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nord_514_2 | Causes of Glanzmann Thrombasthenia | Glanzmann thrombasthenia is inherited in an autosomal recessive pattern. An abnormality in either the gene for aIIb (glycoprotein IIb; GPIIb) or the gene for β3 (glycoprotein IIIa; GPIIIa) results in an abnormal platelet aIIbβ3 (GPIIb/IIIa) integrin family receptor and prevents platelets from forming a plug when bleeding occurs. Many different changes (mutations or variants) in these genes have been identified. Recent evidence suggests that approximately 0.5% of healthy individuals in the general population are probably carrying one gene with an abnormal (pathogenic) variant of αIIb or β3.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. This is true for carriers of Glanzmann thrombasthenia. The risk for two carrier parents to both pass the abnormal gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive the normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Glanzmann Thrombasthenia. Glanzmann thrombasthenia is inherited in an autosomal recessive pattern. An abnormality in either the gene for aIIb (glycoprotein IIb; GPIIb) or the gene for β3 (glycoprotein IIIa; GPIIIa) results in an abnormal platelet aIIbβ3 (GPIIb/IIIa) integrin family receptor and prevents platelets from forming a plug when bleeding occurs. Many different changes (mutations or variants) in these genes have been identified. Recent evidence suggests that approximately 0.5% of healthy individuals in the general population are probably carrying one gene with an abnormal (pathogenic) variant of αIIb or β3.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. This is true for carriers of Glanzmann thrombasthenia. The risk for two carrier parents to both pass the abnormal gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive the normal genes from both parents is 25%. The risk is the same for males and females. | 514 | Glanzmann Thrombasthenia |
nord_514_3 | Affects of Glanzmann Thrombasthenia | Glanzmann thrombasthenia is a rare disorder that affects males and females in equal numbers. The symptoms of this disease are usually apparent at birth (neonates) or during infancy. Approximately 500 cases have been reported, but many cases have probably not been reported. This condition occurs with greater frequency in populations in which intermarriage within a group (consanguinity) is more prevalent such as in some regions of the Middle East, India and France. | Affects of Glanzmann Thrombasthenia. Glanzmann thrombasthenia is a rare disorder that affects males and females in equal numbers. The symptoms of this disease are usually apparent at birth (neonates) or during infancy. Approximately 500 cases have been reported, but many cases have probably not been reported. This condition occurs with greater frequency in populations in which intermarriage within a group (consanguinity) is more prevalent such as in some regions of the Middle East, India and France. | 514 | Glanzmann Thrombasthenia |
nord_514_4 | Related disorders of Glanzmann Thrombasthenia | Symptoms of other disorders listed below can be similar to those of Glanzmann thrombasthenia. Comparisons may be useful for a differential diagnosis:Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by an inactive or deficient blood protein, usually factor VIII or IX, both of which are needed for normal blood clotting. Factors VIII and IX are two of several proteins that enable the blood to clot. Hemophilia due to abnormalities in either factor VIII or IX is found in males almost exclusively because these genes are on the X chromosome and these disorders can be classified as mild, moderate or severe. The most common forms of bleeding are hemorrhage in joints and muscles and the most serious symptom of hemophilia is bleeding in the brain. Bleeding may begin spontaneously, that is, without any apparent cause. Bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal amount of clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in people with this disorder. (For more information on this disorder, choose “hemophilia” as your search term in the Rare Disease Database.)Bernard-Soulier syndrome is a rare inherited blood clotting (coagulation) disorder characterized by abnormalities of platelets, including very large (giant) platelets that do not adhere normally to damaged blood vessels because of an abnormal Glycoprotein Ib/IX/V complex. Symptoms include a tendency to bleed excessively and bruise easily. People with Bernard-Soulier syndrome tend to bleed profusely from cuts and other injuries. Nosebleeds and unusually heavy menstrual flow are also common. Bleeding into the skin may cause small pinpoint hemorrhage (petechiae) or large, purple-colored spots (purpura) in different areas of the body. (For more information on this disorder, choose “Bernard-Soulier” as your search term in the Rare Disease Database.)May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by reduced numbers of very large (giant) platelets. Patients usually do not bleed excessively unless they have very low platelet counts. (For more information on this disorder, choose “May Hegglin” as your search term in the Rare Disease Database.)Storage pool disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets’ inability to store and release certain clotting factors. Symptoms may include mild bleeding, nosebleeds, and heavier than normal menstrual periods. People with some forms of storage pool disease may also have abnormally low levels of blood platelets (thrombocytopenia).Some platelet disorders may be associated with congenital conditions such as Wiskott-Aldrich syndrome and thrombocytopenia with absent radius syndrome. (For more information on these disorders choose “Wiskott Aldrich,” and “thrombocytopenia absent radius,” as your search terms in the Rare Disease Database.) | Related disorders of Glanzmann Thrombasthenia. Symptoms of other disorders listed below can be similar to those of Glanzmann thrombasthenia. Comparisons may be useful for a differential diagnosis:Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by an inactive or deficient blood protein, usually factor VIII or IX, both of which are needed for normal blood clotting. Factors VIII and IX are two of several proteins that enable the blood to clot. Hemophilia due to abnormalities in either factor VIII or IX is found in males almost exclusively because these genes are on the X chromosome and these disorders can be classified as mild, moderate or severe. The most common forms of bleeding are hemorrhage in joints and muscles and the most serious symptom of hemophilia is bleeding in the brain. Bleeding may begin spontaneously, that is, without any apparent cause. Bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal amount of clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in people with this disorder. (For more information on this disorder, choose “hemophilia” as your search term in the Rare Disease Database.)Bernard-Soulier syndrome is a rare inherited blood clotting (coagulation) disorder characterized by abnormalities of platelets, including very large (giant) platelets that do not adhere normally to damaged blood vessels because of an abnormal Glycoprotein Ib/IX/V complex. Symptoms include a tendency to bleed excessively and bruise easily. People with Bernard-Soulier syndrome tend to bleed profusely from cuts and other injuries. Nosebleeds and unusually heavy menstrual flow are also common. Bleeding into the skin may cause small pinpoint hemorrhage (petechiae) or large, purple-colored spots (purpura) in different areas of the body. (For more information on this disorder, choose “Bernard-Soulier” as your search term in the Rare Disease Database.)May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by reduced numbers of very large (giant) platelets. Patients usually do not bleed excessively unless they have very low platelet counts. (For more information on this disorder, choose “May Hegglin” as your search term in the Rare Disease Database.)Storage pool disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets’ inability to store and release certain clotting factors. Symptoms may include mild bleeding, nosebleeds, and heavier than normal menstrual periods. People with some forms of storage pool disease may also have abnormally low levels of blood platelets (thrombocytopenia).Some platelet disorders may be associated with congenital conditions such as Wiskott-Aldrich syndrome and thrombocytopenia with absent radius syndrome. (For more information on these disorders choose “Wiskott Aldrich,” and “thrombocytopenia absent radius,” as your search terms in the Rare Disease Database.) | 514 | Glanzmann Thrombasthenia |
nord_514_5 | Diagnosis of Glanzmann Thrombasthenia | Most individuals affected with Glanzmann thrombasthenia have a normal number of platelets but have a prolonged bleeding time, which means it takes longer than usual for a standardized cut to stop bleeding. Platelet aggregation studies are abnormal and show that platelets are not able to clump together when stimulated as they should to form platelet aggregates. Glanzmann thrombasthenia is definitively diagnosed by tests that determine if there is a deficiency of the αIIbβ3 (GPIIb/IIIa) receptor. These tests usually involve monoclonal antibodies and flow cytometry. Genetic tests can identify the abnormal gene variants responsible for the disorder in the genes ITGA2B and ITGB3.Carrier and prenatal testing by DNA analysis is possible if the specific gene variants been identified in an affected family member. Otherwise, prenatal testing can be performed based on analyzing platelet αIIbβ3 in the fetus. | Diagnosis of Glanzmann Thrombasthenia. Most individuals affected with Glanzmann thrombasthenia have a normal number of platelets but have a prolonged bleeding time, which means it takes longer than usual for a standardized cut to stop bleeding. Platelet aggregation studies are abnormal and show that platelets are not able to clump together when stimulated as they should to form platelet aggregates. Glanzmann thrombasthenia is definitively diagnosed by tests that determine if there is a deficiency of the αIIbβ3 (GPIIb/IIIa) receptor. These tests usually involve monoclonal antibodies and flow cytometry. Genetic tests can identify the abnormal gene variants responsible for the disorder in the genes ITGA2B and ITGB3.Carrier and prenatal testing by DNA analysis is possible if the specific gene variants been identified in an affected family member. Otherwise, prenatal testing can be performed based on analyzing platelet αIIbβ3 in the fetus. | 514 | Glanzmann Thrombasthenia |
nord_514_6 | Therapies of Glanzmann Thrombasthenia | Treatment
Some individuals with GT may require blood platelet transfusions. Since transfusions may continue to be necessary throughout life, affected individuals may benefit from transfusions from HLA-matched donors. Some patients develop antibodies to transfused platelets and these antibodies may diminish the benefit from subsequent platelet transfusions.In 2014, NovoSeven RT, a recombinant factor VIIa product, was approved to treat Glanzmann thrombasthenia. This medication is indicated to treat bleeding episodes and perioperative management when platelet transfusions are not effective. Treatment is usually given prior to most surgical procedures or should be available if needed. Platelet transfusions are usually necessary prior to delivery.Nosebleeds can usually be treated with nasal packing or application of foam soaked in thrombin. Regular dental care is important to prevent bleeding from the gums.Hormonal therapy can be used to suppress menstrual periods.Other treatment of GT is included use of antifibrinolytic agents alone or in combination with other therapies.Genetic counseling is recommended for people with GT and their families. | Therapies of Glanzmann Thrombasthenia. Treatment
