and B. Normally if any area of the ascending aorta is involved in the dissection this is considered group A. If the dissection occurs within the descending aorta this is classified in group B.[16] These two groups can than be broken down into three classes of FAD: Type 1, Type 2 and Type 3. Group A consists of Types 1 and 2, whereas Group B consists only of Type 3. Type 1 encompasses dissection in the distal ascending aorta closest to the heart, not including the aortic arch. Type 2 refers to dissection of the ascending aorta, closer to and including the aortic arch. Type 3 refers to the descending thoracic and abdominal aorta.[7] Group A dissections are the more serious of the two due to the location of the dissection in the ascending aorta, which leads to a higher risk of congestive heart failure and pericardium and/or aortic valve rupture. Individuals also tend to be predisposed to type A if they do have Marfans or Elhers-Danlos syndromes. These contribute to a higher fatality rate in group A dissection if immediate surgery is not performed. The most common corrective surgeries are actual aortic valve replacement and coronary artery bypass. The five year survival rate after surgery is a successful 70.4% due to vigilant monthly physical exams and chest x-rays to monitor progress. Group B dissections typically have a higher surgery mortality rate and are therefore not good candidates. Instead medical management is the common response to treating and keeping dissections of the descending aorta under control.[8] ## Treatment[edit] Type 1 and Type 2 FAD call for the same treatment: immediate surgery to replace the aorta. Surgery is required due to the high risk of mortality. Type 3 is less severe and requires the maintenance of blood pressure through diet and exercise. Upon diagnosing someone with FAD intravenous antihypertensive treatment is frequently used. Often intravenous sodium nitroprusside is used for its efficiency in lessening the pulsatile load thus reducing blood pressure. Reducing this force slows the progression of the dissection. Surgical success depends on age, severity of symptoms, postoperative organ dysfunction and stroke. Surgical intervention is always indicated in Type 1 cases. Aortic surgery is palliative, not curative. The goal is to merely to prevent rupture, restore blood flow, and fix any aortic valve dysfunction.[19] Post operative protocols include frequent monitoring of the aorta diameter. Statins and beta blockers are also popular treatments used to reduce future plaque build up and blockage of epinephrine receptors as a way to control heart rate and blood pressure.[18] Long term treatment should also include regular check ups every 3 to 6 months. A CT scan or MRI is recommended, along with required chest x-rays. Antihypertensive therapy with beta adrenergic antagonists is required regardless of medical versus surgical treatment. Ten to twenty percent of those who choose surgical intervention are re-operated on due to compression, aneurysm development or blood leakage.[19] ## Research directions[edit] Currently, there is controversy over whether or not inheritance truly plays a role in FAD, and if so which gene it acts upon. FAD does not come from strictly one predisposing factor, such as hypertension. It is suggested that the combination of environmental factors along with genetics may contribute to causing FAD. Before newer and more effective cures and therapies can be developed, first the specific gene mutation must be identified. Until such a gene is determined, scientists say patient education, and physician awareness is vital.[17] Currently scientists have found animal models to be beneficial in understanding the pathology behind FAD. In the future there is hope to develop drugs that will better support and strengthen the aortic wall. Endovascular methods of treatment are becoming increasingly popular, and scientists hope to use this technique in both acute and chronic cases.[16] ## References[edit] 1. ^ Nicod P, Bloor C, Godfrey M, et al. (1989). "Familial aortic dissecting aneurysm". Journal of the American College of Cardiology. 13 (4): 811–9. doi:10.1016/0735-1097(89)90221-0. PMID 2647812. 2. ^ a b Disertori M, Bertagnolli C, Thiene G, et al. (August 1991). "[Familial dissecting aortic aneurysm]". Giornale Italiano di Cardiologia (in Italian). 21 (8): 849–53. PMID 1769452. 3. ^ a b Cucchi G. (1997). "[Familial aortic dissection in a young woman. A clinical case and review of the literature]". Cardiologia (in Italian). 42 (2): 211–3. PMID 9138854. 4. ^ Marwick TH, Woodhouse SP, Birchley IN, Strong RW (1987). "Management of familial aortic dissection". Chest. 92 (5): 954–6. doi:10.1378/chest.92.5.954. PMID 3665621. Archived from the original on 2013-04-14. 5. ^ Milewicz DM, Guo DC, Tran-Fadulu V, et al. (2008). "Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction". Annual Review of Genomics and Human Genetics. 9: 283–302. doi:10.1146/annurev.genom.8.080706.092303. PMID 18544034. 6. ^ Guo DC, Pannu H, Tran-Fadulu V, et al. (2007). "Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections". Nature Genetics. 39 (12): 1488–93. doi:10.1038/ng.2007.6. PMID 17994018. 7. ^ a b c Prêtre R, Segesser V, Ludwig K (1997). "Aortic dissection". The Lancet. 349 (9063): 1461–4. doi:10.1016/S0140-6736(96)09372-5. PMID 9164331. 8. ^ a b c d Gallo A, Davies R, Coe M, Elefteriades J, Coady M (2005). "Indications, timing, and prognosis of operative repair of aortic dissections". Seminars in Thoracic and Cardiovascular Surgery. 17 (3): 224–35. doi:10.1053/j.semtcvs.2005.06.004. PMID 16253827. 9. ^ Milewicz D, Chen H, Park E, Petty E, Zaghi H, Pai G, Willing M, Patel V (1998). "Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections". The American Journal of Cardiology. 82 (4): 474–9. doi:10.1016/S0002-9149(98)00364-6. PMID 9723636. 10. ^ Wang L, Guo D, Cao J, Gong L, Kamm K, Regalado E, Li L, Shete S, He W, Zhu M, Offermanns S, Gilchrist D, Elefteriades J, Stull J, Milewicz D (2010). "Mutations in myosin light chain kinase cause familial aortic dissections". American Journal of Human Genetics. 87 (5): 701–7. doi:10.1016/j.ajhg.2010.10.006. PMC 2978973. PMID 21055718. 11. ^ Milewicz D, Regalado E, Guo P (2010). "Treatment guidelines for thoracic aortic aneurysms and dissections based on the underlying causative gene". The Journal of Thoracic and Cardiovascular Surgery. 140 (6): S2–S4. doi:10.1016/j.jtcvs.2010.07.027. PMC 3584588. PMID 21092790. 12. ^ a b Braverman A. (2011). "Aortic dissection: prompt diagnosis and emergency treatment are critical". Cleveland Clinic Journal of Medicine. 78 (10): 685–96. doi:10.3949/ccjm.78a.11053. PMID 21968475. 13. ^ Gleason T. (2005). "Heritable disorders predisposing to aortic dissection". Seminars in Thoracic and Cardiovascular Surgery. 17 (3): 274–81. doi:10.1053/j.semtcvs.2005.06.001. PMID 16253833. 14. ^ a b Nienaber C, Eagle K (2003). "Aortic dissection: new frontiers in diagnosis and management. Part I: from etiology to diagnostic strategies". Circulation. 108 (5): 628–35. doi:10.1161/01.CIR.0000087009.16755.E4. PMID 12900496. 15. ^ Lansman S, McCullough J, Nguyen K, Spielvogel D, Klein J, Galla J, Ergin M, Griepp R (1999). "Subtypes of acute aortic dissection". The Annals of Thoracic Surgery. 67 (6): 1975–8. doi:10.1016/S0003-4975(99)00419-1. PMID 10391351. 16. ^ a b c Golledge J, Eagle K (2008). "Acute aortic dissection". The Lancet. 372 (9632): 55–66. CiteSeerX 10.1.1.523.838. doi:10.1016/S0140-6736(08)60994-0. PMID 18603160. 17. ^ a b Kakko S, Räisänen T, Tamminen M, Airaksinen J, Groundstroem K, Juvonen T, Ylitalo A, Uusimaa P, Savolainen M (2003). "Candidate locus analysis of familial ascending aortic aneurysms and dissections confirms the linkage to the chromosome 5q13-14 in Finnish families". The Journal of Thoracic and Cardiovascular Surgery. 126 (1): 106–13. doi:10.1016/S0022-5223(03)00037-0. PMID 12878945. 18. ^ a b Mukherjee D, Eagle K (2005). "Aortic dissection--an update". Current Problems in Cardiology. 30 (6): 287–325. doi:10.1016/j.cpcardiol.2005.01.002. PMID 15973249. 19. ^ a b Chen K, Varon J, Wenker O, Judge D, Fromm R, Sternbach G (1997). "Acute thoracic aortic dissection: the basics". The Journal of Emergency Medicine. 15 (6): 859–67. doi:10.1016/S0736-4679(97)00196-0. PMID 9404805. ## External links[edit] Classification D * ICD-10: I71.0 * OMIM: 607086 External resources * Orphanet: 229 * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension [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	Familial aortic dissection	c0392775	2,836	wikipedia	https://en.wikipedia.org/wiki/Familial_aortic_dissection	2021-01-18T18:43:37	{"mesh": ["C536230"], "orphanet": ["229"], "wikidata": ["Q5432930"]}
A number sign (#) is used with this entry because properdin deficiency, also known as complement factor properdin deficiency (CFPD), is caused by mutation in the PFC gene (CFP; 300383). Description Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001). Clinical Features Davis and Forristal (1980) studied 2 families with partial properdin deficiency. In 1 family a brother and sister, and a daughter of the brother, showed deficiency. Two brothers were affected in the second family, with normal properdin levels in 4 sibs and both parents. Partial properdin deficiency was found to be innocuous. The fact that partial deficiency resulted in diminished C3 consumption in the presence of activators of both the alternative and the classic complement pathways suggested that complete absence would severely limit complement activation. Sjoholm et al. (1982) described a kindred in which 3 males, each in a different sibship (2 maternal first cousins and a maternal uncle of both), were shown to have a selective deficiency of properdin. One of the 3 died from a fulminant infection with Neisseria meningitidis group C. The family history showed 3 previous cases of similar infections with fatal outcome in males related to the 3 patients studied, in a manner consistent with X-linked recessive inheritance (see Ross and Densen, 1984). Heterozygotes were not clearly distinguished. Densen et al. (1987) reported a large family in which properdin deficiency was associated with meningococcal infection. The proband was a previously healthy 30-year-old man who worked as a logger and died with fulminant group Y meningococcal meningitis. A brother had died of fulminant group B meningococcal disease 16 years earlier at age 18. A second cousin had had 'spinal meningitis' at age 4 and 'black measles' at age 6, and had died of group Y meningococcal disease at age 19 during basic military training. Group Y disease was not epidemic in the recruit camp at that time. Gelfand et al. (1987) described a third family. The proband was a 9-year-old boy with recurrent pneumococcal bacteremia. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was found to be secondary to homozygous deficiency of C2. Both parents had half-normal levels of C2, compatible with autosomal recessive inheritance. The proband had profound deficiency of serum properdin. Properdin levels were normal in the father and half-normal in the mother, suggesting X-linked inheritance. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function. Fijen et al. (1989) presented the pedigree of a very large kindred, showing at least 9 affected males in 3 generations and 6 separate sibships. Properdin deficiency was found in 9 of 46 patients in whom meningococcal disease developed after the age of 10 years. All were males. C3 deficiency syndromes (see 613799) were found in 5, and homozygous deficiency of a terminal component (C5, C6, C7, or C8) was found in 9. Meningococcal infections recurred in 5 of the 9 patients with terminal complement component deficiencies but not in the other patients with complement deficiency. The meningococcal disease investigated was due to rare serotypes X, Y, Z, W135, or 29E. The common sera groups, A, B, and C, are seldom associated with complement deficiencies. Inheritance Multiple studies have shown that properdin deficiency is inherited as an X-linked recessive trait (Sjoholm et al., 1982, Ross and Densen, 1984, Gelfand et al., 1987). Tersmette-Steeynstra et al. (1986) described a family with frequent occurrence of meningococcal infections in males in an X-linked recessive pedigree pattern. The findings were consistent with properdin deficiency. Mensink and Schuurman (1987) stated that 8 families with X-linked recessive inheritance of selective properdin P deficiency were known to them. Some of the patients had fulminant and often fatal meningitis with Neisseria meningitidis. The oldest was 61 years of age. They suggested that this deficiency was not associated with recurrent infections. In the large family described by Densen et al. (1987), the cousin was related to the 2 brothers mentioned through his maternal grandfather. The pedigree and the laboratory findings were consistent with X-linked recessive inheritance. patient's serum fully reconstituted the alternative pathway function. Sjoholm et al. (1988) described a family with an X-linked properdin-dysfunctional state, apparently predisposing the affected persons to meningococcal disease. In the affected individuals, circulating levels of properdin were normal by immunochemical assay, but the properdin was functionally defective. Findings in obligate female carriers were consistent with random inactivation of normal and defective properdin alleles, in accordance with the Lyon hypothesis. Population Genetics In a study of complement deficiencies among patients with meningococcal disease in Israel, Schlesinger et al. (1990) observed properdin deficiency only in Sephardic Jews of Tunisian origin. A pedigree pattern consistent with X-linked recessive inheritance was described. By analyzing the hemolytic activity of the classic (CH50) and the alternative (AP50) complement pathways in the sera of 101 survivors of meningococcal infections and 59 survivors of severe pneumococcal and Haemophilus influenza infections, Schlesinger et al. (1993) found 3 propositi with properdin deficiency and identified 6 additional affected family members. They belonged to 3 unrelated families of Tunisian Jews who came to Israel from different parts of Tunisia. Two patients had a meningococcal infection at 15 and 16 years of age, respectively, and one had Haemophilus influenza meningitis at 1.5 years of age. In contrast to the fulminant and fatal course of meningococcal infection that had previously been described in some properdin-deficient patients, these patients had a relatively mild course. They were, of course, selected for survival. However, Schlesinger et al. (1993) suggested that properdin deficiency may not be as rare as generally thought. Diagnosis In a brother and maternal uncle of the 2 brothers first mentioned by Densen et al. (1987), properdin deficiency was found by laboratory tests. Unaffected male relatives showed properdin antigen levels averaging 128.0 ELISA units/ml whereas 5 obligate carrier females had levels averaging 45.6 units. Mapping In the Swedish family reported by Sjoholm et al. (1982), Goonewardena et al. (1987) tested for linkage with 17 RFLPs of known regional assignment on the X chromosome. Recombination was observed for all except OTC (300461) and DXS7. There were 7 and 5 informative meioses, respectively, for these 2 loci. Goonewardena et al. (1987, 1988) concluded that the locus for properdin deficiency is proximal to the DMD locus. DXS7 is located in band Xp11.3; OTC is located in band Xp21.1; DMD is located in band Xp21.2. Wadelius et al. (1989) also presented linkage data supporting location of the 'properdin deficiency gene' on the proximal part of Xp. Using microsatellite and other X-chromosome polymorphisms, Wadelius et al. (1992) performed linkage studies in 6 multigeneration families with different types of properdin deficiency. Based on multipoint data, it was found that the disease gene maps close to DXS255 (maximum lod = 13.3 at theta = 0.00) and DXS426 (maximum lod = 12.9 at theta = 0.00). There was no indication of genetic heterogeneity among the 6 families. Molecular Genetics Westberg et al. (1995) used direct solid-phase sequencing of the PFC gene to identify point mutations in type I (300383.0001) and type II (300383.0002) properdin deficiency defined as absent or low serum properdin, respectively. In a Dutch family, Fredrikson et al. (1996) identified a mutation in type III (300383.0005) properdin deficiency, defined as the presence of a dysfunctional properdin protein in serum. Kolble et al. (1993) used a dinucleotide repeat containing sequence less than 15 kb downstream of the properdin structural gene (Coleman et al., 1991; Nolan et al., 1992) for carrier detection by microsatellite haplotyping. A nonradioisotopic PCR-based method was used for microsatellite detection. Probable and definite carriers frequently showed properdin levels in the normal range. No recombinants between the microsatellite loci and properdin deficiency were detected, thus allowing identification of the defective allele in 3 pedigrees. In 10 Dutch families, van den Bogaard et al. (2000) identified 2 genetic defects responsible for properdin type I deficiency (300383.0003, 300383.0004). All amino acid substitutions were limited to conserved amino acids in exons 7 and 8, in contrast to premature stops that were found in other exons. Missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolized intracellularly. The decreased properdin levels found in some healthy females carrying 1 mutated properdin gene were studied for X inactivation. Most carriers with extremely low or high properdin levels showed preferential X inactivation for the normal or mutated X chromosome, respectively. The authors observed some exceptions, however, suggesting additional regulation of properdin excretion apart from X inactivation. Three unrelated families had the same mutation in exon 7 and another 3 unrelated families had the same mutation in exon 8, suggesting founder effect; the families with an identical properdin defect originated from the same regions within the Netherlands. INHERITANCE \- X-linked recessive IMMUNOLOGY \- Deficiency of properdin P factor \- Dysfunctional alternative complement pathway LABORATORY ABNORMALITIES \- Deficiency of serum properdin P factor MISCELLANEOUS \- Increased susceptibility to Neisseria infections MOLECULAR BASIS \- Caused by mutations in the properdin P factor gene (PFC, 300383.0001 ) ▲ 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	PROPERDIN DEFICIENCY, X-LINKED	c0398762	2,837	omim	https://www.omim.org/entry/312060	2019-09-22T16:17:41	{"omim": ["312060"], "orphanet": ["2966"], "synonyms": ["Alternative titles", "PROPERDIN P FACTOR DEFICIENCY", "COMPLEMENT FACTOR PROPERDIN DEFICIENCY", "PROPERDIN DEFICIENCY, TYPE I"]}
Sessile serrated lesion Other namesSessile serrated polyp (SSP) Sessile serrated adenoma (SSA) Micrograph of a sessile serrated lesion. H&E stain. SpecialtyGastroenterology SymptomsAsymptomatic ComplicationsColorectal cancer Diagnostic methodColonoscopy TreatmentPolypectomy A sessile serrated lesion (SSL) is a premalignant flat (or sessile) lesion of the colon, predominantly seen in the cecum and ascending colon. SSLs are thought to lead to colorectal cancer through the (alternate) serrated pathway.[1][2] This differs from most colorectal cancer, which arises from mutations starting with inactivation of the APC gene. Multiple SSLs may be part of the serrated polyposis syndrome.[3] ## Contents * 1 Signs and symptoms * 1.1 Serrated polyposis syndrome * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 History * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] SSLs, generally, are asymptomatic. They are typically identified on a colonoscopy and excised for a definitive diagnosis and treatment.[citation needed] ### Serrated polyposis syndrome[edit] Main article: serrated polyposis syndrome The serrated polyposis syndrome (SPS) is a relatively rare condition characterized by multiple and/or large serrated polyps of the colon. Serrated polyps include SSLs, hyperplastic polyps, and traditional serrated adenomas. Diagnosis of this disease is made by the fulfillment of any of the World Health Organization’s (WHO) clinical criteria.[4] ## Diagnosis[edit] SSLs are diagnosed by their microscopic appearance; histomorphologically, they are characterized by (1) basal dilation of the crypts, (2) basal crypt serration, (3) crypts that run horizontal to the basement membrane (horizontal crypts), and (4) crypt branching. The most common of these features is basal dilation of the crypts.[citation needed] Unlike traditional colonic adenomas (e.g. tubular adenoma, villous adenoma), they do not (typically) have nuclear changes (nuclear hyperchromatism, nuclear crowding, elliptical/cigar-shaped nuclei).[citation needed] * Low magnification micrograph of an SSL. * Intermediate magnification micrograph of an SSL. * High magnification micrograph of a SSL showing crypt branching. ## Treatment[edit] Complete removal of a SSL is considered curative. Several SSLs confer a higher risk of subsequently finding colorectal cancer and warrant more frequent surveillance. The surveillance guidelines are the same as for other colonic adenomas. The surveillance interval is dependent on (1) the number of adenomas, (2) the size of the adenomas, and (3) the presence of high-grade microscopic features.[5] ## Epidemiology[edit] Sessile serrated lesions account for about 25% of all serrated polyps.[6] ## History[edit] Sessile serrated adenomas were first described in 1996.[7] In 2019, the World Health Organization recommended the use of the term "sessile serrated lesion," rather than sessile serrated polyp or adenoma.[6] ## See also[edit] * Polyp table * Colonic polyps * Colorectal polyps * Colorectal carcinoma * Microsatellite instability ## References[edit] 1. ^ Rüschoff J, Aust D, Hartmann A (2007). "[Colorectal serrated adenoma: diagnostic criteria and clinical implications]". Verh Dtsch Ges Pathol (in German). 91: 119–25. PMID 18314605. 2. ^ Mäkinen MJ (January 2007). "Colorectal serrated adenocarcinoma". Histopathology. 50 (1): 131–50. doi:10.1111/j.1365-2559.2006.02548.x. PMID 17204027. 3. ^ Rosty, C.; Parry, S.; Young, JP. (2011). "Serrated polyposis: an enigmatic model of colorectal cancer predisposition". Pathol Res Int. 2011: 157073. doi:10.4061/2011/157073. PMC 3109311. PMID 21660283. 4. ^ World J Gastroenterol 2012 May 28; 18(20): 2452–2461 5. ^ Levine JS, Ahnen DJ (December 2006). "Clinical practice. Adenomatous polyps of the colon". N. Engl. J. Med. 355 (24): 2551–7. doi:10.1056/NEJMcp063038. PMID 17167138. 6. ^ a b Crockett, SD; Nagtegaal, ID (October 2019). "Terminology, Molecular Features, Epidemiology, and Management of Serrated Colorectal Neoplasia". Gastroenterology. 157 (4): 949–966.e4. doi:10.1053/j.gastro.2019.06.041. PMID 31323292. 7. ^ Torlakovic, E; Snover, DC (July 2006). "Sessile serrated adenoma: a brief history and current status". Critical Reviews in Oncogenesis. 12 (1–2): 27–39. doi:10.1615/critrevoncog.v12.i1-2.30. PMID 17078205. ## External links[edit] * Pathology of Serrated Colon Adenomas \- Medscape * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor [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	Sessile serrated lesion	c2732618	2,838	wikipedia	https://en.wikipedia.org/wiki/Sessile_serrated_lesion	2021-01-18T18:46:51	{"umls": ["C2732618"], "wikidata": ["Q15730674"]}
Bladder exstrophy Other namesEctopia vesicae Female baby with classical bladder exstrophy SpecialtyMedical genetics Bladder exstrophy is a congenital anomaly that exists along the spectrum of the exstrophy-epispadias complex, and most notably involves protrusion of the urinary bladder through a defect in the abdominal wall. Its presentation is variable, often including abnormalities of the bony pelvis, pelvic floor, and genitalia. The underlying embryologic mechanism leading to bladder exstrophy is unknown, though it is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm.[1] Exstrophy means the inversion of a hollow organ.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Management * 4.1 Surgery * 5 Prognosis * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] The classic manifestation of bladder exstrophy presents with: * A defect in the abdominal wall occupied by both the exstrophied bladder as well as a portion of the urethra * A flattened puborectal sling * Separation of the pubic symphysis * Shortening of a pubic rami * External rotation of the pelvis. Females frequently have a displaced and narrowed vaginal orifice, a bifid clitoris, and divergent labia.[3] ## Cause[edit] The cause is not yet clinically established but is thought to be in part due to failed reinforcement of the cloacal membrane by underlying mesoderm. ## Diagnosis[edit] In a small retrospective study of 25 pregnancies five factors were found to be strongly associated with a prenatal diagnosis of bladder exstrophy: * Inability to visualize the bladder on ultrasound * A lower abdominal bulge * A small penis with anteriorly displaced scrotum * A low set umbilical insertion * Abnormal widening of the iliac crests While a diagnosis of bladder exstrophy was made retrospectively in a majority of pregnancies, in only three cases was a prenatal diagnosis made.[4] ## Management[edit] The extreme rarity of the disease limits the surgical opportunities to practice the complex closure required in these patients. For this reason, patients have the best outcomes when the bladder closures are performed at high volume centers where surgical and nursing teams have extensive experience in caring for the disease. [5] The highest volume center in the United States, and the world, is the Johns Hopkins Hospital in Baltimore, Maryland; they have seen over 1300 exstrophy patients in the past 50 years. [6] Upon delivery, the exposed bladder is irrigated and a non-adherent film is placed to prevent as much contact with the external environment as possible. In the event the child was not born at a medical center with an appropriate exstrophy support team then transfer will likely follow. Upon transfer, or for those infants born at a medical center able to care for bladder exstrophy, imaging may take place in the first few hours of life prior to the child undergoing surgery.[3] Primary (immediate) closure is indicated only in those patients with a bladder of appropriate size, elasticity, and contractility as those patients are most likely to develop a bladder of adequate capacity after early surgical intervention.[7] Conditions that are absolute contraindications despite bladder adequacy include duplication of the penis or scrotum and significant bilateral hydronephrosis. ### Surgery[edit] Watercolour drawing of ectopia vesicae in a man aged 23 years, after operation Modern therapy is aimed at surgical reconstruction of the bladder and genitalia. Both males and females are born with this anomaly. Treatment is similar. In males treatments have been: In the modern staged repair of exstrophy (MSRE) the initial step is closure of the abdominal wall, often requiring a pelvic osteotomy. This leaves the patient with penile epispadias and urinary incontinence. At approximately 2–3 years of age the patient then undergoes repair of the epispadias after testosterone stimulation. Finally, bladder neck repair usually occurs around the age of 4–5 years, though this is dependent upon a bladder with adequate capacity and, most importantly, an indication that the child is interested in becoming continent. In some of the bladder reconstructions, the bladder is augmented with the addition of a segment of the large intestines to increase the volume capacity of the reconstructed bladder. (http://www.med.umich.edu/1libr/urology/BladderAugmentation.pdf) In the complete primary repair of exstrophy (CPRE) the bladder closure is combined with an epispadias repair, in an effort to decrease costs and morbidity.[8] This technique has, however, led to significant loss of penile and corporal tissue, particularly in younger patients.[9] In females treatment has included: Surgical reconstruction of the clitoris which is separated into two distinct bodies. Surgical reconstruction to correct the split of the mons, redefine the structure of the bladder neck and urethra. Vaginoplasty will correct the anteriorly displaced vagina. If the anus is involved, it is also repaired. Fertility remains and women who were born with bladder extrophy usually develop prolapse due to the weaker muscles of the pelvic floor.[10] ## Prognosis[edit] The most important criterion for improving long-term prognosis is success of the initial closure.[11][12] If a patient requires more than one closure their chance of continence drops off precipitously with each additional closure - at just two closures the chance of voiding continence is just 17%.[13] Even with successful surgery, people may have long-term complications.[14] Some of the most common include: * Vesicoureteral reflux * Bladder spasm * Bladder calculus * Urinary tract infections ## Epidemiology[edit] Occurring at a rate between 1 in 10,000 to 1 in 50,000 [15] with a male-to-female ratio of 2.3-6:1,[16][17][18] bladder exstrophy is relatively rare. For those individuals with bladder exstrophy who maintain their ability to reproduce, the risk of bladder exstrophy in their children is approximately 500-fold greater than the general population.[16] ## References[edit] 1. ^ Muecke EC: The role of the cloacal membrane in exstrophy: the first successful experimental study. J Urol 1964; 92:659. 2. ^ Larsen, WJ. (2001). Human embryology (3 ed.). Philadelphia, Pa.: Churchill Livingstone. p. 275. ISBN 0-443-06583-7. 3. ^ a b Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ, ed. Campbell-Walsh Urology. 10th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 124. 4. ^ Gearhart JP, Ben-Chaim J, Jeffs RD, et al: Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol 1995; 85:961. 5. ^ Nelson CP, Dunn RL, Wei JT, Gearhart JP. Surgical repair of bladder exstrophy in the modern era: contemporary practice patterns and the role of hospital case volume. Journal of Urology. 2005 Sep;174(3):1099-102. 6. ^ Kasprenski, M., Benz, K.S., Maruf, M., Jayman, J., DiCarlo, H., Gearhart, J.P. Modern Management of the Failed Bladder Exstrophy Closure: A 50 Year Experience. European Urology Focus. 2018. 7. ^ Gearhart JP, Jeffs RD: The bladder exstrophy-epispadias complex. In: Walsh PC, et al ed. Campbell's urology, 7th ed. Philadelphia: WB Saunders; 1998:1939. 8. ^ Grady, Mitchell, 1999. Grady R, Mitchell ME: Complete repair of exstrophy. J Urol 1999; 162:1415. 9. ^ Husmann, Gearhart, 2004. Husmann DA, Gearhart JP: Loss of penile glans and/or corpora following primary repair of bladder exstrophy using the complete penile disassembly technique. J Urol 2004; 172:1696. 10. ^ Moliterno, David (2013). Therapeutic advances in thrombosis. Chichester, West Sussex: Wiley-Blackwell. pp. 779–798. ISBN 9781405196253. 11. ^ The importance of a successful initial bladder closure in the surgical management of classical bladder exstrophy: analysis of 144 patients treated at the Johns Hopkins Hospital between 1975 and 1985. 1987 Feb;137(2):258–62. 12. ^ Closure of the exstrophic bladder: an evaluation of the factors leading to its success and its importance on urinary continence. 1989 Aug;142(2 Pt 2):522–4–discussion542–3. 13. ^ Failed exstrophy closure: management and outcome. 2010 Aug;6(4):381–4. 14. ^ Gargollo PC, Borer JG (2007). "Contemporary outcomes in bladder exstrophy". Current Opinion in Urology. 17 (4): 272–80. doi:10.1097/MOU.0b013e3281ddb32f. PMID 17558272. S2CID 6290323. 15. ^ Lattimer JK, Smith MJK: Exstrophy closure: a follow up on 70 cases. J Urol 1966; 95:356. 16. ^ a b Shapiro E, Jeffs RD, Gearhart JP, Lepor H: Muscarinic cholinergic receptors in bladder exstrophy: insights into surgical management. J Urol 1985; 134:309. 17. ^ Ives E, Coffey R, Carter CO: A family study of bladder exstrophy. J Med Genet 1980; 17:139. 18. ^ Lancaster PAL: Epidemiology of bladder exstrophy: a communication from the International Clearinghouse for Birth Defects monitoring systems. Teratology 1987; 36:221. ## External links[edit] Classification D * ICD-10: Q64.1 * ICD-9-CM: 753.5 * OMIM: 600057 * MeSH: D001746 * DiseasesDB: 33377 External resources * eMedicine: ped/704 * Orphanet: 93930 Wikimedia Commons has media related to Bladder exstrophy. * 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]: 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	Bladder exstrophy	c0005689	2,839	wikipedia	https://en.wikipedia.org/wiki/Bladder_exstrophy	2021-01-18T18:50:36	{"gard": ["6398"], "mesh": ["D001746"], "umls": ["C0005689"], "icd-10": ["Q64.1"], "orphanet": ["93930"], "wikidata": ["Q258858"]}
A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-4 (CMH4) is caused by heterozygous, homozygous, or compound heterozygous mutation in the gene encoding cardiac myosin-binding protein C (MYBPC3; 600958) on chromosome 11p11. For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600). Clinical Features Xin et al. (2007) studied 23 Old Order Amish infants with severe neonatal hypertrophic cardiomyopathy, 20 from the Geauga County settlement in Ohio, 1 from the Holmes County settlement in Ohio, and 2 from a settlement in New York. All of the infants presented with signs and symptoms of congestive heart failure during the first 3 weeks of life and had hypertrophic nonobstructive cardiomyopathy on echocardiography (ECG); life span averaged 3 to 4 months, and all died before 1 year of age except for 2 children who underwent cardiac transplantation. Kimura et al. (1997) stated that they identified a 2-bp deletion at codon 945 in the MYBPC3 gene in a patient with hypertrophic cardiomyopathy who also displayed Wolff-Parkinson-White ventricular preexcitation (WPW; 194200); they also detected the same mutation in 3 additional CMH patients without WPW. Kimura et al. (1997) noted that although a locus for 'CMH with WPW' had been mapped to chromosome 7q3 (CMH6; 600858), their findings indicated that more than 1 form of CMH is associated with WPW syndrome. Wang et al. (2013) studied a consanguineous Chinese family in which the 21-year-old proband was referred for cardiac evaluation after the sudden cardiac death of his 23-year-old brother, who had been diagnosed with CMH but was not offered an implantable cardioverter-defibrillator due to the lack of clinical symptoms. The proband had a 2-year history of mild chest pain after intense physical exertion, and diffuse repolarization changes with inverted T waves on ECG. Echocardiography showed mid to distal interventricular septal hypertrophy, and cardiac magnetic resonance imaging (CMR) revealed hypertrophy of the mid to distal interventricular septum and the inferior ventricular wall. The proband's younger brother, who was asymptomatic, had similar findings on ECG and echocardiography, with isolated hypertrophic septum and inferior ventricular wall on CMR. Both brothers had preserved cardiac function with left ventricular ejection fractions of 66% and 71%, respectively, normal atrial and ventricular chamber dimensions, no left ventricular outflow tract obstruction at rest or after exercise, and negative late gadolinium enhancement. Mapping Carrier et al. (1993) found evidence of a locus on chromosome 11 responsible for familial hypertrophic cardiomyopathy. In a French pedigree in which the disease was not linked to the MYH7 gene (160760), they found linkage to several microsatellite (CA)n repeats located on chromosome 11. They concluded that the gene could be localized to a 17-cM region in 11p13-q13. Kullmann et al. (1993) reported the case of a patient with Holt-Oram syndrome (142900) who had atrial septal defect and developed hypertrophic cardiomyopathy during the first year of life. A reciprocal translocation was found in this patient between 1p13 and 11q13. Ko et al. (1996) reported results of linkage analysis in a Chinese family with apical hypertrophic cardiomyopathy. Apical hypertrophic cardiomyopathy (Japanese type) appears to be a distinct subtype of hypertrophic cardiomyopathy. It is characterized by giant negative T waves on EKG and left ventricular hypertrophy localized to the apex. The authors reported a maximal lod score of 3.38 at theta = 0.00 between the disease gene and the microsatellite markers D11S905, D11S987, and D11S913, which had been mapped to 11p13-q13. Bonne et al. (1995) concluded that the COX8 gene (123870) that encodes cytochrome c oxidase subunit XIII is probably not the site of the mutation in CMH4, since in affected members of a family with chromosome 11-linked CMH, no deletions or insertions were found in COX8 cDNA or mRNA and no abnormality was detected in the COX8 sequence. Xin et al. (2007) performed genomewide mapping analysis in 3 Old Order Amish infants from 3 different consanguineous families with severe neonatal hypertrophic cardiomyopathy and identified a 4.6-Mb block of homozygosity on chromosome 11p11.2-p11.12, encompassing the MYBPC3 gene (600958). Inheritance The transmission pattern of CMH4 was autosomal dominant in the families reported by Watkins et al. (1995) and autosomal recessive in the family reported by Wang et al. (2013). Molecular Genetics Both Watkins et al. (1995) and Bonne et al. (1995) demonstrated heterozygous mutations in the MYBPC gene that cause CMH4 (600958.0001, 600958.0002, 600958.0003). Incomplete penetrance was observed. Niimura et al. (1998) identified 12 novel mutations in the MYBPC3 gene in probands from 16 families with CMH. The clinical expression of these mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58% of adults under the age of 50 years who had a mutation in the MYBPC3 gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by mutations in other genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly. Niimura et al. (1998) pointed out that delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the MYBPC3 gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy. Hengstenberg et al. (1993, 1994) studied a family with familial hypertrophic cardiomyopathy in which preliminary haplotype analyses excluded linkage to previously identified CMH loci at 14q1, 1q3, 11p13-q13, and 15q2, suggesting the existence of another locus, designated CMH5, for this disorder. Further studies in this family by Richard et al. (1999) demonstrated that of 8 affected family members, 4 had a mutation in the MYH7 gene (160760.0033), 2 had a mutation in the MYBPC3 gene (600958.0014), and 2 were doubly heterozygous for the 2 mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than that in the other affected individuals. In a 28-year-old Australian man with CMH who had previously been studied by Ingles et al. (2005) and found to be compound heterozygous for missense mutations in the MYBPC3 gene (600958.0021 and 600958.0022), Chiu et al. (2007) also identified a heterozygous R73Q substitution in the CALR3 gene (611414). The proband was diagnosed at 18 years of age and had severe asymmetric septal hypertrophy on echocardiography (ECG). His father and 1 brother also had CMH, but declined to participate in the study. Chiu et al. (2007) suggested that calreticulin may be involved in both disease pathogenesis and modification. Lekanne Deprez et al. (2006) reported 2 unrelated Dutch infants with severe hypertrophic cardiomyopathy in whom they identified compound heterozygosity for truncating mutations in the MYBPC3 gene (see, e.g., 600958.0023). The infants died at 5 and 6 weeks of age. The nonconsanguineous asymptomatic parents were heterozygous carriers of 1 of the mutations in each case; 1 of the fathers was found to have mild hypertrophic cardiomyopathy on cardiac MRI. In 23 Old Order Amish infants with severe neonatal hypertrophic cardiomyopathy, 20 of whom were from the Geauga County settlement in Ohio, Xin et al. (2007) identified homozygosity for a splice site mutation in the MYBPC3 gene (3330+2T-G; 600958.0020). In addition, DNA analysis of a Mennonite couple with a child who died of CMH revealed that both parents were heterozygous for the 3330+2T-C mutation. The authors calculated the heterozygous carrier frequency in the Geauga County settlement to be approximately 10%. Noting the many reports of cardiac symptoms, including sudden death, among these probands' parents and relatives, and the close similarity between this mutation and the 3330+5G-C mutation (600958.0001) previously documented by Watkins et al. (1995) as the cause of CMH in heterozygous carriers, Xin et al. (2007) suggested that heterozygotes for the 3330+2T-G mutation may also be at risk for CMH. In 250 unrelated patients with CMH, Frank-Hansen et al. (2008) used SSCP analysis and sequence confirmation of the MYBPC3 gene to determine whether intronic variation flanking the 3 MYBPC3 microexons is disease-causing. Functional studies and segregation analysis indicated that 4 of the 7 mutations they identified are associated with CMH (see, e.g., 600958.0016 and 600958.0017): all 4 mutations result in premature termination codons, suggesting that haploinsufficiency is a pathogenic mechanism of this type of mutation. In 1 family, a second mutation in the MYBPC3 gene was also identified (V1125M; 600958.0018). None of the mutations were found in DNA samples from 192 Caucasian controls. Waldmuller et al. (2003) identified a 25-bp deletion in intron 32 of the MYBPC3 gene (600958.0019) in 2 CMH families, 1 of which was also known to carry a mutation in the MYH7 gene (160760). The authors stated that the relationship to disease was 'not unequivocal' and suggested that the deletion may represent a modifier polymorphism that may enhance the phenotypes of mutations responsible for disease. Dhandapany et al. (2009) analyzed the 25-bp deletion in the MYBPC3 gene in Indian patients with hypertrophic, dilated, and restrictive cardiomyopathies found an association with familial cardiomyopathy and an increased risk of heart failure (overall odds ratio, 6.99; p = 4 x 10(-11)). Analysis of RNA and protein from endomyocardial biopsies of 2 heterozygous individuals revealed 2 transcript structures, a normal transcript and a mutated allele with skipping of the associated exon, but the altered protein was not detected in tissue samples. Expression of mutant and wildtype protein in neonatal rat cardiomyocytes demonstrated a highly disorganized and diffuse pattern of sarcomeric architecture as a result of aberrant incorporation of the mutant protein. The authors concluded that the 25-bp MYBPC3 deletion is associated with a lifelong increased risk of heart failure. Dhandapany et al. (2009) tested 63 world population samples, comprising 2,085 individuals from 26 countries, for the 25-bp deletion, and they identified samples heterozygous for the deletion from Pakistan, Sri Lanka, Indonesia, and Malaysia but not in other samples. Haplotype analysis determined that the common 25-bp deletion likely arose approximately 33,000 years ago on the Indian subcontinent. Ehlermann et al. (2008) screened the MYBPC3 gene in 87 patients with hypertrophic cardiomyopathy and 71 patients with CMD and identified heterozygous mutations in 16 (18.4%) of the CMH patients and in 2 (2.8%) of the CMD patients. However, in the first CMD family, 3 additional carriers of the MYBPC3 missense mutation had no certain pathologic findings, and the authors noted that in the index patient, hypertensive heart disease could not be ruled out as the cause of his CMD phenotype. In the second CMD family, the 2 oldest carriers of the splice site mutation displayed CMD, whereas 4 younger mutation carriers showed CMH; the authors stated that it was mostly likely that the 2 older patients suffered from end-stage CMH with progression to a CMD phenotype. Screening the cohort for variation in 5 additional cardiomyopathy-associated genes (MYH7, 160760; TNNT2, 191045; TNNI3, 191044; ACTC1, 102540; and TPM1, 191010) revealed no further mutations. Of a total of 45 affected individuals, from 12 families and 6 sporadic patients, 23 (51%) suffered an adverse event such as progression to severe heart failure, transient ischemic attack, stroke, or sudden death. Tajsharghi et al. (2010) reported a female infant with fatal cardiomyopathy and skeletal myopathy who was homozygous for a nonsense mutation in the MYBPC3 gene (R943X; 600958.0023). Skeletal muscle biopsy at 2 months of age showed pronounced myopathic changes with numerous small fibers, which all expressed slow/beta-cardiac myosin heavy chain protein (MYH7; 160760). Electron microscopy revealed disorganization of the sarcomeres and partial depletion of thick filaments in the small fibers; immunohistochemical staining showed the presence of cardiac MYBPC in the small abnormal fibers. RT-PCR and sequencing demonstrated the R943X mutation in transcripts of skeletal muscle. Tajsharghi et al. (2010) noted that cardiac MYBPC is not normally expressed in skeletal muscle and stated that the reason for the ectopic expression of cardiac MYBPC remained unknown. The R943X mutation had previously been reported in compound heterozygosity with other truncating MYBPC3 mutations in 2 unrelated Dutch infants with fatal hypertrophic cardiomyopathy (Lekanne Deprez et al., 2006); skeletal myopathy was not mentioned in that report. In a 21-year-old man from a consanguineous Chinese family with hypertrophic cardiomyopathy, Wang et al. (2013) screened 26 CMH-related genes and identified a homozygous missense mutation in the MYBPC3 gene (G490V; 600958.0029). His affected younger brother was also homozygous for the mutation; 6 other relatives, including their unaffected parents, were heterozygous for the mutation. None of the heterozygous carriers had any of the typical clinical manifestations of CMH, including the 2 oldest carriers at ages 62 years and 71 years, and none showed abnormalities on electrocardiography or left ventricular hypertrophy on echocardiography. CMR of 3 heterozygous individuals showed no structural abnormalities or cardiac fibrosis. Family members who did not carry the mutation all had normal electrocardiograms (ECGs) and echocardiograms except for the maternal grandfather, who had a more than 20-year history of uncontrolled hypertension and showed concentric hypertrophy on echocardiography without abnormal T or Q waves or arrhythmia on ECG. Genotype/Phenotype Correlations Calore et al. (2015) screened 97 Italian probands with CMH for mutations in the MYBPC3 gene and identified 16 different mutations in 39 (39.8%); among the MYBPC3 mutation carriers, none had additional mutations in the MYH7, TNNI3, or TNNT2 genes. The same 2-bp deletion (600958.0030) was detected in 19 probands; haplotype analysis revealed a shared 1.29-Mb haplotype, indicating a common founder in these families, which all came from the Veneto region of northeastern Italy. Overall, disease penetrance was incomplete (64.4%), age-related, and greater in men than women (85% vs 48%; p = 0.009). Probands carrying the founder mutation exhibited significantly higher prevalence of nonsustained ventricular tachycardia and implantable cardioverter-defibrillator placement compared to patients without MYBPC3 mutations or with other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD also occurred more frequently after the fourth decade of life in probands carrying the founder mutation than in those without MYBPC3 mutations. Calore et al. (2015) noted that the overall annual mortality rate of 2% among the 48 affected founder-mutation carriers was higher than that previously described in MYBPC3 carriers and in the general population of CMH patients. Animal Model Meurs et al. (2005) identified a reduction in Mybpc3 protein in myocardium from Maine Coon cats with hypertrophic cardiomyopathy in comparison to control cats (P less than 0.001). In affected cats, the authors identified a G-C transversion in exon 3 of the feline Mybpc3 gene, resulting in an ala31-to-pro (A31P) substitution in the linker region between the C0 and C1 domains. The mutation was predicted to alter protein conformation and result in sarcomeric disorganization. Affected cats had some variability of phenotype from mildly affected to severe hypertrophy. Some cats developed congestive heart failure, and others died suddenly. Pohlmann et al. (2007) found that cardiac myocytes from 6-week-old Mybpc3-null mice exhibited mild hypertrophy that became more pronounced by 30 weeks of age. Isolated Mybpc3-null myocytes showed markedly lower diastolic sarcomere length without change in diastolic Ca(2+). This reduced sarcomere length was partially abolished by inhibition of actin-myosin ATPase, indicating residual actin-myosin interaction in diastole. Mybpc3-null myocytes started to contract at lower Ca(2+) concentration, and both sarcomere shortening and Ca(2+) transients were prolonged in Mybpc3-null cells. Isolated Mybpc3-null left atria exhibited a marked increase in sensitivity to external Ca(2+) and, in contrast to wildtype, continued to develop twitch force at low micromolar Ca(2+) concentration. Pohlmann et al. (2007) concluded that MYBPC3 functions as a restraint on myosin-actin interaction at low Ca(2+) concentrations and short sarcomere length to allow complete relaxation during diastole. INHERITANCE \- Autosomal dominant (incomplete penetrance) \- Autosomal recessive CARDIOVASCULAR Heart \- Hypertrophic cardiomyopathy \- Chest pain \- Cardiomegaly \- Bilateral ventricular hypertrophy \- Enlarged right atrium \- Progressive heart failure \- Pericardial effusion \- First-degree atrioventricular block \- Reduced left ventricular systolic function \- Reduced shortening fraction of left ventricle \- Reduced right ventricular systolic function \- Enlarged left ventricular end systolic diameter \- Thickened interventricular septum \- Complete and incomplete left bundle branch block \- Right bundle branch block \- Ventricular fibrillation \- Cardiac arrest Vascular \- Syncope \- Transient ischemic attack \- Stroke RESPIRATORY Lung \- Dyspnea \- Pulmonary edema ABDOMEN \- Ascites Liver \- Hepatomegaly MUSCLE, SOFT TISSUES \- Myopathic changes (seen in homozygous patient) \- Numerous small fibers (seen in homozygous patient) \- Disorganization of sarcomeres on electron microscopy (seen in homozygous patient) \- Partial depletion of thick filaments (seen in homozygous patient) MISCELLANEOUS \- Incomplete penetrance with heterozygous mutations \- Sudden death may occur, particularly during vigorous exercise \- Homozygotes are more severely affected, with death in the neonatal period \- Patients carrying the F305Pfs27 mutation ( 600958.0030 ) are at higher risk of sudden death MOLECULAR BASIS \- Caused by mutation in the myosin-binding protein C gene (MYBPC3, 600958.0001 ) ▲ 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	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4	c1861862	2,840	omim	https://www.omim.org/entry/115197	2019-09-22T16:43:43	{"mesh": ["C566169"], "omim": ["115197"], "genereviews": ["NBK1768"]}