Some individuals with GT may require blood platelet transfusions. Since transfusions may continue to be necessary throughout life, affected individuals may benefit from transfusions from HLA-matched donors. Some patients develop antibodies to transfused platelets and these antibodies may diminish the benefit from subsequent platelet transfusions.In 2014, NovoSeven RT, a recombinant factor VIIa product, was approved to treat Glanzmann thrombasthenia. This medication is indicated to treat bleeding episodes and perioperative management when platelet transfusions are not effective. Treatment is usually given prior to most surgical procedures or should be available if needed. Platelet transfusions are usually necessary prior to delivery.Nosebleeds can usually be treated with nasal packing or application of foam soaked in thrombin. Regular dental care is important to prevent bleeding from the gums.Hormonal therapy can be used to suppress menstrual periods.Other treatment of GT is included use of antifibrinolytic agents alone or in combination with other therapies.Genetic counseling is recommended for people with GT and their families. | 514 | Glanzmann Thrombasthenia |
nord_515_0 | Overview of Glioblastoma | SummaryGlioblastomas are aggressive and malignant grade IV brain tumors that originate from the glial cells of the brain. Malignant tumors are tumors that can spread and infect other nearby cells. Glioblastomas originate from a type of glial cell called the astrocyte, so they are sometimes called astrocytomas. A grading system from I to IV defines the rate of tumor growth with grade I indicating slow growth and grade IV indicating rapid growth. Glioblastomas can often start off as grade IV tumors without any evidence of earlier lower grade tumors.Glioblastomas can be located anywhere in the brain and do not regularly spread outside of the brain. Common symptoms include headaches, seizures, confusion, memory loss, muscle weakness, visual changes, language deficit and cognitive changes. Glioblastomas tend to affect older individuals (age 45 to 70) with rare occurrences in children. Treatment methods typically include a combination of surgery, chemotherapy, radiation therapy and occasionally alternating electric fields therapy. The average survival time for patients with glioblastoma who have undergone combination treatments of surgery, chemotherapy and radiotherapy is 14.6 months.IntroductionThe World Health Organization classifies glioblastomas into 3 main categories. Glioblastoma isocitrate dehydrogenase (IDH)-mutant, glioblastoma IDH-wildtype and glioblastoma NOS (not otherwise specified). These classifications are based on the presence of an enzyme called IDH. Individuals with glioblastoma IDH-mutant protein in their bodies have a higher overall survival rate than those with glioblastoma IDH-wildtype protein. | Overview of Glioblastoma. SummaryGlioblastomas are aggressive and malignant grade IV brain tumors that originate from the glial cells of the brain. Malignant tumors are tumors that can spread and infect other nearby cells. Glioblastomas originate from a type of glial cell called the astrocyte, so they are sometimes called astrocytomas. A grading system from I to IV defines the rate of tumor growth with grade I indicating slow growth and grade IV indicating rapid growth. Glioblastomas can often start off as grade IV tumors without any evidence of earlier lower grade tumors.Glioblastomas can be located anywhere in the brain and do not regularly spread outside of the brain. Common symptoms include headaches, seizures, confusion, memory loss, muscle weakness, visual changes, language deficit and cognitive changes. Glioblastomas tend to affect older individuals (age 45 to 70) with rare occurrences in children. Treatment methods typically include a combination of surgery, chemotherapy, radiation therapy and occasionally alternating electric fields therapy. The average survival time for patients with glioblastoma who have undergone combination treatments of surgery, chemotherapy and radiotherapy is 14.6 months.IntroductionThe World Health Organization classifies glioblastomas into 3 main categories. Glioblastoma isocitrate dehydrogenase (IDH)-mutant, glioblastoma IDH-wildtype and glioblastoma NOS (not otherwise specified). These classifications are based on the presence of an enzyme called IDH. Individuals with glioblastoma IDH-mutant protein in their bodies have a higher overall survival rate than those with glioblastoma IDH-wildtype protein. | 515 | Glioblastoma |
nord_515_1 | Symptoms of Glioblastoma | Patients with glioblastoma present with two types of symptoms, generalized and focal. Generalized symptoms tend to occur in many types of brain tumors. These symptoms include headaches, seizures, nausea/vomiting, memory loss and decrease in normal function. Focal symptoms are dependent on the location and size of the tumor. The size and location of the tumor often influence the signs and symptoms seen in patients. For example, if the tumor is in the part of the brain required for language processing, the patient may have more issues speaking or understanding speech. Other than having language difficulty, other focal symptoms include seizures, muscle weakness, sensory loss and visual changes.Tumors can also cause the brain to swell because they grow. The tumors can push on parts of the brain which can lead to headaches, nausea and vomiting. Glioblastoma is an aggressive, fast-spreading tumor that effects nearby brain tissue. | Symptoms of Glioblastoma. Patients with glioblastoma present with two types of symptoms, generalized and focal. Generalized symptoms tend to occur in many types of brain tumors. These symptoms include headaches, seizures, nausea/vomiting, memory loss and decrease in normal function. Focal symptoms are dependent on the location and size of the tumor. The size and location of the tumor often influence the signs and symptoms seen in patients. For example, if the tumor is in the part of the brain required for language processing, the patient may have more issues speaking or understanding speech. Other than having language difficulty, other focal symptoms include seizures, muscle weakness, sensory loss and visual changes.Tumors can also cause the brain to swell because they grow. The tumors can push on parts of the brain which can lead to headaches, nausea and vomiting. Glioblastoma is an aggressive, fast-spreading tumor that effects nearby brain tissue. | 515 | Glioblastoma |
nord_515_2 | Causes of Glioblastoma | The exact cause of glioblastoma is unknown. However, there are factors that can influence the risk of glioblastomas. A risk factor known to be associated with glioblastoma is prior ionizing radiation therapy that uses high energy waves/particles to destroy cancer cells but can also cause normal cells to be damaged and even lead to new cancer cells forming. Other risk factors include employment in synthetic rubber manufacturing, petroleum refining and exposure to vinyl chloride or pesticides. It is important to note that individuals who are diagnosed with glioblastoma rarely have any of these risk factors. Likewise, those with these risk factors may never develop glioblastoma in their lifetime. Causation due to risk factors has not been established and further research is needed.Rare hereditary diseases such as Turcot syndrome, Li-Fraumeni syndrome and neurofibromatosis are associated with an increased risk of glioblastoma, but they only account for a small number of diagnoses. | Causes of Glioblastoma. The exact cause of glioblastoma is unknown. However, there are factors that can influence the risk of glioblastomas. A risk factor known to be associated with glioblastoma is prior ionizing radiation therapy that uses high energy waves/particles to destroy cancer cells but can also cause normal cells to be damaged and even lead to new cancer cells forming. Other risk factors include employment in synthetic rubber manufacturing, petroleum refining and exposure to vinyl chloride or pesticides. It is important to note that individuals who are diagnosed with glioblastoma rarely have any of these risk factors. Likewise, those with these risk factors may never develop glioblastoma in their lifetime. Causation due to risk factors has not been established and further research is needed.Rare hereditary diseases such as Turcot syndrome, Li-Fraumeni syndrome and neurofibromatosis are associated with an increased risk of glioblastoma, but they only account for a small number of diagnoses. | 515 | Glioblastoma |
nord_515_3 | Affects of Glioblastoma | About 3/100,000 people per year are affected by glioblastoma in the United States. The average age of diagnosis is 64 years of age with a slightly higher rate in men than women. Caucasians have the highest rate of glioblastoma diagnoses compared to other ethnic groups such as African Americans, Asians and Native Americans. | Affects of Glioblastoma. About 3/100,000 people per year are affected by glioblastoma in the United States. The average age of diagnosis is 64 years of age with a slightly higher rate in men than women. Caucasians have the highest rate of glioblastoma diagnoses compared to other ethnic groups such as African Americans, Asians and Native Americans. | 515 | Glioblastoma |
nord_515_4 | Related disorders of Glioblastoma | It is important to differentiate glioblastoma from other tumors that can affect the brain. These include but are not limited to chordomas, central nervous system (CNS) lymphomas, ependymoma, medulloblastomas, lower grade brain tumors and other cancers that have spread to the brain from other areas. Other conditions such as stroke, brain abscesses, brain bleeds and cavernous malformations can be mistaken for glioblastoma and should also be ruled out before a diagnosis is made. | Related disorders of Glioblastoma. It is important to differentiate glioblastoma from other tumors that can affect the brain. These include but are not limited to chordomas, central nervous system (CNS) lymphomas, ependymoma, medulloblastomas, lower grade brain tumors and other cancers that have spread to the brain from other areas. Other conditions such as stroke, brain abscesses, brain bleeds and cavernous malformations can be mistaken for glioblastoma and should also be ruled out before a diagnosis is made. | 515 | Glioblastoma |
nord_515_5 | Diagnosis of Glioblastoma | Individuals who are suspected to have a glioblastoma should first undergo a full physical and neurological examination. Neurological examinations are used to assess patient sensory and muscle responses. If any signs or symptoms of glioblastoma are present, the patient will require brain imaging using contrast-enhanced magnetic resonance imaging (MRI). MRI is often used to identify glioblastomas. It is a technique that creates detailed images of the human body. An MRI machine produces a strong magnetic field and directs radio waves towards the body. Computers interpret changes in the body caused by radio waves and produce images. Contrast dye is used to further enhance imaging. This makes it easier to distinguish tumors from normal cells. Although MRI can help identify possible glioblastomas, a tissue sample from a biopsy is required to make any definite diagnosis. A biopsy is an operation that removes tissues. A diagnosis should only be made when these tissues are confirmed to be a form of glioblastoma.Clinical Testing and Work Up