Congenital disorder in which the pituitary stalk and pituitary are hypoplastic Pituitary stalk interruption syndrome (PSIS) Other namesEctopic neurohypophysis The location of the pituitary gland within the skull (indicated in orange) SpecialtyEndocrinology, neurology, neonatology, paediatrics SymptomsHypoglycaemia, jaudice, micropenis, cryptorchidism, etc. ComplicationsSeizures, retarded physical and intellectual development, delayed puberty, death, etc. TypesCongenital Risk factorsGenetic predisposition (relative(s) with the condition) Diagnostic methodMRI scan TreatmentHormone replacement FrequencyUnclear, ~1,000 cases reported Pituitary stalk interruption syndrome (PSIS) is a congenital disorder characterised by the triad of an absent or exceedingly thin pituitary stalk, an ectopic or absent posterior pituitary and/or absent or hypoplastic anterior pituitary.[1][2] ## Contents * 1 Presentation * 2 Cause * 3 Diagnosis * 4 Management * 5 Prognosis * 6 Epidemiology * 7 References * 8 External links ## Presentation[edit] Affected individuals may present with hypoglycaemia during the neonatal period, or with growth retardation during childhood (those diagnosed in the neonatal period appear to be affected by a particularly severe form of the disorder). PSIS is a common cause of congenital hypopituitarism, and causes a permanent growth hormone deficit. Some PSIS-affected individuals may also present with adrenal hypoplasia (5-29%), diabetes insipidus (5-29%), primary amenorrhea (5-29%), hypothyroidism (30-79%), failure to thrive (80-99%), septooptic dysplasia (5-29%), and Fanconi anaemia. PSIS may be isolated, or, commonly, present with extra-pituitary malformations.[1][2][3] PSIS features in neonates (may) include:[1][2][3] * hypoglycaemia (30-79%) * (prolonged) jaundice * micropenis (30-79%) * cryptorchidism (5-29%) * delayed intellectual development * death in infancy (5-29%) * congenital abnormalities PSIS features in later childhood (may) include:[1][2][3] * short stature (80-99%) * seizures (5-29%) * hypotension * delayed intellectual development * delayed puberty (30-79%) PSIS is associated with a higher frequency of breech presentation, Caeserian section, and/or low Apgar score, though these are likely consequences rather than causes.[3] ## Cause[edit] The cause of the condition is as of yet unknown. Rare genetic mutations may cause familial cases, however, these account for less than 5% of cases.[2] ## Diagnosis[edit] The diagnosis is confirmed through MRI.[2] ## Management[edit] Treatment should commence as soon as a diagnosis is established to avoid complications, and consists of hormone replacement, particularly with growth hormone.[1] ## Prognosis[edit] Prognosis is generally good in cases of prompt diagnosis and management. Delays may lead to seizures (due to hypoglycaemia), hypotension (due to cortisol deficiency), and/or intellectual disability (due to thyroid endocrine deficits). Due to the before-mentioned factors, mortality and morbidity is higher than that of the general population, particularly during the first 2 years of life.[3] ## Epidemiology[edit] The prevalence of PSIS is unknown, however, some 1,000 cases have been reported either with or without the full triad.[3] ## References[edit] 1. ^ a b c d e "Pituitary stalk interruption syndrome". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. U.S. National Institutes of Health. Retrieved 2018-08-11. 2. ^ a b c d e f Bar C, Zadro C, Diene G, Oliver I, Pienkowski C, Jouret B, et al. (November 2015). "Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation". PLOS ONE. 10 (11): e0142354. Bibcode:2015PLoSO..1042354B. doi:10.1371/journal.pone.0142354. PMC 4643020. PMID 26562670. 3. ^ a b c d e f Brauner R. "Pituitary stalk interruption syndrome". Orphanet. Retrieved 2018-08-11. ## External links[edit] Classification D External resources * GARD: Pituitary stalk interruption syndrome * Orphanet: 95496 [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	Pituitary stalk interruption syndrome	c4053775	2,841	wikipedia	https://en.wikipedia.org/wiki/Pituitary_stalk_interruption_syndrome	2021-01-18T18:42:18	{"umls": ["C4053775"], "wikidata": ["Q56277527"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Hyperchloremia" – news · newspapers · books · scholar · JSTOR (May 2015) (Learn how and when to remove this template message) This article needs attention from an expert in medicine. Please add a reason or a talk parameter to this template to explain the issue with the article. WikiProject Medicine may be able to help recruit an expert. (February 2009) Hyperchloremia Chlorine SpecialtyEndocrinology Hyperchloremia is an electrolyte disturbance in which there is an elevated level of the chloride ions in the blood.[1] The normal serum range for chloride is 96 to 106 mEq/L,[2] therefore chloride levels at or above 110 mEq/L usually indicate kidney dysfunction as it is a regulator of chloride concentration.[3] As of now there are no specific symptoms of hyperchloremia, however, it can be the influenced by multiple abnormalities that cause a loss of electrolyte-free fluid, loss of hypotonic fluid, or increased administration of sodium chloride. These abnormalities are caused by diarrhea, vomiting, increased sodium chloride intake, renal dysfunction, diuretic use, and diabetes. Hyperchloremia should not be mistaken for hyperchloremic metabolic acidosis as hyperchloremic metabolic acidosis is characterized by two major changes: a decrease in blood pH and bicarbonate levels, as well as an increase in blood chloride levels.[3] Instead those with hyperchloremic metabolic acidosis are usually predisposed to hyperchloremia. Hyperchloremia prevalence in hospital settings has recently been researched in the medical field since one of the major sources of treatment at hospitals is administering saline solution. Previously, animal models with elevated chloride have displayed more inflammation markers, changes in blood pressure, increased renal vasoconstriction, and less renal blood flow as well at glomerulus filtration, all of which are prompting researchers to investigate if these changes or others may exist in patients. Some studies have reported a possible relationship between increased chloride levels and death or acute kidney injury in severely ill patients that may frequent the hospital or have prolonged visits. There are other studies that have found no relationship. As studies continue, it is important to include a large patient sample size, diverse patient population, and a diverse range of hospitals involved in these studies.[4] ## Contents * 1 Symptoms * 2 Causes * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 Recent research * 7 References * 8 External links ## Symptoms[edit] Hyperchloremia does not have many noticeable symptoms and can only be confirmed with testing, yet, the causes of hyperchloremia do have symptoms. Symptoms of the above stated abnormalities may include:[5] * Dehydration - due to diarrhea, vomiting, sweating * Hypertension - due to increased sodium chloride intake * Cardiovascular dysfunction - due to increased sodium chloride intake * Edema - due to influx in sodium in the body * Weakness - due to loss of fluids * Thirst - due to loss of fluids * Kussmaul breathing \- due to high ion concentrations, loss of fluids, or kidney failure * High blood sugar \- due to diabetes * Hyperchloremic metabolic acidosis - due to severe diarrhea and/or kidney failure * Respiratory alkalosis \- due to renal dysfunction * * ## Causes[edit] There are many scenarios which may results in hyperchloremia. The first instance is when there is a loss of electrolyte-free fluid. This simply means that the body is losing increased amounts of fluids that do not contain electrolytes, like chloride, resulting in high concentration of these ions in the body. This loss of fluids can be due to sweating (due to exercise or fever), skin burns, lack of adequate water intake, hyper-metabolic state, and diabetes insipidus. Losing fluids can lead to feelings of dehydration and dry mucous membrane.[4][5] The second scenario that may lead to hyperchloremia is known as loss of hypotonic fluid which can be a direct result of loss of electrolyte fluid. Normally, water in the body is moving from an area of low ion concentration to an area of high ion concentration. In this case, the water is being excreted in the urine, therefore, less water is available to dilute these areas of high ion concentration. This can be due to diuretic use, diarrhea, vomiting, burns, kidney disease, kidney failure, and renal tubular acidosis . This may also lead to feeling of dehydration.[4][5] The third scenarios that may lead to hyperchloremia is an increase in sodium chloride intake. This can be due to dietary intake or intravenous fluid administration in hospital settings. This can lead to the body experiencing hypertension, edema, and cardiovascular dysfunction.[4][5] ## Mechanism[edit] The nephrons in the kidney are responsible for regulating the level of chloride in the blood. The general mechanism is that as filtrate fluid passes through the nephrons varying concentrations of ions will be secreted into the interstitial fluid or absorbed into the lumen. All along the nephrons are blood capillaries waiting to reabsorb ions from the interstitial fluid to circulate in the body.[6] The amount of chloride to be released in the urine is due to the receptors lining the nephrons and the glomerulus filtration. Normally, chloride reabsorption begins in the proximal tubule and nearly 60% of chloride is filtered here.[7] In a person with hyperchloremia, the absorption of chloride into the interstitial fluid and subsequently into the blood capillaries is increased. This means the concentration of chloride in the filtrate is decreased, therefore, a decreased amount of chloride is being excreted as waste in the urine.[6] In the proximal tubule chloride reabsorption occurs in two parts. In the 1st phase, organic solutes (such as phosphates, amino acids, glucose and anions), sodium ions, and hydronium ions are reabsorbed from the filtrate fluid into the interstitial fluid. This is an important step because this creates the concentration gradient in which chloride concentration in the lumen will increase in comparison to the chloride concentration in the interstitial fluid. In phase 2, chloride will diffuse along the concentration gradient, which means chloride ions will travel from areas of high concentration to areas of low concentration.[5] One suggested mechanism leading to hyperchloremia, there is a decrease in chloride transporter proteins along the nephron. These proteins may include sodium-potassium-2 chloride co-transporter, chloride anion exchangers, and chloride channels. Another suggested mechanism is a depletion in concentration gradient as a result of the reduced activity in these transporters. Such concentration gradient depletion would allow for the passive diffusion of chloride in and out the tubule.[7] ## Diagnosis[edit] Elevated levels of chloride in the blood can be tested simply by requesting a serum chloride test. A doctor would request this test if there are signs their patient is experiencing an imbalance in acid-base levels for a prolonged period of time.[2][8] For the test to occur a healthcare provider must draw a sample of blood from the patient. The sample will then be sent to a laboratory and results will be provided to the patient's physician. As mentioned earlier a normal serum chloride range is from 96 to 106 mEq/L, and hyperchloremic patients will have levels above this range.[2] ## Treatment[edit] As with most types of electrolyte imbalance, the treatment of high blood chloride levels is based on correcting the underlying cause. * If the patient is dehydrated, therapy consists of establishing and maintaining adequate hydration[1] such as drinking 2-3 quarts of water daily. Also, to alleviate symptoms of dehydration like diarrhea or vomiting, it is suggested to take medication.[9] * If the condition is caused or exacerbated by medications or treatments, these may be altered or discontinued, if deemed prudent.[1][9] * If there is underlying kidney disease (which is likely if there are other electrolyte disturbances), then the patient will be referred to a nephrologist for further care.[1] * If there is an underlying dysfunction of the endocrine or hormone system, the patient will likely be referred to an endocrinologist for further assessment.[1] * If the electrolyte imbalance is due to influx of sodium chloride in the body, then it has been suggested to make dietary changes or reduce the rate of administering intravenous fluids.[4] ## Recent research[edit] In patients with sepsis or septic shock they are more susceptible to experience acute kidney injury (AKI) and the factors that may contribute to AKI are still being investigated. In a study conducted by Suetrong et al., (2016) using patients admitted to St. Paul Hospital in Vancouver with sepsis or septic shock had their body concentration of chloride checked over the course of 48 hours to determine if there is a relation between hyperchloremia and AKI. This is an important relationship to study because many times a form of therapy to treat sepsis and septic shock is to administer saline solution, which is a solution containing sodium chloride. Saline has a much higher concentration of chloride than blood. In this study they defined hyperchloremia as concentration of chloride greater than 110 mmol/L. This research demonstrated that hyperchloremia will influence a patient developing AKI. In fact, even patients that had a conservative increase in serum chloride saw some association with developing AKI. This research study suggest that there still needs to be more investigation in the risk of using saline as a form of therapy and the risk of experiencing AKI.[10] In a separate study investigating the relation of critically ill patients and hyperchloremia, researchers found that there seems to be an independent association between ill patients with hyperchloremia and mortality. This study was conducted with septic patients admitted to ICUs for 72 hours. Chloride levels were assessed at baseline and 72 hours, and confounding variables were accounted for. This study is important because this continues to suggest there is increased risk associated with elevated chloride levels in vulnerable populations. Their article also states there needs to be avoidance of using solutions with chloride in specific patient subgroups [11] Several trials have been done comparing balanced fluid (chloride restricted) solution with saline (chloride liberal) with the hypothesis that it may reduce the risk of AKI and mortality. Initial randomized trials in septic shock comparing Plasma-Lyte and 0.9% saline (SPLIT and SALT trials) did not show any risk reduction in AKI.[12][13] However, the later trials with larger sample size in critically and non critically ill adults (SMART and SALT-ED trials) showed reduction in major adverse kidney events.[14][15] Extrapolating from the findings of septic shock, a recent trial comparing plasmalyte with 0.9% saline in DKA also did not show any significant difference in AKI. Hence, the causal link between hyperchloremia and AKI is yet to be conclusively established.[16] ## References[edit] 1. ^ a b c d e Cambier C, Detry B, Beerens D, et al. (October 1998). "Effects of hyperchloremia on blood oxygen binding in healthy calves". J. Appl. Physiol. 85 (4): 1267–72. doi:10.1152/jappl.1998.85.4.1267. PMID 9760315. S2CID 1778217. 2. ^ a b c "Chloride test - blood: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2017-12-12. 3. ^ a b "Hyperchloremic metabolic acidosis". dynamed.com. Retrieved 2017-12-12. 4. ^ a b c d e Bandak, Ghassan; Kashani, Kianoush B. (2017-11-01). "Chloride in intensive care units: a key electrolyte". F1000Research. 6: 1930. doi:10.12688/f1000research.11401.1. PMC 5668919. PMID 29123653. 5. ^ a b c d e Morrison, Gail (1990). Walker, H. Kenneth; Hall, W. Dallas; Hurst, J. Willis (eds.). Clinical Methods: The History, Physical, and Laboratory Examinations (3rd ed.). Boston: Butterworths. ISBN 978-0409900774. PMID 21250151. 6. ^ a b Hall, J, Guyton, A (2016). Textbook of Medical Physiology. Elsevier. ISBN 978-1455770052. 7. ^ a b Nagami, Glenn T. (2016-07-01). "Hyperchloremia – Why and how". Nefrología (English Edition). 36 (4): 347–353. doi:10.1016/j.nefroe.2016.06.006. ISSN 2013-2514. PMID 27267918. 8. ^ Cancer, Cleveland Clinic. "Hyperchloremia (High Chloride) - Managing Side Effects - Chemocare". chemocare.com. Retrieved 2017-12-12. 9. ^ a b "Hyperchloremia (high chloride): Symptoms, causes, and treatments". Medical News Today. Retrieved 2017-12-13. 10. ^ Suetrong, Bandarn; Pisitsak, Chawika; Boyd, John H.; Russell, James A.; Walley, Keith R. (2016-10-06). "Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients". Critical Care. 20 (1): 315. doi:10.1186/s13054-016-1499-7. ISSN 1364-8535. PMC 5053142. PMID 27716310. 11. ^ Neyra, Javier A.; Canepa-Escaro, Fabrizio; Li, Xilong; Manllo, John; Adams-Huet, Beverley; Yee, Jerry; Yessayan, Lenar (September 2015). "Association of Hyperchloremia with Hospital Mortality in Critically Ill Septic Patients". Critical Care Medicine. 43 (9): 1938–1944. doi:10.1097/CCM.0000000000001161. ISSN 0090-3493. PMC 4537691. PMID 26154934. 12. ^ Young, Paul; Bailey, Michael; Beasley, Richard; Henderson, Seton; Mackle, Diane; McArthur, Colin; McGuinness, Shay; Mehrtens, Jan; Myburgh, John; Psirides, Alex; Reddy, Sumeet; Bellomo, Rinaldo (2015-10-27). "Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial". JAMA. 314 (16): 1701–10. doi:10.1001/jama.2015.12334. ISSN 0098-7484. PMID 26444692. 13. ^ Semler, Matthew W.; Wanderer, Jonathan P.; Ehrenfeld, Jesse M.; Stollings, Joanna L.; Self, Wesley H.; Siew, Edward D.; Wang, Li; Byrne, Daniel W.; Shaw, Andrew D.; Bernard, Gordon R.; Rice, Todd W.; Bernard, Gordon R.; Semler, Matthew W.; Noto, Michael J.; Rice, Todd W.; Byrne, Daniel W.; Domenico, Henry J.; Wang, Li; Wanderer, Jonathan P.; Ehrenfeld, Jesse M.; Shaw, Andrew D.; Hernandez, Antonio; Kumar, Avinash B.; Self, Wesley H.; Siew, Edward D.; Dunlap, Debra F.; Stollings, Joanna L.; Sullivan, Mark; Knostman, Molly; Mulherin, David P.; Hargrove, Fred R.; Janz, David R.; Strawbridge, Seth (2017-05-15). "Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial". American Journal of Respiratory and Critical Care Medicine. 195 (10): 1362–1372. doi:10.1164/rccm.201607-1345OC. ISSN 0003-0805. PMC 5443900. PMID 27749094. 14. ^ Semler, Matthew W.; Self, Wesley H.; Wanderer, Jonathan P.; Ehrenfeld, Jesse M.; Wang, Li; Byrne, Daniel W.; Stollings, Joanna L.; Kumar, Avinash B.; Hughes, Christopher G.; Hernandez, Antonio; Guillamondegui, Oscar D.; May, Addison K.; Weavind, Liza; Casey, Jonathan D.; Siew, Edward D.; Shaw, Andrew D.; Bernard, Gordon R.; Rice, Todd W. (March 2018). "Balanced Crystalloids versus Saline in Critically Ill Adults". New England Journal of Medicine. 378 (9): 829–839. doi:10.1056/NEJMoa1711584. ISSN 0028-4793. PMC 5846085. PMID 29485925. 15. ^ Self, Wesley H.; Semler, Matthew W.; Wanderer, Jonathan P.; Wang, Li; Byrne, Daniel W.; Collins, Sean P.; Slovis, Corey M.; Lindsell, Christopher J.; Ehrenfeld, Jesse M.; Siew, Edward D.; Shaw, Andrew D.; Bernard, Gordon R.; Rice, Todd W. (March 2018). "Balanced Crystalloids versus Saline in Noncritically Ill Adults". New England Journal of Medicine. 378 (9): 819–828. doi:10.1056/NEJMoa1711586. ISSN 0028-4793. PMC 5846618. PMID 29485926. 16. ^ Williams, Vijai; Jayashree, Muralidharan; Nallasamy, Karthi; Dayal, Devi; Rawat, Amit (December 2020). "0.9% saline versus Plasma-Lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): a double-blind randomized controlled trial". Critical Care. 24 (1): 1. doi:10.1186/s13054-019-2683-3. ISSN 1364-8535. PMC 6939333. PMID 31898531. ## External links[edit] Classification D * ICD-10: E87.8 * ICD-9-CM: 276.9 * v * t * e Electrolyte imbalances Sodium * High * Salt poisoning * Low * Hypotonic * Isotonic * Cerebral salt-wasting syndrome Potassium * High * Low Chloride * High * Low Calcium * High * Low * Symptoms and signs * Chvostek sign * Trousseau sign * Milk-alkali syndrome * Disorders of calcium metabolism * Calcinosis (Calciphylaxis, Calcinosis cutis) * Calcification (Metastatic calcification, Dystrophic calcification) * Familial hypocalciuric hypercalcemia Phosphate * High * Low Magnesium * High * Low [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	Hyperchloremia	c0085679	2,842	wikipedia	https://en.wikipedia.org/wiki/Hyperchloremia	2021-01-18T19:04:35	{"icd-9": ["276.9"], "icd-10": ["E87.8"], "wikidata": ["Q5898267"]}
sleeping phenomenon combined with wakefulness This article is about the sleep disorder. For other uses, see Sleepwalking (disambiguation) and Sleepwalker (disambiguation). Sleepwalking John Everett Millais, The Somnambulist, 1871 SpecialtyPsychiatry, Sleep medicine Sleepwalking, also known as somnambulism or noctambulism, is a phenomenon of combined sleep and wakefulness.[1] It is classified as a sleep disorder belonging to the parasomnia family.[2] It occurs during slow wave sleep stage, in a state of low consciousness, with performance of activities that are usually performed during a state of full consciousness. These activities can be as benign as talking, sitting up in bed, walking to a bathroom, consuming food, and cleaning, or as hazardous as cooking, driving a motor vehicle,[3][4] violent gestures and grabbing at hallucinated objects.[5] Although sleepwalking cases generally consist of simple, repeated behaviors, there are occasionally reports of people performing complex behaviors while asleep, although their legitimacy is often disputed.[6] Sleepwalkers often have little or no memory of the incident, as their consciousness has altered into a state in which memories are difficult to recall. Although their eyes are open, their expression is dim and glazed over.[7] This may last from 30 seconds to 30 minutes.[5] Sleepwalking occurs during slow-wave sleep (N3) of non-rapid eye movement sleep (NREM sleep) cycles. It typically occurs within the first third of the night when slow-wave sleep is most prominent.[7] Usually, it will occur once in a night, if at all.[5] ## Contents * 1 Signs and symptoms * 1.1 Associated disorders * 1.2 Consequences * 2 Causes * 3 Diagnosis * 3.1 Assessment * 4 Treatment * 4.1 Safety planning * 5 Epidemiology * 6 History * 7 Society and culture * 7.1 Opera * 7.1.1 Jenny Lind and James Braid * 7.2 Drama * 7.3 Literature * 7.4 Sleepwalking as a legal defense * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Sleepwalking is characterized by:[8] * partial arousal during non-rapid eye movement (NREM) sleep, typically during the first third of the night * dream content that may or may not be recalled when awake * dream-congruent motor behavior that may be simple or complex * impaired perception of the environment * impaired judgement, planning and problem-solving. The sleepwalker's eyes are open but may appear as a glassy-eyed stare or blank expression and pupils are dilated. They are often disoriented, consequent to awakening: the sleepwalker may be confused and perplexed, and might not know why or how they got out of bed; however, the disorientation will fade within minutes. They may talk while sleepwalking, but the talk typically does not make sense to the observer. There are varying degrees of amnesia associated with sleepwalking, ranging from no memory at all, vague memories or a narrative.[9] ### Associated disorders[edit] In the study "Sleepwalking and Sleep Terrors in Prepubertal Children"[10] it was found that, if a child had another sleep disorder – such as restless leg syndrome (RLS) or sleep-disorder breathing (SDB) – there was a greater chance of sleepwalking. The study found that children with chronic parasomnias may often also present SDB or, to a lesser extent, RLS. Furthermore, the disappearance of the parasomnias after the treatment of the SDB or RLS periodic limb movement syndrome suggests that the latter may trigger the former. The high frequency of SDB in family members of children with parasomnia provided additional evidence that SDB may manifest as parasomnias in children. Children with parasomnias are not systematically monitored during sleep, although past studies have suggested that patients with sleep terrors or sleepwalking have an elevated level of brief EEG arousals. When children receive polysomnographies, discrete patterns (e.g., nasal flow limitation, abnormal respiratory effort, bursts of high or slow EEG frequencies) should be sought; apneas are rarely found in children. Children's respiration during sleep should be monitored with nasal cannula or pressure transducer system or esophageal manometry, which are more sensitive than the thermistors or thermocouples currently used in many laboratories. The clear, prompt improvement of severe parasomnia in children who are treated for SDB, as defined here, provides important evidence that subtle SDB can have substantial health-related significance. Also noteworthy is the report of familial presence of parasomnia. Studies of twin cohorts and families with sleep terror and sleepwalking suggest genetic involvement of parasomnias. RLS and SDB have been shown to have familial recurrence. RLS has been shown to have genetic involvement. Sleepwalking may also accompany the related phenomenon of night terrors, especially in children. In the midst of a night terror, the affected person may wander in a distressed state while still asleep, and examples of sufferers attempting to run or aggressively defend themselves during these incidents have been reported in medical literature.[11] In some cases, sleepwalking in adults may be a symptom of a psychological disorder. One study suggests higher levels of dissociation in adult sleepwalkers, since test subjects scored unusually high on the hysteria portion of the "Crown-Crisp Experiential Index".[12] Another suggested that "A higher incidence [of sleepwalking events] has been reported in patients with schizophrenia, hysteria and anxiety neuroses".[13] Also, patients with migraine headaches or Tourette syndrome are 4–6 times more likely to sleepwalk. ### Consequences[edit] Most sleepwalkers had injuries at some point during sleepwalking, often minor injuries such as cuts or bruises.[14][15] In rare occasions, however, sleepwalkers have fractured bones and died as the result of a fall.[16][17] Sleepwalkers may also face embarrassment of being found naked in public.[18][19] ## Causes[edit] The cause of sleepwalking is unknown. A number of, as yet unproven, hypotheses are suggested for why it might occur, including: delay in the maturity of the central nervous system,[5] increased slow wave sleep,[20] sleep deprivation, fever, and excessive tiredness. There may be a genetic component to sleepwalking. One study found that sleepwalking occurred in 45% of children who have one parent who sleepwalked, and in 60% of children if both parents sleepwalked.[7] Thus, heritable factors may predispose an individual to sleepwalking, but expression of the behavior may also be influenced by environmental factors.[21] Genetic studies using common fruit flies as experimental models reveal a link between night sleep and brain development mediated by evolutionary conserved transcription factors such as AP-2 [22] Sleepwalking may be inherited as an autosomal dominant disorder with reduced penetrance. Genome-wide multipoint parametric linkage analysis for sleepwalking revealed a maximum logarithm of the odds score of 3.14 at chromosome 20q12-q13.12 between 55.6 and 61.4 cM.[23] Sleepwalking has been hypothesized to be linked to the neurotransmitter serotonin, which also appears to be metabolized differently in migraine patients and people with Tourette syndrome, both populations being four to nine times more likely to experience an episode of sleepwalking.[24] Hormonal fluctuations have been found to contribute to sleepwalking episodes in women, with the likeliness to sleepwalk being higher before the onset of menstruation.[25] It also appears that hormonal changes during pregnancy decrease the likelihood of engaging in sleepwalking [26] Medications, primarily in four classes—benzodiazepine receptor agonists and other GABA modulators, antidepressants and other serotonergic agents, antipsychotics, and β-blockers— have been associated with sleepwalking.[27] The best evidence of medications causing sleepwalking is for Zolpidem and sodium oxybate—all other reports are based on associations noted in case reports.[27] A number of conditions, such as Parkinson's disease, are thought to trigger sleepwalking in people without a previous history of sleepwalking.[28][needs update] ## Diagnosis[edit] Polysomnography is the only accurate assessment of a sleepwalking episode. Because this is costly and sleepwalking episodes are usually infrequent, other measures commonly used include self-, parent-, or partner-report. Three common diagnostic systems that are generally used for sleepwalking disorders are International Classification of Diseases,[1] the International Classification of Sleep Disorders 3,[29] and the Diagnostic and Statistical Manual.[2] Sleepwalking should not be confused with alcohol- or drug-induced blackouts, which can result in amnesia for events similar to sleepwalking. During an alcohol-induced blackout (drug-related amnesia), a person is able to actively engage and respond to their environment (e.g. having conversations or driving a vehicle), however the brain does not create memories for the events.[30] Alcohol-induced blackouts can occur with blood alcohol levels higher than 0.06g/dl.[31] A systematic review of the literature found that approximately 50% of drinkers have experienced memory loss during a drinking episode and have had associated negative consequences similar to sleepwalkers, including injury and death.[30] Other differential diagnoses include Rapid eye movement sleep behavior disorder, confusional arousals, and night terrors. There are two subcategories of sleepwalking: * sleepwalking with sleep-related eating. * sleepwalking with sleep-related sexual behavior (sexsomnia).[2] Sleep eating involves consuming food while asleep. These sleep eating disorders are more often than not induced for stress related reasons. Another major cause of this sleep eating subtype of sleepwalking is sleep medication, such as Ambien for example (Mayo Clinic). There are a few others, but Ambien is a more widely used sleep aid.[32] Because many sleep eaters prepare the food they consume, there are risks involving burns and such with ovens and other appliances. As expected, weight gain is also a common outcome of this disorder, because food that is frequently consumed contains high carbohydrates. As with sleepwalking, there are ways that sleep eating disorders can be maintained. There are some medications that calm the sleeper so they can get longer and better-quality rest, but activities such as yoga can also be introduced to reduce the stress and anxiety causing the action.[33] ### Assessment[edit] An assessment of sleepwalking via polysomnography poses the problem that sleepwalking is less likely to occur in the sleep laboratory, and if an episode occurs, it is usually less complex than what the patient experiences at home.[34][35][36] Therefore, the diagnosis can often be made by assessment of sleep history, time-course and content of the sleep related behaviors.[37] Sometimes, home videos can provide additional information and should be considered in the diagnostic process.[38] Some features that should always be assessed include:[39] * Age of onset * When the episode occurs during the sleep period * How often these episodes occur (frequency) and how long they last (duration) * Description of the episode, including behavior, emotions, and thoughts during and after the event * How responsive the patient is to external stimuli during the episode * How conscious or aware the patient is, when awakened from an episode * If the episode is remembered afterwards * The triggers or precipitating factors * Sleep–wake pattern and sleep environment * Daytime sleepiness * Other sleep disorders that might be present * Family history for NREM parasomnias and other sleep disorders * Medical, psychiatric, and neurological history * Medication and substance use history ## Treatment[edit] There have been no clinical trials to show that any psychological or pharmacological intervention is effective in preventing sleepwalking episodes.[8] Despite this, a wide range of treatments have been used with sleepwalkers. Psychological interventions have included psychoanalysis, hypnosis, scheduled or anticipatory waking, assertion training, relaxation training, managing aggressive feelings, sleep hygiene, classical conditioning (including electric shock), and play therapy. Pharmacological treatments have included an anticholinergic (biperiden), antiepileptics (carbamazepine, valproate), an antipsychotic (quetiapine), benzodiazepines (clonazepam, diazepam, flurazepam, imipramine, and triazolam), melatonin, a selective serotonin reuptake inhibitor (paroxetine), a barbiturate (sodium amytal) and herbs.[8] There is no evidence to show that waking sleepwalkers is harmful or not, though the sleepwalker is likely to be disoriented if awakened as sleepwalking occurs during the deepest stage of sleep.[citation needed] Unlike other sleep disorders, sleepwalking is not associated with daytime behavioral or emotional problems. This may be because the sleepwalker's sleep is not disturbed—unless they are woken, they are still in a sleep state while sleepwalking.[citation needed] Maintaining the safety of the sleepwalker and others and seeking treatment for other sleep problems is recommended.[8] Reassurance is recommended if sleepwalking is not causing any problems.[8] However, if it causes distress or there is risk of harm, hypnosis and scheduled waking are recommended as treatments.[8] ### Safety planning[edit] For those whose sleepwalking episodes turn to be hazardous, a door alarm may offer a measure of protection. There are various kinds of door alarms that can attach to a bedroom door and when the door is opened, the alarm sounds.[40] The intention is that the sound will fully awaken the person and interrupt the sleepwalking episode, or if the sleepwalker lives with others, the sound will prompt them to check on the person. Sleepwalkers should aim to have their bedrooms on the ground floor of a home, apartment, dorm, hotel, etc. Sleepwalkers should not have easily accessible weapons (loaded guns, knives) in the bedroom or any room of the house for that matter. If there are weapons, they should be locked away with keys secluded from the sleepwalker.[9] For partners of sleepwalkers who are violent or disturb their sleep, sleeping in another room may lead to better sleep quality and quantity. ## Epidemiology[edit] The lifetime prevalence of sleepwalking is estimated to be 4.6%–10.3%. A meta-analysis of 51 studies, that included more than 100,000 children and adults, found that sleepwalking is more common in children with an estimated 5%, compared with 1.5% of adults, sleepwalking at least once in the previous 12 months. The rate of sleepwalking has not been found to vary across ages during childhood.[41] ## History[edit] Sleepwalking has attracted a sense of mystery, but was not seriously investigated and diagnosed until the 19th century. The German chemist and parapsychologist Baron Karl Ludwig von Reichenbach (1788–1869) made extensive studies of sleepwalkers and used his discoveries to formulate his theory of the Odic force.[42] Sleepwalking was initially thought to be a dreamer acting out a dream.[5] For example, in one study published by the Society for Science & the Public in 1954, this was the conclusion: "Repression of hostile feelings against the father caused the patients to react by acting out in a dream world with sleepwalking, the distorted fantasies they had about all authoritarian figures, such as fathers, officers and stern superiors."[43] This same group published an article twelve years later with a new conclusion: "Sleepwalking, contrary to most belief, apparently has little to do with dreaming. In fact, it occurs when the sleeper is enjoying his most oblivious, deepest sleep—a stage in which dreams are not usually reported."[44] More recent research has discovered that sleepwalking is actually a disorder of NREM (non-rapid eye movement) arousal.[5] Acting out a dream is the basis for a REM (rapid eye movement) sleep disorder called REM Behavior Disorder (or REM Sleep Behavior Disorder, RSBD).[5] More accurate data about sleep is due to the invention of technologies, such as the electroencephalogram (EEG) by Hans Berger in 1924 and BEAM by Frank Duffy in the early 1980s.[45] In 1907, Sigmund Freud spoke about sleepwalking to the Vienna Psychoanalytic Society (Nunberg and Federn). He believed that sleepwalking was connected to fulfilling sexual wishes and was surprised that a person could move without interrupting their dream. At that time, Freud suggested that the essence of this phenomenon was the desire to go to sleep in the same area as the individual had slept in childhood. Ten years later, he speculated about somnambulism in the article "A Metapsychological Supplement to the Theory of Dreams" (1916–17 [1915]). In this essay, he started to clarify and expand his hypothetical ideas on dreams. The dreams is a fragile equilibrium that is only partially successful because the repressed unconscious impulses of the unconscious system. This does not obey the wishes of the ego and maintain their countercathexis. Another reason why dreams are partially successful is because certain preconscious daytime thoughts can be resistant and these can retain a part of their cathexis as well. It is probable how unconscious impulses and day residues can come together and result in a conflict. Freud then wondered about the outcome of this wishful impulse, which represents an unconscious instinctual demand and then it becomes a dream wish in the preconscious. Furthermore, Freud stated that this unconscious impulse could be expressed as mobility during sleep. This would be what is observed in somnambulism, though what actually makes it possible remains unknown.[46] As of 2002, sleepwalking has not been detected in non-human primates. It is unclear whether it simply hasn't been observed yet, or whether sleepwalking is a uniquely human phenomenon.[47] ## Society and culture[edit] ### Opera[edit] Amina, the somnabuliste, at the mill. Vincenzo Bellini's 1831 Italian opera semiseria, La sonnambula, the plot of which is centered on the question of the innocence of the betrothed and soon-to-be married Amina, who, upon having been discovered in the bedchamber of a stranger, and despite the assurances of that stranger that Amina was entirely innocent, has been rejected by her enraged fiancé, Elvino — who, then, decides to marry another. In fact, when stressed, Amina was susceptible to somnambulism; and had come to be in the stranger's bedchamber by sleep-walking along a high parapet (in full view of the opera's audience). Elvino, who later observes the (exhausted by all the fuss) Amina, sleep-walking across a very high, very unstable, and very rickety bridge at the local mill, realizes his mistake, abandons his plans of marriage to the other woman, and re-unites with Amina. #### Jenny Lind and James Braid[edit] In August 1847, the famous soprano Jenny Lind visited Manchester, and gave two performances as Amina. The outstanding difference between Lind and her contemporaries was that, "whilst the beauty of her voice was far greater than any other in living memory (thus, the Swedish Nightingale), what really set her apart was her outstanding ability to act"; and, moreover, in performing as Amina, rather than walking along a wide and well-protected walkway (as the others did), she routinely acrobatically balanced her way along narrow planks.[48] While she was in Manchester—on the basis that, at the time, many characterized "hypnotism" as "artificial somnambulism",[49] and that, from a rather different perspective, her stage performance could also be described as one of "artificial" (rather than spontaneous) somnambulism—her friends arranged for her to visit the local surgeon James Braid, who had discovered hypnotism in 1841:[50][51] "Mr. Braid, surgeon, whose discoveries in hypnotism are well known, having invited the fair impersonator of a somnambulist to witness some of the abnormal feats of a real somnambulist, artificially thrown into that state, it was arranged that a private séance should take place [on Friday, 3 September 1847]." Manchester Guardian, 8 September 1847. ### Drama[edit] * The sleepwalking scene (Act V Scene 1) from William Shakespeare's tragic play Macbeth (1606) is one of the most famous scenes in all of literature. * In Oulton's two act farce The Sleep-Walker; or, Which is the Lady (1812), "Somno", a histrionic failed-actor-turned-manservant relives his wished-for roles when sleepwalking. ### Literature[edit] * In Bram Stoker's novel Dracula the character Lucy Westenra is described as a sleepwalker. It is while sleepwalking that Count Dracula lures and attacks her. ### Sleepwalking as a legal defense[edit] Sleepwalking can sometimes result in injury, assault, or the death of someone else. Because these sleepwalking behaviours occur without volition, sleepwalking can be used as a legal defense.[52] Alternative explanations, such as malingering and alcohol and drug-induced amnesia, need to be excluded. The differential diagnosis may also include other conditions in which violence related to sleep is a risk, such as REM Sleep Behavior Disorder (RSBD), fugue states, and episodic wandering."[53] In the 1963 case Bratty v Attorney-General for Northern Ireland, Lord Morris stated, "Each set of facts must require a careful examination of its own circumstances, but if by way of taking an illustration it were considered possible for a person to walk in his sleep and to commit a violent crime while genuinely unconscious, then such a person would not be criminally liable for that act."[54] In the case of the law, an individual can be accused of non-insane automatism or insane automatism. The first is used as a defense for temporary insanity or involuntary conduct, resulting in acquittal. The latter results in a "special verdict of not guilty by reason of insanity."[55] This verdict of insanity can result in a court order to attend a mental institution.[56] Other examples of legal cases involving sleepwalking in the defense include: * 1846, Albert Tirrell used sleepwalking as a defense against charges of murdering Maria Bickford, a prostitute living in a Boston brothel. * 1981, Steven Steinberg, of Scottsdale, Arizona was accused of killing his wife and acquitted on the grounds of temporary insanity.[57] * 1991, R v Burgess: Burgess was accused of hitting his girlfriend on the head with a wine bottle and then a video tape recorder. Found not guilty, at Bristol Crown Court, by reason of insane automatism.[58] * 1992, R. v. Parks: Parks was accused of killing his mother-in-law and attempting to kill his father-in-law. He was acquitted by the Supreme Court of Canada.[57] * 1994, Pennsylvania v. Ricksgers: Ricksgers was accused of killing his wife. He was sentenced to life in prison without parole.[59] * 1999, Arizona v. Falater: Falater, of Phoenix, Arizona, was accused of killing his wife. The court concluded that the murder was too complex to be committed while sleepwalking. Falater was convicted of first-degree murder and sentenced to life with no possibility of parole.[57] * 2001, California v. Reitz: Stephen Reitz killed his lover, Eva Weinfurtner. He told police he had no recollection of the attack but he had "flashbacks" of believing he was in a scuffle with a male intruder. His parents testified in court that he had been a sleepwalker from childhood but the court was not convinced and convicted Reitz of first-degree murder in 2004.[59] * 2008, Brian Thomas was accused of killing his wife while he dreamt she was an intruder, whilst on holiday in West Wales.[60] Thomas was found not guilty.[61] ## See also[edit] * Homicidal sleepwalking ## References[edit] 1. ^ a b World Health Organization. (1992). The ICD-10 classification of mental and behavioural disorders: Clinical descriptions and diagnostic guidelines. Version 2016. Geneva: World Health Organization. 2. ^ a b c American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, D.C.: American Psychiatric Publishing. 3. ^ "I went driving and motorbiking in my sleep". BBC News. 2017-12-11. Retrieved 2020-02-27. 4. ^ "SLEEP: Sex While Sleeping Is Real, and May Be No Joke", Michael Smith (June 19, 2006), MedPage Today, access date 08-11-2011 5. ^ a b c d e f g Swanson, Jenifer, ed. "Sleepwalking". Sleep Disorders Sourcebook. MI: Omnigraphics, 1999. 249–254, 351–352. 6. ^ Rachel Nowak (2004-10-15). "Sleepwalking woman had sex with strangers". New Scientist. Retrieved 2007-04-30. 7. ^ a b c Lavie, Peretz, Atul Malhotra, and Giora Pillar. Sleep disorders: diagnosis, management and treatment: a handbook for clinicians. London: Martin Dunitz, 2002. 146–147. 8. ^ a b c d e f Stallman, HM (2017). "Assessment and treatment of sleepwalking in clinical practice". Australian Family Physician. 46 (8): 590–593. PMID 28787563. 9. ^ a b Schenck, Carlos H. Sleep: The Mysteries, The Problems, and The Solutions. New York: Avery/Penguin Group, 2007. Print. 10. ^ Guilleminault, Christian; Palombini, Luciana; Pelayo, Rafael; Chervin, Ronald D. (1 January 2003). "Sleepwalking and Sleep Terrors in Prepubertal Children: What Triggers Them?". Pediatrics. 111 (1): e17–e25. doi:10.1542/peds.111.1.e17. PMID 12509590 – via pediatrics.aappublications.org. 11. ^ "Sleep terrors (night terrors) - Symptoms and causes". Mayo Clinic. Retrieved 2019-03-25. 12. ^ Crisp, A.H.; Matthews, BM; Oakey, M; Crutchfield, M; et al. (1990). "Sleepwalking, night terrors, and consciousness". British Medical Journal. 300 (6721): 360–362. doi:10.1136/bmj.300.6721.360. PMC 1662124. PMID 2106985. 13. ^ Orme, J.E. (1967), "The Incidence of Sleepwalking in Various Groups", Acta Psychiatrica Scandinavica, Vol 43, Iss 3, pp 279–28. 14. ^ Milliet N, Ummenhofer W. Somnambulism and trauma: case report and short review of the literature. J Trauma. 1999;47(2):420–2 15. ^ Sillesen NH, Nielsen LT, Bonde C. Complex injuries associated with somnambulism. Ugeskr Laeger. 2010;172(50):3489–90 16. ^ "Sleepwalker dies after falling from hotel window following night out with work colleagues". 2014-01-03. 17. ^ "Tragedy as sleepwalker plunges to death from hotel window". 2014-01-02. 18. ^ "Naked sleepwalker stumbles out of city hotel then makes an odd request to police". 2016-05-22. 19. ^ "Sleep walker mows lawn naked". 2005-03-21. 20. ^ Pressman. "Factors that predispose, prime and precipitate NREM parasomnias in adults: clinical and forensic implications." Sleep Med Rev 11.1 (2007):5–30. 21. ^ Kales, A.; Soldatos, C. R.; Bixler, E. O.; Ladda, R. L.; Charney, D. S.; Weber, G.; Schweitzer, P. K. (1 August 1980). "Hereditary factors in sleepwalking and night terrors". The British Journal of Psychiatry. 137 (2): 111–118. doi:10.1192/bjp.137.2.111. PMID 7426840. 22. ^ Kucherenko, Mariya M.; Ilangovan, Vinodh; Herzig, Bettina; Shcherbata, Halyna R.; Bringmann, Henrik (2016-01-01). "TfAP-2 is required for night sleep in Drosophila". BMC Neuroscience. 17 (1): 72. doi:10.1186/s12868-016-0306-3. ISSN 1471-2202. PMC 5103423. PMID 27829368. 23. ^ "Neurology" Journal, January 4, 2011 76:12-13 published by the American Academy of Neurology www.Neurology.org 24. ^ Barabas, Gabor; Matthews, Wendy S.; Ferrari, Michael (2008). "Somnambulism in Children with Tourette Syndrome". Developmental Medicine & Child Neurology. 26 (4): 457–460. doi:10.1111/j.1469-8749.1984.tb04471.x. PMID 6148287. S2CID 1759571. 25. ^ Schenck, C. H., & Mahowald, M. W. (1995b). Two cases of premenstrual sleep terrors and injurious sleep-walking. Journal of Psychosomatic Obstetrics & Gynecology, 16, 79–84. 26. ^ Hedman, C., Pohjasvaara, T., Tolonen, U., Salmivaara, A., & Myllyla, V. (2002). Parasomnias decline during pregnancy. Acta Neurologica Scandinavica, 105, 209–214. 27. ^ a b Stallman, HM; Kohler, M; White, J (February 2018). "Medication induced sleepwalking: A systematic review". Sleep Medicine Reviews. 37: 105–113. doi:10.1016/j.smrv.2017.01.005. PMID 28363449. 28. ^ Poryazova, R; Waldvogel, D; Bassetti, CL (October 2007). "Sleepwalking in patients with Parkinson disease". Archives of Neurology. 64 (10): 1524–7. doi:10.1001/archneur.64.10.1524. PMID 17923637. 29. ^ American Academy of Sleep Medicine. (2014). International Classification of Sleep Disorders – Third Edition (ICSD-3). Author. 30. ^ a b Wetherill, Reagan R.; Fromme, Kim (2016). "Alcohol-Induced Blackouts: A Review of Recent Clinical Research with Practical Implications and Recommendations for Future Studies". Alcoholism: Clinical and Experimental Research. 40 (5): 922–935. doi:10.1111/acer.13051. PMC 4844761. PMID 27060868. 31. ^ Hartzler, Bryan; Fromme, Kim (2003). "Fragmentary and en bloc blackouts: Similarity and distinction among episodes of alcohol-induced memory loss". Journal of Studies on Alcohol. 64 (4): 547–550. doi:10.15288/jsa.2003.64.547. PMID 12921196. 32. ^ Staff, Mayo Clinic. "Sleep-related Eating Disorders". Mayo Clinic. Retrieved 5 May 2014. 33. ^ Clinic, Cleveland. "Sleep-Related Eating Disorders". Cleveland Clinic. Retrieved 5 May 2014. 34. ^ Blatt, I., Peled, R., Gadoth, N., & Lavie, P. (1991). The value of sleep recording in evaluating somnambulism in young adults. Electroencephalography & Clinical Neurophysiology, 78, 407–412. 35. ^ Joncas, S., Zadra, A., Paquet, J., & Montplaisir, J. (2002). The value of sleep deprivation as a diagnostic tool in adult sleepwalkers. Neurology, 58, 936–940. 36. ^ Kales, A., Soldatos, C. R., Caldwell, A. B., Kales, J. D., Humphrey, F. J., 2nd, Charney, D. S., & Schweitzer, P. K. (1980). Somnambulism. Clinical characteristics and personality patterns. Archives of General Psychiatry, 37, 1406–1410. 37. ^ Hublin, C., Kaprio, J., Partinen, M., Heikkila, K., & Koskenvuo, M. (1997). Prevalence and genetics of sleepwalking: A population-based twin study. Neurology, 48, 177–181. 38. ^ Kavey, N. B., Whyte, J., Resor, S. R., Jr., & Gidro-Frank, S. (1990). Somnambulism in adults. Neurology, 40, 749–752. 39. ^ Zadra, Antonio; Pilon, Mathieu (2012-03-01). Parasomnias II. Oxford University Press. doi:10.1093/oxfordhb/9780195376203.013.0028. 40. ^ e.g., https://ilcaustralia.org.au/search_category_paths/636 41. ^ Stallman, HM; Kohler, M (2016). "Prevalence of Sleepwalking: A Systematic Review and Meta-Analysis". PLOS ONE. 11 (11): e0164769. Bibcode:2016PLoSO..1164769S. doi:10.1371/journal.pone.0164769. PMC 5104520. PMID 27832078. 42. ^ Kushida, Clete. 2012. Encyclopedia of Sleep.. Academic Press. p. 155. ISBN 1283895471. 43. ^ Society for Science & the Public. "Sleepwalking Cause." The Science News-Letter. 27 February 1954: 132. 44. ^ Society for Science & the Public. "Sleepwalker Not Dreaming." The Science News-Letter, 25 June 1966: 508 45. ^ "Electroencephalography", Medical Discoveries, 2009. 46. ^ "Somnambulism". International Dictionary of Psychoanalysis. 2005. 47. ^ S. S. Kantha. "Is somnambulism a distinct disorder of humans and not seen in non-human primates?". Medical Hypotheses. doi: 10.1016/S0306-9877(03)00206-8 48. ^ Yeates, L.B., James Braid: Surgeon, Gentleman Scientist, and Hypnotist, Ph.D. Dissertation, School of History and Philosophy of Science, Faculty of Arts & Social Sciences, University of New South Wales, January 2013. Yeates (2013), p.788. 49. ^ For example, Pritchard J.C., A Treatise on Insanity and Other Disorders Affecting the Mind, Sherwood, Gilbert and Piper, (London), 1835, p.p.410. 50. ^ "Jenny Lind at the Manufacturing Establishments", Manchester Guardian, No.1947, (Saturday, 4 September 1847), p.7, col.C; "Jenny Lind and the Hypnotic Somnambulist", Manchester Guardian, No.1948, (Wednesday, 8 September 1847), p.5, col.F; "Jenny Lind and the Manchester Somnambulists", Newcastle Courant, No.9015, (Saturday, 17 September 1847), p.2, col.E; "Jenny Lind and Hypnotism", The Medical Times, Vol.16, No.416, (18 September 1847), p.602; and "Jenny Lind and Mesmerism", The Lady's Newspaper, No.39, (Saturday, 25 September 1847) p.294, col.A. 51. ^ Storer, H., "Jenny Lind and the Somnambulist", The Critic: A Journal for Readers, Authors, and Publishers, Vol.6, No.145, (9 October 1847), p.238; Braid, J., "(Letter to Dr. Storer, written on 28 September 1847)", The Critic: A Journal for Readers, Authors, and Publishers, Vol.6, No.145, (9 October 1847), p.238. 52. ^ Popat, S; Winslade, W (2015). "While You Were Sleepwalking: Science and Neurobiology of Sleep Disorders & the Enigma of Legal Responsibility of Violence During Parasomnia". Neuroethics. 8 (2): 203–214. doi:10.1007/s12152-015-9229-4. PMC 4506454. PMID 26203309. 53. ^ Culebras, Antonio. "Somnambulism." Clinical Handbook of Sleep Disorders, Massachusetts: Butterworth-Heinemann, 1996. 317–319. 54. ^ Mackay, Irene (1992). "The Sleepwalker is Not Insane". The Modern Law Review. 55 (5): 715–716. doi:10.1111/j.1468-2230.1992.tb02845.x. 55. ^ Canadian Legal Information Institute. R v. Parks. 1992. 56. ^ Lederman, Eliezer. "Non-Insane and Insane Automatism: Reducing the Significance of a Problematic Distinction." The International and Comparative Law Quarterly 34.4 (1985): 819. 57. ^ a b c Martin, Lawrence. "Can sleepwalking be a murder defense?", 2009. 58. ^ Heaton-Armstrong A (Editor), Shepherd E (Editor), Wolchover D (Editor) (2002). Analysing Witness Testimony: Psychological, Investigative and Evidential Perspectives: A Guide for Legal Practitioners and Other Professionals. Blackstone Press. ISBN 978-1-85431-731-5.CS1 maint: multiple names: authors list (link) CS1 maint: extra text: authors list (link) 59. ^ a b Lyon, Lindsay. "7 Criminal Cases that Involved the 'Sleepwalking Defense.'", US News and World Report. May 2009. 60. ^ de Bruxelles, Simon (18 November 2009). "Sleepwalker Brian Thomas admits killing wife while fighting intruders in nightmare". The Times. London. Retrieved 2009-12-26. 61. ^ "Login". ## External links[edit] Classification D * ICD-10: F51.3 * MeSH: D013009 * DiseasesDB: 36323 * SNOMED CT: 80495009 External resources * MedlinePlus: 000808 * eMedicine: article/1188854 Media related to Sleepwalking at Wikimedia Commons * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring Authority control * GND: 4179666-4 [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	Sleepwalking	c0037672	2,843	wikipedia	https://en.wikipedia.org/wiki/Sleepwalking	2021-01-18T18:38:52	{"mesh": ["D013009"], "icd-9": ["307.4307.4"], "icd-10": ["F51.3"], "wikidata": ["Q388626"]}
A number sign (#) is used with this entry because Wilson disease is caused by homozygous or compound heterozygous mutation in the ATP7B gene (606882) on chromosome 13q14. Description Wilson disease is an autosomal recessive disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neurologic abnormalities. De Bie et al. (2007) provided a detailed review of the molecular pathogenesis of Wilson disease. Clinical Features In Wilson disease, the basal ganglia and liver undergo changes that express themselves in neurologic manifestations and signs of cirrhosis, respectively. A disturbance in copper metabolism is somehow involved in the mechanism. Low ceruloplasmin (117700) is found in the serum. Shokeir and Shreffler (1969) advanced the hypothesis that ceruloplasmin functions in enzymatic transfer of copper to copper-containing enzymes such as cytochrome oxidase. Supporting the hypothesis was the finding of markedly reduced levels of activity of cytochrome oxidase in Wilson disease and moderate reductions in heterozygotes. The Kayser-Fleischer ring is a deep copper-colored ring at the periphery of the cornea which is frequently found in Wilson disease and is thought to represent copper deposits. Bearn and McKusick (1958) and Whelton and Pope (1968) described azure lunulae of the fingernails in patients with Wilson disease. These are presumably of the same significance as the Kayser-Fleischer ring and possibly arise by the same mechanism. Hypercalciuria and nephrocalcinosis are not uncommon in patients with Wilson disease. Hypercalciuria associated with this disorder was first reported by Litin et al. (1959). Wiebers et al. (1979) observed renal stones in 7 of 54 patients with Wilson disease. Penicillamine therapy was accompanied by a decrease in urinary calcium excretion to normal values in 3 patients, but hypercalciuria persisted in 3. Azizi et al. (1989) described hypercalciuria and nephrolithiasis as presenting signs in Wilson disease and postulated tubular defect in calcium reabsorption. Hoppe et al. (1993) described a 17-year-old male with a 6-year history of hypercalciuria, nephrocalcinosis, and nephrolithiasis, in whom Wilson disease was finally diagnosed. Bearn (1960) suggested that Jewish WND patients from eastern Europe are different from other groups of patients in that the age at onset is later, the disease is generally milder, and the serum copper and serum ceruloplasmin levels are 'particularly liable to be of normal concentration.' Bonne-Tamir et al. (1990) provided a full analysis of Wilson disease in Israel. From a study of 28 Canadian families, Cox et al. (1972) suggested that there are at least 3 forms of Wilson disease. In a rare 'atypical form,' the heterozygotes show about 50% of the normal level of ceruloplasmin. This gene may have been of German-Mennonite derivation. In the 2 typical forms heterozygotes have normal ceruloplasmin levels, although they can be identified by decreased reappearance of radioactive copper into serum and ceruloplasmin. The authors referred to the 2 'typical forms' as the Slavic and the juvenile type. The Slavic type has a late age of onset and is predominantly a neurologic disease. The juvenile type, which occurs in western Europeans and several other ethnic groups, has onset before age 16 years and is frequently a hepatic disease. Czaja et al. (1987) demonstrated reduced ceruloplasmin gene transcription in 4 patients with Wilson disease (44% of controls). Low levels of ceruloplasmin are a normal finding in the newborn (Shokeir, 1971). In Israel, Passwell et al. (1977) observed that Arab patients show an earlier age of onset and more severe course than Jewish patients. Within families of both ethnic groups, age of onset and type of disease show a close correlation. Thus, the authors concluded that the interethnic differences may reflect different mutations. Fitzgerald et al. (1975) described a 57-year-old man with liver disease that they concluded represented Wilson disease. Ross et al. (1985) described a patient who was found to have hepatosplenomegaly at age 51, developed hand tremor at 52, and was having difficulty with hand dexterity at 55. The diagnosis of Wilson disease was made at age 58 on the basis of urinary, serum, and hepatic copper studies and liver histology, and despite the absence of Kayser-Fleischer rings. Wilson disease is not generally considered in patients over 30 years of age who present with liver disease and without neurologic signs. Danks et al. (1990) reported 4 such cases: 2 men, aged 43 and 48, and 2 women, aged 44 and 58. The 58-year-old woman had been ill for only 1 week and died in 36 hours of acute hepatorenal failure. Her sister had died of cirrhosis and liver failure at age 28. Alcohol intake was minimal or completely avoided in all. None of the known hepatitis viruses could be identified and no autoantibodies were detected. Kuan (1987) demonstrated manifestations of myocardial involvement in Wilson disease. The occurrence of chondrocalcinosis and osteoarthritis in Wilson disease may be due to copper accumulation similar to the arthropathy of hemochromatosis (HFE; 235200) (Menerey et al., 1988). Starosta-Rubinstein et al. (1987) correlated clinical manifestations with the findings of magnetic resonance imaging (MRI) of the brain. Van Wassenaer-van Hall et al. (1995) also used cranial MRI to study WND patients. Although the most striking findings on their MRI scan were abnormalities of the basal ganglia in generalized cerebral atrophy, they also noted subtle white matter abnormalities in some WND patients, particularly at the dentatorubrothalamic, pontocerebellar, and corticospinal tracts. From Slovenia, Ferlan-Marolt and Stepec (1999) reported a 24-year-old woman with fulminant Wilsonian hepatitis accompanied by hemolytic anemia and leading to death in a few weeks. Kayser-Fleischer rings were said to have been absent, and there were no neurologic abnormalities until the development of the flapping tremor of hepatic failure in the last days of life. Gu et al. (2000) studied mitochondrial function and aconitase activity in Wilson disease liver tissue and compared the results with those in a series of healthy controls and patients without Wilson disease. There was evidence of severe mitochondrial dysfunction in the livers of patients with Wilson disease. Enzyme activities were decreased as follows: complex I by 62%, complex II+III by 52%, complex IV by 33%, and aconitase by 71%. These defects did not seem to be secondary to penicillamine use, cholestasis, or poor hepatocellular synthetic function. Gu et al. (2000) stated that the pattern of enzyme defects suggests that free radical formation and oxidative damage, probably mediated via mitochondrial copper accumulation, are important in Wilson disease pathogenesis, and that their results provide a rationale for a study of the use of antioxidants in Wilson disease. Both Wilson disease and hemochromatosis (235200), characterized by excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles (191170) in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, Hussain et al. (2000) determined the frequency of p53 mutated alleles in nontumorous liver tissue from WND and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249, and C:G to A:T transversions and C:G to T:A transitions at codon 250 were found in liver tissue from WND cases, and a higher frequency of G:C to T:A transversions at codon 249 was also found in liver tissue from hemochromatosis cases. Sixty percent of WND and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggested nitric oxide as a source of increased oxidative stress. The results were consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WND causes mutation in the p53 tumor suppressor gene. Hedera et al. (2002) reported a 13-year-old male with Wilson disease who exhibited leukoencephalopathy early in the disease course. MRI showed increased signal intensities in the basal ganglia and throughout the subcortical white matter in the frontal lobes, which later extended to the parietal and occipital lobes. Takeshita et al. (2002) investigated 2 families with Wilson disease in which sibs showed different clinical phenotypes and different ages at onset. In the first family, the second and fourth male children demonstrated onset of the neurologic type of Wilson disease at 16 and 28 years of age, respectively, and the first female child developed the hepatic type at 38 years of age. In family 2, the second male child showed neurologic symptoms at 32 years of age and was diagnosed as having the hepatoneurologic type of Wilson disease; the 35-year-old first female child was found to have the hepatic type in familial screening. In both families, affected individuals were compound heterozygotes for mutations in the ATP7B gene. In the first family, the mutations were R778L (606882.0009) and R919G (606882.0014). In the second family, the mutations were 2511delA (606882.0015) and A874V (606882.0016). Hlubocka et al. (2002) studied 42 patients with Wilson disease (19 men and 23 women, mean age 34 +/- 10 years) and 42 age- and sex-matched healthy volunteers. All subjects underwent complete echocardiographic examination; 24-hour Holter monitoring was performed in 23 Wilson disease patients. In comparison with healthy subjects, patients with Wilson disease had increased thickness of the interventricular septum and left ventricular (LV) posterior wall. While the 2 groups did not differ in LV mass index, relative LV wall thickness was significantly increased in the Wilson disease patients compared to control subjects. Concentric LV remodeling was present in 9 patients (21%) and LV hypertrophy in 1 patient. Diastolic filling and the frequency of valvular abnormalities were comparable in both groups. Twenty-four-hour Holter monitoring detected ECG abnormalities in 10 patients (42%), the most frequent findings being runs of supraventricular tachycardias and frequent supraventricular ectopic beats. Jung et al. (2005) reported a 17-year-old Korean man with Wilson disease who presented with polyneuropathy at least 6 months before developing more typical symptoms. Initial symptoms included intermittent paresthesia and weakness in both hands and feet with normal sensory examination. Nerve conduction studies and sural nerve biopsy were consistent with a mixed demyelinating and axonal neuropathy. Treatment with penicillamine, zinc sulfate, and vitamin B6 resulted in clinical improvement. Diagnosis Chowrimootoo et al. (1998) investigated the neonatal diagnosis of Wilson disease by measuring ceruloplasmin isoforms in neonatal cord blood samples and venous blood from both healthy adults and patients with Wilson disease. Total ceruloplasmin levels were reduced in all neonatal specimens. The plasma isoform, however, was significantly reduced or absent only in patients with Wilson disease, whereas the biliary isoform was reduced both in healthy neonates and patients with Wilson disease. The authors commented that measurement of ceruloplasmin isoforms in cord blood or dried blood spots may permit neonatal diagnosis of this condition, before substantial tissue damage has occurred. Gow et al. (2000) reported their detailed experience of 30 patients with a diagnosis of Wilson disease seen in 2 Australian centers between 1971 and 1998. Twenty-two patients presented with chronic disease; age at diagnosis ranged from 7 to 58 years. Only 14 of these patients (64%) had Kayser-Fleischer rings; 5 of these had low serum ceruloplasmin concentrations and normal