Many factors can affect disease progression as well as the success of treatment. These are IDH-mutation status, Karnofsky performance status (KPS) and O-6 methylguanine DNA methyltransferase (MGMT) status. Individuals with IDH-mutated genes have less aggressive tumors and respond better to treatment. KPS is an assessment to determine functional capacity. The higher the score, the more activities and independence the patient can experience. A score of 100 indicates a patient can perform all tasks normally with minor signs of the disease while a score of 50 indicates that the patient requires considerable help in everyday life. Those who score higher in the KPS assessment fair better with treatment. MGMT is an enzyme responsible for DNA repair. Methylation profiling can be used to provide information about a patient’s MGMT gene which can influence the effectiveness of chemotherapy for glioblastoma. Individuals with the normal form of this enzyme tend to fare better during and after chemotherapy. | Diagnosis of Glioblastoma. Individuals who are suspected to have a glioblastoma should first undergo a full physical and neurological examination. Neurological examinations are used to assess patient sensory and muscle responses. If any signs or symptoms of glioblastoma are present, the patient will require brain imaging using contrast-enhanced magnetic resonance imaging (MRI). MRI is often used to identify glioblastomas. It is a technique that creates detailed images of the human body. An MRI machine produces a strong magnetic field and directs radio waves towards the body. Computers interpret changes in the body caused by radio waves and produce images. Contrast dye is used to further enhance imaging. This makes it easier to distinguish tumors from normal cells. Although MRI can help identify possible glioblastomas, a tissue sample from a biopsy is required to make any definite diagnosis. A biopsy is an operation that removes tissues. A diagnosis should only be made when these tissues are confirmed to be a form of glioblastoma.Clinical Testing and Work Up
Many factors can affect disease progression as well as the success of treatment. These are IDH-mutation status, Karnofsky performance status (KPS) and O-6 methylguanine DNA methyltransferase (MGMT) status. Individuals with IDH-mutated genes have less aggressive tumors and respond better to treatment. KPS is an assessment to determine functional capacity. The higher the score, the more activities and independence the patient can experience. A score of 100 indicates a patient can perform all tasks normally with minor signs of the disease while a score of 50 indicates that the patient requires considerable help in everyday life. Those who score higher in the KPS assessment fair better with treatment. MGMT is an enzyme responsible for DNA repair. Methylation profiling can be used to provide information about a patient’s MGMT gene which can influence the effectiveness of chemotherapy for glioblastoma. Individuals with the normal form of this enzyme tend to fare better during and after chemotherapy. | 515 | Glioblastoma |
nord_515_6 | Therapies of Glioblastoma | Treatment
Multidisciplinary teams are essential for the treatment of glioblastomas. Each medical professional plays a critical role in treatment. These specialists include but are not limited to neuro-oncologist (diagnose and treat the disease), neurosurgeon (removes tumors), radiation oncologist (provides radiotherapy), nurses (providing necessary support and familiarity for the patient), social workers (help with any social needs), pathologist (distinguish tissue) and neuroradiologist (read MRI images). Treatment options include a combination of surgery, radio therapy, chemotherapy and alternating electric fields therapy.Maximal safe surgical resection of the glioblastoma is the first step in treatment. A maximal safe surgical resection means to remove as much as the tumor as possible while minimizing permanent damage to the brain. There are techniques used to increase the amount of tumor removed which include awake craniotomy, fluorescent dye, intraoperative MRI and endoscopic surgery. Awake craniotomy is performing the surgical removal of the tumor while the patient is awake. For example, if a tumor was located in the part of the brain which is required for speaking, surgery in that area may cause permanent speech deterioration. By having the patient awake and speaking to the surgeon, the patient can guide the surgery and achieve better results. Fluorescent dyes help distinguish the tumor from normal brain tissue when viewed under special light filters in the operating room which enables more of the tumor to be removed. An intraoperative MRI uses radio waves and a magnetic field to create an image of the brain during the operation and is used as a guide for the removal of tumors. An endoscopic surgery, or a minimally invasive surgery, is when a small camera-type device is inserted into the brain through a small opening in the head and is used to identify and remove tumors. It is important to note that surgery is not a cure for glioblastoma. Even if there is a complete removal of the glioblastoma tumor, there are many small undetectable tumor cells still present in the brain.Radiotherapy, or radiation therapy, is the next step in the treatment to manage the remaining tumor cells invading the brain. Radiation therapy damages the DNA of tumor cells. This slows or stops the progression of the disease. However, normal cells may also be damaged by radiation therapy. Common symptoms from receiving radiation therapy include but are not limited to fatigue, loss of hair, loss of appetite and skin problems. Due to the severe side effects, radiation therapy is not continued indefinitely.Chemotherapy can be used during and after radiotherapy as treatment for glioblastoma. Temozolomide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of glioblastoma. Bevacizumab and Gliadel wafer are chemotherapy agents that have also been approved by the FDA for the treatment of glioblastoma with limited success. Bevacizumab helps reduce the number of blood vessels to the tumor site. By reducing the number of blood vessels, the tumor is unable to receive nutrients to grow. Gliadel wafer is the first approved chemotherapy agent to deliver treatment directly to the brain. These wafers are applied to the tumor site. Of these chemotherapy agents, temozolomide is the most effective for the treatment of glioblastoma.Alternating electric fields can be used with chemotherapy, but not with radiation therapy. This treatment has been approved for both newly diagnosed and recurrent glioblastoma. Individuals shave their heads and electrodes are attached onto their scalp. These electrodes must stay on for the majority of the time, the longer the patient undergoes treatment, the better the results. The device generates an electric field that alternates back and forth preventing cancer cells from multiplying. | Therapies of Glioblastoma. Treatment
Multidisciplinary teams are essential for the treatment of glioblastomas. Each medical professional plays a critical role in treatment. These specialists include but are not limited to neuro-oncologist (diagnose and treat the disease), neurosurgeon (removes tumors), radiation oncologist (provides radiotherapy), nurses (providing necessary support and familiarity for the patient), social workers (help with any social needs), pathologist (distinguish tissue) and neuroradiologist (read MRI images). Treatment options include a combination of surgery, radio therapy, chemotherapy and alternating electric fields therapy.Maximal safe surgical resection of the glioblastoma is the first step in treatment. A maximal safe surgical resection means to remove as much as the tumor as possible while minimizing permanent damage to the brain. There are techniques used to increase the amount of tumor removed which include awake craniotomy, fluorescent dye, intraoperative MRI and endoscopic surgery. Awake craniotomy is performing the surgical removal of the tumor while the patient is awake. For example, if a tumor was located in the part of the brain which is required for speaking, surgery in that area may cause permanent speech deterioration. By having the patient awake and speaking to the surgeon, the patient can guide the surgery and achieve better results. Fluorescent dyes help distinguish the tumor from normal brain tissue when viewed under special light filters in the operating room which enables more of the tumor to be removed. An intraoperative MRI uses radio waves and a magnetic field to create an image of the brain during the operation and is used as a guide for the removal of tumors. An endoscopic surgery, or a minimally invasive surgery, is when a small camera-type device is inserted into the brain through a small opening in the head and is used to identify and remove tumors. It is important to note that surgery is not a cure for glioblastoma. Even if there is a complete removal of the glioblastoma tumor, there are many small undetectable tumor cells still present in the brain.Radiotherapy, or radiation therapy, is the next step in the treatment to manage the remaining tumor cells invading the brain. Radiation therapy damages the DNA of tumor cells. This slows or stops the progression of the disease. However, normal cells may also be damaged by radiation therapy. Common symptoms from receiving radiation therapy include but are not limited to fatigue, loss of hair, loss of appetite and skin problems. Due to the severe side effects, radiation therapy is not continued indefinitely.Chemotherapy can be used during and after radiotherapy as treatment for glioblastoma. Temozolomide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of glioblastoma. Bevacizumab and Gliadel wafer are chemotherapy agents that have also been approved by the FDA for the treatment of glioblastoma with limited success. Bevacizumab helps reduce the number of blood vessels to the tumor site. By reducing the number of blood vessels, the tumor is unable to receive nutrients to grow. Gliadel wafer is the first approved chemotherapy agent to deliver treatment directly to the brain. These wafers are applied to the tumor site. Of these chemotherapy agents, temozolomide is the most effective for the treatment of glioblastoma.Alternating electric fields can be used with chemotherapy, but not with radiation therapy. This treatment has been approved for both newly diagnosed and recurrent glioblastoma. Individuals shave their heads and electrodes are attached onto their scalp. These electrodes must stay on for the majority of the time, the longer the patient undergoes treatment, the better the results. The device generates an electric field that alternates back and forth preventing cancer cells from multiplying. | 515 | Glioblastoma |
nord_516_0 | Overview of Glioma | SummaryA glioma is a tumor of the central nervous system that arises from glial stem or progenitor cells. Glial cells are a type of cell widely present in the nervous system. Gliomas mostly occur in the brain and, rarely, in the spinal cord. They occur at various ages depending on the subtype. Gliomas can compress areas of the brain where they occur and cause various symptoms including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, language impairment (aphasia), numbness or weakness of one side of the body (hemiparesis), visual changes and personality changes. The treatment of gliomas often requires a combination of neurosurgical interventions, radiotherapy and chemotherapy.Introduction
Classification of gliomas is based on the microscopic appearance of the tumor and the molecular characteristics such as gene changes (mutations) in the tumor. Tumors are often graded 1-4 based on severity, with 4 being the most aggressive. Information about specific tumor types is available from the National Brain Tumor Society. | Overview of Glioma. SummaryA glioma is a tumor of the central nervous system that arises from glial stem or progenitor cells. Glial cells are a type of cell widely present in the nervous system. Gliomas mostly occur in the brain and, rarely, in the spinal cord. They occur at various ages depending on the subtype. Gliomas can compress areas of the brain where they occur and cause various symptoms including headaches, nausea, vomiting, cognitive impairment, seizures, gait imbalance, language impairment (aphasia), numbness or weakness of one side of the body (hemiparesis), visual changes and personality changes. The treatment of gliomas often requires a combination of neurosurgical interventions, radiotherapy and chemotherapy.Introduction