urinary copper excretion, 2 had normal ceruloplasmin levels and high urinary copper excretion, and 7 had the classic combination of low serum ceruloplasmin and high urinary copper. Eight patients presented with fulminant hepatic failure, with age at diagnosis ranging from 11 to 54 years; only 6 of these had Kayser-Fleischer rings, 7 had low serum ceruloplasmin, and 4 of them had raised urinary copper excretion. The others were anuric. Examination of the livers of these 8 patients, either at autopsy or posttransplantation, showed cirrhosis and elevated copper content. Gow et al. (2000) commented that the diagnosis of Wilson disease depended on the evaluation of clinical and laboratory evidence of abnormal copper metabolism, but that no single feature was reliable in isolation. Further, the authors suggested that Wilson disease should be considered in any patient at any age presenting with unusual liver or neurologic abnormalities. Firneisz et al. (2001) described postmortem (postcremation) diagnosis of Wilson disease on the basis of skin cells left on the deceased's electric shaver. Foye (2001) and Kuruvilla (2001) took these authors to task, noting that the man's DNA added no new information since the same mutation was identified in the man's father and 2 children. Foye (2001) commented that with the growing array of available tests, 'we must always remember in each individual case to stop first and ask not just whether a particular test could be done, but whether it should be done.' Kuruvilla (2001) noted that the man had movement disorder for at least 10 years before his death and presented to his physician with parkinsonian symptoms and florid manifestations of cirrhosis. Because Kayser-Fleischer ring is present in 100% of patients with CNS manifestations of Wilson disease, neuroophthalmologic slit-lamp assessment is mandatory and cost effective in all patients suspected of having this disease. Ferenci (2006) reviewed the geographic distribution of mutations in the ATP7B gene in Wilson disease patients to improve genetic diagnosis of Wilson disease. The most common mutation in patients from Europe is H1069Q (606882.0006). A unique 15-bp deletion in the 5-prime region (606882.0010) is frequent in Sardinia. M645R (606882.0020) is common in Spain, and R778L (606882.0009) is often found in patients from eastern Asia. Ferenci (2006) also presented a clinical algorithm for the diagnosis of Wilson disease. ### Prenatal Diagnosis Cossu et al. (1992) demonstrated how one can use flanking markers to do prenatal diagnosis by the linkage principle in this disorder. The probability of the fetus being affected was estimated to be only 0.007 in the example given. Clinical Management Sokol et al. (1985) successfully treated a 13-year-old girl with fulminant Wilson disease with orthotopic liver transplant. Polson et al. (1987) reported dramatic improvement in neurologic function over a period of 3 or 4 months after orthotopic liver transplantation. However, Guarino et al. (1995) published a case of a man treated with orthotopic liver transplantation who developed postoperative central pontine and extrapontine myelinolysis and then went on to develop new extrapyramidal symptoms 19 months after the liver transplant. Lingam et al. (1987) showed that neurologic abnormalities can be reversed to some extent in children with Wilson disease. In some patients it was necessary to substitute triethylene tetramine (TETA) for penicillamine because of adverse effects of the latter agent. Wilson disease is effectively treated by any 1 of 3 drugs, D-penicillamine, trien, or zinc acetate (Brewer et al., 1987). Brewer et al. (1994) described the successful treatment with zinc acetate of 13 presymptomatic patients identified through screening of sibs. The levels of hepatic copper in response to several years of zinc therapy may remain the same, go down, or go up temporarily. This is a reflection of zinc induction of hepatic metallothionein, which sequesters copper in a nontoxic pool. Hepatic copper levels should not be used to manage therapy. Liver function is well preserved by zinc therapy, and Brewer et al. (1994) observed no zinc toxicity in these 13 patients. Brewer et al. (1994) reported that no patient developed symptoms related to Wilson disease. However, Lang et al. (1993) reported a 30-year-old patient who deteriorated at the end of the first month of zinc therapy and died in hepatic coma. Hoogenraad (1994) expressed doubt that zinc played a causal role in the worsening condition of the patient reported by Lang et al. (1993). Devesa et al. (1995) described an uneventful pregnancy with delivery of a healthy newborn in a woman with Wilson disease who had been on the oral copper-chelating agent trientine (triethylenetetramine dihydrochloride) because of the development of nephrosis when D-penicillamine was used. Hartard and Kunze (1994) reported a successful pregnancy in a patient with Wilson disease treated with D-penicillamine and zinc sulfate 3 years prior to and during the pregnancy. Brewer et al. (1998) presented data on the long-term follow-up of maintenance zinc treatment of 141 symptomatic and presymptomatic patients with Wilson disease. From these data, they concluded that zinc is effective as a sole therapy and that it has low toxicity. The authors also presented limited data on zinc treatment of children and pregnant women with Wilson disease which were also suggestive of efficacy and low toxicity. LeWitt (1999) observed that 'Whereas management of Wilson's disease follows some of the most logical treatment strategies in all of clinical neurology, the optimal means for removing copper from the brain (and elsewhere) have not achieved consensus.' Articles by Walshe (1999), who defended the use of penicillamine, and by Brewer (1999) indicated that the role of penicillamine, now in its fifth decade of use, is still a matter of great controversy. Brewer (1999) suggested that penicillamine should not be used as initial therapy in Wilson disease. He cited a number of instances of penicillamine-induced worsening. He favored the use of zinc acetate for maintenance therapy of Wilson disease and mentioned other alternative therapies. By genetic analysis, Wu et al. (2003) identified 17 presymptomatic patients with Wilson disease. Prophylactic treatment of 14 patients with zinc over 3 to 5 years resulted in decreased levels of urinary copper, which indicated effective control of copper metabolism. None of the patients developed clinical symptoms of Wilson disease or adverse effects of zinc therapy by the end of the study period. In contrast, 3 patients who refused treatment had symptomatic progression of the disease. Wu et al. (2003) concluded that presymptomatic DNA diagnosis of individuals at risk and zinc therapy are effective treatment. Treatment for patients with Wilson disease who present with neurologic manifestations is difficult because penicillamine often makes them neurologically worse and zinc is slow acting. Brewer et al. (2003) performed an open-label study of 55 untreated patients presenting with neurologic Wilson disease and treated them with tetrathiomolybdate varying from 120 to 410 mg/day for 8 weeks and then followed up for 3 years. Only 2 patients treated with tetrathiomolybdate (4%) showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers were higher than in the original 33 patients and appeared to be due primarily to a more rapid dose escalation. Brewer et al. (2003) concluded that tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur. In a randomized controlled double-blind study of 48 patients with neurologic presentation of Wilson disease, Brewer et al. (2006) concluded that tetrathiomolybdate was a better choice than trientine for preserving neurologic function. Six (26%) of 23 patients treated with trientine showed neurologic deterioration during the 8-week study compared to 1 (4%) of 25 patients treated with tetrathiomolybdate. Alvarez et al. (2010) described how tetrathiomolybdate (TM) inhibits proteins that regulate copper physiology. Crystallographic results revealed that the surprising stability of the drug complex with the metallochaperone Atx1 (602270) arises from formation of a sulfur-bridged copper-molybdenum cluster reminiscent of those found in molybdenum and iron sulfur proteins. Spectroscopic studies indicated that this cluster is stable in solution and corresponds to physiologic clusters isolated from TM-treated Wilson disease animal models. Finally, mechanistic studies showed that the drug-metallochaperone inhibits metal transfer functions between copper-trafficking proteins. Alvarez et al. (2010) concluded that their results are consistent with a model wherein TM can directly and reversibly downregulate copper delivery to secreted metalloenzymes. Mapping In a large inbred kindred with affected persons in 2 generations, Frydman et al. (1985) investigated linkage of WND with 27 autosomal markers. A lod score of 3.21 was found at theta = 0.06 for linkage of WND and esterase D on chromosome 13. In a note added in proof, they indicated that they had typed a second unrelated 10-member sibship with WND; the maximum lod score was 1.48 at theta = 0, giving a combined maximum lod score of 4.55 at theta = 0.04. Bonne-Tamir et al. (1985, 1986) corroborated the linkage of WND and esterase D by studies of another inbred group, 2 unrelated Druze kindreds. The combined lod score was 5.49 at theta = 0.03. Bonne-Tamir et al. (1986) confirmed the localization of Wilson disease by demonstration of linkage to DNA markers on chromosome 13; their studies indicated that the WND locus is distal to the ESD locus. Yuzbasiyan-Gurkan et al. (1988) confirmed the linkage to markers on chromosome 13, with a maximum lod score of 2.189 at theta = 0.06 for linkage of Wilson disease to D13S1. One very informative pedigree was Hispanic. One pedigree in which affected persons had normal or low normal levels of serum ceruloplasmin (a finding in only about 15% of WND patients) showed a negative lod score. The proband was not on oral contraceptives, and there was no known ceruloplasmin-inducing factor present. The family was of Russian-Jewish background. By genetic linkage studies, Bowcock et al. (1988) narrowed the assignment of the WND locus to 13q14-q21. Farrer et al. (1988) explored the use of linked genetic markers to identify carriers, normals, and presymptomatic affected persons. A significant decrease on the average was found in serum copper concentrations in heterozygotes, but other sources of variation in serum copper concentration were much greater and precluded use of serum copper for carrier detection. A familial component, independent of WND genotype, appeared to be a major factor accounting for variation in ceruloplasmin levels among unaffected persons. Figus et al. (1989) found no recombination with ESD and found linkage to several RFLPs. With ESD and 1 closely linked RFLP, they could either define the carrier status or exclude homozygosity in most unaffected sibs. The linkage of the WND locus to ESD at 13q14 was first shown by studies using the isozymic polymorphism of esterase D in families of Middle Eastern origin. Using RFLPs detected by the ESD cDNA, Houwen et al. (1990) could not confirm this reported close linkage in an analysis of 17 families of northwestern European origin. However, no crossovers were detected in 63 meioses informative for linkage with marker D13S12, located more distally at 13q21. The data confirmed the assignment of WND to 13q14-q21. Its localization, however, seemed to be more distal to ESD than previously reported. In a study of 20 families, Scheffer et al. (1992) found that D13S31 was the closest proximal marker and D13S55 and D13S26 the closest distal markers. They identified a crossover between WND and D13S31 in 1 family and a crossover between WND and D13S55 in another. These crossover sites could be used as reference points for new chromosome 13q14-q21 markers for a more accurate mapping of the WND locus. Using D13S31 and D13S59 (the closest proximal and distal markers, respectively, for the WND locus) in fluorescence in situ hybridization studies of chromosomal aberrations, Kooy et al. (1993) determined that the Wilson disease locus is located at the junction of bands q14.3 and q21.1. In 51 families with Wilson disease, Thomas et al. (1994) studied DNA haplotypes of CA dinucleotide repeat polymorphisms in the 13q14.3 region. They found that 3 markers (D13S314, D13S133, and D13S316) showed nonrandom distribution on chromosomes carrying the WND mutation. They also found that haplotypes of these 3 markers had highly significant differences between WND and normal haplotypes in northern European families. Molecular Genetics Bull et al. (1993) identified 2 patients with Wilson disease who were homozygous for a 7-bp deletion within the coding region of the ATP7B gene (606882.0001). Tanzi et al. (1993) identified 4 mutations in the ATP7B gene in unrelated persons with Wilson disease: 2 missense mutations (606882.0002-606882.0003) and 2 frameshift mutations resulting in a truncated gene product (606882.0004-606882.0005). The mutations were found among 50 unrelated families derived predominantly from the United States, 18 unrelated families from Russia, and 5 presumably unrelated families from Sicily. Clearly, Bull et al. (1993) and Tanzi et al. (1993) had independently isolated the same gene which was convincingly the one mutant in Wilson disease. Thomas et al. (1995) reviewed the mutations found in the ATP7B gene. Their findings suggest a wide span in the age of onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood at a time when Wilson disease may not be considered in the differential diagnosis. Petrukhin et al. (1993) identified YACs spanning the Wilson disease region and derived cosmid contigs therefrom. Thirteen microsatellite markers were generated from cosmids and used for study of genetic equilibrium (linkage disequilibrium; LD). Strong LD was detected between these markers and the WND locus in 28 families from rural Russia, 43 families from Sardinia, and 67 families of predominantly North American and European descent. From their haplotype and mutation analyses, Petrukhin et al. (1993) predicted that approximately half of all Wilson disease mutations will be rare in the American and Russian populations. Given the difficulties of searching for mutations in a gene spanning more than 80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Thomas et al. (1995) did haplotyping of the Wilson disease gene region in 58 families. These haplotypes, combining 3 markers (D13S314, D13S316, and D13S301), were usually specific for each different mutation. The haplotype data suggested that as many as 20 mutations might still be unidentified; a total of 25 disease-causing mutations had been identified at that time. Genotype/Phenotype Correlations Gromadzka et al. (2005) studied 142 Polish patients with Wilson disease and identified 26 mutations in the ATP7B gene: 11 truncating, 14 missense, and 1 splice site mutation. Patients with 1 or 2 truncating mutations on their alleles had lower serum copper and ceruloplasmin levels and were younger when the first symptoms of the disease appeared compared with individuals with 2 missense mutations, and the effect of truncating mutations on phenotype was dose-dependent. Gromadzka et al. (2005) found no association between type of ATP7B mutation and mode of initial disease presentation (neurologic, hepatic, or mixed). Population Genetics Whereas the worldwide prevalence of Wilson disease is estimated to be on the order of 30 per 1 million, with a gene frequency of 0.56% and a carrier frequency of 1 in 90, a higher prevalence seems to exist in Sardinia, where approximately 10-12 new cases per year are identified. Figus et al. (1995) analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent affected by Wilson disease: 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. There were 5 common haplotypes in Sardinians, 3 in Italians, and 2 in Turks, which accounted for 85%, 32%, and 30% of the Wilson disease chromosomes, respectively. They identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, they detected 5 previously described mutations, e.g., his1070-to-gln (606882.0006), which accounted for 13% of the mutations in WND chromosomes in non-Sardinian Mediterranean populations. In the Sardinian population, one haplotype accounts for 55% of WD chromosomes (Figus et al., 1995). Loudianos et al. (1999) characterized the putative promoter and 5-prime untranslated region of the WD gene and carried out mutation analysis in this region in Sardinian WD patients with the most common haplotype. They detected a single mutation resulting from a 15-nucleotide deletion (606882.0010) in all chromosomes with this common haplotype. With the addition of this mutation, the molecular defect has been found in 92% of the WD chromosomes in Sardinians. Loudianos et al. (1998) performed a mutation screen on the WND gene in 59 patients of Mediterranean origin: 26 Continental Italians, 22 Sardinians, 9 Turkish, and 2 Albanians. They found 31 novel and 3 known mutations. Most of the patients were compound heterozygotes. Because there are so many causative mutations, the preclinical and prenatal diagnosis of Wilson disease should be carried out by a combination of mutation and linkage analysis. Kim et al. (1998) identified 3 novel mutations in the ATP7B gene in Korean patients with Wilson disease. One of these, arg778 to leu (606882.0009), was found in 6 of 8 unrelated patients, giving an allele frequency of 37.5%. Ha-Hao et al. (1998) performed mutation analysis in 33 German and 10 Cuban unrelated Wilson disease patients. The common his1069-to-gln (606882.0006) mutation accounted for 42% of all WND chromosomes in the German series and haplotype C was found to be highly predictive for this mutation. Six previously undescribed WND gene mutations were identified. In 15 German WND index patients and 3 sibs, both WND mutations could be determined and a genotype-phenotype correlation was attempted. Patients homozygous for the his1069-to-gln mutation showed almost a complete range of clinical presentations; thus, in this study, the his1069-to-gln mutation was not associated with a late neurologic presentation. Okada et al. (2000) analyzed the ATP7B gene in 41 unrelated Japanese Wilson disease families, including 47 patients. They identified 21 mutations, 9 of which were novel. Garcia-Villarreal et al. (2000) identified a founder mutation in the ATP7B gene (L708P; 606882.0023) in 18 individuals with Wilson disease from the Canary Islands of Spain. Twelve patients were homozygous for the mutation. Homozygous patients tended to have a neurologic presentation at an average age of 16 years. The L708P mutation was estimated to have arisen in Gran Canaria over 56 generations ago, in pre-Hispanic times. Garcia-Villarreal et al. (2000) estimated a prevalence for Wilson disease of 1 in 2,600 individuals in the Canary Islands. Olivarez et al. (2001) undertook to estimate the frequency of Wilson disease in the U.S. Caucasian population. They used data from 4 studies to determine that approximately one-third of Wilson disease mutations in U.S. Caucasian Wilson disease patients are his1069-to-gln (606882.0006). They then determined the frequency of this mutation in random DNA samples from 2,601 U.S. Caucasian newborns to be 0.285%. Multiplying by 3 gave an estimated Wilson disease heterozygote frequency of 0.855% and an allele frequency of 0.428%, or 0.00428. These data gave a Wilson disease frequency of about 1 in 55,000 births. The 95% confidence interval was rather broad, ranging from about 1 in 18,000 to 1 in 700,000 births. Margarit et al. (2005) analyzed 40 unrelated Spanish patients with Wilson disease and identified 21 different mutations in the ATP7B gene in 35 (87%) patients. The M645R (606882.0020) mutation was particularly prevalent and found in 22 patients (55%), who were all compound heterozygotes for mutation in the ATP7B gene. In 6 patients in whom M645R was combined with a nonsense mutation, there was early onset of the disease, occurring between 5 and 14 years of age. Gupta et al. (2005) analyzed Indian patients with Wilson disease from 62 unrelated families and their first-degree relatives and identified a total of 9 mutations, 5 novel, in the ATP7B gene. The authors noted that homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of disease; in 1 family, 2 sibs with the same pair of mutant chromosomes had remarkably different phenotypes. Gupta et al. (2005) suggested that there may be as yet unidentified modifying loci that account for the observed phenotypic heterogeneity among patients with Wilson disease. In 120 unrelated Korean patients with Wilson disease, Park et al. (2007) identified 28 different mutations, including 6 novel mutations, in the ATP7B gene. R778L (606882.0009) was the most common mutation, occurring in 39.2% of mutant alleles. Mak et al. (2008) sequenced the ATP7B gene in 65 unrelated Han Chinese patients with Wilson disease and identified 126 disease alleles in 129 chromosomes (97.6% detection rate); the most prevalent mutation, R778L, was found in 22 chromosomes. The authors screened 660 healthy Hong Kong Han Chinese for R778L and a 2310C-G SNP in perfect linkage disequilibrium with R778L, and identified 3 carriers of both; neither variant was found in the remaining 657 individuals. Mak et al. (2008) calculated the prevalence of Wilson disease to be 1 in 5,400 in Hong Kong Han Chinese, and the East Asian-specific R778L mutation was estimated to have arisen 5,500 years earlier from a single ancestor. In the Korean population, Park et al. (2009) found that the combined carrier frequency of 3 common ATP7B mutations, R778L, A874V (606882.0016), and N1270S (606882.0017), was 1 in 50 (2%). Extrapolating from this figure, the authors estimated that the carrier frequency of Wilson disease is about 1 in 27 in the Korean population, suggesting that the disorder is more common than in U.S. Caucasian populations. Wang et al. (2011) identified 38 different pathogenic ATP7B mutations in 69 (69.86%) of 73 Chinese patients with Wilson disease. The most common mutation was R778L, which accounted for 23.29% mutant alleles, and the second most common mutation was I1148T (606882.0025), which accounted for 9.59% of mutant alleles. Animal Model Li et al. (1991) found biochemical and morphologic evidence to suggest that the Long-Evans Cinnamon (LEC) rat is an authentic model of Wilson disease. Canine copper toxicosis, an autosomal recessive disorder, is thought to be an authentic model of Wilson disease. Yuzbasiyan-Gurkan et al. (1993) found, however, that in the dog the disorder is not linked (within 13% recombination) to the RB1 locus (614041) or (within 5% recombination) to the ESD locus (133280). Furthermore, ESD and RB1, tightly linked in both the mouse and human genomes, were not found to be closely linked in the canine genome. In the LEC rat, acute hepatitis develops spontaneously about 4 months after birth, with clinical features similar to those seen in human fulminant hepatitis, sometimes a feature of Wilson disease. Survivors of this often-fatal attack continue to suffer from chronic hepatitis and usually develop hepatocellular carcinoma at age 12 months or older. Copper is abnormally high in the liver of LEC rats, and hepatitis can be prevented by treatment with copper-chelating agents such as D-penicillamine. Wu et al. (1994) cloned cDNAs for the rat gene (Atp7b; 606882) homologous to the human Wilson disease gene and used them to identify a partial deletion in the gene in the LEC rat. The deletion removed at least 900 basepairs of the coding region at the 3-prime end, including the crucial ATP-binding domain, and extended downstream of the gene. The usefulness of the model for studying liver pathophysiology, for developing therapy for Wilson disease, and for studying the pathway of copper transport and its possible interaction with other heavy metals was noted. Theophilos et al. (1996) cloned and sequenced the murine homolog of the WND gene (ATP7B). They demonstrated a point mutation in the 'toxic milk' (tx) mouse Wd gene. The coding sequence from the tx WND gene was identical to the sequence from the DL mouse except for a single base change (A4066G) in the mutant sequence. Theophilos et al. (1996) reported that this base change led to a met1356-to-val amino acid substitution within the proposed eighth transmembrane domain of the ATP7B protein. Theophilos et al. (1996) reviewed the pathophysiology of the disorder in the tx mouse. They noted that tx is an autosomal recessive mutation which leads to hepatic accumulation of copper from the third postnatal week. The pups are born with an apparent copper deficiency and the milk of the mutant mothers is deficient in copper, leading to continued copper deficiency in the pups. The authors noted that the pathology observed in the livers of the deficient mice shows significant differences from the liver pathology observed in Wilson disease. Huang and Gitschier (1997) pointed out that tx, in which the milk of mutant dams is fatally deficient in copper, has a parallel in 'lethal milk' (lm) in which the milk of mutant dams is fatally deficient in zinc. Copper deficiency in human milk in Wilson disease has, it seems, not been investigated. The gene that is mutant in 'lethal milk' of the mouse is zinc transporter-4 (602095). The mouse homologs for the Menkes and Wilson disease genes are the mottled (Atp7a; 300011) and toxic milk (Atp7b) genes, respectively. These genes encode similar copper-transporting P-type ATPases. They are expressed in different adult tissues in patterns reflecting disease manifestations. Using RNA in situ hybridization, Kuo et al. (1997) determined the distribution of mottled and toxic milk transcripts during mouse embryonic development. The mottled gene was expressed in all tissues throughout embryogenesis and was particularly strong in the choroid plexuses of the brain. Contrary to the previous observation of absent or very low expression in adult liver, mottled was expressed in embryonic liver. Expression of the toxic milk gene was significantly more delimited, with early expression in the central nervous system, heart, and liver. Later in gestation, toxic milk transcript was clearly seen in liver, intestine, thymus, and respiratory epithelium, including nasopharynx, trachea, and bronchi. In lung, toxic milk expression was restricted to bronchi, while mottled expression was diffuse. Hepatic expression of both toxic milk and mottled was in the parenchyma, as opposed to blood cells. These results suggested that the mottled gene product functions primarily in the homeostatic maintenance of cell copper levels, while the toxic milk gene product may be specifically involved in the biosynthesis of distinct cuproproteins in different tissues. Using homologous recombination to disrupt the normal translation of the Atp7b gene, Buiakova et al. (1999) generated a strain of mice that were homozygous null mutants for the Wilson disease gene. The Atp7b-null mice displayed a gradual accumulation of hepatic copper that increased to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta, and lactating mammary glands of homozygous mutants, although milk from the mutant glands was copper deficient. Morphologic abnormalities resembling cirrhosis developed in most animals older than 7 months of age. Progeny of the homozygous mutant females developed neurologic abnormalities and growth retardation characteristic of copper deficiency. Copper concentrations in the livers of the newborn homozygous null mutants were decreased dramatically. Thus, the authors concluded that inactivation of the murine Atp7b gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in mice. Terada et al. (1998) introduced human ATP7B cDNA into the LEC rat using recombinant adenovirus-mediated gene delivery. An immunofluorescence study and a subcellular fractionation study revealed the transgene expression in liver and its localization to the Golgi apparatus. Moreover, since the synthesis of holoceruloplasmin is disturbed in the LEC rat, the plasma level of holoceruloplasmin, oxidase-active and copper-bound form, was examined to evaluate the function of ATP7B protein with respect to copper transport. Holoceruloplasmin was found in plasma of LEC rats who received ATP7B cDNA. Terada et al. (1998) concluded that introduced ATP7B protein may function in the copper transport coupled with the synthesis of ceruloplasmin and that the Golgi apparatus is the likely site for ATP7B protein to manifest its function. By investigating the common autosomal recessive copper toxicosis in Bedlington terriers, van de Sluis et al. (1999) identified a new locus involved in progressive liver disease. Whereas the ATP7B gene mapped to canine chromosome 22q11, CO4107, a microsatellite marker showing close linkage to copper toxicosis, mapped to canine chromosome 10q26. A transcribed sequence identified from a CO4107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p16-p13, a region devoid of any positional candidate genes. In mouse hepatocytes, Lang et al. (2007) demonstrated that Cu(2+) induced the secretion of activated acid sphingomyelinase (SMPD1; 607608) from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, which are events prevented by inhibition of Smpd1. In LEC rats, deficiency in or pharmacologic inhibition of Smpd1 prevented Cu(2+)-induced hepatocyte apoptosis and protected the rats from acute hepatocyte death, liver failure, and early death. Patients with Wilson disease showed elevated plasma levels of SMPD1 and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Lang et al. (2007) concluded that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase and release of ceramide, suggesting a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease. History A tribute to Dr. S. A. Kinnier Wilson and a comprehensive review of Wilson disease were published in 1988; see Marsden and Fahn (1988), Critchley (1988), Wilson (1988), and Walshe (1988). Walshe (1996) provided a review of the historical background of the treatment of Wilson disease, beginning with BAL, which had practical problems, and continuing with the chelating agent EDTA, which proved disappointing, and ending up with penicillamine (Walshe, 1956). Almost overnight, Wilson disease became one of the few inherited metabolic disorders for which there was effective therapy. So successful did this prove that the fact that zinc salts could block copper from the gut and could be of therapeutic value passed virtually unnoticed. Hoogenraad and van den Hamer (1983) described its use. The third 'decoppering agent,' developed in the 1970s, was triethylene tetramine, as the dihydrochloride (Trientine). Walshe (1996) stated that a major and perhaps unexpected problem when initiating treatment is giving a 'reasonably accurate prognosis.' This may be related to the large number of different mutations and possible compound heterozygotes resulting in the varying clinical syndrome and different responses to treatment. He raised the question that initial deterioration seen in some patients after starting treatment may be due to free radical release in excess of the body's ability to remove them. He stated that the simultaneous administration of a free radical scavenger, such as alpha-tocopherol, might help eliminate the problem. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Kayser-Fleischer ring ABDOMEN Liver \- Atypical or prolonged hepatitis \- Hepatic cirrhosis \- Hepatic coma \- Hepatomegaly \- Liver failure \- High liver copper \- Hepatocellular carcinoma (in some patients) Gastrointestinal \- Esophageal varices GENITOURINARY Kidneys \- Renal tubular dysfunction \- Renal calculi SKELETAL \- Osteoporosis \- Osteomalacia \- Chondrocalcinosis Limbs \- Osteoarthritis \- Joint hypermobility NEUROLOGIC Central Nervous System \- Tremor \- Dysarthria \- Dysphagia \- Personality changes \- Dementia \- Poor motor coordination \- Dystonia \- Drooling Peripheral Nervous System \- Mixed demyelinating and axonal polyneuropathy (rare) ENDOCRINE FEATURES \- Hypoparathyroidism HEMATOLOGY \- Hemolytic anemia LABORATORY ABNORMALITIES \- Low serum ceruloplasmin \- High nonceruloplasmin-bound serum copper \- High urinary copper \- Proteinuria \- Aminoaciduria \- Glycosuria \- Uricaciduria \- Hyperphosphaturia \- Hypercalciuria MISCELLANEOUS \- Incidence in United States of 1 in 55,000 \- Incidence worldwide of 1 in 30,000 to 50,000 MOLECULAR BASIS \- Caused by mutation in the ATPase, Cu++ transporting, beta polypeptide gene (ATP7B, 277900.0001 ) ▲ 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	WILSON DISEASE	c0019202	2,844	omim	https://www.omim.org/entry/277900	2019-09-22T16:21:12	{"doid": ["893"], "mesh": ["D006527"], "omim": ["277900"], "icd-10": ["E83.01"], "orphanet": ["905"], "synonyms": ["Alternative titles", "WND", "HEPATOLENTICULAR DEGENERATION"], "genereviews": ["NBK1512"]}
Autosomal recessive spastic paraplegia type 32 (SPG32) is a rare, complex type of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with walking difficulties appearing at onset at 6-7 years of age) associated with mild intellectual disability. Brain imaging reveals thin corpus callosum, cortical and cerebellar atrophy, and pontine dysraphia. The SPG32 phenotype has been mapped to a locus on chromosome 14q12-q21. [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	Autosomal recessive spastic paraplegia type 32	c1970009	2,845	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171622	2021-01-23T17:01:55	{"gard": ["12749"], "mesh": ["C566983"], "omim": ["611252"], "umls": ["C1970009"], "icd-10": ["G11.4"], "synonyms": ["SPG32"]}
Sitosterolemia Other namesPhytosterolemia[1]:535 Autosomal recessive is the manner in which this condition is inherited. SpecialtyEndocrinology Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols (including the plant phytosterol beta-sitosterol). Healthy persons absorb only about 5% of dietary plant sterols, but sitosterolemia patients absorb 15% to 60% of ingested sitosterol without excreting much into the bile.[2] The phytosterol campesterol is more readily absorbed than sitosterol.[3] Sitosterolemia patients develop hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis, and abnormal hematologic and liver function test results. ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 See also * 7 Notes * 8 References * 9 External links ## Signs and symptoms[edit] Sitosterolemia may share several clinical characteristics with the well-characterized familial hypercholesterolemia (FH), such as the development of tendon xanthomas in the first 10 years of life and the development of premature atherosclerosis. However, in contrast to FH patients, sitosterolemia patients usually have normal to moderately elevated total sterol levels and very high levels of plant sterols (sitosterol, campesterol, stigmasterol, avenosterol) and 5α-saturated stanols in their plasma. Plasma sitosterol levels in sitosterolemia patients are 10–25 times higher than in normal individuals (8–60 mg/dl). Not all patients with sitosterolemia have tendon xanthomas, thus absence of this should not be used to exclude this diagnosis. Xanthomas may appear at any age, even in childhood. These may be present as subcutaneous xanthomas on the buttocks in children or in usual locations (e.g., Achilles tendon, extensor tendons of the hand) in children and adults. Xanthelasma and corneal arcus are less common. Decreased range of motion with possible redness, swelling, and warmth of joints due to arthritis may be present. In addition, sitosterolemia patients may develop hemolytic episodes and splenomegaly. Untreated, the condition causes a significant increase in morbidity and mortality. Coronary heart disease and its inherent health consequences are the primary causes of illness and premature death in untreated patients. This condition is suspected to result in liver dysfunction and cirrhosis, in the context of sitosterolemia, is reported [4] ## Pathogenesis[edit] Mammalian cells cannot use plant sterols. Normally, plant sterols are poorly absorbed from the gastrointestinal tract; fewer than 5% of plant sterols are absorbed compared to approximately 40% of cholesterol absorbed. The liver preferentially excretes plant sterols over cholesterol. Dietary sterols have recently been shown to passively enter intestinal cells, and subsequently the vast majority are pumped back into the gut lumen by ATP-binding cassette transporter (ABC transporter) proteins. Sitosterolemia is inherited as a rare autosomal recessive condition. It has been shown to result from mutations in either of two adjacent and oppositely oriented genes (ABCG5 and ABCG8) located in chromosome 2 in band 2p21 and encode for ABC transporter proteins named sterolin-1 and sterolin-2, respectively. Thus, the active pumping back into the intestine of passively absorbed plant sterols is disrupted, and hepatic secretion of the resultant accumulation of these sterols is decreased. The ability of the liver to preferentially excrete plant sterols into the bile is apparently impaired. While bile acid synthesis remains the same as in healthy people, the total excretion of sterols in the bile is reportedly less than 50% in subjects with sitosterolemia compared to control subjects. The mechanism for decreased hepatic secretion is unknown. Patients have markedly reduced whole-body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-controlling enzyme in the cholesterol biosynthetic pathway. Whether or not the down-regulation is due to accumulated sitosterol is still debatable, but most recent data indicate that secondary effects of unknown regulators other than sitosterol can lead to reduced HMG-CoA reductase activity in the disease. This is coupled with significantly increased low-density lipoprotein (LDL) receptor expression. ## Diagnosis[edit] Diagnosis is made by measuring serum plant sterol concentrations. ## Treatment[edit] The disorder is treated by strictly reducing the intake of foods rich in plant sterols (e.g., vegetable oils, olives and avocados). However, dietary therapy is often never fully sufficient to control this disease since plant sterols are constituents of all plant-based foods. Statins have been used, and while these lower cholesterol levels and may ameliorate atherosclerotic disease, plant sterol levels are insufficiently lowered by their use alone. If dietary treatment alone is insufficient, bile acid-binding resins (e.g., cholestyramine, colestipol) could be considered. In October 2002, a new cholesterol absorption inhibitor, ezetimibe, received US Food and Drug Administration (FDA) approval for use in sitosterolemia. This drug is now the standard of care, as it blocks sterol entry and can be used in combination with bile-acid resins. Finally, ileal bypass has been performed in select cases to decrease the levels of plant sterols in the body, though this therapy was undertaken prior to the advent of ezetimibe. ## Epidemiology[edit] Around 80 cases have been reported in the literature worldwide, hence this condition appears to be relatively rare. More than likely, sitosterolemia is significantly underdiagnosed and many patients are probably misdiagnosed with hyperlipidemia. ## See also[edit] * ABCG5 and ABCG8 Genes * Cerebrotendinous xanthomatosis ## Notes[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH (2000). "Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters" (PDF). Science. 290 (5497): 1771–1775. Bibcode:2000Sci...290.1771B. doi:10.1126/science.290.5497.1771. PMID 11099417. 3. ^ Lütjohann D, Björkhem I, Beil UF, von Bergmann K (1995). "Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment". Journal of Lipid Research. 36 (8): 1763–1773. PMID 7595097. 4. ^ Bazerbachi, F., et al. "Cryptogenic Cirrhosis and Sitosterolemia: A Treatable Disease If Identified but Fatal If Missed." Annals of hepatology 16.6 (2017): 970. ## References[edit] * Lee M, Lu K, Patel SB (2001). "Genetic basis of sitosterolemia". Current Opinion in Lipidology. 12 (2): 141–149. doi:10.1097/00041433-200104000-00007. PMC 1350992. PMID 11264985. * Steiner R D. Sitosterolemia .[online] Available from : http://www.emedicine.com/ped/topic2110.htm [Accessed :12 July 2006] * Bazerbachi F.; et al. (2017). "Cryptogenic Cirrhosis and Sitosterolemia: A Treatable Disease If Identified but Fatal If Missed". Annals of Hepatology. 16 (6): 970–978. doi:10.5604/01.3001.0010.5290. PMID 29055934. ## External links[edit] Classification D * ICD-10: E78.0 * OMIM: 210250 * MeSH: C537345 C537345, C537345 * DiseasesDB: 29796 External resources * eMedicine: ped/2110 * Orphanet: 2882 * v * t * e Genetic disorder, membrane: ABC-transporter disorders ABCA * ABCA1 (Tangier disease) * ABCA3 (Surfactant metabolism dysfunction 3) * ABCA4 (Stargardt disease 1, Retinitis pigmentosa 19) * ABCA12 (Harlequin-type ichthyosis, Lamellar ichthyosis 2) ABCB * ABCB4 (Progressive familial intrahepatic cholestasis 3) * ABCB7 (ASAT) * ABCB11 (Progressive familial intrahepatic cholestasis 2) ABCC * ABCC2 (Dubin–Johnson syndrome) * ABCC6 (Pseudoxanthoma elasticum) * ABCC7 (Cystic fibrosis) * ABCC8 (HHF1, TNDM2) * ABCC9 (Dilated cardiomyopathy 1O) ABCD * ABCD1 (Adrenoleukodystrophy, Adrenomyeloneuropathy) ABCG * ABCG5 (Sitosterolemia) * ABCG8 (Gallbladder disease 4, Sitosterolemia) see also ABC transporters [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	Sitosterolemia	c2749759	2,846	wikipedia	https://en.wikipedia.org/wiki/Sitosterolemia	2021-01-18T18:45:14	{"gard": ["7653"], "mesh": ["C537345"], "umls": ["C2749759"], "orphanet": ["2882", "101022"], "wikidata": ["Q1336034"]}
## Description A clustering of abdominal obesity, high triglycerides, low levels of high density lipoprotein cholesterol (HDLC), high blood pressure, and elevated fasting glucose levels is sometimes called metabolic syndrome X (Reaven, 1988) or abdominal obesity-metabolic syndrome (Bjorntorp, 1991). The syndrome may affect nearly 1 in 4 U.S. adults and is considered a veritable epidemic (Ford et al., 2002). It is a major risk factor for both diabetes mellitus (see 125853 and Haffner et al., 1992) and cardiovascular disease (Isomaa et al., 2001). The etiology is complex, determined by the interplay of both genetic and environmental factors. The prevalence varies substantially among ethnic groups, with the highest rates in Mexican American women (Park et al., 2003). Other factors influencing the metabolic syndrome include age, smoking, alcohol, diet, and physical inactivity. ### Genetic Heterogeneity of Abdominal Obesity-Metabolic Syndrome AOMS2 (605572) has been mapped to chromosome 17p12. AOMS3 (615812) is caused by mutation in the DYRK1B gene (604556) on chromosome 19q13. Biochemical Features Esposito et al. (2003) tested the hypothesis that low serum IL10 (124092) concentrations associate with the metabolic syndrome in obese women. Compared with 50 matched nonobese women, the prevalence of the metabolic syndrome (3 or more of the following abnormalities: waist circumference greater than 88 cm; triglycerides greater than 1.69 mmol/liter; high density lipoprotein cholesterol less than 1.29 mmol/liter; blood pressure greater than 130/85 mm Hg; glucose greater than 6.1 mmol/liter) was higher in 50 obese women (52% vs 16%; P less than 0.01). As a group, obese women had higher circulating levels of IL6 (147620), C-reactive protein (123260), and IL10 than nonobese women. In both obese and nonobese women, IL10 levels were lower in those with than in women without the metabolic syndrome. These results showed that circulating levels of the antiinflammatory cytokine IL10 are elevated in obese women and that low IL10 levels are associated with the metabolic syndrome. Huang et al. (2003) investigated the relationship between plasma adiponectin (605441) levels and blood pressures in 68 nondiabetic female adolescents, who were younger and had healthier metabolic profiles than subjects in previous studies. They found that systolic blood pressure was inversely related to plasma adiponectin levels independent of other variables of the metabolic syndrome and other risk factors of coronary artery disease. Shulman and Mangelsdorf (2005) reviewed the role of retinoid X receptor heterodimers (see RXRA, 180245) in the metabolic syndrome. They suggested that the ability of RXR agonists to regulate target genes of multiple permissive partners implies that in vivo such compounds may have pharmacologic use as panagonists of several metabolically important pathways. The observation that liver-specific deletion of RXR in mice results in abnormalities in all metabolic pathways regulated by RXR heterodimers underscores the central, pleiotropic role of RXR. Although RXR agonists have therapeutic value and might offer enhanced potency through panactivation of permissive heterodimers, this advantage is likely to be offset by poor selectivity. Other Features Among 512 Korean patients with ischemic stroke (see 601367), Bang et al. (2005) found a significant association between intracranial atherosclerotic stroke (143 patients) and components of the metabolic syndrome, compared to those with extracranial atherosclerotic stroke (77 patients) and those with nonatherosclerotic stroke (292 patients). The association was particularly strong with regard to hypertension, abdominal obesity, and HDL cholesterol levels. Mapping As the initial step in identifying major genetic loci influencing these phenotypes, Kissebah et al. (2000) performed a genomewide scan by use of a 10-cM map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3q27 strongly linked to 6 traits (weight, waist circumference, leptin, insulin, insulin/glucose ratio, and hip circumference) representing these fundamental phenotypes (lod scores ranging from 2.4 to 3.5). This QTL exhibited possible epistatic interaction with a second QTL (605572) on chromosome 17p12 that is strongly linked to plasma leptin levels (lod = 5.0). Several candidate genes are located in both regions. The prevalences of coronary heart disease (CHD), type II diabetes (NIDDM; 125853), and the metabolic syndrome in Mauritius are among the highest in the world. Francke et al. (2001) conducted a genomewide scan in 99 independent families of northeastern Indian origin, each containing a proband with onset of CHD before 52 years of age and additional sibs with myocardial infarction or NIDDM. Multipoint linkage analysis revealed a locus for CHD on chromosome 16pter-p13 (lod = 3.06, P = 0.00017), which partially overlapped a high pressure peak. At the same locus, a nominal indication for linkage with NIDDM was found in 35 large NIDDM Pondicherian families of Indian origin. The authors also replicated the previously described locus on 3q27 for the metabolic syndrome and diabetes (Kissebah et al., 2000). In a study of 1,094 female dizygotic twin pairs, Wilson et al. (2006) found suggestive linkage for central fat mass to 12q24 (lod score, 2.2); SNP analysis of 1,102 individuals selected from the twin cohort provided evidence for an association between central fat mass and SNPs in 2 genes located on chromosome 12q24, PLA2G1B (172410) and P2RX4 (600846), with p values of 0.0067 and 0.017, respectively. Hotta et al. (2009) analyzed 336 SNPs in 85 obesity-related genes in 1,080 patients with metabolic syndrome and 528 controls and found 3 SNPs rs1545, rs1547, and rs2294901 in the MKKS gene (604896) that were significantly associated with the metabolic syndrome (p values of 3.3 to 4.3 x 10(-5); OR, 1.45 to 1.46). Analysis of 5 tagging SNPs in the MKKS gene (rs2294901, rs221667, rs6133922, rs6077785, and rs6108572) within 1 linkage disequilibrium block revealed a TGAAA haplotype that was protective against metabolic syndrome (p = 0.0074) and a CCGTT haplotype that was associated with susceptibility for the disorder (p = 0.00070). Hotta et al. (2009) suggested that genetic variation at the MKKS gene may influence the risk of metabolic syndrome. Molecular Genetics McCarthy et al. (2003) surveyed 207 SNPs in 110 candidate genes among coronary artery disease patients, a population enriched for metabolic abnormalities. The number of abnormalities (0 to 5) was determined in 214 male and 91 female patients, and the association with each polymorphism evaluated by means of ordinal regression analysis. Polymorphisms in 8 genes were associated with metabolic syndrome in the whole population (P values ranging from 0.047 to 0.008): LDLR (606945), GBE1 (607839), IL1R1 (147810), TGFB1 (190180), IL6 (147620), COL5A2 (120190), SELE (131210), and LIPC (151670). Variants in 7 additional genes showed significant gene interaction by gender. Separate analyses in men and women revealed a strong association with a silent polymorphism in the gene encoding low density lipoprotein receptor-related protein-associated protein-1 (LRPAP1; 104225) among females (P = 0.0003), but not males (P = 0.292). Several other genes showed association only in females; only 1 gene, PRCP (176785), was significantly associated in men alone (P = 0.039). Among 632 men, Robitaille et al. (2004) found increased frequency of the val162 allele of the leu162-to-val polymorphism in the PPARA gene (V162L; 170998.0001) among those with abdominal obesity, hypertriglyceridemia, high plasma apoB (107730), and low HDL plasma levels, which are components of the metabolic syndrome. The frequency of the V162 allele was approximately 10% in their group. In a cohort of 716 German men genotyped for the I128T polymorphism of the MTP gene (157147.0009), Rubin et al. (2006) found that compared to wildtype homozygotes, carriers of the less common thr128 allele had significantly lower postprandial insulin levels, lower diastolic blood pressure, and a lower prevalence of impaired glucose metabolism and type II diabetes (125853). In a case-control study of 190 patients with type II diabetes and 380 controls, Rubin et al. (2006) observed a significantly lower incidence of type II diabetes in individuals with the thr128 genotype; the authors suggested that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type II diabetes, and other parameters of the metabolic syndrome. Love-Gregory et al. (2008) evaluated 36 tag SNPs across the CD36 gene (173510) in 2,020 African American individuals from the HyperGEN study and identified 5 SNPs that were associated with increased odds for metabolic syndrome (p = 0.0027 to 0.03; odds ratio, 1.3 to 1.4). In contrast, the coding SNP rs3211938 (173510.0002), which resulted in CD36 deficiency in a homozygous individual, was associated with protection against the metabolic syndrome, as well as increased HDL cholesterol and decreased triglycerides. Fifteen additional SNPs were associated with HDLC (p = 0.0028 to 0.044). Love-Gregory et al. (2008) concluded that CD36 variants may impact metabolic syndrome-related pathophysiology and HDL metabolism. ### Associations with Waist-to-Hip Ratio In 2,238 middle-aged (40-59 years old) and older (60-79 years old) Japanese individuals, Okura et al. (2003) analyzed the relationship between the estrogen receptor-alpha (ESR1; 133430) polymorphisms PvuII and XbaI and anthropometric variables, fat mass, and percentage fat mass. They found that middle-aged women with XbaI AG or GG genotypes had significantly greater BMI, fat mass, percentage fat mass, and waist-to-hip ratio (WHR) than those with the AA genotype. Conversely, waist size and fat mass were lower in older women with the GG genotype. Okura et al. (2003) concluded that the XbaI polymorphism, particularly the GG genotype, may contribute to the development of abdominal obesity in middle-aged women, but may decrease the whole-body and abdominal fat tissue of older women. Kim et al. (2004) examined the effects of the pro12-to-ala polymorphism of the PPARG2 gene (P12A; 601487.0002) on body fat distribution and other obesity-related parameters in 1,051 Korean females. Body weight, fat mass, fat percentage, BMI, and WHR were significantly higher in individuals with the PA or AA genotype than those with PP. Among overweight individuals (BMI greater than 25), PA/AA was associated with significantly higher abdominal subcutaneous fat, abdominal visceral fat, and subcutaneous upper and lower thigh fat; there was no association in individuals with a BMI less than 25. Kim et al. (2004) suggested that the PPARG2 PA/AA genotype is associated with increased subcutaneous and visceral fat areas in overweight Korean females. Ukkola et al. (2005) studied the impact of SNPs in the PTPN1 gene (176885) on body fat distribution in 502 white and 276 black individuals. White individuals with the GG genotype at the IVS6+82G-A SNP had significantly higher percentages of body fat, sums of 8 skinfold measurements, and highest amounts of subcutaneous fat on the extremities than those with AA or AG genotypes; however, the trunk-to-extremity skinfold ratio, adjusted for age, sex, and fat mass, was lower in GG than AA or AG individuals. Baker et al. (2005) tested for association between 3 SNPs in the noncoding region of the POMC gene (176830) and obesity phenotypes in 1,428 members of 248 families originally ascertained for essential hypertension. There was significant association between genotypes at the 8246C-T (rs1042571) and 1032C-G (rs1009388) SNPs and WHR corrected for age, sex, smoking, exercise, alcohol consumption, and BMI: each T or G allele was associated with a 0.2-SD higher WHR in a codominant fashion. Baker et al. (2005) concluded that genetic variants at the POMC locus influence body fat distribution. Animal Model Masuzaki et al. (2001) created transgenic mice overexpressing 11-beta-hydroxysteroid dehydrogenase type 1 (600713) selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11-beta-hydroxysteroid type 1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome. Vartanian et al. (2006) found that Neil1 (608844) knockout mice were born at expected mendelian ratios and the phenotype of Neil1 -/- pups was normal through the first 4 to 6 months of life. At about 7 months, however, male Neil1 -/- mice developed severe obesity, and female Neil1 -/- mice were modestly overweight. Mutant mice also showed dyslipidemia, fatty liver disease, and a tendency to develop hyperinsulinemia, similar to metabolic syndrome in humans. Histologic studies showed significant kidney vacuolization, and mitochondrial DNA from Neil1 -/- mice showed increased levels of steady-state DNA damage and deletions, compared to wildtype controls. Lam et al. (2007) found that intracerebroventricular administration of glucose in rats lowered circulating triglycerides through the inhibition of VLDL secretion by the liver. The effect of glucose required its conversion to lactate, leading to activation of ATP-sensitive potassium channels and to decreased hepatic Scd1 (604031) activity. These central effects of glucose, but not those of lactate, were rapidly lost in diet-induced obese rats. Lam et al. (2007) suggested that a defect in brain glucose sensing might play a critical role in the etiology of the metabolic syndrome. Biddinger et al. (2008) generated liver-specific Insr (147670)-knockout (LIRKO) mice and observed a marked predisposition to cholesterol gallstone formation, with all of the LIRKO mice developing gallstones after 12 weeks on a lithogenic diet. This predisposition was due to at least 2 distinct mechanisms: disinhibition of the Foxo1 gene (136533), which increased expression of the biliary cholesterol transporters Abcg5 (605459) and Abcg8 (605460), resulting in an increase in biliary cholesterol secretion; and decreased expression of the bile acid synthetic enzymes, particularly Cyp7b1 (603711), which produced partial resistance to the farnesoid X receptor (NR1H4; 603826), leading to a lithogenic bile salt profile. The authors concluded that hepatic insulin resistance provides the link between the metabolic syndrome and increased cholesterol gallstone susceptibility. INHERITANCE \- Autosomal dominant GROWTH Weight \- Abdominal obesity CARDIOVASCULAR Vascular \- Hypertension LABORATORY ABNORMALITIES \- Elevated fasting glucose levels ▲ 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	ABDOMINAL OBESITY-METABOLIC SYNDROME 1	c1854178	2,847	omim	https://www.omim.org/entry/605552	2019-09-22T16:11:11	{"omim": ["605552"], "synonyms": ["Alternative titles", "METABOLIC SYNDROME X"]}
Mucinous cystadenocarcinoma Atypical goblet cells with focal tufting. The classification of these rare neoplasms is difficult and controversial. There appears to be a spectrum of mucinous cystic tumors ranging from those that are obviously benign (benign epithelium and no tumor invasion into surrounding lung) to those that exhibit invasion into surrounding lung tissue and are, therefore, malignant. In between is a group of neoplasms that exhibit epithelial atypia but no tumor invasion into lung tissue and the malignant potential of these is uncertain. This case appears to fall into that category. Focal cyst rupture with extravasation of mucin into surrounding lung tissue may occur with all types of mucinous cystic tumors. SpecialtyOncology Mucinous cystadenocarcinoma is a type of tumor in the cystadenocarcinoma grouping. It can occur in the breast[1] as well as in the ovary.[2] Tumors are normally multilocular with various smooth, thin walled cysts. Within the cysts is found a haemorrhagic or cellular debris.[2] ## References[edit] 1. ^ Honma N, Sakamoto G, Ikenaga M, Kuroiwa K, Younes M, Takubo K (August 2003). "Mucinous cystadenocarcinoma of the breast: a case report and review of the literature". Arch. Pathol. Lab. Med. 127 (8): 1031–3. doi:10.1043/1543-2165(2003)127<1031:MCOTBA>2.0.CO;2 (inactive 2021-01-10). PMID 12873181.CS1 maint: DOI inactive as of January 2021 (link) 2. ^ a b http://radiopaedia.org/articles/mucinous-cystadenocarcinoma-of-ovary ## External links[edit] Classification D * ICD-10: C56.9 * ICD-O: 8470/3 * MeSH: D018282 * SNOMED CT: 79143006 * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma This article about a neoplasm 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	Mucinous cystadenocarcinoma	c0206699	2,848	wikipedia	https://en.wikipedia.org/wiki/Mucinous_cystadenocarcinoma	2021-01-18T18:52:04	{"mesh": ["D018282"], "umls": ["C0206699"], "icd-10": ["C56.9"], "wikidata": ["Q6931140"]}
Contractures - ectodermal dysplasia - cleft lip/palate is an ectodermal dyplasia syndrome characterized by severe arthrogryposis, multiple ectodermal dysplasia features, cleft lip/palate, facial dysmorphism, growth deficiency and a moderate delay of psychomotor development. Ectodermal dysplasia manifestations include sparse, brittle and hypopigmented hair, xerosis, multiple nevi, small conical shaped teeth and hypodontia, and facial dysmorphism with blepharophimosis, deep-set eyes and micrognathia. [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	Contractures-ectodermal dysplasia-cleft lip/palate syndrome	c1844935	2,849	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1484	2021-01-23T18:24:44	{"gard": ["1515"], "mesh": ["C538135", "C535465"], "omim": ["301815"], "umls": ["C1844935", "C2931745"], "icd-10": ["Q87.8"], "synonyms": ["Ladda-Zonana-Ramer syndrome"]}
Familial generalized lentiginosis is a rare, inherited, skin hyperpigmentation disorder characterized by widespread lentigines without associated noncutaneous abnormalities. Patients present multiple brown to dark brown, non-elevated macula of 0.2 to 1 cm in diameter, spread over the entire body, sometimes including palms or soles, but never oral mucosa. [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	Familial generalized lentiginosis	c3492944	2,850	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231040	2021-01-23T18:55:02	{"mesh": ["C573023"], "omim": ["151001"], "icd-10": ["L81.4"], "synonyms": ["Familial lentigines profusa", "Familial multiple lentigines syndrome without systemic involvement"]}
Bednar tumor is a rare variant of dermatofibrosarcoma protuberans (DFSP), a soft tissue sarcoma that develops in the deep layers of the skin. It accounts for approximately 1% of all DFSP cases. Bednar tumor is also known as pigmented DFSP because it contains dark-colored cells that give may give the tumor a multi-colored (i.e red and brown) appearance. The tumor may begin as a painless, slow-growing papule or patch of skin; however, accelerated growth, bleeding and/or pain are often observed as it grows. The underlying cause of Bednar tumor is unknown. There is currently no evidence of an inherited risk for the condition and most cases occur sporadically in people with no family history of the condition. Treatment varies based on the severity of the condition, the location of the tumor and the overall health of the affected person. The tumor is generally treated with surgery. In advanced cases, radiation therapy and/or systemic therapy may be recommended, as well. [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	Bednar tumor	c0334464	2,851	gard	https://rarediseases.info.nih.gov/diseases/9624/bednar-tumor	2021-01-18T18:01:50	{"mesh": ["D018223"], "umls": ["C0334464"], "synonyms": ["Pigmented dermatofibrosarcoma protuberans"]}
## Clinical Features Dawson et al. (1979) described a patient with severe watery diarrhea and common variable immunodeficiency. Malabsorption for fat, bile acids, vitamin B12, and xylose was demonstrated. The diarrhea responded only to high-dose steroid therapy. Intestinal perfusion studies showed a hitherto undescribed glucose-stimulated water, sodium, and chloride secretion in the jejunum and ileum, whereas normal fluid and electrolyte transport occurred from bicarbonate and mannitol solutions. Glucose absorption itself was normal. Unlike other patients with common variable immunodeficiency, plasma cells were normal in the intestinal mucosa. The father, a paternal aunt, and a paternal uncle had diarrhea intermittently over many years, and the paternal grandfather was said to have pernicious anemia. [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	DIARRHEA, GLUCOSE-STIMULATED SECRETORY, WITH COMMON VARIABLE IMMUNODEFICIENCY	c1852087	2,852	omim	https://www.omim.org/entry/125890	2019-09-22T16:42:16	{"mesh": ["C565099"], "omim": ["125890"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-85 (RP85) is caused by homozygous mutation in the AHR gene (600253) on chromosome 7p21. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Zhou et al. (2018) studied 2 distantly related Indian boys with retinitis pigmentosa, aged 8 years (RD-ICP-79) and 10 years (RD-ICP-78), from a large consanguineous family. Both boys reported early-onset progressive difficulty with night vision and gradually decreasing visual acuity bilaterally. Typical features of RP were observed in both patients, with fundi showing pigment deposits and a pale retina. OCT examination in patient RD-ICP-79 showed disorganized photoreceptor layers, and full-field electroretinography revealed severely reduced scotopic and photopic responses and oscillatory potentials in both eyes. Molecular Genetics In a large consanguineous Indian family in which 2 distantly related boys had RP, Zhou et al. (2018) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the AHR gene (600253.0001) that segregated with disease and was not found in 1,000 ethnically matched controls or in the gnomAD database. In addition, no causal mutations were found in known RP genes. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Progressive reduction in night vision \- Progressive reduction in visual acuity \- Pigment deposits in fundus \- Pale retina \- Disorganized photoreceptor layers seen on optical coherence tomography \- Severely reduced scotopic and photopic responses seen on ERG \- Severely reduced oscillatory potentials seen on ERG MISCELLANEOUS \- Based on a report of one family (last curated March 2019) MOLECULAR BASIS \- Caused by mutation in the aryl hydrocarbon receptor gene (AHR, 600253.0001 ) ▲ 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	RETINITIS PIGMENTOSA 85	c0035334	2,853	omim	https://www.omim.org/entry/618345	2019-09-22T15:42:26	{"mesh": ["D012174"], "omim": ["618345"], "orphanet": ["791"]}
## Summary ### Clinical characteristics. Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course: * 12–24 hours: Elevated concentrations of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and alloisoleucine, as well as a generalized disturbance of amino acid concentration ratios, are present in blood and the maple syrup odor can be detected in cerumen; * Two to three days: Early and nonspecific signs of metabolic intoxication (i.e., irritability, hypersomnolence, anorexia) are accompanied by the presence of branched-chain alpha-ketoacids, acetoacetate, and beta-hydroxybutyrate in urine; * Four to six days: Worsening encephalopathy manifests as lethargy, apnea, opisthotonos, and reflexive "fencing" or "bicycling" movements as the sweet maple syrup odor becomes apparent in urine; * Seven to ten days: Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure. Individuals with intermediate MSUD have partial branched-chain alpha-ketoacid dehydrogenase deficiency that manifests only intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy in the face of sufficient catabolic stress. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed neonatal manifestations of MSUD remain asymptomatic with continued treatment compliance. ### Diagnosis/testing. Suggestive biochemical findings on NBS include whole-blood concentration ratios of (leucine + isoleucine) to alanine and phenylalanine that are above the cutoff values for the particular screening lab. Follow-up plasma amino acid analysis typically demonstrates elevated concentrations of BCAAs and alloisoleucine. The diagnosis of MSUD is confirmed by identification of biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT. ### Management. Treatment of manifestations: Treatment consists of dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring. A BCAA-restricted diet fortified with prescription medical foods can maintain average plasma BCAA concentrations within standard reference intervals and preserves the ratios among them. Use of a "sick-day" formula recipe (devoid of leucine and enriched with calories, isoleucine, valine, and BCAA-free amino acids) combined with rapid and frequent amino acid monitoring allows many catabolic illnesses to be managed in the outpatient setting. Acute metabolic decompensation is corrected by treating the precipitating stress while delivering sufficient calories, insulin, free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues. Some centers use hemodialysis/hemofiltration to remove BCAAs from the extracellular compartment, but this intervention does not alone establish net protein accretion. Brain edema is a common complication of metabolic encephalopathy and requires careful management in an intensive care setting. Adolescents and adults with MSUD are at increased risk for attention-deficit/hyperactivity disorder, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressant medications. Prevention of primary manifestations: Transplantation of allogeneic liver tissue affords affected individuals an unrestricted diet and protects them from metabolic crises, but does not reverse preexisting psychomotor disability or mental illness. In those who have not undergone liver transplantation, strict and consistent metabolic control can decrease the risk of developing neuropsychiatric morbidities. Consider a trial of enteral thiamine to determine if an affected individual may have thiamine-responsive disease. Prevention of secondary complications: Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist. Surveillance: Weekly or twice-weekly assessment of amino acid profile for rapidly growing infants; weekly amino acid profile assessment in children, adolescents, and adults; routine monitoring of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid levels; at least monthly visit with a metabolic specialist in infancy; assessment of developmental milestones at each visit or as needed. Evaluation of relatives at risk: It can be determined if newborn sibs of an affected individual (who have not been tested prenatally) are affected (1) by plasma amino acid analysis at approximately 24 hours of life; or (2) by molecular genetic testing of umbilical cord blood if the family-specific pathogenic variants have been identified. Early diagnosis may allow management of asymptomatic infants out of hospital by experienced providers. Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD. Pregnancy management: For women with MSUD, metabolic control should be rigorously maintained before and throughout pregnancy by frequent monitoring of plasma amino acid concentrations and dietary adjustments to avoid the likely teratogenic effects of elevated maternal leucine plasma concentration. Fetal growth should be monitored to detect any signs of essential amino acid deficiency. The catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation of the affected mother. Appropriate monitoring of the affected mother at a metabolic referral center at the time of delivery and in the postpartum period are recommended. ### Genetic counseling. MSUD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member. ## Diagnosis Maple syrup urine disease (MSUD) is caused by decreased activity of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD), the second enzymatic step in the degradative pathway of the branched-chain amino acids (BCAAs), which includes leucine, isoleucine, and valine. Scenario 1. Abnormal newborn screening (NBS) result * NBS for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dry blood spots. * A positive screening value (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with quantitative plasma amino acid and alloisoleucine analyses. If either is abnormal, treatment (see Management) and testing to establish the diagnosis (see Establishing the Diagnosis) should be initiated concurrently. Note: Individual states set standards for positive or suspected positive screens. * Because leucine-isoleucine and hydroxyproline cannot be differentiated by mass spectrometry, neonates with isolated hydroxyprolinemia will screen positive for MSUD, but confirmatory amino acid analysis will show only increased hydroxyproline (a false positive newborn screening result). * Neonates and infants suspected of having MSUD should never be challenged with higher than normal protein intake during the diagnostic process (see Management). This practice is dangerous; modern diagnostic methods make it unnecessary. Scenario 2. A symptomatic individual with either atypical findings or untreated infantile-onset MSUD (resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not compliant with recommended treatment following a positive NBS result) Supportive clinical and laboratory findings can include the following. Clinical findings * Untreated infant: * Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth. * Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days. * Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available. * Untreated older individuals with milder variants of MSUD: * Anorexia * Poor growth * Irritability * Developmental delays later in infancy or childhood * Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness Laboratory findings * Elevated plasma concentrations of BCAAs and alloisoleucine * Urinary excretion of BCKDs and branched-chain alpha-ketoacids (BCKAs) in infants older than 48-72 hours on an unrestricted diet * Ketonuria detected by standard urine test strips Ketonuria in a newborn should always prompt investigation for metabolic disorders. * Absence of hypoglycemia and hyperammonemia ### Establishing the Diagnosis The diagnosis of MSUD in a proband with suggestive metabolic/biochemical findings is established by identification of biallelic pathogenic variants in one of the genes listed in Table 1 or – in limited instances – by significantly reduced activity of the BCKD enzyme in cultured fibroblasts, leukocytes, or biopsied liver tissue. Because of its relatively high sensitivity, molecular genetic testing can obviate the need for enzymatic testing and, thus, is increasingly the preferred confirmatory test for MSUD. Note: In vitro measurements of BCKD activity do not correlate with measurements of in vivo leucine oxidation [Schadewaldt et al 2001], dietary leucine tolerance [Strauss et al 2010], or in vivo response to BCKD-activating medications [Brunetti-Pierri et al 2011]. Therefore, the authors do not find measurements of BCKD enzyme activity clinically useful. #### Molecular Genetic Testing Approaches Scenario 1. Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of MSUD, the preferred molecular genetic testing approach is use of a multigene panel that contains BCKDHA, BCKDHB, and DBT. In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. * Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. * For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Scenario 2. A symptomatic individual with atypical findings or untreated infantile-onset MSUD (resulting from NBS not performed or false negative NBS result). When the diagnosis of MSUD has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Maple Syrup Urine Disease View in own window Gene 1, 2Proportion of MSUD Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 BCKDHA45%~92%~8% 6, 7 BCKDHB35%~93%~7% DBT20%~86%~14% 8 Unknown 9, 10NA 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. 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. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. 6\. Quental et al [2008] 7\. Rodríguez-Pombo et al [2006] 8\. Herring et al [1992] 9\. Inactivating variants of BCKDK in humans are associated with BCAA deficiency, autism, epilepsy, and intellectual disability that may respond to dietary treatment [Novarino et al 2012]. 10\. Defects of PPM1K may account for a subset of human MSUD but to date no cases have been reported. ## Clinical Characteristics ### Clinical Description Traditionally, the metabolic phenotype of maple syrup urine disease (MSUD) is termed classic or intermediate on the basis of residual branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity. Rarely, affected individuals have partial BCKD enzyme deficiency that manifests only intermittently or responds to dietary thiamine therapy (see Table 2). Phenotypic distinctions are not absolute: individuals with intermediate or intermittent forms of MSUD can experience severe metabolic intoxication and encephalopathy if physiologic stress is sufficient to overwhelm residual BCKD activity or this activity is reduced by transient changes in the phosphorylation state of the enzyme complex. Even in persons with relatively high baseline residual BCKD enzyme activity, episodes of metabolic intoxication can be fatal. ### Table 2. Clinical Phenotypes of Maple Syrup Urine Disease View in own window TypeAge of Onset 1Clinical FeaturesBiochemical Signs 2% with Normal BCKD Activity 3 ClassicNeonatal * Maple syrup odor of cerumen * Poor feeding * Irritability, lethargy * Opisthotonus * Focal dystonia * "Fencing," "bicycling" * Obtundation, coma * Central respiratory failure * ↑ BCAAs in plasma * ↑ plasma alloisoleucine * ↑ BCKAs in urine * Ketonuria 0%-2% IntermediateVariable * Maple syrup odor of cerumen * Poor growth * Poor feeding * Irritability * Developmental delays * Encephalopathy during illness Similar to classic phenotype, though quantitatively less severe3%-30% IntermittentVariable * Normal early growth & development * Episodic decompensations that can be severe * Normal BCAAs when well * Similar to classic biochemical profile during illness 5%-20% Thiamine-responsiveVariableSimilar to intermediate phenotypeImprovement of leucine tolerance & biochemical profile w/thiamine therapy2%-40% BCAAs = branched-chain amino acids; BCKAs = branched-chain alpha-ketoacids 1\. All infants with classic MSUD present during the neonatal period. For other forms, age of presentation depends on several variables, including dietary protein and calorie intake, growth rate, number and severity of infectious illnesses, and rarely, dietary thiamine intake. 2\. Biochemical signs should always be interpreted in the context of dietary leucine tolerance and prevailing clinical circumstances. Dietary leucine tolerance (in mg/kg/day) is defined as the steady-state leucine intake that permits normal growth and maintains plasma leucine concentration within the normal range. 3\. The authors do not rely on tissue measurements of decarboxylation activity but classify affected individuals based on their leucine tolerance and metabolic response to illness. Decarboxylation data are from Chuang & Shih [2001]. Metabolic considerations in establishing MSUD phenotype: * Dietary leucine tolerance. Leucine tolerance is defined as the weight-adjusted daily leucine intake that is sufficient for normal growth and maintains plasma leucine concentration within the normal range (reference mean ±2 SDs). In persons with classic MSUD, in vivo oxidation and urinary losses of branched-chain amino acids (BCAAs) are negligible [Schadewaldt et al 1999b, Levy 2001]. Thus, leucine tolerance reflects a balance between unmeasured protein losses (e.g., sloughed skin, hair, and nails) and the net accretion of body protein, which in turn is linked to growth rate [Strauss et al 2010]. During metabolic crises, changes of plasma leucine mirror whole-body protein turnover, which can be quantified if one assumes the human body is 10%-12% protein, protein is about 10% leucine by weight, and free leucine (molecular weight 131 mg/mmol) is evenly distributed in total body water [Garrow et al 1965, Filho et al 1997]. * Plasma concentration ratios of BCAAs. The wild type BCKD complex maintains stringent stoichiometric relationships among the three BCAAs, such that plasma concentration ratios (µmol/L:µmol/L) of leucine to isoleucine (Leu/Iso) and valine to leucine (Val/Leu) remain close to 2.0 in diverse physiologic contexts, including overnight fasting, protein loading, and catabolic illness. In contrast, these concentration ratios vary across several orders of magnitude in individuals with classic MSUD [Strauss et al 2006]. Individuals with intermediate forms of MSUD are less vulnerable to these volatile changes of plasma BCAA concentrations and less likely to experience prolonged essential amino acid deficiencies. * Plasma alloisoleucine. Alloisoleucine is a chemical derivative of isoleucine and represents the most sensitive and specific diagnostic marker for all forms of MSUD. Plasma alloisoleucine is <5 µmol/L in healthy infants, children, and adults, and exceeds this value in 94% and 99.9% of samples from individuals with intermediate and classic forms of MSUD, respectively [Schadewaldt et al 1999a]. * Rapidity and severity of decompensation during illness. The risk for metabolic crisis in any ill person with MSUD depends on residual in vivo BCKD enzyme activity in relation to the net liberation of free leucine from protein catabolism. Thus, individuals with residual in vivo BCKD enzyme activity enjoy a higher leucine tolerance when well and also tend to have slower and less severe elevations of plasma leucine concentrations during illnesses. #### Classic MSUD Phenotype Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. In untreated neonates, ketonuria, irritability, and poor feeding occur within 48 hours of delivery. Lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days and are followed by coma and central respiratory failure. Preemptive detection of affected newborns, before they exhibit neurologic signs of MSUD, significantly reduces lifetime risk of intellectual disability, mental illness, and global functional impairment [Strauss et al 2012, Muelly et al 2013, Strauss et al 2020]. Following the neonatal period, acute metabolic intoxication (leucinosis) and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection, surgery, injury, or psychological stress (see Figure 1). In infants and toddlers, leucinosis causes nausea, anorexia, altered level of consciousness, acute dystonia, and ataxia. Neurologic signs of intoxication in older individuals vary and can include cognitive impairment, hyperactivity, sleep disturbances, hallucinations, mood swings, focal dystonia, choreoathetosis, and ataxia. As plasma concentrations of leucine and alpha-ketoisocaproic acid (aKIC) increase, individuals become increasingly stuporous and may progress to coma. In persons of all ages with MSUD, nausea and vomiting are common during crisis and often necessitate hospitalization [Morton et al 2002]. #### Figure 1. Serial plasma leucine measurements over a 62-day NICU course in a Mennonite newborn with trisomy 21 and classic MSUD. Plasma leucine levels rise predictably as a result of net protein catabolism provoked by a variety of physiologic stresses, including (more...) Each episode of acute leucinosis is associated with a risk for cerebral edema (see Figure 2) [Levin et al 1993] and death [Strauss et al 2020]. Mechanisms of brain edema in MSUD are not completely understood. Plasma leucine concentration correlates only indirectly with the degree of swelling; severe cerebral edema and neurologic impairment are more directly related to the rate of change of plasma leucine and concomitant decreases in blood osmolarity. During the evolution of leucinosis, cerebral vasopressin release may be provoked by both acute hyperosmolarity (from the accumulation of BCAAs, ketoacids, ketone bodies, and free fatty acids in the circulation) and vomiting. Renal excretion of branched-chain alpha-ketoacids (BCKAs) is accompanied by obligate urine sodium loss, and when this coincides with renal free water retention (antidiuresis), administration of hypotonic or even isotonic fluids can result in hyponatremia and critical brain edema [Strauss & Morton 2003]. #### Figure 2 A. Coronal T2-weighted MRI from a Mennonite boy age five years during an acute metabolic crisis. Diffuse gray matter swelling and signal hyperintensity (on T2-weighted and FLAIR images) involve the cortical mantle, basal ganglia nuclei, hippocampus, and (more...) Transient periods of MSUD encephalopathy appear fully reversible, provided no global or focal ischemic brain damage occurs. In contrast, prolonged amino acid imbalances, particularly if they occur during the early years of brain development, lead to structural and functional neurologic abnormalities that have morbid long-term psychomotor consequences [Carecchio et al 2011, Shellmer et al 2011, Muelly et al 2013, Strauss et al 2020]. Neonatal screening and sophisticated enteral and parenteral treatment protocols (see Management) have significantly improved neurologic outcomes for persons with classic MSUD [Strauss et al 2010, Muelly et al 2013, Strauss et al 2020], but risks of acute brain injury or death are always present, and the long-term neuropsychiatric prognosis is guarded. In two longitudinal studies of individuals with classic MSUD [Muelly et al 2013, Strauss et al 2020], an asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term cognitive outcome and mental health. * Early developmental milestones. Children with MSUD who are diagnosed during the neonatal period and managed prospectively under stringent dietary control can achieve major developmental milestones along time courses similar to their unaffected sibs [Strauss et al 2020]. * Cognitive function. Among individuals with classic MSUD (n = 81, ages 3.6-51.1 years), full scale intelligence quotient (FSIQ) correlates with birthdate (rs = 0.39, p = 0.0044) and is on average 20%-40% lower in affected individuals as compared to their unaffected sibs [Strauss et al 2020]. This difference is most striking for affected individuals born before the advent of newborn screening (NBS) (FSIQ of 62 ± 17, range 40-99). FSIQ correlates directly with the frequency of amino acid monitoring and inversely with both average lifetime plasma leucine and its concentration ratio to valine [Muelly et al 2013]. Prolonged neonatal encephalopathy is the single strongest predictor of neurocognitive disability and global functional impairment [Muelly et al 2013, Strauss et al 2020]. * Mood and anxiety. Among individuals with classic MSUD who complete appropriate objective testing, the probability of affective illness (depression, anxiety, and panic disorder) is between 83% and 100% by age 35 years [Muelly et al 2013, Strauss et al 2020]. Newborns who were encephalopathic at the time of diagnosis are five and ten times more likely, respectively, to later suffer from anxiety and depression (see Table 3) [Muelly et al 2013]. * Attention and hyperactivity. Cumulative lifetime incidence of attention-deficit/hyperactivity disorder (ADHD) exceeds 50% among individuals with MSUD on dietary therapy and may be even higher among those who underwent liver transplantation [Muelly et al 2013]. * Movement disorders. Among 17 adults with MSUD (mean age 27.5 years), 12 (70.6%) had a movement disorder (primarily tremor, dystonia, or a combination of both) on clinical examination [Carecchio et al 2011]. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 affected individuals (64.7%), and a spastic-dystonic gait was observed in six (35.2%). In the authors' experience, such motor disabilities are rare in individuals with MSUD who are managed appropriately from the neonatal period but common among those who did not have the advantage of NBS [Strauss et al 2020]. ### Table 3. Lifetime Relative Risk of Each Finding Based on Condition at the Time of Diagnosis View in own window Ill vs. Well at DiagnosisRelative RiskFisher's Exact p Depression10.30.001 Anxiety5.10.007 Global assessment of functioning <704.00.05 Full scale intelligence quotient <702.90.20 Attention-deficit/hyperactivity1.40.28 Muelly et al [2013] The relative risk in this table compares the likelihood of developing the finding if the affected individual was ill at the time of diagnosis versus if the affected individual was well at the time of diagnosis. Liver transplantation appears to prevent catastrophic brain injuries that can occur during metabolic intoxication [Mazariegos et al 2012] and arrests the progression of neurocognitive impairment [Shellmer et al 2011], but does not reverse preexisting cognitive disability or psychiatric illness [Strauss et al 2020]. Neuropsychiatric morbidity and neurochemistry are similar among individuals with MSUD who have and have not undergone liver transplantation [Muelly et al 2013, Strauss et al 2020]. Non-central nervous system involvement in MSUD can include: * Iatrogenic essential amino acid deficiency. Anemia, acrodermatitis, hair loss, growth failure, arrested head growth, anorexia, and lassitude are complications of chronic deficiency of leucine, isoleucine, or valine [Puzenat et al 2004]. Iatrogenic cerebral essential amino acid deficiency can be a cause of significant neurologic morbidity in any individual ingesting a diet low in natural protein and high in prescription medical protein [Strauss et al 2010, Manoli et al 2016]. * Recurrent oroesophageal candidiasis. Candida infections are common in hospitalized persons with MSUD and may result from T-cell inhibitory effects of elevated plasma leucine [Hidayat et al 2003] or iatrogenic immunodeficiency as a result of inadequate BCAA intake. #### Intermediate MSUD Similar principles govern the acute and chronic management of classic and intermediate forms of MSUD (see Management), and the distinction between them is not absolute (see Genotype-Phenotype Correlations) [Strauss et al 2020]. Individuals with residual BCKD activity (i.e., 3%-30% ex vivo) may appear well during the neonatal period but nevertheless have maple syrup odor in cerumen and a consistently abnormal plasma amino acid profile (see Table 2). Individuals with intermediate MSUD can present with feeding problems, poor growth, and developmental delay during infancy, or may present much later in life with apparently nonsyndromic intellectual disability [Chuang & Shih 2001]. The majority of persons with intermediate MSUD are detected by NBS, although detection later in childhood can occur in settings where newborns are not tested for MSUD. When followed longitudinally, individuals with intermediate forms of MSUD have plasma BCAA concentrations similar to those observed in individuals with the classic form, but tolerate more dietary leucine and require less nutritional support to reverse episodes of metabolic intoxication [Strauss et al 2020]. Children and adults with intermediate MSUD can nevertheless develop severe leucinosis and brain swelling if subjected to sufficient catabolic stress. #### Intermittent MSUD Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death [Chuang & Shih 2001]. These individuals may escape detection by NBS. #### Thiamine-Responsive MSUD It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1,000 mg/day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern [Chuang et al 2004]. Based on in vitro data, Chuang et al [2006] provided a biochemical model of thiamine responsiveness linked to specific pathogenic variants in the E2 subunit of BCKD. It is therefore reasonable to try thiamine supplementation under controlled dietary conditions in any individual with MSUD who has verified BCKDHB pathogenic variants. ### Pathophysiology BCKD has four subunit components (E1a, E1b, E2, and E3). Pathogenic variants in both alleles encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding BCKAs in tissues and plasma [Nellis et al 2003, Chuang et al 2004] (see Nomenclature). For more information on the pathophysiology of MSUD click here (pdf). ### Genotype-Phenotype Correlations The severity of the MSUD metabolic phenotype is determined by the amount of residual BCKD enzyme activity relative to dietary BCAA excess and the large demands for BCAA oxidation that accompany fasting, illness, or other catabolic stresses [Strauss et al 2010]. Although there are some established relationships between genotype and biochemical phenotype (i.e., classic vs intermediate), clinical and functional outcomes (e.g., FSIQ, psychiatric illness, executive dysfunction) cannot be predicted from genotype [Strauss et al 2020]. Individuals with the same MSUD genotype may vary considerably in their cerebral response to metabolic crisis – some being more vulnerable than others to the complications of metabolic encephalopathy, brain edema, and mental illness – and long-term outcomes are largely related to the timing and quality of metabolic control. ### Nomenclature Biochemical derangement caused by biallelic pathogenic variants in BCKDHA encoding BCKA decarboxylase (E1) alpha subunit is sometimes referred to as MSUD type 1A. Biochemical derangement caused by biallelic pathogenic variants in BCKDHB encoding BCKA decarboxylase (E1) beta subunit is sometimes referred to as MSUD type 1B, and biallelic pathogenic variants in DBT encoding dihydrolipoyl transacylase (E2) subunit are sometimes referred to as MSUD type 2. All three are clinically indistinguishable biochemically. Note: Dihydrolipoamide dehydrogenase deficiency, caused by biallelic pathogenic variants in DLD encoding the E3 subunit (lipoamide dehydrogenase) of BCKD, is sometimes referred to as MSUD type 3, although the phenotype is easily distinguishable from MSUD (see Differential Diagnosis). ### Prevalence MSUD is rare in most populations, with incidence estimates of 1:185,000 live births [Chuang & Shih 2001, Nellis et al 2003]. As a result of a founder variant (c.1312T>A) in BCKDHA (E1a), certain Mennonite populations of Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri have a carrier frequency for classic MSUD as high as one in ten and a disease incidence of approximately one in 380 live births [Puffenberger 2003] (see Molecular Genetics). ## Differential Diagnosis Entities to exclude in the encephalopathic neonate include birth asphyxia, hypoglycemia, status epilepticus, kernicterus, meningitis, and encephalitis. The few inborn errors of metabolism that present with neonatal encephalopathy include the following: * Hyperketosis syndromes (e.g., beta-ketothiolase deficiency [OMIM 203750]) * Urea cycle defects (see Urea Cycle Disorders Overview) * Glycine encephalopathy (nonketotic hyperglycinemia) * Propionic acidemia or isolated methylmalonic acidemia (rarely) Among these, MSUD is unique for the sweet odor of cerumen and a positive urine dinitrophenylhydrazine test. Laboratory testing that includes quantitative plasma amino acids, plasma or whole-blood alloisoleucine, serum acylcarnitines, urine organic acids, plasma ammonia concentration, and serum lactate concentration distinguishes among these possibilities. In particular, quantitative analysis of plasma amino acids is generally sufficient to diagnosis MSUD expeditiously. 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), which is thought to be responsible for the characteristic odor of MSUD [Podebrad et al 1999], is also found in maple syrup, fenugreek, and lovage. Maternal ingestion of fenugreek during pregnancy has resulted in false suspicion of MSUD [Korman et al 2001]. Topical benzoin, commonly used in NICUs, also gives off a strong sweet odor. Note: Pathogenic variants in DLD, the gene encoding the E3 subunit, are associated with dihydrolipoamide dehydrogenase deficiency, which produces a different phenotype. Affected infants have hypotonia, developmental delay, dystonia/chorea, and a Leigh-type encephalopathy. BCKD enzyme activity is 0%-25% of control activity. Moderate elevations of plasma concentration of BCAAs, lactic acidemia, and hyperalaninemia are observed. In most cases, the disorder is lethal in infants. ## Management ### Evaluations Following Initial Diagnosis When maple syrup urine disease (MSUD) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of leucine, isoleucine, valine, and/or alloisoleucine), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care with oversight and expertise from a specialized metabolic center. Consensus nutritional guidelines have been published [Frazier et al 2014] (full text) and two peer-reviewed articles provide general guidelines about the comprehensive treatment and monitoring of MSUD: see Strauss et al [2010] (full text), Strauss et al [2020] (full text). To establish the extent of disease and needs in an individual following initial diagnosis of MSUD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis of Maple Syrup Urine Disease View in own window Evaluation/SystemComment Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietician 1 * Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended). * Consider a short hospitalization at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute encephalopathic crises to caregivers). * Determine whether patient has classic or intermediate MSUD through assessment of concentration ratios among the BCAAs & between leucine & other essential & nonessential amino acids. 2, 3, 4, 5 Gastrointestinal/feedingSwallow study as needed for symptomatic persons w/feeding difficulties &/or concern for aspiration Developmental assessmentConsider referral to a developmental pediatrician. Consultation w/neurologistAs needed for those w/neurologic findings Consultation w/psychiatristFor those w/signs of ADHD, anxiety, or depression Consultation w/psychologist &/or social workerTo ensure understanding of the diagnosis & assess parental/patient's coping skills & resources Consultation w/physical therapist, occupational therapist, & speech therapistAs needed when developmental delays are present ADHD = attention-deficit/hyperactivity disorder; BCAAs = branched-chain amino acids (leucine, isoleucine, and valine) 1\. After a new diagnosis of MSUD in an infant or child, the closest hospital and local pediatrician should also be informed. 2\. The following plasma concentration ratios are the most representative of amino acid regulation: leucine:isoleucine, leucine:valine, leucine:tyrosine, leucine:phenylalanine, leucine:glutamate, and leucine:alanine (mol:mol) [Mazariegos et al 2012]. 3\. In MSUD, plasma leucine concentration has the strongest reciprocal relationship to plasma alanine and glutamine concentrations (Spearman correlation coefficient -0.86 and -0.62, respectively; p < 0.0001; see Figure 3) [Strauss et al 2010]. 4\. Severe branched-chain alpha-ketoacid dehydrogenase (BCKD) deficiency (classic MSUD) affects amino acid homeostasis at multiple levels and causes frequent and variable disturbances of plasma amino acid concentration ratios. 5\. In milder intermediate forms of MSUD, plasma BCAAs may be chronically elevated while plasma amino acid concentration ratios tend to be preserved. ### Figure 3. Plasma amino values between ages four and 26 months from a child with classic MSUD show a strong reciprocal relationship between leucine (gray diamonds) and alanine (white circles) (Spearman correlation coefficient= -0.86; p<0.0001). Strauss et al [2010]; republished with permission of Elsevier. ### Treatment of Manifestations All children with MSUD and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing the diet of those with MSUD. The main principles of treatment are age-appropriate tolerance of leucine, isoleucine, and valine, with stable plasma branched-chain amino acid (BCAA) concentrations and BCAA concentration ratios, while avoiding deficiencies of essential amino acids, fatty acids, and micronutrients (see Table 5). ### Table 5. Routine Daily Treatment in Individuals with Maple Syrup Urine Disease View in own window AgePrinciple/ ManifestationTreatmentConsideration/Other Neonate/ InfantLeucine restriction, titrated to leucine tolerance 1BCAA-free powder formulaLeucine tolerance for neonates is 65-85 mg/kg/day Natural protein as a source of essential & nonessential amino acids: 2-3 g/kg/day 2 * Breast milk or regular infant formula can be used as a natural protein source. * For infants w/classic MSUD, breast milk should be expressed & quantified. Maintenance of adequate isoleucine & valine supplements10 mg/mL solutions of isoleucine, valine, & leucine in distilled water * Record of BCAA supplement intake maintained by parents * Dried blood spots by overnight mail for monitoring of amino acid concentrations (see Surveillance) 3 Child/ AdultLeucine restriction, titrated to leucine tolerance 1Leucine tolerance: * Children: 20-40 mg/kg/day * Adults:10-15 mg/kg/day * In persons w/classic MSUD (0%-2% enzyme activity) * See Figure 4. 4 Maintenance of adequate isoleucine & valine supplementsMaintain a plasma leucine-to-valine concentration ratio (mol:mol) of 0.5 or fewer and a leucine-to-isoleucine ratio of approximately 2.0 * Isoleucine supplements can periodically be suspended based on plasma amino acid monitoring, but continuous valine supplementation is recommended. 5 * Continuous valine fortification is directly related to long-term intellectual outcome. 2,6 Neuropsychiatric morbidity 7Standard psychostimulant & antidepressant medications as needed All agesNormal age- & weight-adjusted energy intakeSee Table 6 for patients from birth to age 4 yrs.Information in Table 6 derived from Mennonite children birth to age 4 yrs w/classic MSUD Addressing ↑ energy/caloric demandsFundoplication, gastrostomy, or jejunostomy to address feeding issues as needed in neurologically affected persons * Adequate provision of information & education to parents, patients, & caregivers * For information on treatment during illness or acute decompensation, see Table 7 & Table 8. Gross motor delay * Physical therapy * Aggressive rehabilitation therapy BCAAs = branched-chain amino acids (leucine, isoleucine, and valine) 1\. The dietary requirement for BCAAs varies as a function of age, growth rate, calorie intake, illness, and residual in vivo branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity. 2\. For asymptomatic individuals; see Table 6 and Table 7 for acute management recommendations. 3\. For rapidly growing infants, monitoring weekly or twice weekly is recommended. 4\. Strauss et al [2010] 5\. Valine has a low affinity for the blood-brain barrier LAT1 transporter, which makes it especially vulnerable to competitive inhibition by leucine. 6\. Muelly et al [2013] 7\. Which may include ADHD, depression, or anxiety ### Figure 4. Leucine (A), energy (B), and total protein (C) intakes of 15 stable Mennonite infants with classic MSUD on dietary management Strauss et al [2010]; republished with permission of Elsevier. ### Table 6. Mean and 25th to 75th Percentile Range Nutrient Intakes (per kg-day) by Age Group View in own window NutrientAge in Months (# of Persons) 0-2 (31)3-5 (18)6-8 (21)9-12 (18)13-18 (21)19-24 (18)25-36 (32) Mean Nutrient Intake per kg-day (25th to 75th %ile range) Leucine (mg)72 (64-84)58 (47-68)44 (37-51)35 (30-41)33 (26-39)27 (22-28)21 (20-25) Energy (kcal)111 (103-119)99 (94-107)89 (82-99)78 (71-87)67 (55-77)57 (49-71)38 (39-51) Total protein (g)2.4 (2.1-2.6)2.3 (1.9-2.6)2.2 (1.8-2.5)2.0 (1.5-2.5)2.1 (1.8-2.4)2 (1.7-2.3)1.5 (1.5-2.9) Leucine/energy ratio (mg/kcal)0.65 (0.57-0.72)0.58 (0.48-0.66)0.50 (0.43-0.56)0.46 (0.37-0.53)0.50 (0.43-0.58)0.48 (0.38-0.58)0.54 (0.44-0.55) Strauss et al [2010]; with permission from Elsevier Data derived from Mennonite children from birth to age 4 years with classic MSUD Mild illness. If an affected individual is clinically well despite an intercurrent infectious illness or febrile reaction to vaccinations, emergency outpatient management may be considered (see Table 7). If emergency outpatient treatment can be performed adequately and safely and if the child does not develop concerning symptoms during the illness, maintenance treatment and diet should be reintroduced stepwise over the next 48 (to 72) hours (see Table 5). ### Table 7. Emergency Outpatient Treatment in Individuals with Maple Syrup Urine Disease View in own window Manifestation/ConcernTreatmentConsideration/Other Mildly increased catabolism 1↑ calorie intake & ↓ dietary leucine intake by using BCAA-free amino acid protein supplementation 2 orally or via tube feed. * Trial of outpatient treatment at home for ≤12 hrs w/periodic measurement of urine BCKAs using DNPH strips * Reassessment (~ every 2 hrs) for clinical changes 3 ↑ supplements of isoleucine & valine, 20-40 mg/kg/day each.Measurement of plasma or whole-blood amino acids every 24-48 hrs FeverAdministration of antipyretics (acetaminophen, ibuprofen) if temperatures rises >38.5°C Occasional vomitingAntiemetics 4 BCAA = branched-chain amino acid; BCKAs = branched-chain alpha-ketoacids; DNPH = dinitrophenylhydrazine 1\. Fever <38.5°C (101°F), enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea, and absence of neurologic symptoms (altered consciousness, irritability, hypotonia) 2\. High-calorie BCAA-free "sick day" formulas 3\. Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases 4\. Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital. Acute decompensation. Dietary indiscretion causes plasma BCAAs to increase but only rarely results in acute decompensation and encephalopathy. In contrast, infections and injuries trigger a large endogenous mobilization of muscle protein and can precipitate metabolic crisis and hospitalization. Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma) should be managed symptomatically and with generous caloric support in a hospital setting (see Table 8). Correction of metabolic decompensation is predicated on treating the underlying cause of the decompensation and establishing net protein accretion. ### Table 8. Acute Inpatient Treatment in Individuals with Maple Syrup Urine Disease View in own window Principle Goal/ ManifestationTreatment/Monitoring during Acute TreatmentConsideration/Other To correct metabolic derangements due to MSUD 1 ↓ plasma leucine concentration by 500-1,000 µmol/L per 24 hrs.Provide 1.5x-3x EER as dextrose (50%-70%) & lipid (30%-50%).When central access allows, use 25% dextrose solutions to minimize complications of hypervolemia. Continuous insulin infusion: 0.02-0.15 U/kg/hrTitrate insulin infusion to maintain blood glucose 100-160 mg/dL Total protein intake (enteral + parenteral): 2.0-3.5 g/kg/day as BCAA-free amino acids * Hospitals admitting patients w/MSUD encephalopathy should have an established mechanism for procuring MSUD parenteral amino acid solutions devoid of BCAAs. 2 * For patients of any age who can tolerate enteral feeding (even if intubated), continuous nasogastric delivery (30-60 mL/hr) of a BCAA-free MSUD formula (0.7-1.2 kcal/mL) supplemented w/1% liquid solutions of isoleucine & valine can meet protein goals while providing additional calories. 3 Isoleucine & valine supplements (enteral + parenteral): 20-120 mg/kg per day each; titrate to plasma concentrations of 400-800 µmol/LFor parenteral administration, isoleucine & valine are each prepared as separate 1% solutions in normal saline Consider renal replacement therapies in clinical settings w/appropriate resources & expertise 4 * Peritoneal dialysis & venovenous hemofiltration are less effective & more dangerous than short courses of continuous hemodialysis. 5 * When hemodialysis is used to treat MSUD it must be coupled w/effective nutritional management to constrain catabolic response & prevent recurrent clinical intoxication. 6, 7 To prevent iatrogenic electrolyte abnormalities, 8, 9 which can → cerebral edema & intracranial hypertension Maintain serum osmolality in normal reference range (275-300 mOsm/kg H2O).Establish euvolemia using isotonic sodium chloride solutions Measure serum osmolality & electrolytes every 6-12 hoursPrevent serum osmolality from decreasing >5 mOsm/kg H2O per day (0.20 mOsm/kg H2O per hour) Monitor for other laboratory abnormalities.Serum (&/or point-of-care) glucose every 4-6 hrs Plasma amino acids, serum phosphorus, & magnesium every 12-24 hrsHospitals admitting patients w/MSUD encephalopathy should be able to perform plasma amino acid testing around the clock. Serum lipase, amylase, & transaminases every 24-48 hours Manage cerebral edema.Monitor for signs of intracranial hypertension & impending brain herniation.Management in an intensive care setting w/consultation by neurologist &/or neurointensivist is recommended For obtunded individuals w/cerebral edema, consider endotracheal intubation for airway protection & neurosurgical consultation to consider measures incl e.g., intracranial pressure monitoring & active CSF drainage.Acute neuroimaging may be indicated in some circumstances. 10 Treat symptomatic hypo-osmolality or worsening signs of intracranial hypertension using the following agents alone or in sequence: mannitol 0.5-1 mg/kg per dose; hypertonic (3%) saline 2-3 mEq/kg per dose; furosemide 0.5-1.0 mg/kg per doseIn those w/moderate-to-severe encephalopathy, consider administration of hypertonic (3%) saline drip: 5-15 mEq/kg per day sodium chloride titrated to serum osmolality 290-300 mOsm/kg H2O, serum sodium 138-145 mEq/L, & serum osmolality change <0.2 mOsm/kg H2O per hr (5 mOsm/kg H2O per day) General measures Identify & treat precipitating catabolic stress (e.g., infection, dehydration, trauma).Low clinical threshold for empiric administration of antibiotics when signs of infection are present * Superficial & invasive Candida infections are common. * Persons w/MSUD are vulnerable to bacterial or fungal infection from central venous catheters Schedule antipyretics (e.g., acetaminophen, ibuprofen, ketorolac) to control feverKetorolac contraindicated in those who are dehydrated, known to have kidney disease, or taking other medications that affect renal perfusion Antiemetics to control nausea & vomitingConsider scheduled intravenous ondansetron 0.15 mg/kg per dose every 6-8 hours Limit use of glucocorticoids & vasoactive catecholaminergic agents Other complications Acute pancreatitis 11 * Stop all enteral feeding & measure serum concentrations of lipase & amylase. 12 * Supportive treatment w/BCAA-free parenteral nutrition solutions Dystonia assoc w/metabolic crisis 13Enteral tyrosine at 100-400 mg/kg/dayTyrosine dissolves poorly in aqueous solution, so enteral administration is typically required BCAAs = branch-chain amino acids (leucine, isoleucine, and valine); EER = estimated energy expenditure 1\. Establish central venous access; where regional expertise allows, the authors recommend placement of a peripheral intravenous central catheter (PICC) or other form of central line for treatment of metabolic intoxication. 2\. Parenteral MSUD amino acid solutions are the preferred protein source for individuals with MSUD who have severe metabolic encephalopathy; however, such parenteral solutions are available from a very limited number of specialty pharmacies and often prove difficult to procure in a timely manner. 3\. Nyhan et al [1998], Morton et al [2002] 4\. Nutritional therapy alone can effectively reduce even extremely elevated plasma concentrations of leucine in persons with MSUD of any age and under a wide variety of clinical circumstances [Morton et al 2002, Strauss & Morton 2003]. However, numerous publications have shown that renal replacement methods can achieve rapid corrections of branched-chain amino acids (BCAAs) and branched-chain alpha-ketoacids (BCKAs) during the acute phase of MSUD crisis [Jouvet et al 1997, Schaefer et al 1999, Yoshino et al 1999, Jouvet et al 2001, Puliyanda et al 2002]. 5\. Schaefer et al [1999] 6\. A combined approach to therapy, using hemodialysis with simultaneous anabolic nutritional therapy was shown to be highly effective in one neonate with classic MSUD [Puliyanda et al 2002]. 7\. Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement (in this case ongoing protein degradation due to catabolism). 8\. Most commonly associated with high intravenous fluid, glucose, and insulin infusions. 9\. The most commonly encountered biochemical complications of treatment are hyperglycemia, hypoglyemia, hyponatremia, hypokalemia, and hypophosphatemia. 10\. During episodes of acute encephalopathy, individuals with MSUD are typically too unstable for magnetic resonance imaging. Cranial CT scan is used to evaluate for major indices of cerebral edema, such as decreased volume of cerebral ventricles and basal fluid spaces, or reduced gray-white discrimination (see Figure 2). New scanners are designed for portable use in the intensive care setting. 11\. Signs and symptoms typically include epigastric or mid-back pain, anorexia, and/or vomiting, developing in two to three days into treatment of a metabolic decompensation. 12\. Kahler et al [1994] 13\. During acute metabolic crisis, newborns, infants, and children with MSUD can develop acute focal or generalized dystonic posturing attributed to an increased plasma leucine:tyrosine concentration ratio, restricted brain tyrosine uptake, and reduced cerebral dopamine synthesis [Morton et al 2002, Zinnanti et al 2009]. ### Prevention of Primary Manifestations ### Table 9. Prevention of Primary Manifestations in Individuals with Maple Syrup Urine Disease View in own window Manifestation/ SituationPreventionConsiderations/Other Metabolic cureOrthotopic liver transplantation * Effective for classic MSUD, w/removal of dietary restrictions & complete protection from decompensations during illness 1 * Post transplantation, plasma leucine, isoleucine, & valine concentrations typically normalize w/in 6 hrs & chronically remain ~2x the reference mean on an unrestricted diet. * Disease-free survival & graft survival are high, 100% in a series of 93 patients transplanted at University Pittsburgh Medical Center between 2003 & 2019\. 2 * Risks assoc w/surgery & immunosuppression are similar to those in other pediatric liver transplant populations & may incl EBV-assoc post-transplantation lymphoproliferative disease. * Liver transplantation does not reverse cognitive disability or psychiatric illness in patients w/MSUD but may arrest progression of neurocognitive impairment & prevent life-threatening cerebral edema assoc w/metabolic crisis. 3, 4 Neuropsychiatric morbidityStrict & consistent metabolic control 4 Potential thiamine responsiveness 5Consider a 4-wk trial of enteral thiamine (50-100 mg/day, divided 2x/day)Significant changes in dietary therapy (e.g., BCAA or calorie intake) during treatment period confounds interpretation of a specific thiamine effect. BCAA = branched-chain amino acid; EBV = Epstein-Barr virus 1\. Wendel et al [1999], Bodner-Leidecker et al [2000], Strauss et al [2006], Mazariegos et al [2012] 2\. Strauss et al [2020] 3\. Shellmer et al [2011], Mazariegos et al [2012] 4\. Muelly et al [2013] 5\. The existence of "thiamine-responsive" branched-chain alpha-ketoacid dehydrogenase (BCKD) mutants is controversial. ### Prevention of Secondary Complications Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist. ### Surveillance ### Table 10. Recommended Surveillance for Individuals with Maple Syrup Urine Disease View in own window ManifestationEvaluationFrequency/Comment Control of amino acid & other nutrient levels 1Full amino acid profile (either from plasma or filter paper) * For rapidly growing infants, monitoring 1x or 2x/wk * Weekly in children, adolescents, & adults 2, 3 Measurement of calcium, magnesium, zinc, folate, selenium & omega-3 essential fatty acidAs indicated based on clinical signs of deficiency Visit w/metabolic specialistAt least monthly in infancy Delayed acquisition of developmental milestonesMonitor developmental milestones 4,5At each visit or as needed 1\. See Goals of laboratory monitoring (following) for target concentrations for various amino acids and other nutrients. 2\. The frequency of amino acid monitoring varies by age, metabolic stability, compliance, and regional clinical practice. 3\. The frequency of amino acid monitoring correlates directly with metabolic control [Strauss et al 2020] and long-term measures of intelligence [Muelly et al 2013]. 4\. The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children with MSUD. 5\. School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavior problems [Shellmer et al 2011, Muelly et al 2013]. Goals of laboratory monitoring * Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake * Plasma isoleucine concentration approximately equal to plasma leucine concentration * Plasma valine concentration at least twofold plasma leucine concentration * Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency ### Evaluation of Relatives at Risk Early diagnosis of at-risk sibs of an affected individual may allow asymptomatic infants to be managed out of the hospital by experienced providers. Newborn at-risk sibs who have not undergone prenatal testing can be tested in one of two ways: * Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results. * If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing. Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management With the advent of newborn screening and preventive care, more women with MSUD are surviving to child-bearing age. Successful delivery of a healthy baby is possible for women with classic MSUD [Van Calcar et al 1992, Grünewald et al 1998]. Two women who had biallelic pathogenic BCKDHA variants became pregnant following liver transplantation. Each delivered a healthy baby after remaining on immunosuppressant medication (sirolimus) but observing no special dietary restrictions during pregnancy [Strauss et al 2020]. Elevated maternal leucine plasma concentration, like elevated maternal phenylalanine plasma concentration, is likely teratogenic. If a woman with MSUD is planning a pregnancy, metabolic control should be maintained in a rigorous fashion preceding and throughout gestation. Keeping the maternal plasma levels of the branched-chain amino acids between 100 and 300 μmol/L is compatible with delivery of a normal infant [Grünewald et al 1998]. During the development of the placenta and fetus, maternal BCAA and protein requirements increase, and frequent monitoring of plasma amino acid concentrations and fetal growth may be necessary to avoid essential amino acid deficiencies [Grünewald et al 1998]. The postpartum period is dangerous for the affected mother. Catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation [Chuang & Shih 2001]. Appropriate monitoring at a metabolic referral center is advised at the time of delivery. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. [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	Maple Syrup Urine Disease	c0024776	2,854	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1319/	2021-01-18T21:12:47	{"mesh": ["D008375"], "synonyms": ["BCKD Deficiency", "Branched-Chain Ketoacid Dehydrogenase Deficiency", "Maple Syrup Disease", "MSUD"]}
Not to be confused with Parkinson's disease. Parkinsonism SpecialtyNeurology Causes * Parkinson's disease * Dementia with Lewy bodies * Parkinson's disease dementia * Other neurodegenerative disorders, including multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration * Drugs * Toxins * Metabolic disease Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability.[1][2] These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and many other conditions. A wide range of causes may lead to this set of symptoms, including neurodegenerative conditions, drugs, toxins, metabolic diseases, and neurological conditions other than PD.