Classification of gliomas is based on the microscopic appearance of the tumor and the molecular characteristics such as gene changes (mutations) in the tumor. Tumors are often graded 1-4 based on severity, with 4 being the most aggressive. Information about specific tumor types is available from the National Brain Tumor Society. | 516 | Glioma |
nord_516_1 | Symptoms of Glioma | The symptoms associated with gliomas are similar among all types but can vary depending on the individual and the location of the tumor. Seizures (focal or generalized), language impairment (aphasia), weakness of part of the body (hemiparesis), sensory changes on part of the body and headaches are common. Other possible symptoms include gait disturbances, fatigue, dizziness, visual changes, vomiting and changes in urination. Psychological symptoms such as cognitive impairment, personality changes, depression, anxiety and memory impairment can also occur. Most of the symptoms are a consequence of the compressive effect of the tumor and fluid that surrounds it on the brain. Malignant gliomas (grade 3 and 4) are also associated with the development of blood clots in the deep veins, notably of the legs, (deep vein thrombosis) that can dislodge and migrate to occlude the arteries of the lungs (pulmonary embolism).Gliomas can develop at any age. The average age at which they occur greatly varies depending on the subtype of glioma. Similarly, the survival rate greatly depends on the subtype of glioma. In addition to being used for diagnosis and classification, the gene mutations present in tumor cells are also used to predict disease course and survival (prognosis). Over time, gliomas can increase in grade and, therefore, become more malignant (malignant progression). The rate of malignant progression depends on the subtype of glioma and on the genetic characteristics of affected cells. Higher grade tumors are typically associated with lower survival rates.Cells in gliomas have an altered glucose metabolism and can develop their own blood vessel network which allows them to sustain the high energy requirements for cell division and growth. Inflammation and accumulation of fluid around the tumor are also features of gliomas. Over time, certain types of gliomas can grow and invade healthy brain tissue extensively. | Symptoms of Glioma. The symptoms associated with gliomas are similar among all types but can vary depending on the individual and the location of the tumor. Seizures (focal or generalized), language impairment (aphasia), weakness of part of the body (hemiparesis), sensory changes on part of the body and headaches are common. Other possible symptoms include gait disturbances, fatigue, dizziness, visual changes, vomiting and changes in urination. Psychological symptoms such as cognitive impairment, personality changes, depression, anxiety and memory impairment can also occur. Most of the symptoms are a consequence of the compressive effect of the tumor and fluid that surrounds it on the brain. Malignant gliomas (grade 3 and 4) are also associated with the development of blood clots in the deep veins, notably of the legs, (deep vein thrombosis) that can dislodge and migrate to occlude the arteries of the lungs (pulmonary embolism).Gliomas can develop at any age. The average age at which they occur greatly varies depending on the subtype of glioma. Similarly, the survival rate greatly depends on the subtype of glioma. In addition to being used for diagnosis and classification, the gene mutations present in tumor cells are also used to predict disease course and survival (prognosis). Over time, gliomas can increase in grade and, therefore, become more malignant (malignant progression). The rate of malignant progression depends on the subtype of glioma and on the genetic characteristics of affected cells. Higher grade tumors are typically associated with lower survival rates.Cells in gliomas have an altered glucose metabolism and can develop their own blood vessel network which allows them to sustain the high energy requirements for cell division and growth. Inflammation and accumulation of fluid around the tumor are also features of gliomas. Over time, certain types of gliomas can grow and invade healthy brain tissue extensively. | 516 | Glioma |
nord_516_2 | Causes of Glioma | Gliomas are caused by the accumulation of genetic mutations in glial stem or progenitor cells, leading to their uncontrolled growth. Mutated genes are typically involved in functions such as tumor suppression, DNA repair and regulation of cell growth. Examples of mutated genes in certain types of gliomas include TP53, PTEN (tumor suppressor genes), ATRX (involved in the remodeling of chromatin, a DNA-RNA-protein complex), TERT (encoding a subunit of telomerase, an enzyme that can lead to an infinite division potential in cells) BRAF (involved in cell growth) and IDH (involved in cellular metabolism).The exact underlying cause of glioma development in most individuals is unknown. The only established environmental risk factor associated with gliomas is exposure to ionizing radiation, such as in atomic bomb survivors. Malignant gliomas can arise on their own (de novo) or can result from further accumulation of genetic mutations in low-grade gliomas (malignant progression). Cells from malignant gliomas have typically lost their specialized structure and function (de-differentiation or anaplasia). Initially, all cells in a glioma contain the same genetic code and are identical. Over time, different mutations accumulate in different cells of the tumor, thus leading to different subclones and a genetically heterogeneous tumor. Changes not affecting the genetic code directly, but rather how it is read and expressed (epigenetic modifications) are also involved in the growth and development of gliomas. | Causes of Glioma. Gliomas are caused by the accumulation of genetic mutations in glial stem or progenitor cells, leading to their uncontrolled growth. Mutated genes are typically involved in functions such as tumor suppression, DNA repair and regulation of cell growth. Examples of mutated genes in certain types of gliomas include TP53, PTEN (tumor suppressor genes), ATRX (involved in the remodeling of chromatin, a DNA-RNA-protein complex), TERT (encoding a subunit of telomerase, an enzyme that can lead to an infinite division potential in cells) BRAF (involved in cell growth) and IDH (involved in cellular metabolism).The exact underlying cause of glioma development in most individuals is unknown. The only established environmental risk factor associated with gliomas is exposure to ionizing radiation, such as in atomic bomb survivors. Malignant gliomas can arise on their own (de novo) or can result from further accumulation of genetic mutations in low-grade gliomas (malignant progression). Cells from malignant gliomas have typically lost their specialized structure and function (de-differentiation or anaplasia). Initially, all cells in a glioma contain the same genetic code and are identical. Over time, different mutations accumulate in different cells of the tumor, thus leading to different subclones and a genetically heterogeneous tumor. Changes not affecting the genetic code directly, but rather how it is read and expressed (epigenetic modifications) are also involved in the growth and development of gliomas. | 516 | Glioma |
nord_516_3 | Affects of Glioma | Excluding metastases from other cancers that reach the central nervous system, gliomas make up 26% of all brain tumors, (primary brain tumors) and 81% of all malignant brain tumors. They develop in approximately 6.6 per 100,000 individuals each year and 2.94 per 100,000 individuals under age 14. The median age (meaning that half of affected individuals are younger than this age and the other half are older) for the development of glioma is between 12 and 65 years, depending on the subtype. Pilocytic astrocytoma is the most common glioma in individuals under age 14 (34.4% of all gliomas) whereas glioblastoma is the most common glioma in adults (56.6% of all gliomas) (for more information on these types of gliomas, choose the specific glioma name as your search term in the Rare Disease Database).Gliomas are slightly more common in males. They tend to affect older individuals and are more common in countries with a higher level of development, as these countries generally have a larger proportion of older individuals. There are also several syndromes associated with a higher risk of glioma. | Affects of Glioma. Excluding metastases from other cancers that reach the central nervous system, gliomas make up 26% of all brain tumors, (primary brain tumors) and 81% of all malignant brain tumors. They develop in approximately 6.6 per 100,000 individuals each year and 2.94 per 100,000 individuals under age 14. The median age (meaning that half of affected individuals are younger than this age and the other half are older) for the development of glioma is between 12 and 65 years, depending on the subtype. Pilocytic astrocytoma is the most common glioma in individuals under age 14 (34.4% of all gliomas) whereas glioblastoma is the most common glioma in adults (56.6% of all gliomas) (for more information on these types of gliomas, choose the specific glioma name as your search term in the Rare Disease Database).Gliomas are slightly more common in males. They tend to affect older individuals and are more common in countries with a higher level of development, as these countries generally have a larger proportion of older individuals. There are also several syndromes associated with a higher risk of glioma. | 516 | Glioma |
nord_516_4 | Related disorders of Glioma | Related disorders of Glioma. | 516 | Glioma |
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nord_516_5 | Diagnosis of Glioma | A diagnosis of glioma requires an extensive patient history as well as a complete physical and neurological examination. Signs that further investigation might be required include a new onset of seizures, abrupt onset of cognitive decline and presence of other neurological symptoms. Headaches that develop or worsen abruptly, that begin to occur after age 50, that awaken the affected person from sleep even when they are mild and that are associated with cognitive impairment are warning signs that could indicate a brain mass.The presence of a brain tumor can be suspected with medical imaging. Magnetic resonance imaging (MRI) is the imaging modality of choice for initial evaluation of glioma. The final diagnosis, and therefore plan for treatment, can only be determined after a piece of tumor tissue is analyzed microscopically. Further characterization can be done by testing the DNA of the affected cells to determine if mutations in genes associated with certain subtypes of glioma are present. | Diagnosis of Glioma. A diagnosis of glioma requires an extensive patient history as well as a complete physical and neurological examination. Signs that further investigation might be required include a new onset of seizures, abrupt onset of cognitive decline and presence of other neurological symptoms. Headaches that develop or worsen abruptly, that begin to occur after age 50, that awaken the affected person from sleep even when they are mild and that are associated with cognitive impairment are warning signs that could indicate a brain mass.The presence of a brain tumor can be suspected with medical imaging. Magnetic resonance imaging (MRI) is the imaging modality of choice for initial evaluation of glioma. The final diagnosis, and therefore plan for treatment, can only be determined after a piece of tumor tissue is analyzed microscopically. Further characterization can be done by testing the DNA of the affected cells to determine if mutations in genes associated with certain subtypes of glioma are present. | 516 | Glioma |
nord_516_6 | Therapies of Glioma | Treatment
A large multi-disciplinary team of medical specialists and health professionals is required for the therapeutic management of patients with gliomas. Patients will usually come to the emergency room or be referred by their primary care physician for MRI. The MRI of the patient’s brain will then be interpreted by a radiologist or neuroradiologist and identify a mass. After an initial diagnosis is made, the patient will be considered for neurosurgery to safely remove as much of the tumor as possible (surgical resection. After surgery, a neuropathologist will examine and characterize the tumor under the microscope.The age of the patient, clinical symptoms, imaging findings and pathology analysis help to determine the best treatment options and the prognosis for the patient. Therapeutic management depends on the type of glioma, its size and location and the specific characteristics of the patient. Especially in patients where the tumor cannot be entirely removed because it is invading the brain in crucial areas or is not accessible, chemotherapy and radiotherapy will follow surgery. The collaboration of radiation oncologists and medical oncologists or neuro oncologists will therefore be required. Examples of chemotherapy for glioma include temozolomide and lomustine. These two medications are part of a drug class known as alkylating agents. Their therapeutic effect is to damage DNA of tumor cells that leads to tumor cell death. Well circumscribed gliomas might be managed by surgical resection only. MRI will usually be performed at certain intervals to assess the progression of the tumor and the effects of treatment.In addition to chemotherapy, medication prescribed to individuals with gliomas might include anti-epileptic medication (if the patient has seizures), anti-coagulation medication (if blood clots develop) and corticosteroids (to alleviate neurological symptoms caused by the accumulation of fluid around the tumor). Neurologists and possibly other medical specialists might be required for prescriptions and follow-up of affected individuals.Patients might have to undergo rehabilitation after surgery to recover function affected by the tumor and surgery. Rehabilitation teams comprise many health professionals, including physiotherapists, occupational therapists and nurses. Some patients may benefit from palliative care where they will receive optimal treatment to minimize their symptoms and pain, including analgesic medication, anti-epileptic medication and medication to prevent vomiting (antiemetics). | Therapies of Glioma. Treatment
A large multi-disciplinary team of medical specialists and health professionals is required for the therapeutic management of patients with gliomas. Patients will usually come to the emergency room or be referred by their primary care physician for MRI. The MRI of the patient’s brain will then be interpreted by a radiologist or neuroradiologist and identify a mass. After an initial diagnosis is made, the patient will be considered for neurosurgery to safely remove as much of the tumor as possible (surgical resection. After surgery, a neuropathologist will examine and characterize the tumor under the microscope.The age of the patient, clinical symptoms, imaging findings and pathology analysis help to determine the best treatment options and the prognosis for the patient. Therapeutic management depends on the type of glioma, its size and location and the specific characteristics of the patient. Especially in patients where the tumor cannot be entirely removed because it is invading the brain in crucial areas or is not accessible, chemotherapy and radiotherapy will follow surgery. The collaboration of radiation oncologists and medical oncologists or neuro oncologists will therefore be required. Examples of chemotherapy for glioma include temozolomide and lomustine. These two medications are part of a drug class known as alkylating agents. Their therapeutic effect is to damage DNA of tumor cells that leads to tumor cell death. Well circumscribed gliomas might be managed by surgical resection only. MRI will usually be performed at certain intervals to assess the progression of the tumor and the effects of treatment.In addition to chemotherapy, medication prescribed to individuals with gliomas might include anti-epileptic medication (if the patient has seizures), anti-coagulation medication (if blood clots develop) and corticosteroids (to alleviate neurological symptoms caused by the accumulation of fluid around the tumor). Neurologists and possibly other medical specialists might be required for prescriptions and follow-up of affected individuals.Patients might have to undergo rehabilitation after surgery to recover function affected by the tumor and surgery. Rehabilitation teams comprise many health professionals, including physiotherapists, occupational therapists and nurses. Some patients may benefit from palliative care where they will receive optimal treatment to minimize their symptoms and pain, including analgesic medication, anti-epileptic medication and medication to prevent vomiting (antiemetics). | 516 | Glioma |
nord_517_0 | Overview of Glucose Transporter Type 1 Deficiency Syndrome | SummaryGlucose transporter type 1 deficiency syndrome (Glut1DS) is a rare genetic metabolic disorder characterized by deficiency of a protein that is required for glucose (a simple sugar) to cross the blood-brain barrier and other tissue barriers. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. However, the symptoms and severity of Glut1DS can vary substantially from one person to another. For example, some affected individuals may not develop epilepsy. Additional symptoms that can occur include abnormal eye-head movements, body movement disorders, developmental delays, and varying degrees of cognitive impairment, slurred speech and language abnormalities. Glut1DS is caused by changes (mutations) in the SLC2A1 gene and is inherited in an autosomal dominant pattern. Rarely, the condition also may be inherited in an autosomal recessive pattern. Glut1DS does not respond to traditional epilepsy treatments (e.g., anti-seizure medications), but is successfully treated with the ketogenic diet.IntroductionGlut1DS was first described in the medical literature in 1991 by Dr. De Vivo, et al. The disorder is also known as De Vivo disease. Glut1DS is classified as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity is associated with progressive psychomotor dysfunction. Paroxysmal exercise-induced dyskinesias (PED), also known previously as dystonia 18 and dystonia 9, are now considered part of the Glut1DS spectrum. Epilepsy commonly presents in infancy whereas PED commonly emerges in late childhood and adolescence. | Overview of Glucose Transporter Type 1 Deficiency Syndrome. SummaryGlucose transporter type 1 deficiency syndrome (Glut1DS) is a rare genetic metabolic disorder characterized by deficiency of a protein that is required for glucose (a simple sugar) to cross the blood-brain barrier and other tissue barriers. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. However, the symptoms and severity of Glut1DS can vary substantially from one person to another. For example, some affected individuals may not develop epilepsy. Additional symptoms that can occur include abnormal eye-head movements, body movement disorders, developmental delays, and varying degrees of cognitive impairment, slurred speech and language abnormalities. Glut1DS is caused by changes (mutations) in the SLC2A1 gene and is inherited in an autosomal dominant pattern. Rarely, the condition also may be inherited in an autosomal recessive pattern. Glut1DS does not respond to traditional epilepsy treatments (e.g., anti-seizure medications), but is successfully treated with the ketogenic diet.IntroductionGlut1DS was first described in the medical literature in 1991 by Dr. De Vivo, et al. The disorder is also known as De Vivo disease. Glut1DS is classified as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity is associated with progressive psychomotor dysfunction. Paroxysmal exercise-induced dyskinesias (PED), also known previously as dystonia 18 and dystonia 9, are now considered part of the Glut1DS spectrum. Epilepsy commonly presents in infancy whereas PED commonly emerges in late childhood and adolescence. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_1 | Symptoms of Glucose Transporter Type 1 Deficiency Syndrome | Glut1DS represents a clinical spectrum disease. The symptoms and severity can vary dramatically from one individual to another. Mild cases often go undiagnosed, while other cases can potentially lead to severe, debilitating complications. It is important to note that affected individuals may not have all the classic symptoms discussed below or may have less severe symptoms. Affected individuals should talk to their physician and medical team about their specific clinical features, standard management and prognosis.The classic presentation of Glut1DS is the development of seizures during infancy usually during the first six months of life. The type, frequency and severity of seizures vary from one individual to another. In some individuals, seizures may be a daily occurrence; in other individuals, seizures may be separated by days, weeks, or months. Five different seizure types can occur including generalized tonic or clonic, myoclonic, atypical absence, atonic and unclassified.Generalized tonic-clonic seizures (once known as grand mal seizures), usually last a minute or more and are characterized by stiffening of the limbs (tonic phase) and then repeated jerking of the limbs and face (clonic phase). Generalized tonic-clonic seizures can cause people to momentarily lose consciousness, bite their lips, or drool.Myoclonic seizures are characterized by brief muscle contractions that cause abnormal, jerky movements.Atypical absence seizures are associated with a brief period of unconsciousness usually marked by unresponsive staring. Absence seizures usually begin and end abruptly and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be so mild that they go unnoticed. Often these spells may be misinterpreted as “day-dreaming”.Atonic seizures cause a sudden loss of muscle tone and limpness. They can cause the head to drop or nod, problems with posture or sudden falls. Atonic seizures are also known as drop attacks. Atonic seizures can lead to injuries of the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapse forward or backward at the waist. Atonic seizures may only partially affect consciousness and usually last only a few seconds.Unclassified seizures do not clearly fit into any of the standard seizure categories.Additional symptoms associated with Glut1DS include deceleration of head growth during infancy. Affected individuals can develop mild to moderate delays in attaining developmental milestones. Deceleration of head growth may lead to acquired microcephaly in some individuals, a condition marked by head circumference that falls below the 3rd percentile for age and gender.Individuals with Glut1DS may also develop disorders of movement including diminished muscle tone (hypotonia), poor balance or difficulty coordinating voluntary movements (ataxia), slow, stiff limb movements (spasticity) and awkward postures (dystonia). Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Movement disorders associated with Glut1DS can cause difficulty walking. Such difficulties can be a constant problem or may come and go (episodic or paroxysmal) often triggered by exercise.Individuals with Glut1DS also develop varying degrees of cognitive impairment, which can range from mild learning disabilities to severe intellectual disability. Some degree of speech and language impairment is usually present as well. Individuals may experience difficulty speaking due to abnormalities affecting the muscles that enable speech (dysarthria) and control the smooth flow or expression of speech (dysfluency). Speaking may be marked by frequent pauses or interruptions.Individuals with Glut1DS generally are friendly and enjoy socializing with others. Social adaptive behavior is viewed as a relative strength and affected individuals are comfortable in group situations.Additional symptoms have been reported in individuals with Glut1 deficiency syndrome including mental confusion, lethargy, drowsiness (somnolence), repeated, abnormal, rapid eye and head movements in both horizontal and vertical directions, paralysis of one side of the body (hemiparesis), total body paralysis, and recurrent headaches. Sleep disturbances such as sleep apnea have also been reported in individuals. These various symptoms can fluctuate in severity and may be influenced by additional factors such as fatigue or extended periods of time without eating (fasting). Sleep apnea and abnormal eye-head movements, like seizures, usually present in infancy as one of the first clinical signs and should immediately alert the physician to Glut1DS as a diagnostic possibility. Early diagnosis and treatment is associated with a better long term prognosis.Although most affected individuals develop so-called classic Glut1DS, some individuals develop different (non-classic) presentations (phenotypes). Some affected individuals develop movement disorders and cognitive impairment without epilepsy. In addition, a few individuals have been asymptomatic or had only mild symptoms of the disorder. These individuals might have a mixture of normal and mutated SLC2A1 genes, a condition known as mosaicismSome individuals with mutations in the SLC2A1 gene have also been identified who have paroxysmal exercise-induced dyskinesia (PED), a condition in which episodes of abnormal, involuntary movements occur, brought on by prolonged exercise such as walking or running long distances. These individuals may or may not have epilepsy as well. | Symptoms of Glucose Transporter Type 1 Deficiency Syndrome. Glut1DS represents a clinical spectrum disease. The symptoms and severity can vary dramatically from one individual to another. Mild cases often go undiagnosed, while other cases can potentially lead to severe, debilitating complications. It is important to note that affected individuals may not have all the classic symptoms discussed below or may have less severe symptoms. Affected individuals should talk to their physician and medical team about their specific clinical features, standard management and prognosis.The classic presentation of Glut1DS is the development of seizures during infancy usually during the first six months of life. The type, frequency and severity of seizures vary from one individual to another. In some individuals, seizures may be a daily occurrence; in other individuals, seizures may be separated by days, weeks, or months. Five different seizure types can occur including generalized tonic or clonic, myoclonic, atypical absence, atonic and unclassified.Generalized tonic-clonic seizures (once known as grand mal seizures), usually last a minute or more and are characterized by stiffening of the limbs (tonic phase) and then repeated jerking of the limbs and face (clonic phase). Generalized tonic-clonic seizures can cause people to momentarily lose consciousness, bite their lips, or drool.Myoclonic seizures are characterized by brief muscle contractions that cause abnormal, jerky movements.Atypical absence seizures are associated with a brief period of unconsciousness usually marked by unresponsive staring. Absence seizures usually begin and end abruptly and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be so mild that they go unnoticed. Often these spells may be misinterpreted as “day-dreaming”.Atonic seizures cause a sudden loss of muscle tone and limpness. They can cause the head to drop or nod, problems with posture or sudden falls. Atonic seizures are also known as drop attacks. Atonic seizures can lead to injuries of the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapse forward or backward at the waist. Atonic seizures may only partially affect consciousness and usually last only a few seconds.Unclassified seizures do not clearly fit into any of the standard seizure categories.Additional symptoms associated with Glut1DS include deceleration of head growth during infancy. Affected individuals can develop mild to moderate delays in attaining developmental milestones. Deceleration of head growth may lead to acquired microcephaly in some individuals, a condition marked by head circumference that falls below the 3rd percentile for age and gender.Individuals with Glut1DS may also develop disorders of movement including diminished muscle tone (hypotonia), poor balance or difficulty coordinating voluntary movements (ataxia), slow, stiff limb movements (spasticity) and awkward postures (dystonia). Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Movement disorders associated with Glut1DS can cause difficulty walking. Such difficulties can be a constant problem or may come and go (episodic or paroxysmal) often triggered by exercise.Individuals with Glut1DS also develop varying degrees of cognitive impairment, which can range from mild learning disabilities to severe intellectual disability. Some degree of speech and language impairment is usually present as well. Individuals may experience difficulty speaking due to abnormalities affecting the muscles that enable speech (dysarthria) and control the smooth flow or expression of speech (dysfluency). Speaking may be marked by frequent pauses or interruptions.Individuals with Glut1DS generally are friendly and enjoy socializing with others. Social adaptive behavior is viewed as a relative strength and affected individuals are comfortable in group situations.Additional symptoms have been reported in individuals with Glut1 deficiency syndrome including mental confusion, lethargy, drowsiness (somnolence), repeated, abnormal, rapid eye and head movements in both horizontal and vertical directions, paralysis of one side of the body (hemiparesis), total body paralysis, and recurrent headaches. Sleep disturbances such as sleep apnea have also been reported in individuals. These various symptoms can fluctuate in severity and may be influenced by additional factors such as fatigue or extended periods of time without eating (fasting). Sleep apnea and abnormal eye-head movements, like seizures, usually present in infancy as one of the first clinical signs and should immediately alert the physician to Glut1DS as a diagnostic possibility. Early diagnosis and treatment is associated with a better long term prognosis.Although most affected individuals develop so-called classic Glut1DS, some individuals develop different (non-classic) presentations (phenotypes). Some affected individuals develop movement disorders and cognitive impairment without epilepsy. In addition, a few individuals have been asymptomatic or had only mild symptoms of the disorder. These individuals might have a mixture of normal and mutated SLC2A1 genes, a condition known as mosaicismSome individuals with mutations in the SLC2A1 gene have also been identified who have paroxysmal exercise-induced dyskinesia (PED), a condition in which episodes of abnormal, involuntary movements occur, brought on by prolonged exercise such as walking or running long distances. These individuals may or may not have epilepsy as well. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_2 | Causes of Glucose Transporter Type 1 Deficiency Syndrome | Glut1DS is caused by mutations in the SLC2A1 gene. These mutations are inherited in an autosomal dominant (or rarely recessive) pattern. Most individuals with Glut1DS have a spontaneous genetic change (i.e., new mutation) in the SLC2A1 gene. In essence, the mutation started with the individual, was not inherited from the parents, but can be passed on to future generations.Dominant genetic disorders occur when only one copy of the abnormal gene causes the disease. Recessive genetic disorders require both copies to be abnormal. An abnormal gene can be inherited from either parent or can be the result of a new (de novo) mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The symptoms of Glut1DS result from decreased glucose transport into the brain. Glucose is a simple sugar and is the main source of fuel for brain metabolism. The SLC2A1 gene contains instructions for creating (encoding) a protein known as glucose transporter type 1 (Glut1). Mutations of the SLC2A1 gene result in lower levels of functional Glut1. Without proper levels of Glut1, the body cannot transport sufficient amounts of glucose across the blood-brain barrier and other cell membranes. The blood-brain barrier basically determines what materials from the blood can enter the brain. Without proper levels of glucose, the brain cannot grow and function properly. The exact consequences of reduced brain glucose levels and the links to the symptoms of Glut1DS are not fully understood. | Causes of Glucose Transporter Type 1 Deficiency Syndrome. Glut1DS is caused by mutations in the SLC2A1 gene. These mutations are inherited in an autosomal dominant (or rarely recessive) pattern. Most individuals with Glut1DS have a spontaneous genetic change (i.e., new mutation) in the SLC2A1 gene. In essence, the mutation started with the individual, was not inherited from the parents, but can be passed on to future generations.Dominant genetic disorders occur when only one copy of the abnormal gene causes the disease. Recessive genetic disorders require both copies to be abnormal. An abnormal gene can be inherited from either parent or can be the result of a new (de novo) mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.The symptoms of Glut1DS result from decreased glucose transport into the brain. Glucose is a simple sugar and is the main source of fuel for brain metabolism. The SLC2A1 gene contains instructions for creating (encoding) a protein known as glucose transporter type 1 (Glut1). Mutations of the SLC2A1 gene result in lower levels of functional Glut1. Without proper levels of Glut1, the body cannot transport sufficient amounts of glucose across the blood-brain barrier and other cell membranes. The blood-brain barrier basically determines what materials from the blood can enter the brain. Without proper levels of glucose, the brain cannot grow and function properly. The exact consequences of reduced brain glucose levels and the links to the symptoms of Glut1DS are not fully understood. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_3 | Affects of Glucose Transporter Type 1 Deficiency Syndrome | Glut1DS affects males and females in equal numbers. The incidence and prevalence of Glut1DS in the general population is unknown. Because the disorder may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Several hundred cases have been identified and described in the medical literature since 1991. The prevalence estimates have ranged from 1:90,000 to 1:24,000 suggesting that there are several thousand cases of Glut1DS in the USA. | Affects of Glucose Transporter Type 1 Deficiency Syndrome. Glut1DS affects males and females in equal numbers. The incidence and prevalence of Glut1DS in the general population is unknown. Because the disorder may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Several hundred cases have been identified and described in the medical literature since 1991. The prevalence estimates have ranged from 1:90,000 to 1:24,000 suggesting that there are several thousand cases of Glut1DS in the USA. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_4 | Related disorders of Glucose Transporter Type 1 Deficiency Syndrome | Symptoms of the following disorders can be shared with Glut1DS. Comparisons may be useful for a differential diagnosis.Epilepsy refers to a group of neurological disorders characterized by recurrent seizures and associated with abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion, and disturbances of the autonomic nervous system. Attacks may be preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain. This is often seen in partial-onset seizures. There are many different types of epilepsy and the exact cause is often unknown. Epilepsy can also occur as a sign of different syndromes such as West syndrome, Lennox-Gestaut syndrome, Rett syndrome, Angelman syndrome, Landau-Kleffner syndrome and Dravet syndrome. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Dystonia refers to a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas, or generalized (affecting many major muscle groups simultaneously). There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. The most characteristic finding associated with dystonia is twisting, repetitive movements that affect the neck, torso, limbs, eyes, face, vocal cords, or a combination of these muscle groups. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.)Additional disorders can cause symptoms or physical findings similar to Glut1DS. Such disorders include those that cause chronic or intermittent hypoglycemia, a variety of movement disorders, complicated migraine syndrome and opsoclonus-myoclonus syndrome. | Related disorders of Glucose Transporter Type 1 Deficiency Syndrome. Symptoms of the following disorders can be shared with Glut1DS. Comparisons may be useful for a differential diagnosis.Epilepsy refers to a group of neurological disorders characterized by recurrent seizures and associated with abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion, and disturbances of the autonomic nervous system. Attacks may be preceded by an “aura”, a feeling of unease or sensory discomfort; the aura marks the beginning of the seizure in the brain. This is often seen in partial-onset seizures. There are many different types of epilepsy and the exact cause is often unknown. Epilepsy can also occur as a sign of different syndromes such as West syndrome, Lennox-Gestaut syndrome, Rett syndrome, Angelman syndrome, Landau-Kleffner syndrome and Dravet syndrome. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)Dystonia refers to a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas, or generalized (affecting many major muscle groups simultaneously). There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. The most characteristic finding associated with dystonia is twisting, repetitive movements that affect the neck, torso, limbs, eyes, face, vocal cords, or a combination of these muscle groups. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.)Additional disorders can cause symptoms or physical findings similar to Glut1DS. Such disorders include those that cause chronic or intermittent hypoglycemia, a variety of movement disorders, complicated migraine syndrome and opsoclonus-myoclonus syndrome. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_5 | Diagnosis of Glucose Transporter Type 1 Deficiency Syndrome | A diagnosis of Glut1DS is confirmed by the presence of characteristic clinical features, hypoglycorrhachia and a disease-causing mutation in the SLC2A1 gene.Clinical Testing and Work-UpIndividuals suspected of Glut1DS should undergo a spinal tap (lumbar puncture). During this procedure, a needle is inserted into the spinal canal in the lower back allowing a physician to withdraw cerebrospinal fluid (CSF). The test should be performed in the post-absorptive state 4-6 hours after eating. Low CSF concentration of glucose (hypoglycorrhachia) in the absence of low blood sugar (hypoglycemia) is indicative of Glut1DS. Physicians should also measure lactate levels in the CSF. Lactate is low-normal or low in individuals with Glut1DS. These CSF findings are necessary but not sufficient to make the diagnosis of Glut1DS.The Glut1 protein is also found in red blood cell (erythrocyte) membrane. Testing is available on a research basis to assess erythrocyte glucose transporter activity, which is reduced by approximately 50 percent (35-73%) in individuals with Glut1DS. Decreased erythrocyte transport of glucose is a surrogate for decreased gene dosage (haploinsufficiency) and consistent with the diagnosis of Glut1DS.A positron emission tomography (PET) scan may be used to help support a diagnosis of Glut1DS. During a PET scan, three dimensional images are produced that reflect the brain’s chemical activity. However, the accuracy and reliability of PET scans in identifying reduced chemical activity (hypometabolism) in individuals with Glut1DS has not been established.A diagnosis of Glut1DS can be confirmed by molecular genetic testing that identifies a disease causing SLC2A1 gene mutation associated with the disorder. Hundreds of pathogenic SLC2A1 mutations have been identified. Molecular genetic testing is available through commercial and academic research laboratories | Diagnosis of Glucose Transporter Type 1 Deficiency Syndrome. A diagnosis of Glut1DS is confirmed by the presence of characteristic clinical features, hypoglycorrhachia and a disease-causing mutation in the SLC2A1 gene.Clinical Testing and Work-UpIndividuals suspected of Glut1DS should undergo a spinal tap (lumbar puncture). During this procedure, a needle is inserted into the spinal canal in the lower back allowing a physician to withdraw cerebrospinal fluid (CSF). The test should be performed in the post-absorptive state 4-6 hours after eating. Low CSF concentration of glucose (hypoglycorrhachia) in the absence of low blood sugar (hypoglycemia) is indicative of Glut1DS. Physicians should also measure lactate levels in the CSF. Lactate is low-normal or low in individuals with Glut1DS. These CSF findings are necessary but not sufficient to make the diagnosis of Glut1DS.The Glut1 protein is also found in red blood cell (erythrocyte) membrane. Testing is available on a research basis to assess erythrocyte glucose transporter activity, which is reduced by approximately 50 percent (35-73%) in individuals with Glut1DS. Decreased erythrocyte transport of glucose is a surrogate for decreased gene dosage (haploinsufficiency) and consistent with the diagnosis of Glut1DS.A positron emission tomography (PET) scan may be used to help support a diagnosis of Glut1DS. During a PET scan, three dimensional images are produced that reflect the brain’s chemical activity. However, the accuracy and reliability of PET scans in identifying reduced chemical activity (hypometabolism) in individuals with Glut1DS has not been established.A diagnosis of Glut1DS can be confirmed by molecular genetic testing that identifies a disease causing SLC2A1 gene mutation associated with the disorder. Hundreds of pathogenic SLC2A1 mutations have been identified. Molecular genetic testing is available through commercial and academic research laboratories | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_517_6 | Therapies of Glucose Transporter Type 1 Deficiency Syndrome | TreatmentThere is no cure for Glut1DS. The disorder is treated with the ketogenic diet, which may prevent seizure activity in many individuals with Glut1DS. The response of seizure activity to the ketogenic diet is often prompt and dramatic. It is recommended that the ketogenic diet be started as early as possible and be continued at least until adolescence. Compliance becomes a bigger problem as children grow and become more independent. However, the ketogenic diet seems to help individuals of all ages.The ketogenic diet is a high-fat, low-carbohydrate diet that causes the body to burn fat for energy instead of sugar (glucose). The ketogenic diet requires strict adherence to relatively rigid principles. Individuals who are on the ketogenic diet should be regularly monitored by their physicians, a dietician and a nutritionist because of the need to strictly adhere to the diet’s guidelines and the potential risk of side effects. Affected individuals on the diet will require supplemental treatment with vitamins, minerals and trace elements. Although the ketogenic diet is effective in treating seizures, it is less effective in treating cognitive impairment or behavioral issues. However, there are anecdotal reports that the ketogenic diet frequently leads to subjective improvement of cognition, mental alertness and endurance. But, clinical studies with standard neurocognitive tests have not been performed regarding the effect of the ketogenic diet on cognition in individuals with Glut1DS.The ketogenic diet is also effective in reducing the severity of movement disorders associated with the classical form of Glut1DS in approximately half of cases. It is even more effective in treating movement disorders in individuals with non-classical forms of Glut1DS.Thioctic acid, also known as alpha-lipoic acid, is a naturally occurring compound that is made in small amounts by the human body. Thioctic acid is believed to help glucose transport in the body and has been used as a supplement for some individuals with Glut1DS.Drugs that are used to treat seizures (anti-convulsants) are generally ineffective in treating individuals with Glut1DS. Other drugs including phenobarbital, narcotics and caffeine inhibit the function of Glut1 and can worsen Glut1DS in some affected individuals. Other drugs such as valproate, topiramate, zonisamide and acetazolamide may interfere with a ketogenic diet. All such drugs should be avoided by individuals with Glut1DS.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | Therapies of Glucose Transporter Type 1 Deficiency Syndrome. TreatmentThere is no cure for Glut1DS. The disorder is treated with the ketogenic diet, which may prevent seizure activity in many individuals with Glut1DS. The response of seizure activity to the ketogenic diet is often prompt and dramatic. It is recommended that the ketogenic diet be started as early as possible and be continued at least until adolescence. Compliance becomes a bigger problem as children grow and become more independent. However, the ketogenic diet seems to help individuals of all ages.The ketogenic diet is a high-fat, low-carbohydrate diet that causes the body to burn fat for energy instead of sugar (glucose). The ketogenic diet requires strict adherence to relatively rigid principles. Individuals who are on the ketogenic diet should be regularly monitored by their physicians, a dietician and a nutritionist because of the need to strictly adhere to the diet’s guidelines and the potential risk of side effects. Affected individuals on the diet will require supplemental treatment with vitamins, minerals and trace elements. Although the ketogenic diet is effective in treating seizures, it is less effective in treating cognitive impairment or behavioral issues. However, there are anecdotal reports that the ketogenic diet frequently leads to subjective improvement of cognition, mental alertness and endurance. But, clinical studies with standard neurocognitive tests have not been performed regarding the effect of the ketogenic diet on cognition in individuals with Glut1DS.The ketogenic diet is also effective in reducing the severity of movement disorders associated with the classical form of Glut1DS in approximately half of cases. It is even more effective in treating movement disorders in individuals with non-classical forms of Glut1DS.Thioctic acid, also known as alpha-lipoic acid, is a naturally occurring compound that is made in small amounts by the human body. Thioctic acid is believed to help glucose transport in the body and has been used as a supplement for some individuals with Glut1DS.Drugs that are used to treat seizures (anti-convulsants) are generally ineffective in treating individuals with Glut1DS. Other drugs including phenobarbital, narcotics and caffeine inhibit the function of Glut1 and can worsen Glut1DS in some affected individuals. Other drugs such as valproate, topiramate, zonisamide and acetazolamide may interfere with a ketogenic diet. All such drugs should be avoided by individuals with Glut1DS.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive. | 517 | Glucose Transporter Type 1 Deficiency Syndrome |