[3] ## Contents * 1 Causes * 1.1 Drug-induced * 1.2 Toxins * 2 Diagnosis * 2.1 Essential tremor * 3 References * 4 External links ## Causes[edit] ### Drug-induced[edit] About 7% of people with parkinsonism developed symptoms as a result of side effects of medications, mainly neuroleptic antipsychotics especially the phenothiazines (such as perphenazine and chlorpromazine), thioxanthenes (such as flupenthixol and zuclopenthixol) and butyrophenones (such as haloperidol), and rarely, antidepressants. The incidence of drug-induced parkinsonism increases with age. Drug-induced parkinsonism tends to remain at its presenting level and does not worsen like Parkinson's disease.[4] ### Toxins[edit] Evidence exists of a link between exposure to pesticides and herbicides and PD; a two-fold increase in risk was seen with paraquat or maneb/mancozeb exposure.[5] Chronic manganese (Mn) exposure has been shown to produce a parkinsonism-like illness characterized by movement abnormalities.[6] This condition is not responsive to typical therapies used in the treatment of PD, suggesting an alternative pathway than the typical dopaminergic loss within the substantia nigra.[6] Manganese may accumulate in the basal ganglia, leading to the abnormal movements.[7] A mutation of the SLC30A10 gene, a manganese efflux transporter necessary for decreasing intracellular Mn, has been linked with the development of this Parkinsonism-like disease.[8] The Lewy bodies typical to PD are not seen in Mn-induced parkinsonism.[7] ## Diagnosis[edit] Parkinsonism occurs in many conditions. Neurodegenerative conditions and Parkinson plus syndrome[9] * Corticobasal degeneration[9] * Dementia with Lewy bodies[9] * Frontotemporal dementia (Pick's disease)[10] * Gerstmann–Sträussler–Scheinker syndrome[9] * Huntington's disease[9] * Lytico-bodig disease (ALS complex of Guam)[9] * Multiple system atrophy (Shy–Drager syndrome)[9] * Neuroacanthocytosis[9] * Neuronal ceroid lipofuscinosis[9] * Olivopontocerebellar atrophy[9] * Pantothenate kinase-associated neurodegeneration, also known as neurodegeneration with brain iron accumulation[9] * Parkin mutation (hereditary juvenile dystonia)[9] * Parkinson's disease[9] * Parkinson's disease dementia[11] * Progressive supranuclear palsy[9] * Wilson's disease[9] * X-linked dystonia parkinsonism (Lubag syndrome)[9] Drug-induced ("pseudoparkinsonism") * Antipsychotics[9] * Lithium[9] * Metoclopramide[12] * MDMA addiction and frequent use[13][14] * Tetrabenazine[9] Infectious * Creutzfeldt–Jakob disease[9][15] * Encephalitis lethargica[1] * HIV infection[9] and AIDS[9][16] Toxins * Annonaceae[17] * Carbon monoxide[9] * Carbon disulfide[9] * Cyanide[9] * Ethanol[9] * Hexane[18] * Maneb/Mancozeb[5] * Manganese[9][6] * Mercury[9] * Methanol[9] * MPTP[9][19] * Paraquat[20][5] * Rotenone[20] * Toluene[21] (inhalant abuse: "huffing")[22] Trauma * Chronic traumatic encephalopathy (boxer's dementia or pugilistic encephalopathy)[9] Vascular * Binswanger's disease (subcortical leukoencephalopathy)[9] * Vascular dementia (multi-infarct)[9] Other * Damage to the brain stem (especially dopaminergic nuclei of the substantia nigra),[23][24] basal ganglia (especially globus pallidus)[25] and the thalamus.[26] * Hypothyroidism[9] * Orthostatic tremor[27] * Paraneoplastic syndrome: neurological symptoms caused by antibodies associated with cancers[28] * Rapid onset dystonia parkinsonism[29] * Autosomal recessive juvenile parkinsonism[30] ### Essential tremor[edit] A 2018 review article said that the relationship (if any) between Parkinson's disease and essential tremor is not clear.[31] ## References[edit] 1. ^ a b Aminoff MJ, Greenberg DA, Simon RP (2005). "Chapter 7: Movement disorders". Clinical Neurology (6th ed.). Lange: McGraw-Hill Medical. pp. 241–45. ISBN 978-0-07-142360-1. 2. ^ Ogawa T, Fujii S, Kuya K, Kitao SI, Shinohara Y, Ishibashi M, Tanabe Y (September 2018). "Role of neuroimaging on differentiation of Parkinson's disease and its related diseases". Yonago Acta Med (Review). 61 (3): 145–55. doi:10.33160/yam.2018.09.001. PMC 6158357. PMID 30275744. "Parkinsonian syndromes are a group of movement disorders characterized by classical motor symptoms such as tremors, bradykinesia, and rigidity. They are most frequently due to primary neurodegenerative disease, resulting in the loss of dopaminergic nerve terminals along the nigrostriatal pathway, similar to idiopathic PD, MSA, PSP, CBD, and DLB." 3. ^ Christine CW, Aminoff MJ (September 2004). "Clinical differentiation of parkinsonian syndromes: prognostic and therapeutic relevance". The American Journal of Medicine. 117 (6): 412–9. doi:10.1016/j.amjmed.2004.03.032. PMID 15380498. 4. ^ "Information Sheet: Drug-induced Parkinsonism" (PDF). Parkinson’s Disease and Society. Archived from the original (PDF) on 2013-06-26. Retrieved 2013-04-15. 5. ^ a b c Pezzoli G, Cereda E (May 2013). "Exposure to pesticides or solvents and risk of Parkinson disease". Neurology (Meta-analysis). 80 (22): 2035–41. doi:10.1212/WNL.0b013e318294b3c8. PMID 23713084. S2CID 13628268. 6. ^ a b c Guilarte TR, Gonzales KK (August 2015). "Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson's Disease: Environmental and Genetic Evidence". Toxicological Sciences (Review). 146 (2): 204–12. doi:10.1093/toxsci/kfv099. PMC 4607750. PMID 26220508. 7. ^ a b Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M (July 2015). "Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features". International Journal of Environmental Research and Public Health (Review). 12 (7): 7519–40. doi:10.3390/ijerph120707519. PMC 4515672. PMID 26154659. 8. ^ Peres TV, Schettinger MR, Chen P, Carvalho F, Avila DS, Bowman AB, Aschner M (November 2016). "Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies". BMC Pharmacology & Toxicology (Review). 17 (1): 57. doi:10.1186/s40360-016-0099-0. PMC 5097420. PMID 27814772. 9. ^ 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 ah Jankovic J, Lang AE (2004). "Diagnosis and Assessment". In Bradley, Walter George (ed.). Neurology in Clinical Practice: Principles of diagnosis and management. Volume 1. Taylor & Francis. pp. 295–96. ISBN 9789997625885. 10. ^ Finger EC (April 2016). "Frontotemporal Dementias". Continuum (Review). 22 (2 Dementia): 464–89. doi:10.1212/CON.0000000000000300. PMC 5390934. PMID 27042904. 11. ^ McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. (July 2017). "Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium". Neurology (Review). 89 (1): 88–100. doi:10.1212/WNL.0000000000004058. PMC 5496518. PMID 28592453. 12. ^ Shuaib UA, Rajput AH, Robinson CA, Rajput A (March 2016). "Neuroleptic-induced Parkinsonism: Clinicopathological study". Movement Disorders. 31 (3): 360–5. doi:10.1002/mds.26467. PMC 5064745. PMID 26660063. 13. ^ Louis ED, Ottman R (November 2013). "Is there a one-way street from essential tremor to Parkinson's disease? Possible biological ramifications". European Journal of Neurology (Review). 20 (11): 1440–4. doi:10.1111/ene.12256. PMC 3801177. PMID 24033795. 14. ^ Fabrizi, Monaco, Dalla Libera (2004). "Parkinsonian syndrome following MDMA (Ecstasy) addiction". Movement Disorders. 19: S73–S74.CS1 maint: multiple names: authors list (link) 15. ^ Maltête D, Guyant-Maréchal L, Mihout B, Hannequin D (March 2006). "Movement disorders and Creutzfeldt-Jakob disease: a review". Parkinsonism & Related Disorders. 12 (2): 65–71. doi:10.1016/j.parkreldis.2005.10.004. PMID 16364674. 16. ^ Tse W, Cersosimo MG, Gracies JM, Morgello S, Olanow CW, Koller W (August 2004). "Movement disorders and AIDS: a review". Parkinsonism & Related Disorders. 10 (6): 323–34. doi:10.1016/j.parkreldis.2004.03.001. PMID 15261874. 17. ^ Carod-Artal FJ (2003). "[Neurological syndromes linked with the intake of plants and fungi containing a toxic component (I). Neurotoxic syndromes caused by the ingestion of plants, seeds and fruits]". Revista de Neurología (Review) (in Spanish). 36 (9): 860–71. PMID 12717675. 18. ^ Kim EA, Kang SK (December 2010). "Occupational neurological disorders in Korea". Journal of Korean Medical Science (Review). 25 (Suppl): S26-35. doi:10.3346/jkms.2010.25.S.S26. PMC 3023358. PMID 21258587. 19. ^ Watanabe Y, Himeda T, Araki T (January 2005). "Mechanisms of MPTP toxicity and their implications for therapy of Parkinson's disease" (PDF). Medical Science Monitor. 11 (1): RA17-23. PMID 15614202. 20. ^ a b Nandipati S, Litvan I (September 2016). "Environmental Exposures and Parkinson's Disease". International Journal of Environmental Research and Public Health (Review). 13 (9): 881. doi:10.3390/ijerph13090881. PMC 5036714. PMID 27598189. 21. ^ Weiss J. Chapter 151. Toluene and Xylene. In: Olson KR, ed. Poisoning & Drug Overdose. 6th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55982958. Accessed April 21, 2013. 22. ^ Uitti RJ, Snow BJ, Shinotoh H, Vingerhoets FJ, Hayward M, Hashimoto S, Richmond J, Markey SP, Markey CJ, Calne DB (May 1994). "Parkinsonism induced by solvent abuse". Annals of Neurology. 35 (5): 616–9. doi:10.1002/ana.410350516. PMID 8179306. S2CID 23657208. 23. ^ Jubault T, Brambati SM, Degroot C, Kullmann B, Strafella AP, Lafontaine AL, Chouinard S, Monchi O (December 2009). Gendelman HE (ed.). "Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI". PLOS ONE. 4 (12): e8247. Bibcode:2009PLoSO...4.8247J. doi:10.1371/journal.pone.0008247. PMC 2784293. PMID 20011063. 24. ^ Port, Dr Beckie (2018-06-04). "What brain areas are affected by Parkinson's?". Medium. Retrieved 2019-03-28. 25. ^ Kuoppamäki M, Rothwell JC, Brown RG, Quinn N, Bhatia KP, Jahanshahi M (April 2005). "Parkinsonism following bilateral lesions of the globus pallidus: performance on a variety of motor tasks shows similarities with Parkinson's disease". Journal of Neurology, Neurosurgery, and Psychiatry. 76 (4): 482–90. doi:10.1136/jnnp.2003.020800. PMC 1739601. PMID 15774432. 26. ^ Halliday, Glenda M. (2009-12-15). "Thalamic changes in Parkinson's disease". Parkinsonism & Related Disorders. 15: S152–S155. doi:10.1016/S1353-8020(09)70804-1. PMID 20082979. 27. ^ Apartis E, Tison F, Arné P, Jedynak CP, Vidailhet M (November 2001). "Fast orthostatic tremor in Parkinson's disease mimicking primary orthostatic tremor". Movement Disorders. 16 (6): 1133–6. doi:10.1002/mds.1218. PMID 11748748. S2CID 36301428. 28. ^ Panzer J, Dalmau J (August 2011). "Movement disorders in paraneoplastic and autoimmune disease". Current Opinion in Neurology. 24 (4): 346–53. doi:10.1097/WCO.0b013e328347b307. PMC 3705177. PMID 21577108. 29. ^ Liu Y, Lu Y, Zhang X, Xie S, Wang T, Wu T, Wang C (November 2016). "A case of rapid-onset dystonia-parkinsonism accompanied by pyramidal tract impairment". BMC Neurology. 16 (1): 218. doi:10.1186/s12883-016-0743-8. PMC 5105251. PMID 27835968. 30. ^ Saito M, Maruyama M, Ikeuchi K, Kondo H, Ishikawa A, Yuasa T, Tsuji S (September 2000). "Autosomal recessive juvenile parkinsonism". Brain & Development. 22 Suppl 1: S115-7. doi:10.1016/s0387-7604(00)00137-6. PMID 10984671. S2CID 22733500. 31. ^ Algarni M, Fasano A (January 2018). "The overlap between Essential tremor and Parkinson disease". Parkinsonism & Related Disorders. 46 Suppl 1: S101–S104. doi:10.1016/j.parkreldis.2017.07.006. PMID 28729090. ## External links[edit] Classification D * ICD-10: G21, G22 * ICD-9-CM: 332 * MeSH: D020734 * DiseasesDB: 24212 External resources * MedlinePlus: 000759 * GeneReviews/NIH/NCBI/UW entry on Perry syndrome * GeneReviews/NCBI/NIH/UW entry on X-Linked Dystonia-Parkinsonism * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Antiparkinson agents (N04) Dopaminergics DA precursors * Levodopa# * Melevodopa DA receptor agonists * Apomorphine * Bromocriptine * Cabergoline * Dihydroergocryptine * Lisuride * Pergolide * Piribedil * Pramipexole * Ropinirole * Rotigotine MAO-B inhibitors * Rasagiline * Safinamide * Selegiline COMT inhibitors * Entacapone * Opicapone * Tolcapone AAAD inhibitors * Benserazide * Carbidopa# Anticholinergics * Benzatropine * Biperiden# * Bornaprine * Chlorphenoxamine * Cycrimine * Dexetimide * Diphenhydramine * Etanautine * Etybenzatropine * Mazaticol * Metixene * Orphenadrine * Phenglutarimide * Piroheptine * Procyclidine * Profenamine * Trihexyphenidyl * Tropatepine Others * Amantadine * Budipine * Istradefylline * Methylxanthines (e.g., caffeine) * Rimantadine * #WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III [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	Parkinsonism	c0242422	2,855	wikipedia	https://en.wikipedia.org/wiki/Parkinsonism	2021-01-18T18:32:58	{"mesh": ["D020734"], "umls": ["C0242422"], "icd-9": ["332"], "icd-10": ["G21", "G22"], "orphanet": ["68402"], "wikidata": ["Q1531991"]}
Gram-negative rosacea SpecialtyDermatology Gram-negative rosacea is a cutaneous condition that clinically looks like stage II or III rosacea.[1] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). Page 692. McGraw-Hill. ISBN 0-07-138076-0. This cutaneous condition 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	Gram-negative rosacea	None	2,856	wikipedia	https://en.wikipedia.org/wiki/Gram-negative_rosacea	2021-01-18T19:05:19	{"wikidata": ["Q5593572"]}
Acute promyelocytic leukemia (APL) is an aggressive type of acute myeloid leukemia in which there are too many immature blood-forming cells (promyelocytes) in the blood and bone marrow. This build up of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body. The signs and symptoms of APL include an increased risk to both bleed and form blood clots. Individuals may also experience excessive tiredness, pain in affected areas, loss of appetite, and weight loss. APL usually occurs in middle-aged adults, but can be diagnosed at any age. It is caused by a mutation that is acquired over a person's lifetime, usually involving a translocation between chromosomes 15 and 17. Treatment may include the use of all-trans retinoic acid (ATRA) and arsenic trioxide or anthracycline-based chemotherapy. [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	Acute promyelocytic leukemia	c0023487	2,857	gard	https://rarediseases.info.nih.gov/diseases/538/acute-promyelocytic-leukemia	2021-01-18T18:02:18	{"mesh": ["D015473"], "omim": ["612376"], "umls": ["C0023487"], "orphanet": ["520"], "synonyms": ["Acute myeloblastic leukemia type 3", "Acute myeloid leukemia with t(15;17)(q22;q12);(PML/RARalpha) and variants", "AML M3", "AML with t(15;17)(q22;q12);(PML/RARalpha) and variants", "Acute myeloblastic leukemia 3", "APML"]}
Sick sinus syndrome is a rare cardiac rhythm disease, usually of the elderly, characterized by electrocardiographic findings of sinus bradycardia, atrial fibrillation, atrial tachycardia sinus arrest, or sino-atrial block, and that manifest with symptoms like syncope, dizziness, palpitations, fatigue, or even heart failure. It results from malfunction of the cardiac conduction system, probably secondary to degenerative fibrosis of nodal tissue in the elderly or secondary to cardiac disorders in younger patients. [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	Familial sick sinus syndrome	c0037052	2,858	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166282	2021-01-23T18:42:23	{"mesh": ["D012804"], "omim": ["163800", "182190", "608567", "614090"], "umls": ["C0037052"], "icd-10": ["I49.5"]}
Disease mongering SpecialtyPharmaceutical lobby medicalization Differential diagnosisquestionable disease A collection of articles on disease mongering in PLoS Medicine (2006) Disease mongering is a term for the practice of widening the diagnostic boundaries of illnesses and aggressively promoting their public awareness in order to expand the markets for treatment. Among the entities benefiting from selling and delivering treatments are pharmaceutical companies, physicians, alternative practitioners and other professional or consumer organizations. It is distinct from the promulgation of bogus or unrecognised diagnoses. ## Contents * 1 Term * 2 Examples * 3 See also * 4 References * 5 Further reading ## Term[edit] The term “monger” has ancient roots, providing the basis for many common compound forms such as cheesemonger, fishmonger, and fleshmonger for those who peddle such wares respectively. “Disease mongering” as a label for the "invention" or promotion of diseases in order to capitalize on their treatment was first used in 1992 by health writer Lynn Payer, who applied it to the Listerine mouthwash campaign against halitosis (bad breath). Payer defined disease mongering as a set of practices which include the following:[1] * Stating that normal human experiences are abnormal and in need of treatment * Claiming to recognize suffering which is not present * Defining a disease such that a large number of people have it * Defining a disease's cause as some ambiguous deficiency or hormonal imbalance * Associating a disease with a public relations spin campaign * Directing the framing of public discussion of a disease * Intentionally misusing statistics to exaggerate treatment benefits * Setting a dubious clinical endpoint in research * Advertising a treatment as without side effect * Advertising a common symptom as a serious disease The incidence of conditions not previously defined as illness being medicalised as "diseases" is difficult to scientifically assess due to the inherent social and political nature of the definition of what constitutes a disease, and what aspects of the human condition should be managed according to a medical model.[2] For example, halitosis, the condition which prompted Payer to coin the phrase "disease mongering", isn't merely an imagined social stigma but can stem from any of a wide spectrum of conditions spanning from bacterial infection of the gums to kidney failure, and is recognized by the Scientific Council of the American Dental Association as "a recognizable condition which deserves professional attention".[3] ## Examples[edit] Australian journalist Ray Moynihan has argued that the pharmaceutical industry engages in disease mongering to enlarge its profits, and that it harms citizens.[4] His use of osteoporosis as an example of a "made up" disease in this article prompted an angry retort from the president of the British National Osteoporosis Society, stating that the article was insulting to people with osteoporosis and vastly understated the risk of disabling fractures associated with the disorder.[5] Moynihan published a satire of disease mongering in the 2006 April Fool's Day issue of BMJ titled "Scientists find new disease: motivational deficiency disorder".[6] Other conditions which have been cited as examples of disease mongering include restless leg syndrome,[7] testosterone deficiency,[8] erectile dysfunction,[9] hypoactive sexual desire disorder.[10] Some of these conditions are recognized as medical disorders by professional medical societies[11] and the National Institute of Health and Clinical Excellence.[12] In 2014 an FDA advisory committee voted to limit the use of testosterone replacement therapy products due to potentially increased cardiovascular risk associated with their use.[13] A 2006 Newcastle, New South Wales international conference, reported in PLoS Medicine, explored the phenomenon of disease mongering.[14] ## See also[edit] * medicine portal * Inverse benefit law * Medicalization * Quaternary prevention * Schooliosis – an example of disease mongering due to overdiagnosis ## References[edit] 1. ^ Payer, Lynn (1992). Disease-mongers : how doctors, drug companies, and insurers are making you feel sick. New York: J. Wiley. ISBN 978-0471543855. 2. ^ Frosch DL, Grande D, Tarn DM, Kravitz RL (January 2010). "A decade of controversy: balancing policy with evidence in the regulation of prescription drug advertising". Am J Public Health. 100 (1): 24–32. doi:10.2105/AJPH.2008.153767. PMC 2791253. PMID 19910354. 3. ^ "nypediatricdds.com" (PDF). Archived from the original (PDF) on 2014-10-18. 4. ^ Moynihan R, Heath I, Henry D (2002). "Selling sickness: the pharmaceutical industry and disease mongering". BMJ. 324 (7342): 886–91. doi:10.1136/bmj.324.7342.886. PMC 1122833. PMID 11950740. 5. ^ Edwards L (July 2002). "The pharmaceutical industry and disease mongering. Article was insulting to people with osteoporosis". BMJ. 325 (7357): 216, author reply 216. doi:10.1136/bmj.325.7357.216. PMC 1123728. PMID 12143857. 6. ^ Moynihan R (2006). "Scientists find new disease: motivational deficiency disorder". BMJ. 332 (7544): 745. doi:10.1136/bmj.332.7544.745-a. PMC 1420696. "[Neurologist Leth Argos and a team...] at the University of Newcastle in Australia say that in severe cases motivational deficiency disorder can be fatal, because the condition reduces the motivation to breathe." 7. ^ Moynihan R, Henry D (April 2006). "The fight against disease mongering: generating knowledge for action". PLOS Med. 3 (4): e191. doi:10.1371/journal.pmed.0030191. PMC 1434508. PMID 16597180. 8. ^ Vitry AI, Mintzes B (June 2012). "Disease mongering and low testosterone in men: the tale of two regulatory failures". Med. J. Aust. 196 (10): 619–21. doi:10.5694/mja11.11299. PMID 22676868. 9. ^ Moynihan R, Heath I, Henry D (April 2002). "Selling sickness: the pharmaceutical industry and disease mongering". BMJ. 324 (7342): 886–91. doi:10.1136/bmj.324.7342.886. PMC 1122833. PMID 11950740. 10. ^ Tiefer L (April 2006). "Female sexual dysfunction: a case study of disease mongering and activist resistance". PLOS Med. 3 (4): e178. doi:10.1371/journal.pmed.0030178. PMC 1434501. PMID 16597176. 11. ^ Hatzimouratidis K, Amar E, Eardley I, et al. (May 2010). "Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation". Eur. Urol. 57 (5): 804–14. doi:10.1016/j.eururo.2010.02.020. PMID 20189712. 12. ^ "www.guidelines.co.uk". Archived from the original on 2014-10-18. 13. ^ "FDA Panel: Limit Testosterone Drug Use – WebMD". 14. ^ Moynihan R, Henry D (eds). "A Collection of Articles on Disease Mongering". PLoS medicine, 2006. Archived from the original on 2006-09-01. Retrieved 2007-06-12. ## Further reading[edit] * Conrad, Peter (2007). The Medicalization of Society: On the Transformation of Human Conditions into Treatable Disorders. Baltimore: Johns Hopkins University Press. ISBN 978-0-8018-8585-3. * Dalrymple, Theodore (September 2006). "Forced Smiles". New Criterion. 25. * Day, Michael (29 August 2004). "Doctors' body accuses drug firms of 'disease mongering'". The Daily Telegraph. Archived from the original on 30 August 2004. Retrieved 26 July 2019. * Doran, Evan; Hogue, Clare (2014). "Potency, Hubris, and Susceptibility: The Disease Mongering Critique of Pharmaceutical Marketing" (PDF). Qualitative Report. 19: 78. * Moynihan, R; Henry, D (2006). "The fight against disease mongering: Generating knowledge for action". PLOS Medicine. 3 (4): e191. doi:10.1371/journal.pmed.0030191. PMC 1434508. PMID 16597180. * v * t * e Unnecessary health care Causes * Direct-to-consumer advertising * Overscreening * Overdiagnosis * Fee-for-service * Defensive medicine * Unwarranted variation * Overmedication * Overmedicalization * Prescription cascade * Quaternary prevention * Disease mongering * Political abuse of psychiatry Overused health care * Caesarean delivery on maternal request * Antibiotic misuse * Benzodiazepine use disorder * Effects of long-term benzodiazepine use * Opioid use disorder * Psychoactive drug * Proton-pump inhibitor * Polypharmacy * treatment of incidentaloma Tools and Situations * Deprescribing * Choosing Wisely * Medication discontinuation * Withdrawal syndrome * Antidepressant discontinuation syndrome * Benzodiazepine withdrawal syndrome Works about unnecessary health care * Overtreated * The Treatment Trap * Selling Sickness * Overdosed America [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	Disease mongering	None	2,859	wikipedia	https://en.wikipedia.org/wiki/Disease_mongering	2021-01-18T19:02:39	{"wikidata": ["Q1228633"]}
Group of neurological disorders This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Gray matter heterotopia" – news · newspapers · books · scholar · JSTOR (October 2015) (Learn how and when to remove this template message) MRI of a child experiencing seizures. There are small foci of grey matter heterotopia in the corpus callosum, deep to the dysplastic cortex. (double arrows) Gray matter heterotopias are neurological disorders caused by clumps of gray matter (nodules of neurons) located in the wrong part of the brain.[1] A grey matter heterotopia is characterized as a type of focal cortical dysplasia. The neurons in heterotopia appear to be normal, except for their mislocation; nuclear studies have shown glucose metabolism equal to that of normally positioned gray matter.[2] The condition causes a variety of symptoms, but usually includes some degree of epilepsy or recurring seizures, and often affects the brain's ability to function on higher levels. Symptoms range from nonexistent to profound; the condition is occasionally discovered as an incidentaloma when brain imaging performed for an unrelated problem and has no apparent ill effect on the patient. At the other extreme, heterotopia can result in severe seizure disorder, loss of motor skills, and mental retardation. Fatalities are practically unknown, other than the death of unborn male fetuses with a specific genetic defect. ## Contents * 1 Preliminary Material: Neurological Development of the Human Fetus * 2 Heterotopia * 2.1 Periventricular or subependymal * 2.2 Focal subcortical * 2.3 Band form * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Footnotes * 7 Further reading ## Preliminary Material: Neurological Development of the Human Fetus[edit] The development of the brain in the human fetus is extraordinarily complex and is still not fully understood. Neural matter originates in the outer, ectodermic layer of the gastrula; thus, it originates from the cell layer primarily responsible for skin, hair, nails, etc., rather than from the layers that develop into other internal organs. The nervous system originates as a tiny, simple open tube called the neural tube;[3] the front of this tube develops into the brain (and retinas of the eye), while the spinal cord develops from the very back end. Neurons begin to form early, but most of them become structural rather than active nerve cells. The brain generally forms from the inside-out, especially in the case of the neocortex. The difficulties arising from this are readily apparent, as each successive layer of cells must travel through the previous layer to reach its destination. Therefore, nervous tissue develops ladders made of radial glial cells that neurons climb, through the previous layers, to reach their proper destination. Some destinations, such as the cerebral cortex, even have "placeholder" neurons that travel up the ladder to form a structure; when the final neurons germinate, they find a correct placeholder and then the placeholder cell dies. ## Heterotopia[edit] Further information: Neuronal migration disorder The complexity of neural development makes it fraught with opportunities for error. Grey matter heterotopia[4] is such an example. It is believed that gray matter heterotopia are caused by arrested migration of neurons to the cerebral cortex; that is, when neurons that are supposed to form part of the cerebral cortex.[5] fail to climb to the end of their ladder correctly and are permanently situated in the wrong location. Gray matter heterotopia are common malformations of cortical development classed as neuronal migration disorders. Heterotopias are classed in two groups: nodular and diffuse. Nodular types are subependymal and subcortical; diffuse types are termed band heterotopias. Affected patients are generally divided into three groups, depending on the location of the formation: subependymal, subcortical, and band heterotopia. In addition, especially with heterotopia that are genetically linked, there are gender differences, men suffering more severe symptoms than women with similar formations. In general, band heterotopia, also known as double cortex syndrome,[6] are seen exclusively in women; men with a mutation of the related gene (called XLIS or DCX) usually die in utero or have a much more severe brain anomaly. Symptoms in affected women vary from normal to severe developmental delay or mental retardation; the severity of the syndrome is related to the thickness of the band of arrested neurons. Nearly all affected patients that come to medical attention have epilepsy, with partial complex and atypical absence epilepsy being the most common syndromes. Some of the more severely affected patients develop drop attacks. ### Periventricular or subependymal[edit] Periventricular means beside the ventricle, while subependymal (also spelled subepydymal) means beneath the ependyma; because the ependyma is the thin epithelial sheet lining the ventricles of the brain, these two terms are used to define heterotopia occurring directly next to a ventricle. This is by far the most common location for heterotopia. Patients with isolated subependymal heterotopia usually present with a seizure disorder in the second decade of life. Subependymal heterotopia present in a wide array of variations. They can be a small single node or a large number of nodes, can exist on either or both sides of the brain at any point along the higher ventricle margins, can be small or large, single or multiple, and can form a small node or a large wavy or curved mass. Symptomatic women with subependymal heterotopia typically present with partial epilepsy during the second decade of life; development and neurologic examinations up to that point are typically normal. Symptoms in men with subependymal heterotopia vary, depending on whether their disease is linked to their X-chromosome. Men with the X-linked form more commonly have associated anomalies, which can be neurological or more widespread, and they usually suffer from developmental problems. Otherwise (i.e., in non-X-linked cases) the symptomology is similar in both sexes. ### Focal subcortical[edit] Subcortical heterotopia form as distinct nodes in the white matter, "focal" indicating specific area. In general, patients present fixed neurologic deficits and develop partial epilepsy between the ages of 6 and 10. The more extensive the subcortical heterotopia, the greater the deficit; bilateral heterotopia are almost invariably associated with severe developmental delay or mental retardation. The cortex itself often suffers from an absence of gray matter and may be unusually thin or lack deep sulci. Subependymal heterotopia are frequently accompanied by other structural abnormalities, including an overall decrease in cortical mass. Patients with focal subcortical heterotopia have a variable motor and intellectual disturbance depending on the size and site of the heterotopion. ### Band form[edit] Like focal subcortical heterotopia, "band" heterotopia form in the white matter beneath the cortex, but the gray matter is more diffuse and is symmetric between the hemispheres. On imaging, band heterotopia appears as bands of gray matter situated between the lateral ventricle and cerebral cortex and separated from both by a layer of normal appearing white matter. Band heterotopia may be complete, surrounded by simple white matter, or partial. The frontal lobes seem to be more frequently involved when it is partial. Patients with band heterotopia may present at any age with variable developmental delay and seizure disorder, which vary widely in severity. Subcortical band heterotopia, also known as “double cortex” syndrome, refers to a band of subcortical heterotopia neurons, located midway between the ventricles and the cerebral cortex. The disorder is seen primarily in females and typically causes varying degrees of mental retardation and almost all of them have epilepsy. Approximately two thirds of patients with epilepsy ultimately develop intractable seizures. MRI of the brain in subcortical band heterotopia demonstrates two parallel layers of gray matter: a thin outer ribbon and a thick inner band, separated by a very thin layer of white matter between them. The severity of epilepsy and developmental delay is directly correlated with the degree of migration arrest, as indicated by the thickness of the subcortical band heterotopia. Subcortical band heterotopia is caused by mutations in the microtubule-associated DCX gene. The DCX protein is thought to direct neuronal migration by regulating the organization and stability of microtubules, necessary for neuronal motility. The malformation is seen only in females, as the gene is found on the X-chromosome. Since there are two X chromosomes in females, after X-inactivation, only some neurons lose doublecortin function. These neurons with the mutant DCX gene fail to migrate into the cortex and thus form the underlying heterotopic band, while neurons which express the normal gene successfully migrate out to the cortical plate. Males with DCX mutations develop classical lissencephaly. ## Diagnosis[edit] Detection of heterotopia generally occurs when a patient receives brain imaging—usually an MRI or CT scan—to diagnose seizures that are resistant to medication. Correct diagnosis requires a high degree of radiological skill, due to the heterotopia's resemblance to other masses in the brain. ## Treatment[edit] When seizures are present in any forms of cortical dysplasia, they are resistant to medication. Frontal lobe resection provides significant relief from seizures to a minority of patients with periventricular lesions. ## Prognosis[edit] In general, gray matter heterotopia is fixed in both its occurrence and symptoms; that is, once symptoms occur, it does not tend to progress. Varying results from surgical resection of the affected area have been reported. Although such surgery cannot reverse developmental disabilities, it may provide full or partial relief from seizures. Heterotopia are most commonly isolated anomalies, but may be part of a number of syndromes, including chromosomal abnormalities and fetal exposure to toxins (including alcohol). ## Footnotes[edit] 1. ^ Gaillard, Frank. "Grey matter heterotopia \| Radiology Reference Article \| Radiopaedia.org". Radiopaedia. 2. ^ uhrad.com - Neuroradiology Imaging Teaching Files 3. ^ For a good illustration of the neural tube, see https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=dbio.figgrp.2886 4. ^ "Hetero" is from Greek "different" (e.g., heterosexual = "different sex") and "topia" from "place" (e.g., utopia = "ideal place"); thus, heterotopia means "different place". 5. ^ Many parts of the brain, in addition to the cerebrum, contain grey matter. 6. ^ Gaillard, Frank. "Band heterotopia \| Radiology Reference Article \| Radiopaedia.org". Radiopaedia. ## Further reading[edit] * GeneReviews/NCBI/NIH/UW entry on X-Linked Periventricular Heterotopia * Ferland, Russell J.; Batiz, Luis Federico; Neal, Jason; Lian, Gewei; Bundock, Elizabeth; Lu, Jie; Hsiao, Yi-Chun; Diamond, Rachel; Mei, Davide; Banham, Alison H.; Brown, Philip J.; Vanderburg, Charles R.; Joseph, Jeffrey; Hecht, Jonathan L.; Folkerth, Rebecca; Guerrini, Renzo; Walsh, Christopher A.; Rodriguez, Esteban M.; Sheen, Volney L. (2009). "Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia". Human Molecular Genetics. 18 (3): 497–516. doi:10.1093/hmg/ddn377. PMC 2722192. PMID 18996916. [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	Gray matter heterotopia	c3806556	2,860	wikipedia	https://en.wikipedia.org/wiki/Gray_matter_heterotopia	2021-01-18T18:49:47	{"umls": ["C3806556"], "wikidata": ["Q5598270"]}
Anonychia congenita is a condition that affects the fingernails and toenails. Individuals with this condition are typically missing all of their fingernails and toenails (anonychia). This absence of nails is noticeable from birth (congenital). In some cases, only part of the nail is missing (hyponychia) or not all fingers and toes are affected. All of the other tissues at the tips of the fingers and toes, including structures that usually support the nail and its growth (such as the nail bed), are normal. Individuals with anonychia congenita do not have any other health problems related to the condition. ## Frequency Anonychia congenita is a rare condition; its prevalence is unknown. ## Causes Mutations in the RSPO4 gene cause anonychia congenita. The RSPO4 gene provides instructions for making a protein called R-spondin-4. R-spondin-4 plays a role in the Wnt signaling pathway, a series of steps that affect the way cells and tissues develop. Wnt signaling is important for cell division, attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities. During early development, Wnt signaling plays a critical role in the growth and development of nails. R-spondin-4 is active in the skeleton and contributes to limb formation, particularly at the ends of the fingers and toes where nail development occurs. RSPO4 gene mutations lead to the production of a protein with little or no function. As a result, R-spondin-4 cannot participate in the Wnt signaling pathway and nails develop improperly or not at all. Anonychia congenita can also be part of syndromes that affect multiple parts of the body, including Coffin-Siris syndrome and nail-patella syndrome. When anonychia congenita is part of a syndrome, it is caused by mutations in the gene associated with that syndrome. ### Learn more about the gene associated with Anonychia congenita * RSPO4 ## Inheritance Pattern Anonychia congenita resulting from RSPO4 gene mutations 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 [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	Anonychia congenita	c3277900	2,861	medlineplus	https://medlineplus.gov/genetics/condition/anonychia-congenita/	2021-01-27T08:24:47	{"gard": ["12930"], "omim": ["206800"], "synonyms": []}
This article is about a medical condition. For other uses, see Frostbite (disambiguation). Frostbite Other namesFrostnip Frostbitten toes two to three days after mountain climbing SpecialtyDermatology Emergency medicine, orthopedics SymptomsNumbness, feeling cold, clumsy, pale color[1] ComplicationsHypothermia, compartment syndrome[2][1] TypesSuperficial, deep[2] CausesTemperatures below freezing[1] Risk factorsAlcohol, smoking, mental health problems, certain medications, prior cold injury[1] Diagnostic methodBased on symptoms[3] Differential diagnosisFrostnip, pernio, trench foot[4] PreventionAvoid cold, wear proper clothing, maintain hydration and nutrition, stay active without becoming exhausted[2] TreatmentRewarming, medication, surgery[2] MedicationIbuprofen, tetanus vaccine, iloprost, thrombolytics[1] FrequencyUnknown[5] Frostbite occurs when exposure to low temperatures causes freezing of the skin or other tissues.[1] The initial symptom is typically numbness.[1] This may be followed by clumsiness with a white or bluish color to the skin.[1] Swelling or blistering may occur following treatment.[1] The hands, feet, and face are most commonly affected.[4] Complications may include hypothermia or compartment syndrome.[2][1] People who are exposed to low temperatures for prolonged periods, such as winter sports enthusiasts, military personnel, and homeless individuals, are at greatest risk.[6][1] Other risk factors include drinking alcohol, smoking, mental health problems, certain medications, and prior injuries due to cold.[1] The underlying mechanism involves injury from ice crystals and blood clots in small blood vessels following thawing.[1] Diagnosis is based on symptoms.[3] Severity may be divided into superficial (1st and 2nd degree) or deep (3rd and 4th degree).[2] A bone scan or MRI may help in determining the extent of injury.[1] Prevention is through wearing proper clothing, maintaining hydration and nutrition, avoiding low temperatures, and staying active without becoming exhausted.[2] Treatment is by rewarming.[2] This should be done only when refreezing is not a concern.[1] Rubbing or applying snow to the affected part is not recommended.[2] The use of ibuprofen and tetanus toxoid is typically recommended.[1] For severe injuries iloprost or thrombolytics may be used.[1] Surgery is sometimes necessary.[1] Amputation, however, should generally be delayed for a few months to allow determination of the extent of injury.[2] The number of cases of frostbite is unknown.[5] Rates may be as high as 40% a year among those who mountaineer.[1] The most common age group affected is those 30 to 50 years old.[4] Evidence of frostbite occurring in people dates back 5,000 years.[1] Frostbite has also played an important role in a number of military conflicts.[1] The first formal description of the condition was in 1813 by Dominique Jean Larrey, a physician in Napoleon's army, during its invasion of Russia.[1] ## Contents * 1 Signs and symptoms * 1.1 First degree * 1.2 Second degree * 1.3 Third degree * 1.4 Fourth degree * 2 Causes * 2.1 Risk factors * 3 Mechanism * 3.1 Freezing * 3.2 Rewarming * 3.3 Non-freezing cold injury * 3.4 Pathophysiology * 4 Diagnosis * 5 Prevention * 6 Treatment * 6.1 Rewarming * 6.2 Medications * 6.3 Surgery * 7 Prognosis * 7.1 Grades * 8 Epidemiology * 9 History * 10 Society and culture * 11 Research directions * 12 References * 13 External links ## Signs and symptoms[edit] Frostbite Areas that are usually affected include cheeks, ears, nose and fingers and toes. Frostbite is often preceded by frostnip.[2] The symptoms of frostbite progress with prolonged exposure to cold. Historically, frostbite has been classified by degrees according to skin and sensation changes, similar to burn classifications. However, the degrees do not correspond to the amount of long term damage.[7] A simplification of this system of classification is superficial (first or second degree) or deep injury (third or fourth degree).[8] ### First degree[edit] * First degree frostbite is superficial, surface skin damage that is usually not permanent. * Early on, the primary symptom is loss of feeling in the skin. In the affected areas, the skin is numb, and possibly swollen, with a reddened border. * In the weeks after injury, the skin's surface may slough off.[7] ### Second degree[edit] * In second degree frostbite, the skin develops clear blisters early on, and the skin's surface hardens. * In the weeks after injury, this hardened, blistered skin dries, blackens, and peels. * At this stage, lasting cold sensitivity and numbness can develop.[7] ### Third degree[edit] * In third degree frostbite, the layers of tissue below the skin freeze. * Symptoms include blood blisters and "blue-grey discoloration of the skin".[9][citation needed] * In the weeks after injury, pain persists and a blackened crust (eschar) develops. * There can be longterm ulceration and damage to growth plates. ### Fourth degree[edit] Frostbite 12 days later * In fourth degree frostbite, structures below the skin are involved like muscles, tendon, and bone. * Early symptoms include a colorless appearance of the skin, a hard texture, and painless rewarming. * Later, the skin becomes black and mummified. The amount of permanent damage can take one month or more to determine. Autoamputation can occur after two months.[7] ## Causes[edit] ### Risk factors[edit] The major risk factor for frostbite is exposure to cold through geography, occupation and/or recreation. Inadequate clothing and shelter are major risk factors. Frostbite is more likely when the body's ability to produce or retain heat is impaired. Physical, behavioral, and environmental factors can all contribute to the development of frostbite. Immobility and physical stress (such as malnutrition or dehydration) are also risk factors.[6] Disorders and substances that impair circulation contribute, including diabetes, Raynaud's phenomenon, tobacco and alcohol use.[8] Homeless individuals and individuals with some mental illnesses may be at higher risk.[6] ## Mechanism[edit] ### Freezing[edit] In frostbite, cooling of the body causes narrowing of the blood vessels (vasoconstriction). Temperatures below −4 °C (25 °F) are required to form ice crystals in the tissues.[8] The process of freezing causes ice crystals to form in the tissue, which in turn causes damage at the cellular level. Ice crystals can damage cell membranes directly.[10] In addition, ice crystals can damage small blood vessels at the site of injury.[8] Scar tissue forms when fibroblasts replace the dead cells.[10] ### Rewarming[edit] Rewarming causes tissue damage through reperfusion injury, which involves vasodilation, swelling (edema), and poor blood flow (stasis). Platelet aggregation is another possible mechanism of injury. Blisters and spasm of blood vessels (vasospasm) can develop after rewarming.[8] ### Non-freezing cold injury[edit] The process of frostbite differs from the process of non-freezing cold injury (NFCI). In NFCI, temperature in the tissue decreases gradually. This slower temperature decrease allows the body to try to compensate through alternating cycles of closing and opening blood vessels (vasoconstriction and vasodilation). If this process continues, inflammatory mast cells act in the area. Small clots (microthrombi) form and can cut off blood to the affected area (known as ischemia) and damage nerve fibers. Rewarming causes a series of inflammatory chemicals such as prostaglandins to increase localized clotting.[10] ### Pathophysiology[edit] The pathological mechanism by which frostbite causes body tissue injury can be characterized by four stages: Prefreeze, freeze-thaw, vascular stasis, and the late ischemic stage.[11] 1. Prefreeze phase: involves the cooling of tissues without ice crystal formation.[11] 2. Freeze-thaw phase: ice-crystals form, resulting in cellular damage and death.[11] 3. Vascular stasis phase: marked by blood coagulation or the leaking of blood out of the vessels.[11] 4. Late ischemic phase: characterized by inflammatory events, ischemia and tissue death.[11] ## Diagnosis[edit] Frostbite is diagnosed based on signs and symptoms as described above, and by patient history. Other conditions that can have a similar appearance or occur at the same time include: * Frostnip is similar to frostbite, but without ice crystal formation in the skin. Whitening of the skin and numbness reverse quickly after rewarming. * Trench foot is damage to nerves and blood vessels that results exposure to wet, cold (non-freezing) conditions. This is reversible if treated early. * Pernio or chilblains are inflammation of the skin from exposure to wet, cold (non-freezing) conditions. They can appear as various types of ulcers and blisters.[7] * Bullous pemphigoid is a condition that causes itchy blisters over the body that can mimic frostbite.[12] It does not require exposure to cold to develop. * Levamisole toxicity is a vasculitis that can appear similar to frostbite.[12] It is caused by contamination of cocaine by levamisole. Skin lesions can look similar those of frostbite, but do not require cold exposure to occur. People who have hypothermia often have frostbite as well.[7] Since hypothermia is life-threatening this should be treated first. Technetium-99 or MR scans are not required for diagnosis, but might be useful for prognostic purposes.[13] ## Prevention[edit] The Wilderness Medical Society recommends covering the skin and scalp, taking in adequate nutrition, avoiding constrictive footwear and clothing, and remaining active without causing exhaustion. Supplemental oxygen might also be of use at high elevations. Repeated exposure to cold water makes people more susceptible to frostbite.[14] Additional measures to prevent frostbite include:[2] * Avoiding temperatures below −15 °C (5 °F) * Avoiding moisture, including in the form of sweat and/or skin emollients * Avoiding alcohol and drugs that impair circulation or natural protective responses * Layering clothing * Using chemical or electric warming devices * Recognizing early signs of frostnip and frostbite[2] ## Treatment[edit] Individuals with frostbite or potential frostbite should go to a protected environment and get warm fluids. If there is no risk of re-freezing, the extremity can be exposed and warmed in the groin or underarm of a companion. If the area is allowed to refreeze, there can be worse tissue damage. If the area cannot be reliably kept warm, the person should be brought to a medical facility without rewarming the area. Rubbing the affected area can also increase tissue damage. Aspirin and ibuprofen can be given in the field[6] to prevent clotting and inflammation. Ibuprofen is often preferred to aspirin because aspirin may block a subset of prostaglandins that are important in injury repair.[15] The first priority in people with frostbite should be to assess for hypothermia and other life-threatening complications of cold exposure. Before treating frostbite, the core temperature should be raised above 35 °C. Oral or intravenous (IV) fluids should be given.[6] Other considerations for standard hospital management include: * wound care: blisters can be drained by needle aspiration, unless they are bloody (hemorrhagic). Aloe vera gel can be applied before breathable, protective dressings or bandages are put on. * antibiotics: if there is trauma, skin infection (cellulitis) or severe injury * tetanus toxoid: should be administered according to local guidelines. Uncomplicated frostbite wounds are not known to encourage tetanus. * pain control: NSAIDs or opioids are recommended during the painful rewarming process. ### Rewarming[edit] If the area is still partially or fully frozen, it should be rewarmed in the hospital with a warm bath with povidone iodine or chlorhexidine antiseptic.[6] Active rewarming seeks to warm the injured tissue as quickly as possible without burning. The faster tissue is thawed, the less tissue damage occurs.[16] According to Handford and colleagues, "The Wilderness Medical Society and State of Alaska Cold Injury Guidelines recommend a temperature of 37–39 °C, which decreases the pain experienced by the patient whilst only slightly slowing rewarming time." Warming takes 15 minutes to 1 hour. Rewarming can be very painful, so pain management is important.[6] ### Medications[edit] People with potential for large amputations and who present within 24 hours of injury can be given TPA with heparin.[1] These medications should be withheld if there are any contraindications. Bone scans or CT angiography can be done to assess damage.[17] Blood vessel dilating medications such as iloprost may prevent blood vessel blockage.[6] This treatment might be appropriate in grades 2–4 frostbite, when people get treatment within 48 hours.[17] In addition to vasodilators, sympatholytic drugs can be used to counteract the detrimental peripheral vasoconstriction that occurs during frostbite.[18] A systematic review and metaanalysis revealed that iloprost alone or iloprost plus recombinant tissue plasminogen activator (rtPA) may decrease amputation rate in case of severe frostbite in comparison to buflomedil alone with no major adverse events reported from iloprost or iloprost plus rtPA in the included studies.[19] ### Surgery[edit] Various types of surgery might be indicated in frostbite injury, depending on the type and extent of damage. Debridement or amputation of necrotic tissue is usually delayed unless there is gangrene or systemic infection (sepsis).[6] This has led to the adage "Frozen in January, amputate in July".[20] If symptoms of compartment syndrome develop, fasciotomy can be done to attempt to preserve blood flow.[6] ## Prognosis[edit] 3 weeks after initial frostbite Tissue loss and autoamputation are potential consequences of frostbite. Permanent nerve damage including loss of feeling can occur. It can take several weeks to know what parts of the tissue will survive.[8] Time of exposure to cold is more predictive of lasting injury than temperature the individual was exposed to. The classification system of grades, based on the tissue response to initial rewarming and other factors is designed to predict degree of longterm recovery.[6] ### Grades[edit] Grade 1: if there is no initial lesion on the area, no amputation or lasting effects are expected Grade 2: if there is a lesion on the distal body part, tissue and fingernails can be destroyed Grade 3: if there is a lesion on the intermediate or near body part, autoamputation and loss of function can occur Grade 4: if there is a lesion very near the body (such as the carpals of the hand), the limb can be lost. Sepsis and/or other systemic problems are expected.[6] A number of long term sequelae can occur after frostbite. These include transient or permanent changes in sensation, paresthesia, increased sweating, cancers, and bone destruction/arthritis in the area affected.[21] ## Epidemiology[edit] There is a lack of comprehensive statistics about the epidemiology of frostbite. In the United States, frostbite is more common in northern states. In Finland, annual incidence was 2.5 per 100,000 among civilians, compared with 3.2 per 100,000 in Montreal. Research suggests that men aged 30–49 are at highest risk, possibly due to occupational or recreational exposures to cold.[22] ## History[edit] Frostbite has been described in military history for millennia. The Greeks encountered and discussed the problem of frostbite as early as 400 BCE.[8] Researchers have found evidence of frostbite in humans dating back 5,000 years, in an Andean mummy. Napoleon's Army was the first documented instance of mass cold injury in the early 1800s.[6] According to Zafren, nearly 1 million combatants fell victim to frostbite in the First and Second World Wars, and the Korean War.[8] ## Society and culture[edit] Mountaineer Nigel Vardy in hospital after suffering frostbite when benighted on Denali in 1999. His nose, fingers and toes were subsequently amputated. Several notable cases of frostbite include: Captain Lawrence Oates, an English army captain and Antarctic explorer who in 1912 died of complications of frostbite;[23] noted American rock climber Hugh Herr, who in 1982 lost both legs below the knee to frostbite after being stranded on Mount Washington (New Hampshire) in a blizzard;[24] Beck Weathers, a survivor of the 1996 Mount Everest disaster who lost his nose and hands to frostbite;[25] Scottish mountaineer Jamie Andrew, who in 1999 had all four limbs amputated due to sepsis from frostbite sustained after becoming trapped for four nights whilst climbing Les Droites in the Mont Blanc massif.[26] ## Research directions[edit] Evidence is insufficient to determine whether or not hyperbaric oxygen therapy as an adjunctive treatment can assist in tissue salvage.[27] Cases have been reported, but no randomized control trial has been performed on humans.[28][29][30][31][32] Medical sympathectomy using intravenous reserpine has also been attempted with limited success.[21] Studies have suggested that administration of tissue plasminogen activator (tPa) either intravenously or intra-arterially may decrease the likelihood of eventual need for amputation.[33] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w Handford, C; Thomas, O; Imray, CHE (May 2017). "Frostbite". Emergency Medicine Clinics of North America. 35 (2): 281–299. doi:10.1016/j.emc.2016.12.006. PMID 28411928. 2. ^ a b c d e f g h i j k l m McIntosh, Scott E.; Opacic, Matthew; Freer, Luanne; Grissom, Colin K.; Auerbach, Paul S.; Rodway, George W.; Cochran, Amalia; Giesbrecht, Gordon G.; McDevitt, Marion (2014-12-01). "Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite: 2014 update". Wilderness & Environmental Medicine. 25 (4 Suppl): S43–54. doi:10.1016/j.wem.2014.09.001. ISSN 1545-1534. PMID 25498262. 3. ^ a b Singleton, Joanne K.; DiGregorio, Robert V.; Green-Hernandez, Carol (2014). Primary Care, Second Edition: An Interprofessional Perspective. Springer Publishing Company. p. 172. ISBN 9780826171474. 4. ^ a b c Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 502. ISBN 9780323529570. 5. ^ a b Auerbach, Paul S. (2011). Wilderness Medicine E-Book: Expert Consult Premium Edition - Enhanced Online Features. Elsevier Health Sciences. p. 181. ISBN 978-1455733569. 6. ^ a b c d e f g h i j k l m Handford, Charles; Buxton, Pauline; Russell, Katie; Imray, Caitlin EA; McIntosh, Scott E; Freer, Luanne; Cochran, Amalia; Imray, Christopher HE (2014-04-22). "Frostbite: a practical approach to hospital management". Extreme Physiology & Medicine. 3: 7. doi:10.1186/2046-7648-3-7. ISSN 2046-7648. PMC 3994495. PMID 24764516. 7. ^ a b c d e f "Frostbite Clinical Presentation". emedicine.medscape.com. Archived from the original on 2017-03-02. Retrieved 2017-03-02. 8. ^ a b c d e f g h Zafren, Ken (2013). "Frostbite: Prevention and Initial Management". High Altitude Medicine & Biology. 14 (1): 9–12. doi:10.1089/ham.2012.1114. PMID 23537254. S2CID 3036889. 9. ^ Zonnoor B (29 July 2019). "What are the characteristics of third-degree frostbite?". Medscape. Retrieved 10 May 2020. 10. ^ a b c Sachs, Christoph; Lehnhardt, Marcus; Daigeler, Adrien; Goertz, Ole (2017-03-01). "The Triaging and Treatment of Cold-Induced Injuries". Deutsches Ärzteblatt International. 112 (44): 741–747. doi:10.3238/arztebl.2015.0741. ISSN 1866-0452. PMC 4650908. PMID 26575137. 11. ^ a b c d e McIntosh, SE; Opacic, M; Freer, L; Grissom, CK; Auerbach, PS; Rodway, GW; Cochran, A; Giesbrecht, GG; McDevitt, M; Imray, CH; Johnson, EL; Dow, J; Hackett, PH; Wilderness Medical, Society. (December 2014). "Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite: 2014 update". Wilderness & Environmental Medicine. 25 (4 Suppl): S43-54. doi:10.1016/j.wem.2014.09.001. PMID 25498262. 12. ^ a b "VisualDx - Frostbite". VisualDx. Archived from the original on 2017-03-03. Retrieved 2017-03-03. 13. ^ "Frostbite". us.bestpractice.bmj.com. Archived from the original on 2017-03-04. Retrieved 2017-03-04. 14. ^ Fudge J (2016). "Preventing and Managing Hypothermia and Frostbite Injury". Sports Health. 8 (2): 133–9. doi:10.1177/1941738116630542. PMC 4789935. PMID 26857732. 15. ^ Heil, K; Thomas, R; Robertson, G; Porter, A; Milner, R; Wood, A (March 2016). "Freezing and non-freezing cold weather injuries: a systematic review". British Medical Bulletin. 117 (1): 79–93. doi:10.1093/bmb/ldw001. PMID 26872856. 16. ^ Mistovich, Joseph; Haffen, Brent; Karren, Keith (2004). Prehospital Emergency Care. Upsaddle River, NJ: Pearson Education. p. 506. ISBN 0-13-049288-4. 17. ^ a b "Frostbite". www.uptodate.com. Archived from the original on 2017-03-04. Retrieved 2017-03-03. 18. ^ Sachs, C; Lehnhardt, M; Daigeler, A; Goertz, O (30 October 2015). "The Triaging and Treatment of Cold-Induced Injuries". Deutsches Ärzteblatt International. 112 (44): 741–7. doi:10.3238/arztebl.2015.0741. PMC 4650908. PMID 26575137. 19. ^ Lorentzen, Anne Kathrine; Davis, Christopher; Penninga, Luit (2020-12-20). "Interventions for frostbite injuries". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd012980.pub2. ISSN 1465-1858. 20. ^ Golant, A; Nord, RM; Paksima, N; Posner, MA (Dec 2008). "Cold exposure injuries to the extremities". J Am Acad Orthop Surg. 16 (12): 704–15. doi:10.5435/00124635-200812000-00003. PMID 19056919. 21. ^ a b Marx 2010, p. 1866 harvnb error: no target: CITEREFMarx2010 (help) 22. ^ "Frostbite: Background, Pathophysiology, Etiology". Medscape. Medscape, LLC. 2017-02-02. Archived from the original on 2017-03-02. 23. ^ "British History in depth: The Race to the South Pole". BBC - History. Archived from the original on 2017-02-13. Retrieved 2017-03-04. 24. ^ "Hugh Herr's Best Foot Forward \| Boston Magazine". Boston Magazine. 2009-02-18. Archived from the original on 2017-03-30. Retrieved 2017-03-04. 25. ^ "Beck Weathers Says Fateful Everest Climb Saved His Marriage". PEOPLE. 2015-09-16. Archived from the original on 2017-03-04. Retrieved 2017-03-04. 26. ^ Heawood, Jonathan (2004-03-27). "I'll get there, even if it kills..." The Guardian. ISSN 0261-3077. Archived from the original on 2017-03-04. Retrieved 2017-03-04. 27. ^ Marx 2010 harvnb error: no target: CITEREFMarx2010 (help) 28. ^ Finderle Z, Cankar K (April 2002). "Delayed treatment of frostbite injury with hyperbaric oxygen therapy: a case report". Aviat Space Environ Med. 73 (4): 392–4. PMID 11952063. 29. ^ Folio LR, Arkin K, Butler WP (May 2007). "Frostbite in a mountain climber treated with hyperbaric oxygen: case report". Mil Med. 172 (5): 560–3. doi:10.7205/milmed.172.5.560. PMID 17521112. 30. ^ Gage AA, Ishikawa H, Winter PM (1970). "Experimental frostbite. The effect of hyperbaric oxygenation on tissue survival". Cryobiology. 7 (1): 1–8. doi:10.1016/0011-2240(70)90038-6. PMID 5475096. 31. ^ Weaver LK, Greenway L, Elliot CG (1988). "Controlled Frostbite Injury to Mice: Outcome of Hyperbaric Oxygen Therapy". J. Hyperbaric Med. 3 (1): 35–44. Archived from the original on 10 July 2009. Retrieved 20 June 2008. 32. ^ Ay H, Uzun G, Yildiz S, Solmazgul E, Dundar K, Qyrdedi T, Yildirim I, Gumus T (2005). "The treatment of deep frostbite of both feet in two patients with hyperbaric oxygen". Undersea Hyperb. Med. 32 (1 Suppl). ISSN 1066-2936. OCLC 26915585. Archived from the original on 15 September 2008. Retrieved 30 June 2008. 33. ^ Bruen, KJ; Ballard JR; Morris SE; Cochran A; Edelman LS; Saffle JR (2007). "Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy". Archives of Surgery. 142 (6): 546–51. doi:10.1001/archsurg.142.6.546. PMID 17576891. ## External links[edit] Classification D * ICD-10: T33-T35 * ICD-9-CM: 991.0-991.3 * MeSH: D005627 * DiseasesDB: 31167 External resources * MedlinePlus: 000057 * eMedicine: emerg/209 med/2815 derm/833 ped/803 * Patient UK: Frostbite Wikimedia Commons has media related to Frostbite. Wikivoyage has a travel guide for Travelling in cold weather. * Mayo Clinic * Definition * v * t * e General wounds and injuries Abrasions * Abrasion * Avulsion Blisters * Blood blister * Coma blister * Delayed blister * Edema blister * Fracture blister * Friction blister * Sucking blister Bruises * Hematoma/Ecchymosis * Battle's sign * Raccoon eyes * Black eye * Subungual hematoma * Cullen's sign * Grey Turner's sign * Retroperitoneal hemorrhage Animal bites * Insect bite * Spider bite * Snakebite Other: * Ballistic trauma * Stab wound * Blunt trauma/superficial/closed * Penetrating trauma/open * Aerosol burn * Burn/Corrosion/Chemical burn * Frostbite * Occupational injuries * Traumatic amputation By region * Hand injury * Head injury * Chest trauma * Abdominal trauma * v * t * e Consequences of external causes Temperature Elevated Hyperthermia Heat syncope Reduced Hypothermia Immersion foot syndromes Trench foot Tropical immersion foot Warm water immersion foot Chilblains Frostbite Aerosol burn Cold intolerance Acrocyanosis Erythrocyanosis crurum Radiation Radiation poisoning Radiation burn Chronic radiation keratosis Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Radiation acne Radiation-induced cancer Radiation recall reaction Radiation-induced erythema multiforme Radiation-induced hypertrophic scar Radiation-induced keloid Radiation-induced morphea Air * Hypoxia/Asphyxia * Barotrauma * Aerosinusitis * Decompression sickness * High altitude * Altitude sickness * Chronic mountain sickness * Death zone * HAPE * HACE Food * Starvation Maltreatment * Physical abuse * Sexual abuse * Psychological abuse Travel * Motion sickness * Seasickness * Airsickness * Space adaptation syndrome Adverse effect * Hypersensitivity * Anaphylaxis * Angioedema * Allergy * Arthus reaction * Adverse drug reaction Other * Electrical injury * Drowning * Lightning injuries Ungrouped skin conditions resulting from physical factors * Dermatosis neglecta * Pinch mark * Pseudoverrucous papules and nodules * Sclerosing lymphangitis * Tropical anhidrotic asthenia * UV-sensitive syndrome environmental skin conditions Electrical burn frictional/traumatic/sports Black heel and palm Equestrian perniosis Jogger's nipple Pulling boat hands Runner's rump Surfer's knots Tennis toe Vibration white finger Weathering nodule of ear Wrestler's ear Coral cut Painful fat herniation Uranium dermatosis iv use Skin pop scar Skin track Slap mark Pseudoacanthosis nigricans Narcotic dermopathy [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	Frostbite	c0016736	2,862	wikipedia	https://en.wikipedia.org/wiki/Frostbite	2021-01-18T19:01:01	{"mesh": ["D005627"], "icd-9": ["991.0", "991.3"], "icd-10": ["T33", "T35"], "wikidata": ["Q1350326"]}
A number sign (#) is used with this entry because of evidence that immunodeficiency-27A (IMD27A), an autosomal recessive disorder, is caused by homozygous or compound heterozygous mutation in the IFNGR1 gene (107470) on chromosome 6q23. Immunodeficiency-27B (IMD27B; 615978), an autosomal dominant disorder, is allelic. Description Immunodeficiency-27A results from autosomal recessive (AR) IFNGR1 deficiency. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Plasma from patients with complete AR IFNGR1 deficiency usually contains large amounts of IFNG (147570), and their cells do not respond to IFNG in vitro. In contrast, cells from patients with partial AR IFNGR1 deficiency, which is caused by a specific mutation in IFNGR1, retain residual responses to high IFNG concentrations. Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008). Clinical Features Families with multiple cases of disseminated atypical mycobacteriosis, a rare disorder, were reported by Engbaek (1964) and Uchiyama et al. (1981). Uchiyama et al. (1981) reported fatal disseminated atypical mycobacteriosis in 2 young Mexican-American girls. The atypical mycobacterium was of a different serotype in the 2 sisters. One of the sisters died in 1964 and the other in 1977. Studies by the authors suggested a congenital defect in monocyte microbicidal activity. Fischer et al. (1980) observed defective monocyte function in a 12-month-old child with fatal disseminated BCG infection. Levin et al. (1995) described 6 children with disseminated atypical mycobacterial infection and no recognized form of immunodeficiency. Four, including 2 brothers, came from a village in Malta, and 2 were brothers of Greek Cypriot origin. They presented with fever, weight loss, lymphadenopathy, and hepatosplenomegaly. They had anemia and an acute phase response. A range of different mycobacteria (Mycobacterium fortuitum, M. chelonei, and 4 strains of M. avium intracellulare) were isolated. Treatment with multiple antibiotics failed to eradicate the infection, although treatment with gamma-interferon was associated with improvement. Three of the children had died and the 3 survivors had chronic infection. TNF-alpha (191160) production in response to endotoxin and gamma-interferon was found to be defective in the patients and their parents. T-cell proliferative responses to mycobacterial and recall antigens were reduced in parents of affected children, and gamma-interferon production was diminished in the patients and their parents. Levin et al. (1995) suggested that these patients are phenotypically similar to Lsh/Ity/Bcg susceptible mice (see ANIMAL MODEL). Toyoda et al. (2004) examined the immunologic abnormality of a patient with recurrent Mycobacterium avium infection. The patient had reduced expression of IL12RB1 and IL12RB2 and a decreased ability to produce IFNG (147570) and to proliferate in response to IL12. However, the patient exhibited no deficiency in IL12-induced tyrosine and serine phosphorylation of STAT4 (600558) in mitogen-activated T cells. EMSA, confocal laser microscopy, and Western blot analysis demonstrated that nuclear translocation of STAT4 in response to IL12 was reduced in the patient compared with healthy control subjects. Pharmacologic treatment indicated that the defect was not due to upregulated STAT4 export from the nucleus. No mutations in IL12RB1, IL12RB2, STAT4, or the IFNG STAT4-binding sequence were identified, and the exact mechanism for the defect could not be determined. Diagnosis Fieschi et al. (2001) found that children with complete IFNGR deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNG in their plasma. Fieschi et al. (2001) proposed this measurement as a simple, inexpensive, and accurate diagnostic test for complete IFNGR deficiency. They noted that early identification of such children, who do not respond to exogenous IFNG or antibiotics, may improve management by leading to the consideration of bone marrow transplantation. Molecular Genetics Newport et al. (1996) and Jouanguy et al. (1996) demonstrated that mutations in the interferon-gamma-receptor-1 gene (IFNGR1; 107470) conferred autosomal recessive susceptibility to mycobacterium infection. Al-Muhsen and Casanova (2008) and Cottle (2011) reviewed genetic heterogeneity of susceptibility to mycobacterial disease. Genotype/Phenotype Correlations Dorman et al. (2004) compared the clinical features of recessive and dominant IFNGR1 deficiencies using a worldwide cohort of patients. They assessed the patients by medical histories and genetic and immunologic studies. Recessive deficiency, which Dorman et al. (2004) identified in 22 patients, results in complete loss of cellular response to IFNG and absence of surface IFNGR1 expression. Dominant deficiency, which they identified in 38 patients, is typically due to cytoplasmic domain truncations resulting in accumulation of nonfunctional IFNGR1 proteins that may impede the function of molecules encoded by the wildtype allele, thereby leading to diminished but not absent responsiveness to IFNG. Although the clinical phenotypes are related, Dorman et al. (2004) found that patients with the recessive form had an earlier age of onset (3 vs 13 years), more mycobacterial disease episodes (19 vs 8 per 100 person years of observation), more severe mycobacterial disease (involvement of 4 vs 2 organs), shorter mean disease-free intervals (1.6 vs 7.2 years), and lower Kaplan-Meier survival probability. Recessive patients also had more frequent disease from rapidly growing mycobacteria. Patients with a dominant mutation, however, were more likely to have M. avium complex osteomyelitis, and only dominant patients had osteomyelitis without other organ involvement. Dorman et al. (2004) concluded that there is a strong correlation between the IFNGR1 genotype, clinical disease features, and the cellular responsiveness to IFNG. They suggested that subtle defects in IFNG production, signaling, or related pathways may predispose to diseases caused by virulent mycobacteria, including M. tuberculosis. Animal Model There is a mouse gene, variously symbolized Lsh, Ity, and Bcg, on murine chromosome 1 which encodes resistance to bacterial and parasitic infections and affects the function of macrophages (Skamene et al., 1982; Brown et al., 1982; Goto et al., 1984; Plant et al., 1982; Swanson and O'Brien, 1983; Nickol and Bonventre, 1985). Bcg is expressed in 2 allelic forms, the dominant resistance allele and the recessive susceptibility allele. The Bcg region on proximal mouse chromosome 1 shows homology of synteny with the telomeric portion of human 2q; a 35-cM fragment around the murine Bcg locus (from Col3a1 (120180) to Col6a3 (120250)), has been conserved between the 2 species, the human region being 2q32-q37. History Schurr et al. (1991) studied linkage of genetic markers on distal chromosome 2q with susceptibility to tuberculosis and found a lod score of 2.4. Shaw et al. (1993), however, could not confirm this finding. They performed linkage analysis using a panel of markers from the 2q33-q37 region in 35 multicase families with infection by Mycobacterium leprae, M. tuberculosis, and Leishmania sp. Data from all 3 types of families were pooled to produce a detailed RFLP map of the region. The order of genes in the human was consistent with that determined for the same loci in the mouse. Nonetheless, Shaw et al. (1993) could not demonstrate linkage of infection susceptibility to this region. Newport et al. (1995) excluded NRAMP (600266) as the site of the mutation causing this disorder, which they referred to as familial disseminated atypical mycobacterial infection, in a Maltese kindred. They typed 8 markers in the region of 2q34-q37 where NRAMP maps. INHERITANCE \- Autosomal recessive IMMUNOLOGY \- Increased susceptibility to Mycobacterial infections \- Increased susceptibility to Salmonella infections \- Poor or absent response to gamma-interferon MISCELLANEOUS \- Onset in early childhood \- May be fatal \- Patients may develop disseminated disease after BCG vaccination \- Patients may respond well to treatment with gamma-interferon MOLECULAR BASIS \- Caused by mutation in the interferon-gamma receptor 1 gene (IFNGR1, 107470.0001 ) ▲ 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	IMMUNODEFICIENCY 27A	c2930924	2,863	omim	https://www.omim.org/entry/209950	2019-09-22T16:30:36	{"mesh": ["C535530"], "omim": ["209950"], "orphanet": ["99898", "319569"], "synonyms": ["Alternative titles", "IMMUNODEFICIENCY 27A, MYCOBACTERIOSIS, AUTOSOMAL RECESSIVE", "IFNGR1 DEFICIENCY, AUTOSOMAL RECESSIVE"]}
Anisomastia, or mammary asymmetry, is a common problem in developing adolescent girls. Stratakis et al. (2000) evaluated a 22-year-old female patient who had severe anisomastia (which had been repaired by surgery) associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high-resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STSs) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 (16q12-cen, 66 cM from 16p terminus) and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in 2 maternal (and 1 paternal) copies of that region of chromosome 16. The location was further confirmed by BACs that were obtained from a commercially available library, labeled, and used for FISH studies. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed 2 regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed 1 hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. [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	ANISOMASTIA	c1854013	2,864	omim	https://www.omim.org/entry/605746	2019-09-22T16:11:04	{"mesh": ["C565299"], "omim": ["605746"]}
IgG4-related dacryoadenitis and sialoadenitis (formerly called Mikulicz disease) is an IgG4-related disease characterized by inflammation of the lacrimal glands (which produce tears), parotid glands, and submandibular glands (two of the major salivary glands). In some cases, it also affects other glands or organs. The condition is usually painless, mainly causing mouth and eye dryness, and swelling over the affected glands. When other organs are affected, it can be accompanied by complications such as autoimmune pancreatitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. The underlying cause of IgG4-related disease is still not known. Treatment involves corticosteroids, which are usually effective. Medicines that suppress the immune system (immunosuppressants) may also be used in cases that do not respond to corticosteroids. IgG4-related dacryoadenitis and sialoadenitis was previously considered a subtype of Sjogren syndrome, but it is now known to be a distinct condition. [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	IgG4-related dacryoadenitis and sialadenitis	c0026103	2,865	gard	https://rarediseases.info.nih.gov/diseases/7043/igg4-related-dacryoadenitis-and-sialadenitis	2021-01-18T17:59:48	{"mesh": ["D008882"], "umls": ["C0026103"], "orphanet": ["79078"], "synonyms": ["Mikulicz's disease (former)", "Mikulicz disease (former)", "Mikulicz syndrome (former)", "Chronic dacryoadenitis and sialadenitis"]}
Bronchomalacia Larynx, trachea and bronchi. SpecialtyRespirology Bronchomalacia is a term for weak cartilage in the walls of the bronchial tubes, often occurring in children under six months. Bronchomalacia means 'floppiness' of some part of the bronchi. Patients present with noisy breathing and/or wheezing. There is collapse of a main stem bronchus on exhalation. If the trachea is also involved the term tracheobronchomalacia (TBM) is used. If only the upper airway the trachea is involved it is called tracheomalacia (TM). There are two types of bronchomalacia. Primary bronchomalacia is due to a deficiency in the cartilaginous rings. Secondary bronchomalacia may occur by extrinsic compression from an enlarged vessel, a vascular ring or a bronchogenic cyst. Though uncommon, idiopathic (of unknown cause) tracheobronchomalacia has been described in older adults. ## Contents * 1 Cause * 2 Diagnosis * 2.1 Classification * 2.2 Primary bronchomalacia * 2.3 Secondary bronchomalacia * 3 Treatment * 4 Notes * 5 References * 6 External links ## Cause[edit] Bronchomalacia can best be described as a birth defect of the bronchus in the respiratory tract. Congenital malacia of the large airways is one of the few causes of irreversible airways obstruction in children, with symptoms varying from recurrent wheeze and recurrent lower airways infections to severe dyspnea and respiratory insufficiency. It may also be acquired later in life due to chronic or recurring inflammation resulting from infection or other airway disease.[1][2][3][4][5] ## Diagnosis[edit] ### Classification[edit] * Primary Bronchomalacia * Secondary Bronchomalacia ### Primary bronchomalacia[edit] * Primary Bronchomalacia is classified as congenital. * Primary Bronchomalacia is caused by a deficiency in the cartilaginous rings. * Primary airway malacia was defined as airway malacia in otherwise normal infants.[6] ### Secondary bronchomalacia[edit] * Secondary Bronchomalacia is acquired. * Secondary Bronchomalacia may occur by extrinsic compression from an enlarged vessel, a vascular ring or a bronchogenic cyst. * Secondary airway malacia was defined as airway malacia secondary to esophageal atresia, VATER/VACTERL association (condition with vertebral anomalies, anal atresia, congenital heart disease, tracheoesophageal fistula or esophageal atresia, renourinary anomalies, or radial limb defects), vascular or other external compression of the airways, or specific syndromes. ## Treatment[edit] 1. Time 1. Minimally Invasive, usually in conjunction with Continuous Positive Airflow Pressure. 2. Continuous Positive Airflow Pressure 1. A method of respiratory ventilation. 3. Tracheotomy 1. Surgical procedures on the neck to open a direct airway through an incision in the trachea (the windpipe). 4. Prosthesis 1. Insertion of a prosthesis to keep the bronchial tube open. ## Notes[edit] 1. ^ Carden, KA, Boiselle, PM, Waltz, DA, et al. (2005) Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest 127,984-1005. 2. ^ Clements, B Congenital malformations of the lungs and airways. Taussig, LM Landau, LI eds. Pediatric respiratory medicine 1999,1106-1136 Mosby. St. Louis, MO 3. ^ Austin, J, Ali, T Tracheomalacia and bronchomalacia in children: pathophysiology, assessment, treatment and anaesthesia management. Paediatr Anaesth 2003;13,3-11 4. ^ McNamara, VM, Crabbe, DC Tracheomalacia. Paediatr Respir Rev 2004;5,147-154 5. ^ Carden, K. A.; Boiselle, P. M.; Waltz, D. A.; Ernst, A (2005). "Tracheomalacia and tracheobronchomalacia in children and adults: An in-depth review". Chest. 127 (3): 984–1005. doi:10.1378/chest.127.3.984. PMID 15764786. 6. ^ Benjamin, B Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol 1984;93,438-442 ## References[edit] * Carden, KA, Boiselle, PM, Waltz, DA, et al. (2005) Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest 127,984-1005. * Clements, B Congenital malformations of the lungs and airways. Taussig, LM Landau, LI eds. Pediatric respiratory medicine 1999,1106-1136 Mosby. St. Louis, MO * Austin, J, Ali, T Tracheomalacia and Bronchomalacia in children: pathophysiology, assessment, treatment and anaesthesia management. Paediatr Anaesth 2003;13,3-11 * McNamara, VM, Crabbe, DC Tracheomalacia. Paediatr Respir Rev 2004;5,147-154 * Benjamin, B Tracheomalacia in infants and children. Ann Otol Rhinol Laryngol 1984;93,438-442 ## External links[edit] Classification D * ICD-10: Q32.2 * ICD-9-CM: 748.3 * MeSH: D055091 * SNOMED CT: 54203008 * v * t * e Congenital malformations and deformations of respiratory system (Q30-Q34, 748) Nose Choanal atresia Larynx Laryngocele \- Laryngomalacia Trachea and bronchus Tracheomalacia \- Bronchomalacia Lung Bronchiectasis \- Pulmonary sequestration \- Congenital cystic adenomatoid malformation see also non-congenital (J, 460-519) [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	Bronchomalacia	c0264353	2,866	wikipedia	https://en.wikipedia.org/wiki/Bronchomalacia	2021-01-18T18:52:03	{"mesh": ["D055091"], "umls": ["C0264353"], "icd-9": ["748.3"], "icd-10": ["Q32.2"], "wikidata": ["Q4973832"]}
A Rickettsial disease characterized by malaise and vague symptoms before the onset of high fever, headache, severe myalgias and less commonly petechial rash on the trunk and limbs, nausea, vomiting, coughing and pneumonia. Most patients also have some central nervous system disturbances, such as meningeal irritation, confusion, drowsiness, seizures, coma, and hearing loss. [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	Epidemic typhus	c0041473	2,867	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=83314	2021-01-23T18:44:13	{"mesh": ["D014438"], "umls": ["C0041473"], "icd-10": ["A75.0"]}
A rare ophthalmic disorder characterized by 3 stages: vasculitis, occlusion, and retinal neovascularization, leading to recurrent vitreous hemorrhages and vision loss. ## Epidemiology The prevalence is unknown. The disorder has been reported worldwide but is more commonly observed in the Indian subcontinent where the estimated annual incidence is 1/135-1/200 ophthalmic patients. Males are predominantly affected. Of late, the disease incidence seems to be reducing. ## Clinical description The predominant age of onset is 20-30 years (earlier in Asians). The disorder can appear in adolescence. Eales disease (ED) is characterized by 3 sequential vascular responses that determine the course of the disease: inflammation (peripheral retinal perivasculitis); occlusion (peripheral retinal capillary non-perfusion); and neovascularisation of the retina or disk, which often leads to vitreous hemorrhage. The first 2 stages are generally asymptomatic while vitreous hemorrhage (often sudden and unilateral) is characterized by small specks, floaters, ''cobwebs'' and a decrease in visual acuity (often remission). The fellow eye is affected in 50-90% of cases after a gap of 3-10 years. Recurrences are common. Recurrent bleeds result in tractional retinal detachments, retinal tears, and epimacular membranes. Others may show a mild reduction of vision associated with retinal vasculitis (without vitreous hemorrhage). In addition, headache, variation in peripheral circulation, dyspepsia, chronic constipation, and epistaxis have also been associated with ED. Saxena and Kumar classification is based on visual outcomes and is as follows: Stage 1: periphlebitis of small (1a) and large (1b) calibre vessels with superficial retinal hemorrhages; Stage 2a: capillary non-perfusion, 2b: neovascularization elsewhere/of the disc; Stage 3a: fibrovascular proliferation, 3b: vitreous hemorrhage; Stage 4a: traction/combined rhegmatogenous retinal detachment and 4b: rubeosis iridis, neovascular glaucoma, complicated cataract and optic atrophy. ## Etiology The etiology of ED remains elusive; Several immunological, molecular biological, and biochemical studies have indicated the roles of human leukocyte antigen, retinal S-antigen autoimmunity, Mycobacterium tuberculosis genome, free radical damage, and hyperhomocysteinemia in the pathogenesis of Eales disease. An increase of peptide growth factors like platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, transforming growth factors alpha and bêta, vascular endothelial growth factor, urokinase, metalloprotease enzymes, and a 88 kDa protein has been reported. ## Diagnostic methods Diagnosis is based on fundus fluorescein angiography (FFA) findings that may show early changes such as periphlebitis, vascular sheathing or peripheral nonperfusion and neovascularization. Wide field angiography is useful for the detection of peripheral lesions in the retina. Ultrasonography is needed to rule out associated retinal detachment and ocular coherence tomography (OCT) offers high-resolution imaging of the retina. ## Differential diagnosis Differential diagnosis includes retinopathy of prematurity (ROP) sequelae, familial exudative vitreoretinopathy, sarcoidosis, Behçet disease, sickle cell anemia, Terson syndrome, posttraumatic vitreous hemorrhage, juvenile diabetes and primary branch retinal vein occlusion. ## Management and treatment Management is symptomatic and depends on the stage of the disease. It includes periodic assessment (in the regressed stage of periphlebitis s or fresh vitreous hemorrhage), steroids (periocular injections or systemic) and antitubercular drugs (in the active perivasculitis stage). Laser photocoagulation is used in case of neovascularisation of retina or gross capillary nonperfusion. Vitreous surgery is indicated in non-resolving vitreous hemorrhage (usually > 3 months). Intravitreal anti-VEGF therapy is currently being tested as a definitive therapy for ED. ## Prognosis Isolated episodes of vitreous hemorrhage usually settle down without visual deficit. However, some patients may lose vision significantly due to recurrent episodes of vitreous hemorrhage, macular changes, and tractional or combined retinal detachment involving the macula. Blindness due to ED is rare. There is no known mortality associated with 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	Eales disease	c0271073	2,868	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=40923	2021-01-23T19:06:20	{"gard": ["6309"], "mesh": ["C538011"], "umls": ["C0271073"], "icd-10": ["H35.0"], "synonyms": ["Idiopathic retinal perivasculitis", "Idiopathic retinal vasculitis"]}
A number sign (#) is used with this entry because familial Creutzfeldt-Jakob disease can be caused by mutation in the prion protein gene (PRNP; 176640). Gerstmann-Straussler disease (GSD; 137440) and familial fatal insomnia (FFI; 600072) are 2 other allelic inherited prion diseases caused by mutation in the PRNP gene. Description The human prion diseases occur in inherited, acquired, and sporadic forms. Approximately 15% are inherited and associated with coding mutations in the PRNP gene. Acquired prion diseases include iatrogenic CJD, kuru (245300), variant CJD (vCJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle. Variant CJD is believed to be acquired from cattle infected with BSE. However, the majority of human cases of prion disease occur as sporadic CJD (sCJD) (Collinge et al., 1996; Parchi et al., 2000; Hill et al., 2003). Johnson and Gibbs (1998) provided a comprehensive review of Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. Tyler (2003) described the characteristics of sporadic CJD as encapsulated by C. Miller Fisher in 1960. Clinical Features Jakob et al. (1950) gave a follow-up on the first reported family, in which members of 3 generations may have been affected. Male-to-male transmission was documented. Davidson and Rabiner (1940) described 3 affected sibs. Friede and Dejong (1964) and later May et al. (1968) described an affected father and 3 daughters. Onset was between 38 and 45 years with a short duration of 10 months to 2 years. The disorder began with forgetfulness and nervousness, and progressed to jerky, trembling movements of the hands, loss of facial expression, and unsteady gait. Pathologic findings included severe status spongiosus, diffuse nerve cell degeneration, and some glial proliferation. Rosenthal et al. (1976) reported a family in which 16 members had a neurologic disease ranging from subacute and chronic dementia to various motor system abnormalities without dementia. Inheritance was autosomal dominant. Although the proband had typical CJD with neuropathologic demonstration of spongiform encephalopathy, a first cousin had chronic dementia without spongiform changes. Both patients had PAS-positive, eosinophilic plaques throughout the brain. The authors suggested that susceptibility for neurologic disease in this family was inherited as an autosomal dominant trait. Buge et al. (1978) reported a family in which 8 members spanning 3 generations had CJD. The family originated from southeast England and settled in France in 1870. Cathala et al. (1980) identified a second affected branch of the family reported by Buge et al. (1978), bringing the total number of people affected to 14. The pattern of inheritance was clearly autosomal dominant. Bertoni et al. (1983) reported 7 individuals with CJD in 3 generations of a large kindred. They pointed out that 3 of 4 patients studied in detail were first observed with supranuclear gaze paralysis, gait ataxia, and rapidly progressive dementia. Most of the affected persons were farmers. In a Chilean family, Cartier et al. (1985) described a brother and sister and possibly a third sib who had an unusual form of Creutzfeldt-Jakob disease with prominent ataxia. Brown et al. (1984) found that 5 to 10% of CJD patients had a relatively long course lasting more than 2 years. Of this group, approximately 30% had familial disease. In addition, they had a younger age at onset (average, 48 years), and lower frequency of myoclonus (79%) and periodic EEG activity (45%) than unselected cases. The longest course was 13 years in a case proved by transmissibility. Of 225 transmitted cases, 15 (7%) had a prolonged course. The incubation period and duration of illness after injection into primates bore no relation to the duration of illness in patients. In a consecutive series of 230 patients with neuropathologically verified CJD, Brown et al. (1986) found that men and women were affected about equally with a mean age of onset of 61.5 years. Familial cases accounted for 4 to 8% of the series. Most of the early neurologic symptoms were cerebellar or visual. Extrapyramidal muscular rigidity, myoclonus, and characteristic periodic EEG complexes were observed comparatively late. The median duration of illness was 4 months and the mean was 7.6 months; 90% of patients died within a year of onset. ### Variant Creutzfeldt-Jakob Disease (vCJD) Will et al. (1996) reported a 'new variant' of CJD in the UK. Ten of 270 cases of CJD ascertained in the UK since 1990 had clinical and neuropathologic findings that distinguished them from the other cases. Disease onset in these cases occurred between 1994 and 1995. Age at onset ranged from 16 to 39 years, with a mean of 29 years, and duration ranged from 7.5 to 22.5 months. Nine of the patients had behavioral changes as an early feature and were referred to a psychiatrist. Three patients had dysesthesias as the presenting symptom, 9 developed ataxia early in the disease, 7 developed myoclonus late in the disease course, and 3 had choreoathetosis. All patients eventually developed dementia. None of the cases had EEG features usually associated with CJD. Neuropathologic examination showed spongiform changes, neuronal loss, and gliosis most notably in the basal ganglia and thalamus, although all areas of the cerebral cortex were also affected. All cases had diffuse localization of PrP-positive plaques resembling those seen in kuru. Will et al. (1996) suggested a link between the new variant CJD and bovine spongiform encephalopathy. All 8 cases genotyped were homozygous for the met129 polymorphism in the PRNP gene (176640.0005) and had no other PRNP mutations. Deslys et al. (1997) found that a French patient with new variant CJD first reported by Chazot et al. (1996) had PrP immunostaining and electrophoretic patterns similar to those seen in vCJD patients from the UK, suggesting that vCJD is a unique, and homogeneous, disease variant. In a review of clinical, genetic, neuropathologic, and biochemical data of 23 French patients and 162 British patients with vCJD, Brandel et al. (2009) concluded that almost all data were similar, indicating a common infectious strain. The only difference was age at onset, which was delayed by about 8 years in French patients; disease duration was the same between the 2 populations. All of the 23 French patients and all tested British patients were homozygous for met129. Western blot analysis in the 2 groups of patients showed a type 2B PRNP isoform. The findings suggested that the French vCJD was related to imported contaminated beef products from the UK. Brandel et al. (2009) postulated that the later age of onset and death among French patients resulted from a difference in exposure or dietary habits. ### Heidenhain Variant Heidenhain (1928) reported a variant of sporadic CJD in which patients had prominent early visual symptoms. The term 'Heidenhain variant' has since been used to refer to cases in which visual symptoms occur along with otherwise characteristic features of CJD (Cooper et al., 2005). In a retrospective review of 594 pathologically proven cases of sCJD, Cooper et al. (2005) identified 22 cases with isolated visual symptoms at onset. The mean age at disease onset was 67 years, and the mean illness duration was 4 months. Seventeen (77%) were first referred to an ophthalmologist for symptoms including decreased visual acuity, blurred vision, peripheral visual field defect, visual distortions, and impaired color vision. Two had cataract surgery. Most patients showed myoclonus, pyramidal signs, and a delay in onset of dementia for several weeks. All 16 tested cases were homozygous for met129. Cooper et al. (2005) noted the diagnostic difficulties associated with this group of patients and emphasized the risk of transmission due to ocular intervention before correct diagnosis. Keyrouz et al. (2006) reported a 51-year-old woman who presented with rapidly progressive memory loss, language impairment, and difficulty performing routine activities. She had previously been in a psychiatric ward for visual hallucinations and abnormal behavior. Other features included cortical blindness, spasticity with hyperreflexia, and myoclonic jerks. CSF 14-3-3 protein was increased. She died 4 months later. Keyrouz et al. (2006) concluded that she had the Heidenhain variant of CJD, which was characterized by pronounced hyperintensities in the occipital lobes on diffusion-weighted brain MRI. Other Features Stoeck et al. (2005) observed significantly increased cerebrospinal fluid levels of the antiinflammatory cytokine IL10 (124092) in 20 patients with sporadic CJD compared to patients with other forms of dementia, motoneuron disease, normal pressure hydrocephalus, and normal controls. Patients with CJD also had increased levels of IL4 (147780) compared to patients with motoneuron disease, normal pressure hydrocephalus, and controls, but not compared to other forms of dementia. The findings suggested that these cytokines may modulate the neurodegenerative process in CJD. Pathogenesis Bockman et al. (1985) found that purified fractions from the brains of 2 patients with CJD contained protease-resistant proteins ranging in molecular mass from 10 to 50 kD. These proteins reacted with antibodies raised against the scrapie prion protein PrP 27-30. Rod-shaped particles found in the brain tissue of the patients were similar to those from rodents with either scrapie or experimental CJD. After staining with Congo red dye, the protein polymers from patients with CJD showed green birefringence under polarized light. Bockman et al. (1985) suggested that the amyloid plaques of CJD were paracrystalline arrays of prions similar to those found in scrapie-infected hamsters (DeArmond et al., 1985). Based on their studies in PrP-null mice, Collinge et al. (1994) concluded that prion protein is necessary for normal synaptic function. They postulated that inherited prion disease may result from a dominant-negative effect with generation of PrP(Sc), the posttranslationally modified form of cellular PrPc, ultimately leading to progressive loss of functional PrPc. Miele et al. (2001) demonstrated that a dramatic decrease in expression of a transcript specific to the erythroid lineage cells (EDRF; 605821) is a common feature of transmissible spongiform encephalopathies (TSEs). Miele et al. (2001) suggested a previously unrecognized role for involvement of the erythroid lineage in the etiology of TSE pathogenesis. Head et al. (2003) found that presumptive centrifugal spread of PrP(Sc) from the brain through the optic nerve occurred in both sporadic and variant CJD. Given that routine decontamination might not remove PrP(Sc) from surgical instruments, the authors proposed that a careful risk assessment be made of possible iatrogenic spread of sporadic and variant CJD after surgery on the retina or optic nerve. Zanusso et al. (2003) studied 9 patients with neuropathologically confirmed sporadic CJD and found that PrP(Sc) was present in olfactory cilia and central olfactory pathway, but not in the respiratory mucosa. They concluded that olfactory biopsy may prove diagnostically useful, and that the olfactory pathway may represent a route of infection and a means of spreading prions. Zanusso et al. (2007) reported an atypical case of sCJD associated with a novel prion protein conformation. The patient was a 69-year-old woman with rapid progression of behavioral disturbances and dementia, resulting in akinetic mutism and death approximately 13 months after disease onset. Postmortem examination showed spongiform degeneration, intracellular prion protein deposition, and axonal swellings filled with Prp-positive fibrils. Biochemical analysis detected a novel prion protein tertiary structure, which was predominantly unglycosylated. No mutation in the PRNP gene was found, and all bank voles inoculated with brain suspension from the patient developed disease. Prion incubation periods in experimental animals vary inversely with expression level of cellular prion protein. Sandberg et al. (2011) demonstrated that prion propagation in brain proceeds via 2 distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration that rapidly reaches a maximal prion titer, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrated an uncoupling of infectivity and toxicity. Sandberg et al. (2011) suggested that prions themselves are not neurotoxic but catalyze the formation of such species from PrPC. Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway. ### Variant Creutzfeldt-Jakob Disease (vCJD) Collinge et al. (1996) reported that 'new variant' CJD (vCJD) is associated with the unique and highly consistent appearance of protease-resistant PrP on Western blots involving a characteristic pattern of glycosylation. They also reported that transmission of CJD to inbred mice produced a PrP(Sc) pattern characteristic of the inoculated CJD. Transmission of bovine spongiform encephalopathy (BSE) prion produced a glycoform ratio pattern of PrP closely similar to that of new variant CJD. They found that the PrP(Sc) from experimental BSE in macaques and naturally acquired BSE in domestic cats showed a glycoform pattern indistinguishable from that of experimental murine BSE and new variant CJD. The report of Collinge et al. (1996) was reviewed by Aguzzi and Weissmann (1996), who concluded that Collinge et al. (1996) had provided further evidence that the BSE agent has been transmitted to man. In 3 patients with vCJD, Haik et al. (2003) found pathologic accumulation of PrP(Sc) in neurons of the sympathetic ganglia of the autonomic nervous system, including the celiac, superior mesenteric, and stellate ganglia. No PrP(Sc) was detected in the corresponding ganglia from sporadic or iatrogenic cases of CJD. Consistent with these observations, the Western blot pattern of PrP(Sc) in vCJD showed migration of a 19-kD protein, which is specific to vCJD. Haik et al. (2003) concluded that the sympathetic nervous system is involved in the pathogenesis of vCJD and suggested a role for gut-associated sympathetic neurons in prion propagation after oral contamination. Tyler (2003) reviewed the clinical findings in cases of variant CJD, which differed dramatically from those in sporadic cases. The recognition that patients with new variant CJD have CJD prions in extraneural sites, including lymphoreticular tissues, led to the use of tonsil biopsy as an important diagnostic test. Similarly detectable lymphoreticular reservoirs were not present in sporadic cases of CJD. Inheritance Masters et al. (1979) found that about 15% of CJD cases are familial. From a study of 73 families, Masters et al. (1981) concluded that 15% of cases of CJD have a family history consistent with autosomal dominant transmission. Onset of disease was significantly earlier in familial cases. Temporal and spatial separations between affected relatives suggested that incubation periods ranged at least from 1 to 4 decades. Affected sibs tended to die at the same age and not at the same time. In 4 families, CJD occurred in members related by marriage. Minikel et al. (2014) found no evidence for genetic anticipation among 217 individuals with CJD due to the PRNP E200K mutation (176640.0006). The authors concluded that any reports of anticipation in genetic prion disease result from ascertainment bias. ### Transmission Gibbs et al. (1968) reported a transmissible agent that reproduced CJD in a chimpanzee injected with brain material from a 59-year-old English male with CJD. Ferber et al. (1974) succeeded in transmitting the familial disease to the chimpanzee where the findings were the same as those from transmission of the sporadic disease. One of the families studied by Gajdusek (1973) had 14 affected members. The disease from 1 of these patients was transmitted to the chimpanzee. Zlotnik et al. (1974) transmitted the disease to the squirrel monkey. Haltia et al. (1979) reported on 9 cases in 3 generations of a Finnish family. They raised the possibility of genomic integration of a virus, although in light of subsequent discoveries of transmission via abnormal prion protein, this now seems unlikely (Prusiner and Hsaio, 1994). Transmission through males and occurrence in only one of a pair of twins argued against transplacental passage or transmission via mother's milk. Person-to-person transmission through a corneal transplant was suggested by the experience reported by Duffy et al. (1974). The transmission through cadaver-derived human growth hormone and through transplants, homografts, and surgical instruments was referred to as 'friendly fire' in medicine by Brown et al. (1992). Laurenson et al. (1999) reported a study supporting the hypothesis that surgical procedures may serve as unrecognized contamination events (Collins et al., 1999) and account for a proportion of cases of CJD. Because prions exhibit an unusual resistance to conventional chemical and thermal decontamination methods, surgical instruments must be promptly and effectively cleaned before thermal or chemical disinfections or sterilization. The authors summarized the causes of cleaning failures and proposed effective preventive measures. Brown et al. (1994) tested 15 cases of iatrogenic CJD that represented central infection (from dura mater or corneal homografts and stereotactic EEG electrodes), 11 cases peripherally infected (from native human growth hormone or gonadotropin), and 110 control individuals for the presence of mutations in the chromosome 20 amyloid gene (as that group terms the prion gene). No patient or control had any of the known pathogenic point or insertional mutations found in the familial disease, but allelic homozygosity at the PRNP met129val polymorphism (176640.0005) was present in all but 2 (92%) of the 26 patients, compared with 54 (50%) of the 110 controls (p less than 0.001). Pooled data from all identified and tested cases of iatrogenic disease yielded a worldwide total of 56 patients, of whom all but 4 were homozygous at codon 129 (p less than 0.001). Diagnosis Zerr et al. (2009) assessed the diagnostic accuracy of brain MRI by evaluating 436 patients with sporadic Creutzfeldt-Jakob disease and 141 controls from 12 countries. The optimum diagnostic accuracy in the differential diagnosis of rapidly progressive dementia due to sCJD was obtained when either at least 2 cortical regions (temporal, parietal, or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery (FLAIR) or diffusion-weight imaging (DWI) MRI. These MRI findings were positive in 83% of cases. Zerr et al. (2009) proposed an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include specific brain MRI findings in addition to characteristic periodic sharp wave complexes on EEG and 14-3-3 protein detection in the CSF. In all definite cases, the amended criteria would be positive in 98% of cases. As part of a large prospective study, Lee et al. (2009) analyzed early diffusion MRI scans of 14 patients with CJD due to the E200K mutation (176640.0006), 20 healthy mutation carriers, and 20 controls, and they found that both patients and mutation carriers had significantly reduced diffusion in the thalamostriatal network, comprising the putamen and mediodorsal, ventrolateral, and pulvinar thalamic nuclei. With disease onset, these diffusion reductions intensified but did not spread to other brain regions, except for also affecting the caudate. These findings indicated that cerebral diffusion reductions can be detected early in the course of CJD, even years before symptomatic onset in mutation carriers. In addition, the results suggested that the thalamostriatal network is involved in the pathogenesis of the disease. Molecular Genetics In affected members of a family with inherited Creutzfeldt-Jakob disease, Owen et al. (1989, 1990) identified a 144-bp insertion in the PRNP gene (176640.0001). The insertion coded for 6 extra octanucleotide repeats in the N-terminal region of the protein between codons 51 and 91. In 2 patients with Creutzfeldt-Jakob disease from the same family, Goldgaber et al. (1989) identified a glu200-to-lys (E200K; 176640.0006) substitution. Studying an unusual cluster of cases of CJD in rural Slovakia, Goldfarb et al. (1990) found the E200K mutation in many cases of CJD in rural Slovakia. Goldfarb et al. (1991) identified the E200K mutation in 45 of 55 CJD-affected families studied at the NIH laboratory. The families contained a total of 87 patients and originated from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Jackson et al. (2001) demonstrated a significantly reduced frequency of the HLA class II type DQ7 in British Caucasians with variant Creutzfeldt-Jakob disease, but not in those with classic CJD. Beck et al. (2008) presented evidence that variation in the SPRN gene (610447) may be associated with Creutzfeldt-Jakob disease. Two of 107 patients with variant CJD were found to have a 1-bp insertion in the SPRN gene, which was not identified in 861 controls (p = 0.01). In addition, 2 linked SNPs in the SPRN gene were associated with risk of sporadic CJD (p = 0.009). ### Sporadic Creutzfeldt-Jakob Disease (sCJD) In the UK general population, Palmer et al. (1991) found the frequency of met129 homozygotes to be 37% and val/met129 heterozygotes to be 51%. In contrast, the frequency of met129 homozygotes and val/met129 heterozygotes among patients with sporadic CJD was 83% and 9%, respectively. The authors concluded that homozygosity for met129 confers susceptibility for the development of sporadic CJD. Parchi et al. (1999) delineated 6 subtypes of sCJD according to PrP(Sc) type, PRNP codon 129 genotype (176640.0005), and disease phenotype. Seventy percent of patients showed the classic phenotype, PrP(Sc) type 1, and at least 1 met allele at codon 129. Among 300 cases of sCJD, 71.6% were homozygous for met129, 11.75% were met/val heterozygous, and 16.7% were val homozygous. Prp(Sc) type 1 was identified in 95% of met homozygotes, 3.7% of met/val heterozygotes, and 1.4% of val homozygotes, whereas type 2 was identified in 14% met/met, 31.4% met/val, and 54.6% val/val. The relative proportion of each of the 3 PrP(Sc) glycosylation forms showed significant heterogeneity. Using microarray analysis to examine postmortem frontal cortex from 15 unrelated patients with sCJD, Xiang et al. (2005) identified 79 genes that were upregulated at least 1.5-fold and 275 genes that were downregulated at least 2-fold compared to 5 control brains. In general, upregulated genes included those encoding immune and stress-response factors and elements involved in cell death and cell cycle; downregulated genes included those encoding synaptic proteins. Genotype/Phenotype Correlations ### Sporadic Creutzfeldt-Jakob Disease (sCJD) Molecular subtypes of sCJD, as identified by Parchi et al. (1999), differ in phenotypic disease expression. The most common types, MM1 and MV1 (70%) are characterized by periodic sharp-wave complexes on EEG, increased T2-, fluid attenuated inversion recovery (FLAIR), and diffusion-weighted images (DWI) signals in the basal ganglia, and 14-3-3 protein in the CSF. The second most common type, VV2 (25%), is characterized by ataxia and dementia as presenting features, median survival of 7.5 months, and absence of typical EEG findings. The rarest subtype is VV1 (1.4%) and is characterized by young age at onset, long disease duration, and slowly progressive dementia. The phenotype of VV1 is similar to variant CJD (Meissner et al., 2005). Meissner et al. (2005) reported 9 unrelated German patients, including 8 men and 1 woman, with the rare VV1 subtype of sCJD. None had mutations in the PRNP gene. Mean age at onset was 44 years (range 19 to 55) and median duration of the illness was 21 months (17 to 49 months). The main presenting symptoms included slowly developing dementia and personality changes, including aggression, childish behavior, fear, and paranoia. Two patients had headache in addition to dementia, and 1 had apraxia of the right hand as the first sign. Eight of 9 patients later developed tonus abnormalities, such as rigidity and spasticity, and 5 had either ataxia or myoclonus. Other features included focal neurologic signs, visual and sensory disturbances, hallucinations, seizures, and chorea-ballismus. EEGs showed focal slowing without periodic sharp-wave complexes. All 7 patients imaged showed increased signals in the temporal lobes, followed by the insula and hippocampus, cingulate gyrus, and other lobes. Eight of 9 patients had increased 14-3-3 protein in the CSF, although in 1 patient, the 14-3-3 protein was no longer detectable 14 months after onset. Meissner et al. (2005) emphasized the prolonged course of these patients compared to other CJD patients and noted that suspicion of this form of sCJD disease may occur during a later stage. Population Genetics Creutzfeldt-Jakob disease occurs in unusually high frequency in Chile (Masters et al., 1979). Kahana et al. (1974) described an aggregation of cases among Libyan Jews, a finding that supports the viral or the genetic hypothesis or perhaps both. In a country-wide survey of CJD in Israel, Zilber et al. (1991) diagnosed 114 cases, among them 49 Libyan-born, with onset of disease during the years 1963-1987. After age adjustment, the mean annual incidence rate per million population was 43 among Libyan-born and 0.9 in the rest of the population. Among Jews born in Egypt and Tunisia, countries neighboring Libya, the adjusted rates were higher than in the other Israelis (3.5 and 2.3 per million, respectively). Among Libyan Jews, there was no association between incidence rate of CJD and age at immigration, i.e., duration of exposure to a hypothetical infectious factor in Libya. The percentage of familial cases among Libyan Jews (41 to 47%) is one of the highest known. Kahana et al. (1991) reported that the clinical presentation and evolution of the disease were very similar in patients born in Libya and others without Libyan ancestry but tended to be more classic in the Libyan patients, with higher frequency of myoclonic jerks and periodic EEG and a progressive course of shorter duration. Meiner et al. (1997) reviewed familial Creutzfeldt-Jakob disease with particular reference to the E200K mutation (176640.0006), which is unusually frequent in Libyan Jews. Animal Model Gray tremor (gt) in the mouse is a transmissible spongiform encephalopathy that behaves as an autosomal recessive mutation. It has a complex phenotype including pigmentation defects, tremor, seizures, hypo- and dysmyelination in central and peripheral nervous systems, spongiform encephalopathy, and early death. The heterozygote is phenotypically normal but develops a mild spongiform encephalopathy from 2 months of age onward. Sidman et al. (1985) produced the later-expressed vacuolating disorder in genetically normal mice in transmission experiments. All 7 mice of 3 strains who were allowed to survive for the unusually long interval of 682 to 721 days after intracerebral inoculation of gt/gt brain homogenate in the neonatal period, developed spongiform changes distributed as in the mutant phenotype. In Italy, Casalone et al. (2004) identified a novel form of BSE, which they called bovine amyloidotic spongiform encephalopathy (BASE). In 2 affected cattle, older than other affected bovines, the prion protein glycotype was clearly different from the BSE-associated prion protein molecule, and widespread prion-amyloid plaques were seen in supratentorial brain regions. Unlike typical BSE, the brainstem was less involved and no prion deposition was detected in the dorsal nucleus of the vagus nerve. Strikingly, the molecular signature of this previously undescribed bovine prion protein was similar to that encountered in a distinct subtype of sporadic CJD in humans. Asante et al. (2006) found that transgenic mice expressing human met/val129 and inoculated with type 4 PrP(Sc), which is associated with vCJD, did not develop characteristic vCJD neuropathology. Depending on the source of the inoculum, which was derived from human and bovine prion isolates, the mice developed 4 different disease phenotypes. Mice challenged with vCJD prions had higher rates of infection than BSE-challenged mice. The findings suggested that PRNP 129 heterozygotes may be more susceptible to infection with human-passaged vCJD prions than primary infection with bovine-derived prions. Dossena et al. (2008) generated a transgenic mouse model expressing the mouse homolog of the D178N/M129V mutation (176640.0007). These mice developed clinical and pathologic features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral prion protein deposition, and gliosis. Other features included EEG abnormalities and severe alterations of sleep-wake patterns similar to those observed in human patients. Neurons from the mutant mice showed swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant prion protein, suggesting that ER dysfunction could contribute to the pathology of CJD. The mutant protein was protease-resistant and formed aggregations. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Loss of facial expression NEUROLOGIC Central Nervous System \- Diminished visual activity \- Supranuclear gaze paralysis \- Gait ataxia \- Extrapyramidal muscular rigidity \- Cerebellar signs (more common in variant CJD) \- Memory loss \- Confusion \- Dementia \- Aphasia \- Hemiparesis \- Myoclonus \- Pathology includes spongiform changes, diffuse nerve cell degeneration and glial proliferation \- Brain PrP-immunoreactive amyloid plaques (in 10% if patients with sporadic CJD and in variant CJD) \- Characteristic periodic EEG complexes (only in sporadic and familial CJD, not in variant CJD) Behavioral Psychiatric Manifestations \- Psychiatric abnormalities (more common presentation in variant CJD) \- Depression \- Personality changes \- Irritability \- Anxiety \- Apathy \- Hallucinations \- Delusions LABORATORY ABNORMALITIES \- Normal cerebrospinal fluid \- Occasionally mild elevation of CSF protein MISCELLANEOUS \- Mean age at onset for sporadic CJD is 60 years (range, 50 to 70 years) \- Mean age at onset for variant CJD is 29 years (before age 45 years) \- Rapid progression \- Mean survival 5 months \- Three forms of CJD: acquired (including variant), sporadic, and inherited \- Incidence of all forms of CJD is 0.5 to 1.5 per million per year \- 15% cases are familial \- Most cases are sporadic \- Patients with variant CJD are homozygous for met129 polymorphism ( 176640.0005 ) MOLECULAR BASIS \- Caused by mutations in the prion protein gene (PRNP, 176640.0001 ) ▲ 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	CREUTZFELDT-JAKOB DISEASE	c0022336	2,869	omim	https://www.omim.org/entry/123400	2019-09-22T16:42:47	{"doid": ["11949"], "mesh": ["D007562"], "omim": ["123400"], "icd-9": ["046.11", "046.1"], "icd-10": ["A81.0", "A81.01", "A81.00", "A81.09"], "orphanet": ["204", "454700", "282166"], "synonyms": ["Alternative titles", "CREUTZFELDT-JAKOB DISEASE, FAMILIAL"], "genereviews": ["NBK1229"]}
Singleton et al. (1960) reported a form of dysostosis limited essentially to the tubular bones of the hands and feet. The epiphyses in the fingers are conical with their apex set into the metaphyseal ends of the phalanges (which look like the bottom of wine bottles). The cone-shaped epiphyses in the phalanges with a paucity of signs and symptoms elsewhere is characteristic. Bachman and Norman (1967) reported affected mother and her son and daughter; the mother, aged 47, was 61.5 inches tall, had short fingers, and suffered from severe osteoarthritis of the hips. See 105835 for a reinterpretation of the family reported by Bachman and Norman (1967) as an example of angel-shaped phalango-epiphyseal dysplasia (ASPED). This is probably a heterogeneous category in which one entity, termed acrodysostosis (101800), has the additional features of pug nose, open mouth and prognathism, and mental deficiency. Changes were almost limited to the hands and feet in the patient reported by Cohen and Van Creveld (1963). The facies were characterized by pug nose and sunken bridge but the skull did not suggest achondroplasia. Intelligence was considered normal. Singleton and Siggers (1974) gave a follow-up of the case of Singleton et al. (1960). The appearance of the patient was remarkably like that in the patients with autosomal recessive peripheral dysostosis reported by Goodman et al. (1974). Brooks and Wynne-Davies (1980) reported 2 sisters with diaphyseal aclasis inherited from the father and peripheral dysostosis inherited from the mother. Joints \- Osteoarthritis of hips Limbs \- Short fingers \- Dysostosis of hand and foot tubular bones Radiology \- Conical phalangeal epiphyses 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	PERIPHERAL DYSOSTOSIS	c0220659	2,870	omim	https://www.omim.org/entry/170700	2019-09-22T16:36:26	{"mesh": ["C538179"], "omim": ["170700"], "orphanet": ["1795"], "synonyms": []}
Congenital isolated hyperinsulinism (CHI), a rare endocrine disease is the most frequent cause of severe and persistent hypoglycemia in the neonatal period and early infancy and is characterized by an excessive or uncontrolled insulin secretion (inappropriate for the level of glycemia) and recurrent episodes of profound hypoglycemia requiring rapid and intensive treatment to prevent neurological sequelae. CHI comprises 2 different forms: diazoxide-sensitive diffuse hyperinsulinism and diazoxide-resistant hyperinsulinism (see these terms). ## Epidemiology Prevalence is estimated at 1/50,000 live births, but it may be as high as 1/2,500 in communities with substantial consanguinity. ## Clinical description CHI onset varies from birth through early adulthood. Neonatal onset is the most frequent; newborns, often macrosomic present with poor feeding, intolerance to fasting and persistent hypoglycemia. Hypoglycemic episodes range from mild (lethargy, hypotonia and irritability) to severe and potentially fatal episodes (apnea, seizures or coma) that lead to neurologic sequelae. In late onset CHI, patients generally present with features of hypoglycemia (pallor, profuse sweating and tachycardia). In some forms hypoglycemia may be triggered by anaerobic exercise (exercise-induced hyperinsulinism) or protein rich meals (hyperinsulinism-hyperammonemia syndrome and hyperinsulinism due to 3-hydroxylacyl-CoA dehydrogenase deficiency, see these terms). ## Etiology Nine genes are associated to CHI among which mutations in the genes encoding the ATP-sensitive potassium channel in pancreatic beta cells (ABCC8, KCNJ11) represent the most common defect. ## Diagnostic methods Persistent hypoglycemic episodes (that require intravenous glucose infusion rates of >8 mg/kg/min to maintain normoglycemia) and responsiveness to glucagon are highly indicative of CHI. Detectable serum insulin/C-peptide, low ketone bodies, suppressed fatty acids and suppressed branch chain-amino acids during hypoglycemic episodes (glycemia of <3 mmol/l) all indicate CHI. Later onset CHI may require provocative testing (e.g. oral glucose or leucine loading; formal exercise testing). Cases unresponsive to diazoxide should be classified in to focal and diffuse HI by genetic testing for (ABCC8/ KCNJ11mutations and imaging, particularly DOPA-Positron emission tomography (PET). ## Differential diagnosis Differential diagnosis includes transient hyperinsulinemic hypoglycemia in newborns of mothers with diabetes mellitus or after perinatal stress. Many syndromes present with hypoglycemia: PMM2-CDG and MPI-CDG (congenital disorder of glycosylation Ia and Ib) and the Beckwith-Wiedemann, Perlman, insulin resistance, Sotos, Timothy, Ondine and Usher 1 syndromes. Insulinoma (see these terms) and drug induced hypoglycemia (beta blockers, cibenzoline, and leukocyte growth factors) must be considered in late-onset CHI. ## Antenatal diagnosis Antenatal genetic testing is possible when a proband has been identified. ## Genetic counseling Genetic testing may be offered in affected families when a proband has been identified. ## Management and treatment Normoglycemia must be rapidly recovered and maintained to prevent irreversible brain damage. Acute management includes continuous glucose infusion by a central intravenous along, oral feeding with a glucose polymer and intravenous fluids. In severe cases glucagon may be administered. Diazoxide is the first line of medical therapy and Octreotide is added as an adjunct. Pancreatic resection is offered to focal HI (located by PET); Near-total pancreatectomy may be reserved to patients resistant to diet and medical treatment. Diazoxide responders are assessed for fasting tolerance and then followed carefully to monitor growth and development. ## Prognosis Long term complications include neurological sequelae and in cases of subtotal pancreatectomy, glucose intolerance and diabetes mellitus. [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	Congenital isolated hyperinsulinism	c0027773	2,871	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=657	2021-01-23T18:07:09	{"gard": ["3947"], "mesh": ["D044903", "D046768"], "umls": ["C0027773", "C1257959", "C3888018"], "icd-10": ["E16.1"], "synonyms": ["CHI", "PHHI", "Persistent hyperinsulinemic hypoglycemia of infancy"]}
Dilated cardiomyopathy with hypergonadotropic hypogonadism (DCMHH) is a condition that primarily affects the heart and gonads (male testes or female ovaries). It is characterized by a disease of the heart muscle (dilated cardiomyopathy) and little or no production of sex hormones due to a problem with the pituitary gland or hypothalamus (hypergonadotropic hypogonadism). Other symptoms might include: characteristic facial features, intellectual disability, mild skeletal anomalies, and abnormalities of the metabolic system. Some cases of DCMHH are caused by mutations in the LMNA gene. Both autosomal dominant and autosomal recessive inheritance patterns have been described. Although there is no specific treatment or cure for DCMHH, there are ways to manage the symptoms. A team of doctors or specialists is often needed to figure out the treatment options for 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	Dilated cardiomyopathy with hypergonadotropic hypogonadism	c0796031	2,872	gard	https://rarediseases.info.nih.gov/diseases/3373/dilated-cardiomyopathy-with-hypergonadotropic-hypogonadism	2021-01-18T18:00:52	{"mesh": ["C535703"], "omim": ["212112"], "umls": ["C0796031"], "orphanet": ["2229"], "synonyms": ["Cardiogenital syndrome", "Najjar syndrome", "Malouf syndrome", "Genital anomaly with cardiomyopathy", "Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome"]}
A rare primary bone dysplasia characterized by micromelia with rhizomelic shortening, metaphyseal widening of the long bones, brachydactyly, small scapulae, micrognathia and thoracic insufficiency requiring tracheostomy and ventilation, and severe myopia and sensorineural hearing loss. Further dysmorphic craniofacial features include frontal bossing, proptosis, epicanthal folds, short nose, flat nasal bridge, anteverted nares, midfacial retrusion, and cleft palate. [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	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome	None	2,873	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=440354	2021-01-23T17:05:10	{"synonyms": ["Autosomal dominant myopia-midfacial retrusion-sensorineural deafness-rhizomelic dysplasia syndrome"]}
Hypophosphatemic rickets is a group of genetic diseases characterized by hypophosphatemia, rickets, and normal serum levels of calcium. ## Clinical description Characteristic clinical features include slow growth, bone pain and bone deformities. ## Etiology These diseases comprise the FGF23-dependent forms (X-linked, autosomal dominant, and autosomal recessive hypophosphatemic rickets; see these terms) that are caused by mutations in various genes involved in regulating renal phosphate reabsorption (PHEX, FGF23, DMP1, ENPP1) that induce an elevation in circulating levels of FGF23 and the FGF23-independent forms, such as hereditary hypophosphatemic rickets with hypercalciuria (HHRH; see this term), which is caused by mutations in a gene encoding a sodium-dependent phosphate transporter (SLC34A3). [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	Hypophosphatemic rickets	c1704375	2,874	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=437	2021-01-23T17:14:44	{"gard": ["6735"], "mesh": ["D063730"], "umls": ["C1704375", "C2363065", "C3536983"], "icd-10": ["E83.3"]}
Keratoconus is the degeneration of the structure of the cornea, which is the clear tissue covering the front of the eye. In this condition, the shape of the cornea slowly changes from the normal round shape to a cone shape. Most people who develop keratoconus start out nearsighted, which tends to become worse over time. The earliest symptom is a slight blurring of vision that cannot be corrected with glasses. Over time, there may be eye halos, glare, or other night vision problems.The cause is unknown, but the tendency to develop keratoconus is probably present from birth. Keratoconus is thought to involve a defect in collagen, the tissue that makes up most of the cornea. Some researchers believe that allergy and eye rubbing may play a role. Treatment for keratoconus depends on the severity of your condition and how quickly the condition is progressing. Mild to moderate keratoconus can be treated with eyeglasses or contact lenses. In some people the cornea becomes scarred or wearing contact lenses becomes difficult. In these cases, surgery might be necessary. [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	Keratoconus	c0022578	2,875	gard	https://rarediseases.info.nih.gov/diseases/6824/keratoconus	2021-01-18T17:59:37	{"mesh": ["D007640"], "omim": ["148300"], "umls": ["C0022578"], "orphanet": ["156071"], "synonyms": ["Noninflammatory corneal thining", "KC"]}
A rare tumor characterized by a rapidly growing mass usually arising along the midline, defined by the presence of NUTM1 rearrangements. Histopathological examination shows a poorly differentiated carcinoma, often with evidence of squamous differentiation. Patients present with unspecific signs and symptoms due to mass effect, depending on the location. Extensive local invasion of adjacent structures, lymph node involvement, and distant metastatic disease are often present at the time of diagnosis. Prognosis is generally poor. [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	NUT midline carcinoma	c1707291	2,876	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=443167	2021-01-23T17:52:30	{"icd-10": ["C80.9"], "synonyms": ["NMC"]}
A number sign (#) is used with this entry because of evidence that keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) is caused by homozygous mutation in the POMP gene (613386) on chromosome 13q12. Clinical Features Pujol et al. (1989) described 4 Spanish sibs with an autosomal recessive keratinizing disorder thought to represent an entity that should be classified among congenital syndromes. The most striking feature of the patients' skin was the early appearance of linear hyperkeratosis without evidence of Koebner phenomenon. Vahlquist et al. (1997) described an isolated case of what was thought to be the same disorder, which they referred to as KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma). The 32-year-old patient had a moderate, nonblistering ichthyosis since birth and longstanding palmoplantar keratoderma with pseudoainhum and a sclerosing flexion deformity of the fingers. Longitudinal, noninflamed keratotic striae, which had appeared spontaneously, were seen around his wrists, in the armfolds, and behind the knees. The patient was otherwise physically and mentally healthy and had no history of dental, nail, hair, or mucous membrane problems. The parents were nonconsanguineous, and all 5 of his half sibs were healthy and without skin symptoms. The condition improved on oral etretinate therapy. On light microscopy, the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis. Electron microscopy disclosed numerous large keratohyaline granules in superficial keratinocytes. Vahlquist et al. (1997) suggested that the condition is due to a genetic defect in the formation of keratohyaline granules. Inheritance Vahlquist et al. (1997) suggested that KLICK syndrome is an autosomal recessive disorder. Dahlqvist et al. (2010) confirmed autosomal recessive inheritance of the disorder. Mapping Dahlqvist et al. (2010) performed whole-genome SNP analysis on DNA from 3 Spanish sibs and 3 Swedish sporadic cases with KLICK syndrome and identified a 1.5-Mb homozygous candidate region on chromosome 13q. Microsatellite marker analysis further refined the critical region to an approximately 0.8-Mb interval spanning 10 annotated genes and 2 pseudogenes. Molecular Genetics In 12 patients from 8 European families with KLICK syndrome mapping to chromosome 13q, Dahlqvist et al. (2010) analyzed candidate genes and identified homozygosity for a 1-bp deletion in the POMP gene (613386.0001). Segregation analysis showed that the 6 available parents were heterozygous and the 5 available healthy sibs were either heterozygous or noncarriers for the deletion, which was not found in 280 Swedish control chromosomes. Immunohistochemical staining of patient skin biopsies revealed an altered distribution of POMP and proteasome subunits during formation of the horny layer, suggesting that KILCK syndrome is caused by proteasome insufficiency at a specific stage of epidermal differentiation. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Ichthyosis, congenital, nonblistering \- Linear arrays of macular hyperkeratoses in flexural areas \- Honeycomb palmoplantar keratoderma \- Pseudoainhum Skin Histology \- Acanthosis with hypergranulosis and hyperkeratosis in affected skin \- Parakeratosis \- Mild superficial perivascular lymphohistiocytic infiltrates Electron Microscopy \- Numerous large keratohyaline granules in superficial keratinocytes Nails \- Nail dystrophy with overcurvature MOLECULAR BASIS \- Caused by mutation in the proteasome maturation protein gene (POMP, 613386.0001 ) ▲ 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	KERATOSIS LINEARIS WITH ICHTHYOSIS CONGENITA AND SCLEROSING KERATODERMA	c1866029	2,877	omim	https://www.omim.org/entry/601952	2019-09-22T16:14:09	{"mesh": ["C566600"], "omim": ["601952"], "orphanet": ["281201"], "synonyms": ["Alternative titles", "KLICK SYNDROME"]}
Secondary hypertension SpecialtyCardiology, nephrology Secondary hypertension (or, less commonly, inessential hypertension) is a type of hypertension which by definition is caused by an identifiable underlying primary cause. It is much less common than the other type, called essential hypertension, affecting only 5-10% of hypertensive patients. It has many different causes including endocrine diseases, kidney diseases, and tumors. It also can be a side effect of many medications. ## Contents * 1 Types * 1.1 Kidney * 1.1.1 Renovascular hypertension * 1.1.2 Kidney * 1.1.3 Hypertension secondary to other renal disorders * 1.2 Hypertension secondary to endocrine disorders * 1.2.1 Adrenal * 1.3 Other secondary hypertension * 1.4 Medication side effects * 1.5 Pregnancy * 1.6 Sleep disturbances * 1.7 Arsenic exposure * 1.8 Potassium deficiency * 2 Diagnosis * 3 References * 4 External links ## Types[edit] ### Kidney[edit] #### Renovascular hypertension[edit] It has two main causes: fibromuscular dysplasia and atherosclerosis of the renal artery resulting in stenosis. * See main article at Renovascular hypertension. #### Kidney[edit] Other well known causes include diseases of the kidney. This includes diseases such as polycystic kidney disease which is a cystic genetic disorder of the kidneys, PKD, which is characterized by the presence of multiple cysts (hence, "polycystic") in both kidneys, can also damage the liver, pancreas, and rarely, the heart and brain.[1][2][3][4] It can be autosomal dominant or autosomal recessive, with the autosomal dominant form being more common and characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts, with concurrent development of hypertension, chronic kidney disease and kidney pain.[5] Or chronic glomerulonephritis which is a disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys.[6][7][8] Hypertension can also be produced by diseases of the renal arteries supplying the kidney. This is known as renovascular hypertension; it is thought that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin–angiotensin system.[9][10][11] Also, some renal tumors can cause hypertension. The differential diagnosis of a renal tumor in a young patient with hypertension includes Juxtaglomerular cell tumor, Wilms' tumor, and renal cell carcinoma, all of which may produce renin.[12] #### Hypertension secondary to other renal disorders[edit] * Chronic kidney disease * Kidney disease / renal artery stenosis – the normal physiological response to low blood pressure in the renal arteries is to increase cardiac output (CO) to maintain the pressure needed for glomerular filtration. Here, however, increased CO cannot solve the structural problems causing renal artery hypotension, with the result that CO remains chronically elevated. * Renal segmental hypoplasia (Ask-Upmark kidney) ### Hypertension secondary to endocrine disorders[edit] * Neurogenic hypertension – excessive secretion of norepinephrine and epinephrine which promotes vasoconstriction resulting from chronic high activity of the sympathoadrenal system, the sympathetic nervous system and the adrenal gland. The specific mechanism involved is increased release of the "stress hormones", epinephrine (adrenaline) and norepinephrine which increase blood output from the heart and constrict arteries. People with neurogenic hypertension respond poorly to treatment with diuretics as the underlying cause of their hypertension is not addressed.[13] * Pheochromocytoma – a tumor which results in an excessive secretion of norepinephrine and epinephrine which promotes vasoconstriction * Hyperaldosteronism (Conn's syndrome) – idiopathic hyperaldosteronism, liddle's syndrome (also called pseudoaldosteronism), glucocorticoid remediable aldosteronism * Cushing's syndrome – an excessive secretion of glucocorticoids causes the hypertension * Hyperparathyroidism * Acromegaly * Hyperthyroidism * Hypothyroidism #### Adrenal[edit] A variety of adrenal cortical abnormalities can cause hypertension, In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.[14] Congenital adrenal hyperplasia, a group of autosomal recessive disorders of the enzymes responsible for steroid hormone production, can lead to secondary hypertension by creating atypically high levels of mineralocorticoid steroid hormones. These mineralocorticoids cross-react with the aldosterone receptor, activating it and raising blood pressure. * 17 alpha-hydroxylase deficiency causes an inability to produce cortisol. Instead, extremely high levels of the precursor hormone corticosterone are produced, some of which is converted to 11-Deoxycorticosterone (DOC), a potent mineralocorticoid not normally clinically important in humans. DOC has blood-pressure raising effects similar to aldosterone, and abnormally high levels result in hypokalemic hypertension.[15] * 11β-hydroxylase deficiency, aka apparent mineralocorticoid excess syndrome, involves a defect in the gene for 11β-hydroxysteroid dehydrogenase, an enzyme that normally inactivates circulating cortisol to the less-active metabolite cortisone.[16] At high concentrations cortisol can cross-react and activate the mineralocorticoid receptor, leading to aldosterone-like effects in the kidney, causing hypertension.[17] This effect can also be produced by prolonged ingestion of liquorice (which can be of potent strength in liquorice candy), by causing inhibition of the 11β-hydroxysteroid dehydrogenase enzyme and likewise leading to secondary apparent mineralocorticoid excess syndrome.[18][19][20] Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present.[19] Cortisol induced hypertension cannot be completely explained by the activity of Cortisol on Aldosterone receptors. Experiments show that treatment with Spironolactone (an inhibitor of the aldosterone receptor), does not prevent hypertension with excess cortisol. It seems that inhibition of nitric oxide synthesis may also play a role in cortisol induced hypertension.[21] Yet another related disorder causing hypertension is glucocorticoid remediable aldosteronism, which is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient, causing of primary hyperaldosteronism, the Gene mutated will result in an aldosterone synthase that is ACTH-sensitive, which is normally not.[22][23][24][25][26] GRA appears to be the most common monogenic form of human hypertension.[27] Compare these effects to those seen in Conn's disease, an adrenocortical tumor which causes excess release of aldosterone,[28] that leads to hypertension.[29][30][31] Another adrenal related cause is Cushing's syndrome which is a disorder caused by high levels of cortisol. Cortisol is a hormone secreted by the cortex of the adrenal glands. Cushing's syndrome can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH).[32] More than 80% of patients with Cushing's syndrome develop hypertension.,[33] which is accompanied by distinct symptoms of the syndrome, such as central obesity, lipodystrophy, moon face, sweating, hirsutism and anxiety.[34] Neuroendocrine tumors are also a well known cause of secondary hypertension. Pheochromocytoma[35] (most often located in the adrenal medulla) increases secretion of catecholamines such as epinephrine and norepinephrine, causing excessive stimulation of adrenergic receptors, which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid). ### Other secondary hypertension[edit] * Hormonal contraceptives * Neurologic disorders * Obstructive sleep apnea * Liquorice (when consumed in excessive amounts) * Scleroderma * Neurofibromatosis * Pregnancy: unclear cause. * Cancers: tumours in the kidney can operate in the same way as kidney disease. More commonly, however, tumors cause inessential hypertension by ectopic secretion of hormones involved in normal physiological control of blood pressure. * Drugs: In particular, alcohol, nasal decongestants with adrenergic effects, NSAIDs, MAOIs, adrenoceptor stimulants, and combined methods of hormonal contraception (those containing ethinylestradiol) can cause hypertension while in use. * Heavy alcohol use * Steroid use * Nicotine use.[36] * Malformed aorta, slow pulse, ischemia: these cause reduced blood flow to the renal arteries, with physiological responses as already outlined. * Coarctation of the aorta * Atherosclerosis * Anemia: unclear cause. * Fever: unclear cause. * White coat hypertension, that is, elevated blood pressure in a clinical setting but not in other settings, probably due to the anxiety some people experience during a clinic visit. * Perioperative hypertension is development of hypertension just before, during or after surgery. It may occur before surgery during the induction of anesthesia; intraoperatively e.g. by pain-induced sympathetic nervous system stimulation; in the early postanesthesia period, e.g. by pain-induced sympathetic stimulation, hypothermia, hypoxia, or hypervolemia from excessive intraoperative fluid therapy; and in the 24 to 48 hours after the postoperative period as fluid is mobilized from the extravascular space. In addition, hypertension may develop perioperatively because of discontinuation of long-term antihypertensive medication.[37] ### Medication side effects[edit] Certain medications, including NSAIDs (Motrin/Ibuprofen) and steroids can cause hypertension.[38][39][40][41][42] Other medications include extrogens (such as those found in oral contraceptives with high estrogenic activity), certain antidepressants (such as venlafaxine), buspirone, carbamazepine, bromocriptine, clozapine, and cyclosporine.[36] High blood pressure that is associated with the sudden withdrawal of various antihypertensive medications is called rebound hypertension.[43][44][45][46][47][48][49] The increases in blood pressure may result in blood pressures greater than when the medication was initiated. Depending on the severity of the increase in blood pressure, rebound hypertension may result in a hypertensive emergency. Rebound hypertension is avoided by gradually reducing the dose (also known as "dose tapering"), thereby giving the body enough time to adjust to reduction in dose. Medications commonly associated with rebound hypertension include centrally-acting antihypertensive agents, such as clonidine[50] and methyl-dopa.[49] Other herbal or "natural products" which have been associated with hypertension include ma huang, St John's wort, and licorice.[36] ### Pregnancy[edit] Few women of childbearing age have high blood pressure, up to 11% develop hypertension of pregnancy.[51] While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary.[52][53] ### Sleep disturbances[edit] Another common and under-recognized cause of hypertension is sleep apnea,[54][55] which is often best treated with nocturnal nasal continuous positive airway pressure (CPAP), but other approaches include the Mandibular advancement splint (MAS), UPPP, tonsillectomy, adenoidectomy, septoplasty, or weight loss. Another cause is an exceptionally rare neurological disease called Binswanger's disease, causing dementia; it is a rare form of multi-infarct dementia, and is one of the neurological syndromes associated with hypertension.[56] ### Arsenic exposure[edit] Because of the ubiquity of arsenic in ground water supplies and its effect on cardiovascular health, low dose arsenic poisoning should be inferred as a part of the pathogenesis of idiopathic hypertension. Idiopathic and essential are both somewhat synonymous with primary hypertension. Arsenic exposure has also many of the same signs of primary hypertension such as headache, somnolence, [57] confusion, proteinuria [58] visual disturbances, and nausea and vomiting [59] ### Potassium deficiency[edit] Due to the role of intracellular potassium in regulation of cellular pressures related to sodium, establishing potassium balance has been shown to reverse hypertension. [60] ## Diagnosis[edit] The ABCDE mnemonic can be used to help determine a secondary cause of hypertension * A: Accuracy, Apnea, Aldosteronism * B: Bruits, Bad Kidney * C: Catecholamines, Coarctation of the Aorta, Cushing's Syndrome * D: Drugs, Diet * E: Erythropoietin, Endocrine Disorders [61] ## References[edit] 1. ^ Ecder T, Schrier RW (April 2009). "Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease". Nature Reviews Nephrology. 5 (4): 221–28. doi:10.1038/nrneph.2009.13. PMC 2720315. PMID 19322187. 2. ^ Gross P (May 2008). "Polycystic kidney disease: will it become treatable?". Polskie Archiwum Medycyny Wewnȩtrznej. 118 (5): 298–301. PMID 18619180. Retrieved 19 June 2009. 3. ^ Masoumi A, Reed-Gitomer B, Kelleher C, Schrier RW (2007). "Potential pharmacological interventions in polycystic kidney disease". Drugs. 67 (17): 2495–510. doi:10.2165/00003495-200767170-00004. PMID 18034588. S2CID 7041761. 4. ^ Chapman AB (May 2007). "Autosomal dominant polycystic kidney disease: time for a change?". Journal of the American Society of Nephrology. 18 (5): 1399–407. doi:10.1681/ASN.2007020155. PMID 17429048. Retrieved 19 June 2009. 5. ^ Chapman AB (July 2008). "Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies". Clinical Journal of the American Society of Nephrology. 3 (4): 1197–204. doi:10.2215/CJN.00060108. PMID 18579674. Retrieved 19 June 2009. 6. ^ Berthoux FC, Mohey H, Afiani A (January 2008). "Natural history of primary IgA nephropathy". 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"The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA. 289 (19): 2560–72. doi:10.1001/jama.289.19.2560. PMID 12748199. 37. ^ Varon J, Marik PE (2008). "Perioperative hypertension management". Vasc Health Risk Manag. 4 (3): 615–27. doi:10.2147/VHRM.S2471. PMC 2515421. PMID 18827911. 38. ^ Simone Rossi, ed. (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 978-0-9757919-2-9.[page needed] 39. ^ White WB (May 2009). "Defining the problem of treating the patient with hypertension and arthritis pain". The American Journal of Medicine. 122 (5 Suppl): S3–9. doi:10.1016/j.amjmed.2009.03.002. PMID 19393824. 40. ^ Mackenzie IS, Rutherford D, MacDonald TM (2008). "Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis". 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Retrieved 2 December 2007.CS1 maint: uses authors parameter (link) ## External links[edit] Classification D * ICD-10: I15 * ICD-9-CM: 405 * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension [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	Secondary hypertension	c0155616	2,878	wikipedia	https://en.wikipedia.org/wiki/Secondary_hypertension	2021-01-18T19:08:55	{"umls": ["C0155616"], "wikidata": ["Q987319"]}
Megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13) is a rare subtype of acute myeloid leukemia with recurrent cytogenetic abnormalities characterized by clonal proliferation of myeloid blasts with predominantly megakaryoblastic differentiation in the bone marrow and blood, often with extensive infiltration of the abdominal organs. It occurs typically in infants and usually presents with hepatosplenomegaly, anemia, thrombocytopenia and nonspecific symptoms related to ineffective hematopoiesis (fatigue, bleeding and bruising, recurrent infections). Myelofibrosis and fibrosis of other infiltrated organs is also characteristic of this 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	Megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13)	c4706584	2,879	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=402023	2021-01-23T17:48:35	{"icd-10": ["C94.2"], "synonyms": ["Megakaryoblastic AML with t(1;22)(p13;q13)"]}
A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 54-61 years, progressive Alzheimer's disease-like dementia, and absence of intracerebral hemorrhages. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels. [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	ABeta amyloidosis, Arctic type	c2931672	2,880	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324723	2021-01-23T19:00:22	{"mesh": ["C537944"], "omim": ["605714"], "icd-10": ["E85.4+", "I68.0*"], "synonyms": ["ABetaE22G amyloidosis", "HCHWA, Arctic type", "Hereditary cerebral hemorrhage with amyloidosis, Arctic type"]}
Macroorchidism SpecialtyUrology This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (December 2013) (Learn how and when to remove this template message) Macroorchidism is a disorder found in males where a subject has abnormally large testes. The condition is commonly inherited in connection with fragile X syndrome, which is also the second most common genetic cause of intellectual disability. The opposite side of the spectrum is called microorchidism, which is the condition of abnormally small testes. Other possible causes of macroorchidism are long-standing primary hypothyroidism, adrenal remnants in congenital adrenal hyperplasia, follicle stimulating hormone (FSH)-secreting pituitary macroadenomas, local tumors, lymphomas, or aromatase deficiency.[1] ## References[edit] 1. ^ Álvarez-Acevedo García, M.; Molina Rodríguez, M.aA.; González Casado, I.; Nistal Martín De Serrano, M.; Gracia Bouthelier, R. (2006). "Macroorquidismo: A propósito de un caso" [Macroorchidism: a case report]. Anales de Pediatría (in Spanish). 64 (1): 89–92. doi:10.1016/S1695-4033(06)70015-7. PMID 16539923. ## Further reading[edit] * Definition from the National Library of Medicine ## External links[edit] Classification D * DiseasesDB: 27460 This article about a disease of the genitourinary system 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	Macroorchidism	c1263023	2,881	wikipedia	https://en.wikipedia.org/wiki/Macroorchidism	2021-01-18T18:38:06	{"umls": ["C1263023"], "wikidata": ["Q6725487"]}
Condition in which a patient is aware but completely paralysed Locked-in syndrome Other namesCerebromedullospinal disconnection,[1] de-efferented state, pseudocoma,[2] ventral pontine syndrome Locked-in syndrome can be caused by a stroke at the level of the basilar artery denying blood to the pons, among other causes. SpecialtyNeurology, Psychiatry Locked-in syndrome (LIS), also known as pseudocoma, is a condition in which a patient is aware but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for vertical eye movements and blinking. The individual is conscious and sufficiently intact cognitively to be able to communicate with eye movements.[3] Electroencephalography results are normal in locked-in syndrome. Total locked-in syndrome, or completely locked-in state (CLIS), is a version of locked-in syndrome wherein the eyes are paralyzed as well.[4] Fred Plum and Jerome Posner coined the term for this disorder in 1966.[5][6] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Similar conditions * 4 Treatment * 5 Prognosis * 6 Research * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Locked-in syndrome is usually characterized by quadriplegia and the inability to speak in otherwise cognitively intact individuals. Those with locked-in syndrome may be able to communicate with others through coded messages by blinking or moving their eyes, which are often not affected by the paralysis. The symptoms are similar to those of sleep paralysis. Patients who have locked-in syndrome are conscious and aware, with no loss of cognitive function. They can sometimes retain proprioception and sensation throughout their bodies. Some patients may have the ability to move certain facial muscles, and most often some or all of the extraocular muscles. Individuals with the syndrome lack coordination between breathing and voice.[7] This prevents them from producing voluntary sounds, though the vocal cords may not be paralysed.[7] ## Causes[edit] In children, the most common cause is a stroke of the ventral pons.[8] Unlike persistent vegetative state, in which the upper portions of the brain are damaged and the lower portions are spared, locked-in syndrome is caused by damage to specific portions of the lower brain and brainstem, with no damage to the upper brain.[citation needed] Possible causes of locked-in syndrome include: * Poisoning cases – More frequently from a krait bite and other neurotoxic venoms, as they cannot usually cross the blood–brain barrier[citation needed] * Brainstem stroke[citation needed] * Diseases of the circulatory system * Medication overdose[examples needed] * Damage to nerve cells, particularly destruction of the myelin sheath, caused by disease or osmotic demyelination syndrome (formerly designated central pontine myelinolysis) secondary to excessively rapid correction of hyponatremia [>1 mEq/L/h])[9] * A stroke or brain hemorrhage, usually of the basilar artery[citation needed] * Traumatic brain injury[citation needed] * Result from lesion of the brain-stem Curare poisoning mimics a total locked-in syndrome by causing paralysis of all voluntarily controlled skeletal muscles.[10] The respiratory muscles are also paralyzed, but the victim can be kept alive by artificial respiration, such as mouth-to-mouth resuscitation. In a study of 29 army volunteers who were paralyzed with curare, artificial respiration kept oxygen saturation above 85%,[11] a level at which there is no evidence of altered state of consciousness.[12] Spontaneous breathing is resumed after the end of the duration of action of curare, which is generally between 30 minutes[13] and eight hours,[14] depending on the variant of the toxin and dosage. ## Diagnosis[edit] Locked-in syndrome can be difficult to diagnose. In a 2002 survey of 44 people with LIS, it took almost three months to recognize and diagnose the condition after it had begun.[15] Locked-in syndrome may mimic loss of consciousness in patients, or, in the case that respiratory control is lost, may even resemble death. People are also unable to actuate standard motor responses such as withdrawal from pain; as a result, testing often requires making requests of the patient such as blinking or vertical eye movement.[citation needed] Brain imaging may provide additional indicators of locked-in syndrome, as brain imaging provides clues as to whether or not brain function has been lost. Additionally, an EEG can allow the observation of sleep-wake patterns indicating that the patient is not unconscious but simply unable to move.[16] ### Similar conditions[edit] * Amyotrophic lateral sclerosis (ALS) * Bilateral brainstem tumors * Brain death (of the whole brain or the brain stem or other part) * Coma (deep or irreversible) * Guillain–Barré syndrome * Myasthenia gravis * Poliomyelitis * Polyneuritis * Vegetative state (chronic or otherwise) ## Treatment[edit] Neither a standard treatment nor a cure is available. Stimulation of muscle reflexes with electrodes (NMES) has been known to help patients regain some muscle function. Other courses of treatment are often symptomatic.[17] Assistive computer interface technologies such as Dasher, combined with eye tracking, may be used to help people with LIS communicate with their environment.[citation needed] ## Prognosis[edit] It is extremely rare for any significant motor function to return. The majority of locked-in syndrome patients do not regain motor control. However, some people with the condition continue to live much longer,[18][19] while in exceptional cases, like that of Kerry Pink,[20] Gareth Shepherd,[21] Jacob Haendel[22] and Kate Allatt[23] a full spontaneous recovery may be achieved. ## Research[edit] New brain-computer interfaces (BCIs) may provide future remedies. One effort in 2002 allowed a fully locked-in patient to answer yes-or-no questions.[24][25] In 2006, researchers created and successfully tested a neural interface which allowed someone with locked-in syndrome to operate a web browser.[26] Some scientists have reported that they have developed a technique that allows locked-in patients to communicate via sniffing.[27] ## See also[edit] * Akinetic mutism * List of people with locked-in syndrome * The Diving Bell and the Butterfly: memoirs of journalist Jean-Dominique Bauby about his life with the condition ## References[edit] 1. ^ Nordgren RE, Markesbery WR, Fukuda K, Reeves AG (1971). "Seven cases of cerebromedullospinal disconnection: the "locked-in" syndrome". Neurology. 21 (11): 1140–8. doi:10.1212/wnl.21.11.1140. PMID 5166219. 2. ^ Flügel KA, Fuchs HH, Druschky KF (1977). "The "locked-in" syndrome: pseudocoma in thrombosis of the basilar artery (author's trans.)". Dtsch. Med. Wochenschr. (in German). 102 (13): 465–70. doi:10.1055/s-0028-1104912. PMID 844425. 3. ^ Duffy, Joseph. motor speech disorders substrates, differential diagnosis, and management. Elsevier. p. 295. 4. ^ Bauer, G.; Gerstenbrand, F. & Rumpl, E. (1979). "Varieties of the locked-in syndrome". Journal of Neurology. 221 (2): 77–91. doi:10.1007/BF00313105. PMID 92545. 5. ^ Agranoff, Adam B. "Stroke Motor Impairment". eMedicine. Retrieved 2007-11-29. 6. ^ Plum, F; Posner, JB (1966), The diagnosis of stupor and coma, Philadelphia, PA, USA: FA Davis, 197 pp. 7. ^ a b Fager, Susan; Beukelman, Dave; Karantounis, Renee; Jakobs, Tom (2006). "Use of safe-laser access technology to increase head movements in persons with severe motor impairments: a series of case reports". Augmentative and Alternative Communication. 22 (3): 222–29. doi:10.1080/07434610600650318. PMID 17114165. 8. ^ Bruno MA, Schnakers C, Damas F, et al. (October 2009). "Locked-in syndrome in children: report of five cases and review of the literature". Pediatr. Neurol. 41 (4): 237–46. doi:10.1016/j.pediatrneurol.2009.05.001. PMID 19748042. 9. ^ Aminoff, Michael (2015). Clinical Neurology (9nth ed.). Lange. p. 76. ISBN 978-0-07-184142-9. 10. ^ Page 357 in: Damasio, Antonio R. (1999). The feeling of what happens: body and emotion in the making of consciousness. San Diego: Harcourt Brace. ISBN 978-0-15-601075-7. 11. ^ Page 520 in: Paradis, Norman A. (2007). Cardiac arrest: the science and practice of resuscitation medicine. Cambridge, UK: Cambridge University Press. ISBN 978-0-521-84700-1. 12. ^ Oxymoron: Our Love-Hate Relationship with Oxygen, By Mike McEvoy at Albany Medical College, New York. 10/12/2010 13. ^ For therapeutic dose of tubocurarine by shorter limit as given at page 151 in: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. OCLC 51622037. 14. ^ For 20-fold paralytic dose of toxiferine ("calebas curare"), according to: Page 330 in: The Alkaloids: v. 1: A Review of Chemical Literature (Specialist Periodical Reports). Cambridge, Eng: Royal Society of Chemistry. 1971. ISBN 978-0-85186-257-6. 15. ^ León-Carrión, J.; van Eeckhout, P.; Domínguez-Morales Mdel, R.; Pérez-Santamaría, F. J. (2002). "The locked-in syndrome: a syndrome looking for a therapy". Brain Inj. 16 (7): 571–82. doi:10.1080/02699050110119781. PMID 12119076. 16. ^ Maiese, Kenneth (March 2014). "Locked-in Syndrome". 17. ^ Locked-in syndrome at NINDS 18. ^ Joshua Foer (October 2, 2008). "The Unspeakable Odyssey of the Motionless Boy". Esquire. 19. ^ Piotr Kniecicki "An art of graceful dying". Clitheroe: Łukasz Świderski, 2014, s. 73. ISBN 978-0-9928486-0-6 20. ^ Stephen Nolan (August 16, 2010). "I recovered from locked-in syndrome". BBC Radio 5 Live. 21. ^ "He crashed his motorbike and had a stroke - but Hampshire man Gareth Shepherd is back on his feet". Daily Echo. November 8, 2016. 22. ^ "Jacob Haendel Recovery Channel". Jacob Handel Recovery. June 29, 2020. 23. ^ "Woman's recovery from 'locked-in' syndrome". BBC News. March 14, 2012. 24. ^ Parker, I., "Reading Minds," The New Yorker, January 20, 2003, 52–63 25. ^ Keiper, Adam (Winter 2006). "The Age of Neuroelectronics". The New Atlantis. pp. 4–41. Archived from the original on 2016-02-12. 26. ^ Karim AA, Hinterberger T, Richter J, Mellinger J, Neumann N, Flor H, Kübler A, Birbaumer N. "Neural internet: Web surfing with brain potentials for the completely paralyzed". Neurorehabilitation & Neural Repair. 40 (4): 508–515. 27. ^ "'Locked-In' Patients Can Follow Their Noses". Science Mag. 26 Jul 2010. Retrieved 27 Dec 2016. ## Further reading[edit] * Piotr Kniecicki (2014). An Art of Graceful Dying. Lukasz Swiderski ISBN 978-0-9928486-0-6 (Autobiography, written while residual wrist movements and specially adapted computer) ## External links[edit] Classification D * ICD-10: G93.8 * ICD-9-CM: 344.81 * MeSH: D011782 * v * t * e Disorders of consciousness Unconsciousness * Minimally conscious state * Persistent vegetative state * Obtundation * Coma * Brain stem death * Stupor * Sopor * Sleep * Somnolence * Cataplexy Syncope * Heat syncope * Vasovagal episode Alteration of consciousness * Locked-in syndrome * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [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	Locked-in syndrome	c0023944	2,882	wikipedia	https://en.wikipedia.org/wiki/Locked-in_syndrome	2021-01-18T18:53:08	{"gard": ["6919"], "mesh": ["D011782"], "umls": ["C0023944"], "orphanet": ["2406"], "wikidata": ["Q794457"]}
Aromatase deficiency is a condition characterized by reduced levels of the female sex hormone estrogen and increased levels of the male sex hormone testosterone. Females with aromatase deficiency have a typical female chromosome pattern (46,XX) but are born with external genitalia that do not appear clearly female or male (ambiguous genitalia). These individuals typically have normal internal reproductive organs, but develop ovarian cysts early in childhood, which impair the release of egg cells from the ovaries (ovulation). In adolescence, most affected females do not develop secondary sexual characteristics, such as breast growth and menstrual periods. They tend to develop acne and excessive body hair growth (hirsutism). Men with this condition have a typical male chromosome pattern (46,XY) and are born with male external genitalia. Some men with this condition have decreased sex drive, abnormal sperm production, or testes that are small or undescended (cryptorchidism). There are other features associated with aromatase deficiency that can affect both males and females. Affected individuals are abnormally tall because of excessive growth of long bones in the arms and legs. The abnormal bone growth results in slowed mineralization of bones (delayed bone age) and thinning of the bones (%%PX0000U8osteoporosis%%), which can lead to bone fractures with little trauma. Males and females with aromatase deficiency can have abnormally high blood sugar (hyperglycemia) because the body does not respond correctly to the hormone insulin. In addition, they can have excessive weight gain and a fatty liver. Women who are pregnant with fetuses that have aromatase deficiency often experience mild symptoms of the disorder even though they themselves do not have the disorder. These women may develop hirsutism, acne, an enlarged clitoris (clitoromegaly), and a deep voice. These features can appear as early as 12 weeks of pregnancy and go away soon after delivery. ## Frequency The prevalence of aromatase deficiency is unknown; approximately 20 cases have been described in the medical literature. ## Causes Mutations in the CYP19A1 gene cause aromatase deficiency. The CYP19A1 gene provides instructions for making an enzyme called aromatase. This enzyme converts a class of hormones called androgens, which are involved in male sexual development, to different forms of estrogen. In females, estrogen guides female sexual development before birth and during puberty. In both males and females, estrogen plays a role in regulating bone growth and blood sugar levels. During fetal development, aromatase converts androgens to estrogens in the placenta, which is the link between the mother's blood supply and the fetus. This conversion in the placenta prevents androgens from directing sexual development in female fetuses. After birth, the conversion of androgens to estrogens takes place in multiple tissues. CYP19A1 gene mutations that cause aromatase deficiency decrease or eliminate aromatase activity. A shortage of functional aromatase results in an inability to convert androgens to estrogens before birth and throughout life. As a result, there is a decrease in estrogen production and an increase in the levels of androgens, including testosterone. In affected individuals, these abnormal hormone levels lead to impaired female sexual development, unusual bone growth, insulin resistance, and other signs and symptoms of aromatase deficiency. In women who are pregnant with an affected fetus, excess androgens in the placenta pass into the woman's bloodstream, which may cause her to have temporary signs and symptoms of aromatase deficiency. ### Learn more about the gene associated with Aromatase deficiency * CYP19A1 ## 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 [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	Aromatase deficiency	c1960539	2,883	medlineplus	https://medlineplus.gov/genetics/condition/aromatase-deficiency/	2021-01-27T08:25:37	{"gard": ["365"], "mesh": ["C537436"], "omim": ["613546"], "synonyms": []}
Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an inherited condition that causes overactivity of the parathyroid glands (hyperparathyroidism). These glands regulate the body's use of calcium, so overactivity can lead to high calcium levels in the blood (hypercalcemia). The syndrome typically begins in late adolescence or early adulthood. The hyperparathyroidism in people with HPT-JT is usually caused by a benign tumor in the parathyroid gland called a parathyroid adenoma. In some people with HPT-JT, it is caused by a cancerous (malignant) tumor called a parathyroid carcinoma. Signs and symptoms of hyperparathyroidism may include kidney stones, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and constipation. Some people with HPT-JT also develop a benign tumor in the jaw called an ossifying fibroma. These tumors can grow quickly if not treated. Other features of HPT-JT may include kidney growths such as cysts, hamartomas, or rarely, Wilms tumor. Women with HPT-JT may develop benign or malignant tumors in the uterus. HPT-JT is caused by mutations in the CDC73 gene and inheritance is autosomal dominant. The diagnosis is based on the presence of signs and symptoms (identified with blood tests for hyperparathyroidism and imaging studies for tumors) and genetic testing. Treatment may involve surgery to remove a parathyroid gland with a tumor, and to remove a jaw tumor. People who are unable to have tumors removed may need a medication called cinacalcet hydrochloride to treat severe hypercalcemia. [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	Hyperparathyroidism-jaw tumor syndrome	c1704981	2,884	gard	https://rarediseases.info.nih.gov/diseases/10829/hyperparathyroidism-jaw-tumor-syndrome	2021-01-18T17:59:56	{"mesh": ["C563273"], "omim": ["145001"], "orphanet": ["99880"], "synonyms": ["HPT-JT", "Hyperparathyroidism 2", "HRPT2", "Familial primary hyperparathyroidism with multiple ossifying jaw fibromas", "Hereditary hyperparathyroidism-jaw tumor syndrome"]}
A number sign (#) is used with this entry because of evidence that Brugada syndrome-9 (BRGDA9) is caused by heterozygous mutation in the KCND3 gene (605411) on chromosome 1p13. Description Brugada syndrome is characterized by ST segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but also occurs in infants and children (summary by Antzelevitch et al., 2005). For a discussion of genetic heterogeneity of Brugada syndrome, see BRGDA1 (601144). Clinical Features Giudicessi et al. (2011) reported 2 unrelated patients with Brugada syndrome and mutations in the KCND3 gene (see MOLECULAR GENETICS). The first patient was a 45-year-old man with a history of heart palpitations at rest. No arrhythmias were documented, but ST segment elevation in leads V1 and V2 of the resting Holter electrocardiogram (ECG) was suggestive of Brugada syndrome, and flecainide testing induced a type 1 ECG pattern. The patient had no history of syncope or cardiac events, and family history was negative. The second patient, a 22-year-old man who had a history of heart palpitations and presyncope, was found unconscious and unresponsive in bed. While hospitalized, he had an ECG that revealed ST segment elevation in leads V1 to V3, with a corrected QT interval of 523 ms. Complete cardiac evaluation, including echocardiography and coronary angiography, was normal, as were drug and toxicology screenings. Follow-up ECG revealed downsloping ST segment elevation in the right precordial leads (V1-V3) with a normal PR interval of 150 ms, and a slightly prolonged QT interval. The patient had a significant paternal family history of sudden cardiac death: his paternal grandfather died suddenly at age 39 years, and a paternal uncle died suddenly at age 35 years. Given the abnormal ECG findings that were suggestive of Brugada syndrome, the patient underwent implantation of an internal cardiac defibrillator. Molecular Genetics In a cohort of 86 patients with a diagnosis of Brugada syndrome who were negative for mutation in 8 known Brugada-associated genes, Giudicessi et al. (2011) analyzed the candidate gene KCND3 and identified 2 heterozygous missense mutations, L450F (605411.0005) and G600R (605411.0006), in 2 unrelated patients. Functional analysis demonstrated that both variants were gain-of-function mutations. Using DNA samples from 123 cases of sudden unexplained death that had already been screened for mutation in 7 major and 12 minor channelopathy-associated genes, Giudicessi et al. (2012) analyzed the KCND3 gene and identified heterozygosity for missense mutations in 2 cases: the G600R mutation was detected in a 23-year-old asymptomatic male athlete who had cardiopulmonary arrest while swimming laps, and a V392I mutation (605411.0007) was identified in a 20-year-old man with a history of syncopal episodes who was found unresponsive in bed by his parents and could not be resuscitated. Premortem ECGs and DNA from family members were unavailable. Giudicessi et al. (2012) also studied DNA samples from 192 cases of sudden infant death syndrome (SIDS; see 272120) and identified heterozygosity for an S530P variant in KCND3 in 1 case; however, studies in HEK293 cells revealed S530P to be a functionally wildtype-like variant without definite pathogenic influence. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Palpitations \- Syncope or presyncope \- Sudden unexplained death \- ST segment elevation over precordial leads on ECG LABORATORY ABNORMALITIES \- Flecainide administration unmasks a coved-type (type 1) ECG pattern MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, SHAL-related subfamily member-3 gene (KCND3, 605411.0005 ) ▲ 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	BRUGADA SYNDROME 9	c1142166	2,885	omim	https://www.omim.org/entry/616399	2019-09-22T15:49:04	{"doid": ["0110226"], "mesh": ["D053840"], "omim": ["616399"], "orphanet": ["130"], "genereviews": ["NBK1517"]}
Gnathitis SpecialtyENT surgery Gnathitis is jaw inflammation.[1] ## References[edit] 1. ^ "Gnathitis" at Dorland's Medical Dictionary ## External links[edit] Classification D * ICD-10: K10.2 * ICD-9-CM: 526.4 * v * t * e Dental disease involving the jaw General * Jaw abnormality * malocclusion * Orthodontics * Gnathitis Size * Micrognathism * Maxillary hypoplasia Maxilla and Mandible * Cherubism * Congenital epulis * Torus mandibularis * Torus palatinus Other * Jaw and base of cranium * Prognathism * Retrognathism * Dental arch * Crossbite * Overbite * Temporomandibular joint disorder This article about a disease, disorder, or medical condition 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	Gnathitis	None	2,886	wikipedia	https://en.wikipedia.org/wiki/Gnathitis	2021-01-18T18:28:00	{"icd-9": ["526.4"], "icd-10": ["K10.2"], "wikidata": ["Q2553217"]}
## Description Stature (adult height) is an example of a complex genetic trait involving multiple genetic loci. Although complex traits are often difficult to study by linkage analysis, Hirschhorn et al. (2001) suggested that stature is a suitable complex trait for study because of the high heritability and the relatively limited contribution of environmental factors. Thus, linkage analysis has been used to identify quantitative trait loci for stature (STQTL) including STQTL1 on chromosome 6q24, STQTL2 (606256) on chromosome 7q31-q36, STQTL3 (606257) on chromosome 12p11-q14, STQTL4 (606258) on chromosome 13q32-q33, STQTL5 (608982) on chromosome 3p26, STQTL6 (300591) on chromosome Xq24, STQTL7 (609822) on chromosome 1p21, STQTL8 (610114) on chromosome 9q22, STQTL9 (611547) on chromosome 12q14.3, STQTL10 (612221) on chromosome 3q23, STQTL11 (612223) on chromosome 7q21-q22, STQTL12 (612224) on chromosome 4q28-q32, STQTL13 (612226) on chromosome 4p13.3, STQTL14 (612228) on chromosome 20q11.22, STQTL15 (612578) on chromosome 8q21.13, STQTL16 (612579) on chromosome 15q22.31, STQTL17 (612737) on chromosome 7p15, STQTL18 (612892) on chromosome 6p22.1, STQTL19 (612893) on chromosome 6p21.31, STQTL20 (612894) on chromosome 13q14.3, STQTL21 (613440) on chromosome 2q37.1, STQTL22 (613547) on chromosome 16q24, STQTL23 (613548) on chromosome 1p32, and STQTL24 (613549) on chromosome 2p16. See also X-linked short stature (300582) associated with mutations in the SHOX gene (312865). Inheritance The genetics of stature has been studied at least since 1903, when measurements of height in families suggested a high heritability (Pearson and Lee, 1903). The studies also demonstrated that adult height follows a normal distribution, suggesting that multiple factors interact to affect stature, perhaps in an additive fashion. Estimates of heritability range from 76 to 90%. Yang et al. (2010) estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. They showed that 45% of variance could be explained by considering all SNPs simultaneously. Thus, most of the heritability was not missing but had not previously been detected because the individual effects were too small to pass stringent significance tests. Yang et al. (2010) provided evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to that time. Mapping ### Stature Quantitative Trait Locus 1 (STQTL1) Hirschhorn et al. (2001) reanalyzed genomewide scans from 4 populations: the Botnia region of Finland, other parts of Finland, southern Sweden, and a region of Quebec. The 6q24-q25 region showed significant evidence for linkage to stature in the Botnian population (maximum lod = 3.85 at D6S1007, genomewide p less than 0.06). Xu et al. (2002) performed segregation and linkage analyses for adult height in a population of 200 Dutch families, each of which was ascertained through a proband with asthma. The best-fit model from the segregation analysis was a major recessive gene with a significant residual polygenic background. A genomewide scan confirmed previous linkage results for 6q25 (lod = 3.06 at D6S2436), 9p1 (lod = 2.09 at D9S301), and 12q1 (lod = 1.86 at D12S375). In 513 sib pairs from 174 Dutch families for whom complete genome scans and adult height data were available, Willemsen et al. (2004) found the strongest evidence for linkage on chromosome 6, near markers D6S1053 and D6S1031 (lod = 2.32). In a metaanalysis of genomewide association study data of height for 15,821 individuals at 2.2 million SNPs, in which the strongest findings were followed up in greater than 10,000 subjects, Lettre et al. (2008) found association of a SNP, rs4896582, in the GPR126 gene (612243) on chromosome 6q24.1, with adult stature (combined p = 2.4 x 10(-18)). Independently, in a genomewide association study of height involving approximately 34,000 individuals in the discovery phase and followed by typing of the 40 most significant SNPs in a further 5,517 individuals, Gudbjartsson et al. (2008) found association with a SNP in the GPR126 gene, rs3748069 (combined p = 4.5 x 10(-14)). To identify loci associated with stature, Soranzo et al. (2009) performed a genomewide scan of 12,611 participants followed by replication in an additional 7,187 individuals. They confirmed linkage of the GPR126 gene region, finding strong association with rs12189801 (combined p = 1.2 x 10(-10)) and rs6570507 (combined p = 4.4 x 10(-11)). ### Associations Pending Confirmation Mukhopadhyay et al. (2003) attempted to map loci influencing normal adult height in 335 families from the Framingham (Massachusetts) Heart Study. They observed a peak on chromosome 9p21 near D9S319 with a maximum lod score of 1.65 when only male height phenotypes were used. When only female phenotypes were used, a peak with a maximum lod score of 1.85 was observed on chromosome 11q25-qter near D11S2359. The region of interest on chromosome 9 had been implicated by 2 previous studies (Hirschhorn et al., 2001; Xu et al., 2002). ### Population Stratification Campbell et al. (2005) studied a European American panel discordant for height, a heritable trait that varies widely across Europe. Genotyping 178 SNPs and applying standard analytical methods yielded no evidence of stratification. However, they found that the -13910C-T polymorphism in the MCM6 gene (601806.0001) (which they designated LCT -13910C-T) was strongly associated with height (p less than 10(-6)). The T allele was strongly associated with tall stature. However, this apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. Campbell et al. (2005) concluded that the failure of standard methods to detect this stratification indicates that new methods may be required. Molecular Genetics ### Associations Pending Confirmation Chaves et al. (2004) analyzed the influence of SNPs in components of the renin-angiotensin system (RAS) on height in 370 (194 women) healthy normotensive Caucasian subjects aged 25 to 50 years who were selected from the general population. They found that a 573C-T polymorphism of the AGTR1 gene (106165) on chromosome 3q21-q25 and the I/D polymorphism of the ACE gene (106180.0001) on chromosome 17q23 were associated with final height in women, but not men. These genetic variants showed a clear gene dosage, independent, and additive effect on height. To identify specific genes underlying human stature, Lei et al. (2009) performed genomewide association study in 1,000 unrelated homogeneous Caucasian subjects using a microarray. Seven contiguous markers in the region of the SBF2 gene (607697) on chromosome 11p15 were associated with stature. Three SNPs in the filamin B gene (FLNB; 603381) on chromosome 3p14 were also associated with stature. In independent replication studies, rs10734652 in SBF2 was significantly (p = 0.036) and suggestively (p = 0.07) associated with stature in Caucasian families and 1,306 unrelated Caucasian subjects, respectively, and rs9834312 in FLNB was also associated with stature in 2 such independent Caucasian populations (p = 0.008 in unrelated sample and p = 0.049 in family sample). Additional significant replication association signals were detected between rs9834312 and stature in 619 unrelated northern Chinese subjects (p = 0.017), as well as between rs10734652 and stature in 2,953 unrelated southern Chinese subjects (p = 0.048). Estrada et al. (2009) performed a genomewide association study (GWAS) of body height using 2.2 million markers in 10,074 individuals from 3 Dutch and 1 German population-based cohorts. Upon genotyping the 12 most significantly height-associated single-nucleotide polymorphisms (SNPs) in 6,912 additional individuals of Dutch and Swedish origin, Estrada et al. (2009) found that a single-nucleotide polymorphism (SNP), rs10472828, located on 5p14 showed suggestive evidence for association with height in the combined data set (combined p = 2.1 x 10(-7)). The SNP rs10472828 is located only 100 kb upstream of the natriuretic peptide receptor-3 gene (NPR3; 108962), which encodes a receptor for NPPC (600296), a candidate for influencing height variation linked to chromosome 2q37 (STQTL21; 613440). Tonjes et al. (2009) performed a genomewide association study of adult height in 929 individuals from the self-contained Sorbian population of eastern Germany. Metaanalysis of the strongest SNPs in the Sorbian sample combined with 2 independent European cohorts identified a significant association between adult height and 2 variants, rs1569019 (p = 1.02 x 10(-6)) and rs1976930 (p = 3.37 x 10(-7)), in the GPR133 gene (613639) that are in linkage disequilibrium. The 2 SNPs were also associated with height in the 2 independent European cohorts individually. Replication of the findings in 2 non-Sorbian German cohorts for rs1569019 showed significant effects on height in the Leipzig cohort in men and women and in 577 men of the Berlin cohort, though not in 1,151 women. The combined analysis of all 5 cohorts, which consisted of 6,687 individuals, resulted in an effect size of 0.949 cm (p = 4.7 x 10(-8)). Tonjes et al. (2009) proposed GPR133 to be a novel gene associated with adult height. Widen et al. (2010) performed a genomewide scan for genes influencing pubertal height growth in 5,038 Finnish individuals and identified strong association between variants near the LIN28B gene (611044) on chromosome 6q21 and pubertal growth (female p = 4 x 10(-9), male p = 1.5 x 10(-4), and combined p - 5 x 10(-11) for the 5-prime LIN28B SNP rs7759938). Noting that correlated SNPs have been associated with age at menarche (see MENAQ2, 612882), Widen et al. (2010) performed multiple regression analysis, which suggested that the timing of pubertal growth and age of menarche may be mediated through a common underlying mechanism. In addition, because a partially correlated intronic LIN28B SNP, rs314277, was previously associated with final height (Lettre et al., 2008), Widen et al. (2010) tested both rs7759938 and rs314277 for independent effects on postnatal growth in 8,903 individuals. They found that the pubertal timing-associated marker rs7759938 affected prepubertal growth in females (p = 7 x 10(-5)) and final height in males (p = 5 x 10(-4)), whereas rs314277 had sex-specific effects on growth (p for interaction = 0.005) that were distinct from those observed at rs7759938. Widen et al. (2010) concluded that partially correlated variants in the LIN28B region tag distinctive, complex, and sex-specific height- and growth-regulating effects, influencing the entire period of postnatal growth, thus implying a critical role for LIN28B in the regulation of human growth. Lango Allen et al. (2010) used 183,727 individuals to demonstrate that hundreds of genetic variants, in at least 180 loci, influence adult height. The large number of loci revealed patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci were not random, but instead were enriched for genes that are connected in biologic pathways (p = 0.016) and that underlie skeletal growth defects (p less than 0.001). Second, the likely causal gene was often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci had multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants were enriched for likely functional effects on genes, being overrepresented among variants that alter amino acid structure of proteins and expression levels of nearby genes. Lango Allen et al. (2010) concluded that their data explained approximately 10% of the phenotypic variation in height, and they estimated that unidentified common variants of similar effect sizes would increase the figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Okada et al. (2010) performed a genomewide association study (GWAS) for adult height in 19,633 Japanese subjects. Of 8 significantly associated loci, the association to the LHX3 (600577)-QSOX2 (612860) locus was entirely novel (rs12338076, p = 2.2 x 10(-8)). Association to the IGF1 (147440) locus was also established; conditional analysis of this locus with the most significantly associated SNP suggested the existence of an additional independent association with height to this locus. There were large differences in IGF1 allele frequencies between Japanese and Caucasian populations, thereby suggesting weak statistical powers for the IGF1 locus in previous Caucasian GWASs for height. The combination of the height-associated loci identified in the study of Okada et al. (2010) and previous GWAS demonstrated an effect size of 1.26 cm (95% confidence interval: 1.18-1.34) per 1.0 increase of the normalized Z score for height-increasing alleles, explaining 4.6% of the total variance of adult height. Nelson et al. (2015) used a genetic approach to investigate the association between height and coronary artery disease (CAD), using 180 height-associated genetic variants. The authors tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, they also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. Nelson et al. (2015) observed a relative increase of 13.5% (95% CI, 5.4-22.1; p less than 0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (OR for height quartile 4 vs quartile 1, 0.74; 95% CI, 0.68-0.84; p less than 0.001). Of the 12 risk factors studied, significant associations were observed only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). Nelson et al. (2015) identified several overlapping pathways involving genes associated with both development and atherosclerosis. Signaling pathways involving NKX2-5 (600584), STAT3 (102582), BMP (see 112264), growth hormone (see 139250), TGFB (190180), and IGF1 (147440) were implicated. To test the association between 241,453 variants and adult height variation, Marouli et al. (2017) conducted single-variant metaanalyses in a discovery sample of 458,927 individuals, of whom 381,625 were of European ancestry, and validated the association results in an independent set of 252,501 participants. Marouli et al. (2017) reported 83 height-associated coding variants with lower minor allele frequencies (in the range of 0.1 to 4.8%) and effects of up to 2 centimeters per allele (such as those in IHH (600726), STC2 (603665), AR (313700), and CRISPLD2 (612434)), greater than 10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 giving an increase of 1 to 2 centimeters per allele compromised proteolytic inhibition of PAPPA (176385) and increased cleavage of IGFBP4 (146733) in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlapped genes that are mutated in monogenic growth disorders and highlighted novel biological candidates, such as ADAMTS3 (605011), IL11RA (600939), and NOX4 (605261), and pathways, such as proteoglycan and glycosaminoglycan synthesis, involved in growth. [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	STATURE AS A QUANTITATIVE TRAIT	c1853478	2,887	omim	https://www.omim.org/entry/606255	2019-09-22T16:10:33	{"omim": ["606255"]}
Ptosis-vocal cord paralysis syndrome is a rare, hereditary disorder with ptosis characterized by the combination of congenital bilateral recurrent laryngeal nerve paralysis and congenital bilateral ptosis. There have been no further descriptions in the literature since 1983. [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	Ptosis-vocal cord paralysis syndrome	c1860403	2,888	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2997	2021-01-23T17:15:03	{"gard": ["427"], "mesh": ["C536923"], "omim": ["193240"], "umls": ["C1860403"], "synonyms": ["Tucker syndrome"]}
A number sign (#) is used with this entry because of evidence that hyperprolactinemia (HPRL) is caused by heterozygous or compound heterozygous mutation in the PRLR gene (176761) on chromosome 5p13. Description Hyperprolactinemia unrelated to pregnancy occurs in approximately 0.1 to 0.3% of the general population and may result in infertility, hypogonadism, and galactorrhea. Such nonphysiologic hyperprolactinemia is caused mainly by drugs or by tumors in the anterior pituitary gland, primarily prolactinomas (see 102200). However, 10 to 60% of patients with hyperprolactinemia who undergo MRI have normal findings (summary by Newey et al., 2013). Patients with hyperprolactinemia may also experience agalactia (Kobayashi et al., 2018). Clinical Features Newey et al. (2013) studied 3 sisters with familial idiopathic hyperprolactinemia. The proband was a 41-year-old woman with a 2-year history of oligomenorrhea and menorrhagia who was found to have hyperprolactinemia. Between age 18 and 31 years, she gave birth to 4 children, and at the cessation of breastfeeding after each pregnancy, she required dopamine agonist therapy to terminate persistent galactorrhea. She had no clinical features of hypopituitarism and was taking no medication; MRI of the pituitary was normal. A 38-year-old sister with a 3-year history of primary infertility and a 43-year-old sister with longstanding oligomenorrhea were both also found to have persistent hyperprolactinemia with a normal MRI of the pituitary gland. In addition, the proband's father and son were found to have persistent hyperprolactinemia. None of the affected family members had immunologic abnormalities. Kobayashi et al. (2018) reported a 35-year-old woman with regular menstrual cycles who presented at age 28 with a 1-year history of infertility and was found to have hyperprolactinemia. Pregnancy was achieved on second intrauterine insemination; in the postpartum and puerperal periods, she had agalactia and experienced neither breast engorgement nor galactorrhea. A second pregnancy was achieved without infertility treatment, and again she had postpartum agalactia. Her prolactin levels remained elevated; brain MRI showed no evidence of a pituitary tumor. Her mother had no history of menstrual irregularities or infertility and had breast-fed each of her 3 children, but stated that she had been concerned about insufficient production of breast milk and supplemented with synthetic milk. Lactation ceased spontaneously within 3 months after each childbirth. The proband's father was healthy and fertile; both parents had normal prolactin levels, as did an unaffected sister and brother. Molecular Genetics In the proband of a 3-generation family segregating autosomal dominant hyperprolactinemia, who was known to be negative for mutation in the MEN1 (613733), AIP (605555), and PRL (176760) genes, Newey et al. (2013) identified heterozygosity for a missense mutation in the PRLR gene (H188R; 176761.0002). The mutation segregated with disease in the family and was not found in 110 ethnically matched controls or in more than 13,000 alleles from the NHLBI GO Exome Sequencing Project. The proband's 13-year-old prepubertal daughter, who carried the mutation but did not have hyperprolactinemia, was thought to represent age-related penetrance for the disease. Studies in transfected HEK293 cells demonstrated that H188R is a loss-of-function mutation. The H118R mutation is also denoted as H212R (Kobayashi et al., 2018). Harris (2014), Grossmann (2014), and Molitch (2014) questioned the relationship between the H188R (H212R) loss-of-function mutation and the reproductive abnormalities and galactorrhea reported in the family studied by Newey et al. (2013). Newey et al. (2014) proposed the involvement of a hypothetical second receptor mediating peripheral effects of hyperprolactinemia as a possible explanation for the paradoxical occurrence of the loss-of-function mutation in PRLR with hyperprolactinemia and variable reproductive abnormalities, and cited previous studies associating prolactin levels with reproductive function (Bronstein, 2010; Garzia et al., 2004; Li et al., 2013). Newey et al. (2014) also noted that their results showed that the PRLR loss-of-function mutation cosegregated with familial hyperprolactinemia with odds of more than 125 to 1 favoring linkage, and that the mutation was associated with a phenotype similar to that in Prlr-null mice. In a 35-year-old woman with hyperprolactinemia and agalactia, Kobayashi et al. (2018) sequenced the PRLR gene and identified compound heterozygosity for a nonsense mutation (R171X; 176761.0003) and a missense mutation (P269L; 176761.0004). The proband's parents were each heterozygous for 1 of the mutations, neither of which were found in her unaffected brother and sister. The authors noted that the 3 identified variant receptors (H212R, R171X, and P269L) exhibit similar residual signal-transduction function as well as absence of robust dominant-negative effects, and suggested that other factors that modulate prolactin receptor signaling might explain the difference in phenotype between this family and the family with PRLR-associated hyperprolactinemia reported by Newey et al. (2013). INHERITANCE \- Autosomal dominant \- Autosomal recessive CHEST Breasts \- Galactorrhea (in some patients) \- Agalactia (in some patients) GENITOURINARY Internal Genitalia (Female) \- Oligomenorrhea (in some patients) \- Infertility (in some patients) \- Menorrhagia (in some patients) ENDOCRINE FEATURES \- Elevated prolactin levels MOLECULAR BASIS \- Caused by mutation in the prolactin receptor gene (PRLR, 176761.0002 ) ▲ 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	HYPERPROLACTINEMIA	c0020514	2,889	omim	https://www.omim.org/entry/615555	2019-09-22T15:51:37	{"mesh": ["D006966"], "omim": ["615555"], "icd-10": ["E22.1"], "orphanet": ["397685"], "synonyms": ["Familial isolated prolactin receptor deficiency"]}
Urban–Rogers–Meyer syndrome Other namesPrader–Willi habitus, osteopenia, and camptodactyly This condition is inherited in an autosomal recessive manner SpecialtyMedical genetics Urban–Rogers–Meyer syndrome, also known as Prader–Willi habitus, osteopenia, and camptodactyly or Urban syndrome,[1] is an extremely rare inherited congenital disorder first described by Urban et al. (1979).[2][3] It is characterized by genital anomalies, mental retardation, obesity, contractures of fingers, and osteoporosis,[3] though further complications are known.[4][5] ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 264010 2. ^ Urban MD, Rogers JG, Meyer WJ (Jan 1979). "Familial syndrome of mental retardation, short stature, contractures of the hands, and genital anomalies". J. Pediatr. 94 (1): 52–55. doi:10.1016/S0022-3476(79)80349-2. PMID 758422. 3. ^ a b Pagnan NA, Gollop TR (Dec 1988). "Prader-Willi habitus, osteopenia, and camptodactyly (Urban–Rogers–Meyer syndrome): a probable second report". Am. J. Med. Genet. 31 (4): 787–792. doi:10.1002/ajmg.1320310410. PMID 3239569. 4. ^ "Urban Rogers Meyer syndrome". Orphanet. Retrieved Aug 29, 2010. 5. ^ "Urban-Rogers-Meyer syndrome". Jablonski's Syndromes Database (closed). NLM. Retrieved Aug 29, 2010. ## Further reading[edit] * Prader–Willi habitus, osteopenia, and camptodactyly; Urban–Rogers–Meyer syndrome at NIH's Office of Rare Diseases * Jablonski's Syndromes Database: Bibliography * Camera G, Marugo M, Cohen MM (Nov 1993). "Another postnatal-onset obesity syndrome". Am. J. Med. Genet. 47 (6): 820–822. doi:10.1002/ajmg.1320470605. PMID 8279478. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 264010 * MeSH: C538276 * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome This genetic disorder 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	Urban–Rogers–Meyer syndrome	c0796189	2,890	wikipedia	https://en.wikipedia.org/wiki/Urban%E2%80%93Rogers%E2%80%93Meyer_syndrome	2021-01-18T18:32:17	{"gard": ["5426"], "mesh": ["C538276"], "umls": ["C0796189"], "orphanet": ["3409"], "wikidata": ["Q7900262"]}
An isolated constitutional thrombocytopenia characterized by an isolated and severe decrease in the number of platelets and megakaryocytes during the first years of life that develops into bone marrow failure with pancytopenia later in childhood. ## Epidemiology Congenital amegakaryocytic thrombocytopenia (CAMT) prevalence is unknown and less than 100 cases have been reported in the literature. In addition, the incidence may be underestimated due to difficult and inconsistent diagnosis of the disease. ## Clinical description CAMT manifests since birth, often in the first day or at least within the first month of life, with petechiae, purpura, and gastrointestinal, pulmonary or intracranial hemorrhage due to isolated thrombocytopenia and a near absence of megakaryocytes in the bone marrow. Two types of CAMT have been identified. Type I-CAMT is the severe form of the disease and is characterized by persistently low platelet counts and early progression (usually by the age of 2 years) to bone marrow aplasia associated with pancytopenia. Type II-CAMT is a milder form which presents with transient increase of platelet counts over 50x109/L during the first year of life and late (by the age of 3-6 years) or no development of pancytopenia. Cardiac defects (atrial and ventricular septal defects), abnormalities of the central nervous system (cerebral and cerebellar hypoplasia), and retardation of psychomotor development have occasionally been reported. ## Etiology CAMT is due to mutations in the MPL gene (1p34) coding for Thrombopoietin (TPO) receptor (c-MPL), expressed in pluripotent hematopoietic stem cells and cells of the megakaryocyte lineage. The binding of TPO to c-MPL stimulates platelet and megakaryocyte production. Different types of mutations have been associated with different phenotypes. Nonsense mutations predicted to result in a complete loss of function of the TPO receptor lead to type I-CAMT, whereas missense mutations predicted to lead to a residual function of the receptor are associated with type II-CAMT. Cases with no defects in the MPL gene are referred to as type III-CAMT. Recently, a 21q22 deletion resulting in RUNX1 haploinsufficiency has been reported in a case of CAMT associated with various anomalies (growth retardation, hearing deficits, hernias, poor feeding). ## Diagnostic methods Diagnosis is based on clinical signs, on the evidence by blood tests of thrombocytopenia (platelet count below 50x109/L) with a normal mean platelet volume and of highly elevated serum levels of TPO, and on the observation in a bone marrow aspirate of absent or very few megakaryocytes. Genetic testing can confirm the diagnosis. ## Differential diagnosis The initial presentation of CAMT with isolated thrombocytopenia can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP), while the late pancytopenic phase is indistinguishable from aplastic anemia. Fanconi anemia, thrombocytopenia-absent radius (TAR), syndrome and Wiscott-Aldrich syndrome (WAS) should be also ruled out. ## Antenatal diagnosis Prenatal diagnosis is possible for families in which the disease-causing mutation has been identified. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. ## Management and treatment Management is supportive, mainly consisting of multiple platelet transfusions. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy. ## Prognosis Prognosis is poor and with supportive therapy, progression to full marrow failure (tri-linear marrow aplasia) occurs during the first years of life. 30% of patients with CAMT die due to bleeding complications before the HSCT and 20% due to the HSCT. [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	Congenital amegakaryocytic thrombocytopenia	c1327915	2,891	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3319	2021-01-23T18:56:33	{"gard": ["640"], "mesh": ["C535982"], "omim": ["604498"], "umls": ["C1327915"], "icd-10": ["D61.0"], "synonyms": ["CAMT"]}
Keratoconus is an eye condition that affects the shape of the cornea, which is the clear outer covering of the eye. In this condition, the cornea thins and bulges outward, eventually resembling a cone shape. These corneal abnormalities, which worsen over time, can lead to nearsightedness (myopia), blurred vision that cannot be improved with corrective lenses (irregular astigmatism), and vision loss. Other corneal changes typical of keratoconus that can be seen during an eye exam include iron deposits in the cornea that form a yellow-to-brownish ring, called the Fleischer ring, surrounding the colored part of the eye (iris). Affected individuals may also develop Vogt's striae, which are thin, vertical, white lines in the tissue at the back of the cornea. Keratoconus may affect only one eye at first, but eventually the corneas of both eyes become misshapen, although they might not be affected with the same severity. As keratoconus worsens, people with this condition can develop corneal scarring, often caused by exposure of the abnormally thin cornea to prolonged contact lens use or excessive eye rubbing. The eye changes characteristic of keratoconus typically begin in adolescence and slowly worsen until mid-adulthood at which point the shape of the cornea remains stable. ## Frequency Keratoconus is estimated to affect 1 in 500 to 2,000 individuals worldwide. ## Causes The cause of keratoconus is unknown. Researchers have studied many different factors, both genetic and environmental, that are thought to influence the risk of developing keratoconus. The environmental factors that may contribute to keratoconus include excessive eye rubbing and the tendency to develop allergic disorders (atopy). Excessive and vigorous eye rubbing can cause trauma to the cornea and may lead to its thinning. However, it is unclear whether eye rubbing leads to keratoconus or if eye rubbing is a response to eye discomfort in the early stages of the condition. If eye rubbing is not involved in the development of keratoconus, it likely contributes to worsening of the condition. Approximately one-third of individuals with keratoconus have an allergic disorder, although it is unclear how allergic disorders are related to the development of keratoconus. Allergies might trigger eye rubbing, which can aggravate eye problems. Changes in multiple genes have been associated with developing keratoconus. Many of these variants have been found only in small populations or single families. In most individuals with keratoconus, a combination of genetic and environmental factors is needed for the condition to develop. However, some affected individuals seem to have a largely environmental cause for the condition while others seem to have a largely genetic cause. Individuals with a relative who has keratoconus have an increased risk of developing the condition compared to people without a family history. More than a dozen genes have been associated with keratoconus. These genes have varied functions. The most frequently associated genes play roles in eye development, the formation and structure of the cornea, the intricate lattice of proteins and other molecules that forms in the space between cells (extracellular matrix), an immune system response called inflammation, and the regulation of cell growth. It is thought that a disruption in one of these processes, in combination with an environmental trigger, may lead to the development of keratoconus. Keratoconus can be a feature of genetic syndromes, such as Leber congenital amaurosis and arterial tortuosity syndrome. When it is part of a syndrome, keratoconus is caused by the same genetic mutation that causes the syndrome. Mutations in the genes that cause syndromes with keratoconus have not been found to cause keratoconus without other features. ### Learn more about the genes associated with Keratoconus * COL4A3 * COL4A4 * COL5A1 * IL1A * RAB3GAP1 * TGFBI * WNT10A Additional Information from NCBI Gene: * CAST * DOCK9 * FNDC3B * FOXO1 * HGF * IL1RN * LOX * MIR184 * SLC4A11 * VSX1 * ZEB1 * ZNF469 ## Inheritance Pattern In most cases, keratoconus is not inherited and occurs in individuals with no family history of the disorder. The condition can also occur in families. In some cases, keratoconus is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person often has one parent with the condition, although some people who have a gene variant never develop the condition, a situation known as reduced penetrance. Keratoconus can also be inherited in an autosomal recessive pattern, which means variants occur in both copies of the gene in each cell. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition. [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	Keratoconus	c1835677	2,892	medlineplus	https://medlineplus.gov/genetics/condition/keratoconus/	2021-01-27T08:25:19	{"gard": ["6824"], "mesh": ["C563649"], "omim": ["148300", "608932", "608586", "609271", "614622", "614623", "614629", "614628"], "synonyms": []}
Sialolithiasis Calculi (salivary gland stones) removed from the sublingual gland SpecialtyOral surgery Sialolithiasis (also termed salivary calculi,[1] or salivary stones),[1] is a condition where a calcified mass or sialolith forms within a salivary gland, usually in the duct of the submandibular gland (also termed "Wharton's duct"). Less commonly the parotid gland or rarely the sublingual gland or a minor salivary gland may develop salivary stones. The usual symptoms are pain and swelling of the affected salivary gland, both of which get worse when salivary flow is stimulated, e.g. with the sight, thought, smell or taste of food, or with hunger or chewing. This is often termed "mealtime syndrome".[2] Inflammation or infection of the gland may develop as a result. Sialolithiasis may also develop because of the presence of existing chronic infection of the glands, dehydration (e.g. use of phenothiazines), Sjögren's syndrome and/or increased local levels of calcium, but in many instances the cause is idiopathic (unknown). The condition is usually managed by removing the stone, and several different techniques are available. Rarely, removal of the submandibular gland may become necessary in cases of recurrent stone formation. Sialolithiasis is common, accounting for about 50% of all disease occurring in the major salivary glands and causing symptoms in about 0.45% of the general population. Persons aged 30–60 and males are more likely to develop sialolithiasis.[2] ## Contents * 1 Classification * 2 Signs and symptoms * 3 Causes * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Classification[edit] The term is derived from the Greek words sialon (saliva) and lithos (stone), and the Greek -iasis meaning "process" or "morbid condition". A calculus (plural calculi) is a hard, stone-like concretion that forms within an organ or duct inside the body. They are usually made from mineral salts, and other types of calculi include tonsiloliths (tonsil stones) and renal calculi (kidney stones). Sialolithiasis refers to the formation of calculi within a salivary gland. If a calculus forms in the duct that drains the saliva from a salivary gland into the mouth, then saliva will be trapped in the gland. This may cause painful swelling and inflammation of the gland. Inflammation of a salivary gland is termed sialadenitis. Inflammation associated with blockage of the duct is sometimes termed "obstructive sialadenitis". Because saliva is stimulated to flow more with the thought, sight or smell of food, or with chewing, pain and swelling will often get suddenly worse just before and during a meal ("peri-prandial"), and then slowly decrease after eating, this is termed meal time syndrome. However, calculi are not the only reasons that a salivary gland may become blocked and give rise to the meal time syndrome. Obstructive salivary gland disease, or obstructive sialadenitis, may also occur due to fibromucinous plugs, duct stenosis, foreign bodies, anatomic variations, or malformations of the duct system leading to a mechanical obstruction associated with stasis of saliva in the duct.[2] Salivary stones may be divided according to which gland they form in. About 85% of stones occur in the submandibular gland,[3] and 5–10% occur in the parotid gland.[2] In about 0–5% of cases, the sublingual gland or a minor salivary gland is affected.[2] When minor glands are rarely involved, caliculi are more likely in the minor glands of the buccal mucosa and the maxillary labial mucosa.[4] Submandibular stones are further classified as anterior or posterior in relation to an imaginary transverse line drawn between the mandibular first molar teeth. Stones may be radiopaque, i.e. they will show up on conventional radiographs, or radiolucent, where they not be visible on radiographs (although some of their effects on the gland may still be visible). They may also symptomatic or asymptomatic, according to whether they cause any problems or not. ## Signs and symptoms[edit] Swelling of the submandibular gland as seen from the outside The stone seen in the submandibular duct on the persons right side Signs and symptoms are variable and depend largely upon whether the obstruction of the duct is complete or partial, and how much resultant pressure is created within the gland.[1] The development of infection in the gland also influences the signs and symptoms. * Pain, which is intermittent, and may suddenly get worse before mealtimes, and then slowly get better (partial obstruction).[3] * Swelling of the gland, also usually intermittent, often suddenly appearing or increasing before mealtimes, and then slowly going down (partial obstruction).[3] * Tenderness of the involved gland.[3] * Palpable hard lump, if the stone is located near the end of the duct.[1][3] If the stone is near the submandibular duct orifice, the lump may be felt under the tongue. * Lack of saliva coming from the duct (total obstruction).[3] * Erythema (redness) of the floor of the mouth (infection).[3] * Pus discharging from the duct (infection).[3] * Cervical lymphadenitis (infection).[3] * Bad breath.[3] Rarely, when stones form in the minor salivary glands, there is usually only slight local swelling in the form of a small nodule and tenderness.[1] ## Causes[edit] The major salivary glands (paired on each side). 1. Parotid gland, 2. Submandibular gland, 3. Sublingual gland. There are thought to be a series of stages that lead to the formation of a calculus (lithogenesis). Initially, factors such as abnormalities in calcium metabolism,[3] dehydration,[2] reduced salivary flow rate,[2] altered acidity (pH) of saliva caused by oropharyngeal infections,[2] and altered solubility of crystalloids,[2] leading to precipitation of mineral salts, are involved. Other sources state that no systemic abnormality of calcium or phosphate metabolism is responsible.[1] The next stage involves the formation of a nidus which is successively layered with organic and inorganic material, eventually forming a calcified mass.[2][3] In about 15-20% of cases the sialolith will not be sufficiently calcified to appear radiopaque on a radiograph,[3] and will therefore be difficult to detect. Other sources suggest a retrograde theory of lithogenesis, where food debris, bacteria or foreign bodies from the mouth enter the ducts of a salivary gland and are trapped by abnormalities in the sphincter mechanism of the duct opening (the papilla), which are reported in 90% of cases. Fragments of bacteria from salivary calculi were reported to be Streptococci species which are part of the normal oral microbiota and are present in dental plaque.[2] Stone formation occurs most commonly in the submandibular gland for several reasons. The concentration of calcium in saliva produced by the submandibular gland is twice that of the saliva produced by the parotid gland.[3] The submandibular gland saliva is also relatively alkaline and mucous. The submandibular duct (Wharton's duct) is long, meaning that saliva secretions must travel further before being discharged into the mouth.[3] The duct possesses two bends, the first at the posterior border of the mylohyoid muscle and the second near the duct orifice.[3] The flow of saliva from the submandibular gland is often against gravity due to variations in the location of the duct orifice.[3] The orifice itself is smaller than that of the parotid.[3] These factors all promote slowing and stasis of saliva in the submandibular duct, making the formation of an obstruction with subsequent calcification more likely. Salivary calculi sometimes are associated with other salivary diseases, e.g. sialoliths occur in two thirds of cases of chronic sialadenitis,[4] although obstructive sialadenitis is often a consequence of sialolithiasis. Gout may also cause salivary stones,[4] although in this case they are composed of uric acid crystals rather than the normal composition of salivary stones. ## Diagnosis[edit] Ultrasound image of sialolithiasis Play media Stone resulting in inflammation and dilation of the duct[5] Diagnosis is usually made by characteristic history and physical examination. Diagnosis can be confirmed by x-ray (80% of salivary gland calculi are visible on x-ray), by sialogram, or by ultrasound. ## Treatment[edit] Salivary gland stone and the hole left behind from the operation Some current treatment options are: * Non-invasive: * For small stones, hydration, moist heat therapy, NSAIDs (nonsteroidal anti-inflammatory drugs) occasionally, and having the patient take any food or beverage that is bitter and/or sour. Sucking on citrus fruits, such as a lemon or orange, may increase salivation and promote spontaneous expulsion of the stone.(Examples of size: 2–10 mm) [6] * Some stones may be massaged out by a specialist. * Shock wave therapy (Extracorporeal shock wave lithotripsy).[7] * Minimally invasive: * Sialendoscopy * Surgical: * An ENT or oral/maxillofacial surgeon may cannulate the duct to remove the stone (sialectomy). * A surgeon may make a small incision near the stone to remove it. * In some cases when stones continually reoccur the offending salivary duct is removed. * Supporting treatment: * To prevent infection while the stone is lodged in the duct, antibiotics are sometimes used. ## Epidemiology[edit] The prevalence of salivary stones in the general population is about 1.2% according to post mortem studies, but the prevalence of salivary stones which cause symptoms is about 0.45% in the general population.[2] Sialolithiasis accounts for about 50% of all disease occurring in major salivary glands, and for about 66% of all obstructive salivary gland diseases. Salivary gland stones are twice as common in males as in females. The most common age range in which they occur is between 30 and 60, and they are uncommon in children.[2] ## References[edit] 1. ^ a b c d e f Neville BW, Damm DD, Allen CA, Bouquot JE (2002). Oral & maxillofacial pathology (2nd ed.). Philadelphia: W.B. Saunders. pp. 393–395. ISBN 0721690033. 2. ^ a b c d e f g h i j k l m Capaccio, P; Torretta, S; Ottavian, F; Sambataro, G; Pignataro, L (August 2007). "Modern management of obstructive salivary diseases". Acta Otorhinolaryngologica Italica. 27 (4): 161–72. PMC 2640028. PMID 17957846. 3. ^ a b c d e f g h i j k l m n o p q r Hupp JR, Ellis E, Tucker MR (2008). Contemporary oral and maxillofacial surgery (5th ed.). St. Louis, Mo.: Mosby Elsevier. pp. 398, 407–409. ISBN 9780323049030. 4. ^ a b c Rice, DH (February 1984). "Advances in diagnosis and management of salivary gland diseases". The Western Journal of Medicine. 140 (2): 238–49. PMC 1021605. PMID 6328773. 5. ^ "UOTW #70 - Ultrasound of the Week". Ultrasound of the Week. 24 April 2016. Retrieved 27 May 2017. 6. ^ [1] – Oral surgery: Self-milking the sialolith (UK) 7. ^ [2] – Overview of stones by the National Institutes of Health (US) ## External links[edit] Classification D * ICD-10: K11.5 * ICD-9-CM: 527.5 * MeSH: D015494 * DiseasesDB: 29364 Wikimedia Commons has media related to Sialolithiasis. * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic 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	Sialolithiasis	c0036091	2,893	wikipedia	https://en.wikipedia.org/wiki/Sialolithiasis	2021-01-18T18:57:20	{"mesh": ["D020792", "D015494"], "umls": ["C0036091"], "wikidata": ["Q1627831"]}
## Clinical Features Congenital palatopharyngeal incompetence is characterized by cleft palate speech (rhinolalia aperta) in the absence of overt cleft palate. About a fourth of cases are 'unmasked' by adenoidectomy. Abnormalities of the uvula, soft palate and hard palate may be visible. The inability to limit the flow of air-sound through the nose is responsible for the speech defect described as 'hypernasality' or 'nasal speech.' Occasionally dominant inheritance may obtain, with great variability, making this essentially a multifactorial trait. Andres et al. (1981) presented a family with the trait in multiple sibships of 3 generations with male-to-male transmission. The authors suspected a syndromal relationship to deafness in their family. Vantrappen et al. (2002) described a kindred in which 10 members of 3 successive generations had isolated velopharyngeal insufficiency in an autosomal dominant pattern including 5 examples of male-to-male transmission. The index patient was referred for severe velopharyngeal insufficiency without overt or submucous cleft of the soft palate. A short and totally immobile soft palate was found with anatomic disproportion of the velopharyngeal structures. A younger brother had the same anomaly. He also presented with delayed speech development and hypernasal speech, due to the same radiologically confirmed short and immobile soft palate. Speech therapy was without avail; a pharyngoplasty brought moderate improvement. No abnormalities of mental and physical development and no cardiac abnormalities were found in members of this family. Karyotype was normal, and a deletion in 22q11 was excluded. None had manifestations of the velocardiofacial syndrome (192430). Kannu et al. (2003) reported a family in which father-to-son transmission demonstrated autosomal dominant inheritance of velopharyngeal insufficiency. The 34-year-old father had nasal speech during childhood. He was unable to drink through straws or to speak loudly. Pharyngoplasty was performed at 8 years of age, with correction of speech. One of his 3 children had nasal speech at the age of 4.5 years and was found to have velopharyngeal insufficiency. Pharyngoplasty improved his speech quality. FISH analysis for the 22q11.2 deletion was negative, and a 550-resolution band karyotype was normal. Mapping Zori et al. (1998) performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 16 patients with velopharyngeal insufficiency of unknown cause and found that 6 had a deletion in the region. In the families with velopharyngeal insufficiency described by Vantrappen et al. (2002) and Kannu et al. (2003), deletion in the 22q11 region was excluded. Voice \- Cleft palate speech Mouth \- Congenital palatopharyngeal incompetence Inheritance \- Multifactorial ▲ 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	PALATOPHARYNGEAL INCOMPETENCE	c1997202	2,894	omim	https://www.omim.org/entry/167500	2019-09-22T16:36:46	{"omim": ["167500"], "orphanet": ["2291"], "synonyms": ["Alternative titles", "VELOPHARYNGEAL INCOMPETENCE", "VELOPHARYNGEAL INSUFFICIENCY"]}
Granulomatous prostatitis Micrograph showing a granulomatous prostatitis due to BCG treatment for bladder cancer. H&E stain. SpecialtyUrology Granulomatous prostatitis is an uncommon disease of the prostate, an exocrine gland of the male reproductive system. It is a form of prostatitis (prostate inflammation), resulting from infection[1] (bacterial, viral, or fungal), BCG vaccine, malacoplakia or systemic granulomatous diseases which involve the prostate. ## Contents * 1 Pathogenesis * 1.1 Histopathology * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Pathogenesis[edit] Prostatic secretions escape into the stroma and elicit an inflammatory response. ### Histopathology[edit] Noticeable destruction of Acini, surrounded by epitheloid cells, giant cells, lymphocytes, [2]plasma cells and dense fibrosis. ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## References[edit] 1. ^ Eziyi, Amogu K.; Oluogun, Waheed A.; Adedokun, Kamoru A.; Oyeniyi, Ganiyu A. (2020-01-01). "Prostate tuberculosis: A rare complication of pulmonary tuberculosis with malignant features mimicking prostate cancer". Urological Science. 31 (1): 36. doi:10.4103/UROS.UROS_80_19. ISSN 1879-5226. 2. ^ Eziyi, Amogu K.; Oluogun, Waheed A.; Adedokun, Kamoru A.; Oyeniyi, Ganiyu A. (2020-01-01). "Prostate tuberculosis: A rare complication of pulmonary tuberculosis with malignant features mimicking prostate cancer". Urological Science. 31 (1): 36. doi:10.4103/UROS.UROS_80_19. ISSN 1879-5226. ## External links[edit] Classification D External resources * eMedicine: article/2019731 This article about a disease of the genitourinary system 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	Granulomatous prostatitis	c0018204	2,895	wikipedia	https://en.wikipedia.org/wiki/Granulomatous_prostatitis	2021-01-18T19:00:10	{"umls": ["C0018204"], "wikidata": ["Q5596833"]}
Rat-bite fever (RBF) is a systemic bacterial zoonosis occurring in individuals that have been bitten or scratched by Streptobacillus moniliformis or Spirillum minus-infected rats and characterized by high fever, a rash on the extremities, and arthralgia. ## Epidemiology The exact incidence is unknown. ## Clinical description The clinical manifestations include high fever followed by headaches, chills, vomiting, a rash generally developing on the palms and soles, and symmetric polyarthritis of the joints that generally restricts movement. ## Etiology Most reported cases of rat-bite fever in the USA are caused by S. moniliformis (streptobacillary rat-bite fever), whereas in Asia the disease is mainly due to Spirillum minus (spirillary rat-bite fever; see these terms). Rat-bite fever is also contracted through contact with secretions of infected rats and less often through contact with other S. moniliformis and S. minus hosts, such as gerbils, mice and squirrels. In rare cases, the disease is transmitted through animal hosts such as dogs, cats and ferrets. ## Diagnostic methods Diagnosis is mainly based on the clinical symptoms, reported occurrence of a rat bite, clinical course and characteristic growth of the infectious agents in cultures from blood, synovial fluid or wound tissue. ## Differential diagnosis The differential diagnosis includes Haverhill fever (caused by S. moniliformis but transmitted via the consumption of water, milk or food contaminated by rat excrement; see this term) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthemas, and secondary syphilis). ## Management and treatment Management requires a prophylactic (avoiding direct or indirect contact with host animals) and therapeutic approach (local treatment and antimicrobial therapy). The most effective antibiotic treatment is penicillin G administration in non-allergic patients, and tetracycline and streptomycin in penicillin-allergic patients. ## Prognosis Prognosis is excellent if the disease is treated. If left untreated, RBF presents a mortality rate of approximately 10% due to complications. [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	Rat-bite fever	c0034686	2,896	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=31205	2021-01-23T17:22:52	{"gard": ["9557"], "mesh": ["D011906"], "umls": ["C0034686"], "icd-10": ["A25.0", "A25.1", "A25.9"]}
A number sign (#) is used with this entry because of evidence that type 2 (incomplete) X-linked congenital stationary night blindness is caused by mutation in the retina-specific calcium channel alpha-1-subunit gene (CACNA1F; 300110). Aland Island eye disease (300600), which has a similar phenotype, is caused by mutation in the same gene. For a general phenotypic description and discussion of genetic heterogeneity of congenital stationary night blindness, see CSNB1A (310500). Clinical Features X-linked congenital stationary night blindness is a nonprogressive retinal disorder characterized by decreased visual acuity and loss of night vision. Bergen et al. (1995) stated that X-linked CSNB (CSNBX) is clinically heterogeneous with respect to the involvement of retinal rods and/or cones in the disease. The classic form of X-linked congenital stationary night blindness (CSNB1; 310500) is associated with myopia. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa. Mapping The classic form of X-linked congenital stationary night blindness, CSNB1, shows mapping to Xp11.3. Bergen et al. (1995) localized a new locus for CSNBX to Xp21.1, thus providing evidence that X-linked CSNB is genetically as well as clinically heterogeneous. No clear correlation could be found between phenotypic differences and different map locations. The new CSNBX gene was closely linked to the RP3 gene region (see 312610), which supported the hypothesis that there is a functional relationship between congenital stationary night blindness and retinitis pigmentosa. Such a relationship is indicated by the fact that some mutations in the rhodopsin gene (RHO; 180380) cause congenital stationary night blindness (see 610445), although most cause retinitis pigmentosa. Autosomal dominant congenital stationary night blindness has also been related to mutations in the PDEB gene (180072), which maps to 4p16.3. Other mutations in the PDEB gene cause autosomal recessive retinitis pigmentosa. Bergen et al. (1996) reported findings they considered conclusive evidence for a distinct congenital stationary night blindness locus in Xp21.1. They described the results of linkage analysis in another large family, confirming the findings in the first family. The second locus is closely linked to the X-linked retinitis pigmentosa type 3 gene (RPGR; 312610) in Xp21.1. Boycott et al. (1998) studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form. Critical recombination events in the families with complete CSNB localized a disease gene to the region between DXS556 and DXS8083, in Xp11.4-p11.3. The critical recombination events in the set of families with incomplete CSNB localized a disease gene to the region between DXS722 and DXS8023 in Xp11.23. Further analysis of the incomplete CSNB families by means of disease associated-haplotype construction identified 17 families of apparent Mennonite ancestry that shared portions of an ancestral chromosome. The results of this analysis refined the location of the gene for incomplete CSNB to the region between DXS722 and DXS255, a distance of 1.2 Mb. Genetic and clinical analyses of this set of 32 families with X-linked CSNB, together with the family studies reported in the literature, strongly suggest that 2 loci, 1 for complete (CSNB1; 310500) and 1 for incomplete (CSNB2) X-linked CSNB, can account for all reported mapping information. Hardcastle et al. (1997) used the symbol CSNB4 for a second form of CSNB encoded by a gene on Xp. They described a new location for the form of CSNB on the proximal part of Xp, Xp11.4-p11.3, between the RP2 (312600) and RP3 loci. They found that 'CSNB4' is not allelic with any previously reported X-linked RP loci; however, the interval overlapped the locus reported to contain the CORDX1 gene (304020). Molecular Genetics Conducting mutation analysis in 13 families with the incomplete form of X-linked congenital stationary night blindness type 2, Strom et al. (1998) identified 9 different mutations in the CACNA1F gene in 10 families, including 3 nonsense and 1 frameshift mutation (see, e.g., 300110.0001-300110.0002). Similarly, by mutation analysis of the CACNA1F gene in 20 families with incomplete CSNB, Bech-Hansen et al. (1998) found 6 different mutations, all of which predicted premature protein truncation (see, e.g., 300110.0003-300110.0004). In 7 Japanese patients from 5 unrelated families with incomplete CSNB, Nakamura et al. (2001) identified 5 different mutations in the CACNA1F gene. Clinically, each patient had essentially normal fundi, mildly reduced corrected visual acuity, and slight myopia or hyperopia with astigmatism. Electrophysiologically, the mixed rod-cone ERG showed a negative configuration with recordable oscillatory potentials. The rod ERG was recordable but subnormal, and the cone and 30-Hz flicker ERGs were markedly depressed. Nakamura et al. (2001) concluded that in most Japanese patients with incomplete CSNB, the phenotype is caused by mutation in the CACNA1F gene. Pathogenesis The key symptoms of CSNB2 are impaired night vision and decreased visual acuity. The electrophysiologic hallmark is the Schubert and Bornschein type electroretinogram, in which the amplitude of the scotopic b-wave is smaller than that of the normal-sized a-wave. This finding suggests that the pathologic correlate of the disease is localized most likely at the photoreceptor-to-bipolar synapse. Baumann et al. (2004) found that the CACNA1F protein constitutes the major molecular correlate of the retinal L-type calcium current. Its intrinsic biophysical properties, in particular its unique inactivation properties, enable it to provide a sustained calcium current over the voltage range required for tonic glutamate release at the photoreceptor synapse. Animal Model Mansergh et al. (2005) generated a mouse with a loss-of-function mutation in exon 7 of the mouse Cacna1f gene. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wildtype mouse and absence of the postreceptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging of retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wildtype mice. The absence of postreceptoral ERG responses and the diminished photoreceptor calcium signals were consistent with a loss of Ca(2+) channel function in photoreceptors. Immunocytochemistry showed no detectable Cav1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Mansergh et al. (2005) concluded that the Cav1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses. Eyes \- Congenital stationary night blindness \- Decreased visual acuity \- Loss of night vision Inheritance \- X-linked form \- heterogeneous ▲ 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	NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE 2A	c0339535	2,897	omim	https://www.omim.org/entry/300071	2019-09-22T16:20:54	{"doid": ["0110871"], "mesh": ["C536122"], "omim": ["300071"], "orphanet": ["215"], "synonyms": ["Alternative titles", "CSNB, INCOMPLETE, X-LINKED", "NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE 2"], "genereviews": ["NBK1245"]}
A rare disorder of sexual maturation characterized by gonadotropin (Gn) deficiency with low sex steroid levels associated with low levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). ## Epidemiology Exact prevalence is unknown but is likely to be around 1/5,000. ## Clinical description CHH may be suspected at birth in males with micropenis (often associated with cryptorchidism), during adolescence due to the absence of puberty or during adulthood as a result of infertility. CHH is referred to as isolated (IHH) when the deficiency is restricted to the gonadal axis. Two subtypes of IHH have been defined: Kallmann syndrome (CHH with anosmia) mainly associated with abnormal embryonic migration of the Gn-releasing hormone (GnRH)-synthesizing neurons, and normosmic IHH (nIHH), in which HH is the only manifestation, mainly associated with anomalies in the regulation of GnRH signaling and secretion. CHH may also occur in association with other endocrine diseases such as multiple pituitary hormone deficiency, leptin deficiency, prohormone convertase-1 deficiency and adrenal hypoplasia. CHH is also a feature of several syndromes including the Prader-Willi, Bardet-Biedl, Laurence-Moon and CHARGE syndromes. ## Diagnostic methods Diagnosis is based on clinical evaluation of the hypogonadism (using the Tanner scale for patients diagnosed during adolescence) and laboratory findings from LHRH tests and measurements of LH and FSH levels to confirm the Gn deficiency. Laboratory tests should be performed either in the first six months of life or after patients reach a bone age of 13 years. Molecular analysis of candidate genes is also a useful diagnostic strategy. The following investigations are useful for guiding the molecular diagnosis and for determining the cause of CHH: familial and patient history, tests for anosmia and hearing loss, evaluation for signs associated with dental agenesis and developmental anomalies of the hands and feet, and MRI for identifying olfactory bulb and/or sulcus anomalies and for detecting developmental anomalies of the pituitary or pituitary stalk interruption syndrome. ## Differential diagnosis Differential diagnoses should include other causes of micropenis and cryptorchidism at birth (syndromic or isolated), transitory HH (associated with constitutional delay of puberty), hypothyroidism, and secondary causes of HH (hypothalamic-pituitary tumors or adenomas, surgical or radiation therapy-induced sequelae, etc.). ## Genetic counseling Genetic counseling may be proposed depending on the underlying disorder (syndromic or isolated) and mode of transmission (X-linked, or autosomal recessive or dominant). ## Management and treatment Management depends on the age of the patient: hormone therapy for treatment of micropenis during the neonatal period, induction of puberty at adolescence (estrogen therapy for females and testosterone for males), and fertility in adulthood. ## Prognosis The prognosis is generally good, with the outcome for fertility depending on the severity of the sex hormone deficiency and the age of initiation of treatment. Rare cases of complete resolution have been described but the physiopathology of the disease in these patients is not understood. [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	Isolated congenital hypogonadotropic hypogonadism	None	2,898	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=238666	2021-01-23T18:04:39	{"icd-10": ["E23.0"], "synonyms": ["Gonadotropic deficiency", "Isolated congenital gonadotropin deficiency", "Isolated gonadotropin-releasing hormone deficiency"]}
Benign type of pneumoconiosis Baritosis Barium SpecialtyPulmonology Baritosis is a benign type of pneumoconiosis, which is caused by long-term exposure to barium dust. Barium has a high radio-opacity and the disease may develop after few months of exposure. Extremely dense, discrete small opacities of 2–4 mm diameter, sometimes of a star-like configuration, are seen on the radiograph. Their distribution is uniform. When they are very numerous, superimposition may give the impression of confluency, but this does not seem to occur in reality. The hilar lymph nodes can be very opaque but not enlarged. After cessation of exposure, there is a gradual clearing of the opacities. ## Contents * 1 Symptoms and signs * 2 Diagnosis * 3 Treatment * 4 Reference * 5 External links ## Symptoms and signs[edit] * Cough * Wheezing * Nasal irritation In some cases, it is asymptomatic.[citation needed] ## Diagnosis[edit] The barium particles can be seen as opaque shadows on the chest X-rays of people with baritosis. However, being a benign condition, it neither interferes with lung function nor causes symptoms other than a mild cough.[citation needed] After exposure to barium dust ceases, the X-ray abnormalities gradually resolve.[1] ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## Reference[edit] 1. ^ Doig AT (February 1976). "Baritosis: a benign pneumoconiosis". Thorax. 31 (1): 30–9. doi:10.1136/thx.31.1.30. PMC 470358. PMID 1257935. * http://www.wrongdiagnosis.com/b/baritosis/intro.htm ## External links[edit] Classification D * ICD-9-CM: 503 * MeSH: C537080 C537080, C537080 * 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 This article about a medical condition affecting the respiratory system 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	Baritosis	c0340177	2,899	wikipedia	https://en.wikipedia.org/wiki/Baritosis	2021-01-18T18:50:26	{"gard": ["8371"], "mesh": ["C537080"], "umls": ["C0340177"], "icd-9": ["503"], "wikidata": ["Q2906693"]}

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