nord_518_0 | Overview of Glucose-6-Phosphate Dehydrogenase Deficiency | SummaryGlucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic abnormality caused by deficiency of the enzyme G6PD. This enzyme is critical for the proper function of red blood cells: when the level of this enzyme is too low, red blood cells can break down prematurely (hemolysis). When the body cannot compensate for accelerated loss, anemia develops. However, deficiency of this enzyme is not sufficient to cause hemolysis on its own; additional factors are required to “trigger” the onset of symptoms. Triggers of hemolysis in G6PD-deficient persons include certain infectious diseases, certain drugs, and eating fava beans: this can cause a potentially serious acute hemolytic anemia known as favism. Symptoms can include fatigue, pale color, jaundice or yellow skin color, shortness of breath, rapid heartbeat, dark urine and enlarged spleen (splenomegaly).Most important, in the absence of triggering factors, the majority of people with G6PD deficiency are normal, and they sail through life without any knowledge or any noticeable symptoms of the disorder. G6PD deficiency is caused by alterations (mutations) in the G6PD gene, and it maps to the X chromosome.IntroductionAs many as 400 different genetic variants of G6PD deficiency have been reported, and for 186 the precise mutation is known. The World Health Organization (WHO) has classified variants on the basis of residual enzyme activity and of disease severity. Class I are the most severe variants: those in which there is chronic hemolysis even in the absence of any triggering factor. Class II and III are variants with marked enzyme deficiency but no chronic hemolysis; class IV are variants with normal enzyme activity; class V was designed for variants with increased enzyme activity. Among the variants of which the clinical implications have been best characterized are G6PD Mediterranean, G6PD A- and G6PD Mahidol. | Overview of Glucose-6-Phosphate Dehydrogenase Deficiency. SummaryGlucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic abnormality caused by deficiency of the enzyme G6PD. This enzyme is critical for the proper function of red blood cells: when the level of this enzyme is too low, red blood cells can break down prematurely (hemolysis). When the body cannot compensate for accelerated loss, anemia develops. However, deficiency of this enzyme is not sufficient to cause hemolysis on its own; additional factors are required to “trigger” the onset of symptoms. Triggers of hemolysis in G6PD-deficient persons include certain infectious diseases, certain drugs, and eating fava beans: this can cause a potentially serious acute hemolytic anemia known as favism. Symptoms can include fatigue, pale color, jaundice or yellow skin color, shortness of breath, rapid heartbeat, dark urine and enlarged spleen (splenomegaly).Most important, in the absence of triggering factors, the majority of people with G6PD deficiency are normal, and they sail through life without any knowledge or any noticeable symptoms of the disorder. G6PD deficiency is caused by alterations (mutations) in the G6PD gene, and it maps to the X chromosome.IntroductionAs many as 400 different genetic variants of G6PD deficiency have been reported, and for 186 the precise mutation is known. The World Health Organization (WHO) has classified variants on the basis of residual enzyme activity and of disease severity. Class I are the most severe variants: those in which there is chronic hemolysis even in the absence of any triggering factor. Class II and III are variants with marked enzyme deficiency but no chronic hemolysis; class IV are variants with normal enzyme activity; class V was designed for variants with increased enzyme activity. Among the variants of which the clinical implications have been best characterized are G6PD Mediterranean, G6PD A- and G6PD Mahidol. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_1 | Symptoms of Glucose-6-Phosphate Dehydrogenase Deficiency | As stated above, most G6PD-deficient persons are asymptomatic most of the time; however, any one of them, when exposed to certain triggering factors, can develop acute hemolytic anemia (AHA), which may be life-threatening especially in children. Triggers for AHA in G6PD deficient persons include: (a) certain drugs (see Causes section), (b) certain infectious diseases, (c) ingestion of fava beans. The onset of symptoms is within 2-3 days after exposure to the trigger (even less with fava beans).A hemolytic anemia episode may be preceded by behavioral changes such as irritability or lethargy. Most episodes, even severe ones, are usually self-limiting and resolve on their own. The severity of episodes can vary greatly. Symptoms can include fatigue, pale color, shortness of breath, rapid heartbeat, dark urine, a sudden rise in body temperature, lower back pain, and an enlarged spleen (splenomegaly). Yellowing of the eyes, mucous membranes and skin (jaundice) is common. Gastrointestinal symptoms such as diarrhea, nausea or abdominal discomfort or pain may also occur.G6PD deficiency can cause neonatal jaundice, which is one of the most common conditions requiring medical attention in newborns. Jaundice is caused by excess levels of bilirubin in the blood. Bilirubin is an orange-yellow bile pigment that is a byproduct of the natural breakdown of hemoglobin in red blood cells. In rare cases in certain populations, if untreated, neonatal jaundice can progress to cause neurological issues such as kernicterus, a condition characterized by the accumulation of toxic levels of bilirubin in the brain, which cause lack of energy, poor feeding, fever, and vomiting.Acute hemolytic anemia from eating fava beans (favism) can be rapid. Favism can occur at any age, but occurs more often and more severely in children. A child may have a slightly elevated temperature within 24-48 hours and can become irritable and unruly, or subdued and lethargic. Nausea, abdominal pain and diarrhea may develop. Vomiting only occurs rarely. Within 6 to 24 hours, urine may become noticeably dark and can appear red, brown or even black. Affected children may become pale and their resting heartrate may be high (tachycardia). Jaundice can also develop and the liver and spleen may become enlarged. In severe cases, evidence may be seen of hypovolemic shock, in which blood and fluid loss is so severe that the heart cannot pump enough blood to the body, or, less likely, heart failure.In rare cases, certain affected individuals (i.e. those with class I variants) may experience chronic hemolytic anemia that is ongoing and occurs without the need for a triggering factor. These individuals may be referred to as having a type of congenital nonspherocytic hemolytic anemia. Such individuals are almost always male and usually develop neonatal jaundice. Affected children may also have an enlarged spleen. Most have a mild to moderate anemia, but severe, transfusion-dependent anemia can develop. Affected individuals can potentially develop severe complications such as hypovolemic shock. In rare cases, severe acute hemolysis has led to acute kidney failure. | Symptoms of Glucose-6-Phosphate Dehydrogenase Deficiency. As stated above, most G6PD-deficient persons are asymptomatic most of the time; however, any one of them, when exposed to certain triggering factors, can develop acute hemolytic anemia (AHA), which may be life-threatening especially in children. Triggers for AHA in G6PD deficient persons include: (a) certain drugs (see Causes section), (b) certain infectious diseases, (c) ingestion of fava beans. The onset of symptoms is within 2-3 days after exposure to the trigger (even less with fava beans).A hemolytic anemia episode may be preceded by behavioral changes such as irritability or lethargy. Most episodes, even severe ones, are usually self-limiting and resolve on their own. The severity of episodes can vary greatly. Symptoms can include fatigue, pale color, shortness of breath, rapid heartbeat, dark urine, a sudden rise in body temperature, lower back pain, and an enlarged spleen (splenomegaly). Yellowing of the eyes, mucous membranes and skin (jaundice) is common. Gastrointestinal symptoms such as diarrhea, nausea or abdominal discomfort or pain may also occur.G6PD deficiency can cause neonatal jaundice, which is one of the most common conditions requiring medical attention in newborns. Jaundice is caused by excess levels of bilirubin in the blood. Bilirubin is an orange-yellow bile pigment that is a byproduct of the natural breakdown of hemoglobin in red blood cells. In rare cases in certain populations, if untreated, neonatal jaundice can progress to cause neurological issues such as kernicterus, a condition characterized by the accumulation of toxic levels of bilirubin in the brain, which cause lack of energy, poor feeding, fever, and vomiting.Acute hemolytic anemia from eating fava beans (favism) can be rapid. Favism can occur at any age, but occurs more often and more severely in children. A child may have a slightly elevated temperature within 24-48 hours and can become irritable and unruly, or subdued and lethargic. Nausea, abdominal pain and diarrhea may develop. Vomiting only occurs rarely. Within 6 to 24 hours, urine may become noticeably dark and can appear red, brown or even black. Affected children may become pale and their resting heartrate may be high (tachycardia). Jaundice can also develop and the liver and spleen may become enlarged. In severe cases, evidence may be seen of hypovolemic shock, in which blood and fluid loss is so severe that the heart cannot pump enough blood to the body, or, less likely, heart failure.In rare cases, certain affected individuals (i.e. those with class I variants) may experience chronic hemolytic anemia that is ongoing and occurs without the need for a triggering factor. These individuals may be referred to as having a type of congenital nonspherocytic hemolytic anemia. Such individuals are almost always male and usually develop neonatal jaundice. Affected children may also have an enlarged spleen. Most have a mild to moderate anemia, but severe, transfusion-dependent anemia can develop. Affected individuals can potentially develop severe complications such as hypovolemic shock. In rare cases, severe acute hemolysis has led to acute kidney failure. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_2 | Causes of Glucose-6-Phosphate Dehydrogenase Deficiency | G6PD deficiency is caused by an alteration (mutation) in the G6PD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In people with G6PD deficiency, the gene mutation and resultant enzyme deficiency is not sufficient by itself to cause symptoms. The development of symptoms requires the specific interaction of an alteration in the G6PD gene in combination with a specific environmental factor.The G6PD gene contains instructions for creating (encoding) an enzyme known as glucose-6-phosphate dehydrogenase. As part of a chemical reaction, this enzyme brings about (catalyzes) the coenzyme NADPH, which protects cells from oxidative damage. A mutation in the G6PD gene results in low levels of functional glucose-6-phosphate dehydrogenase, which in turn leads to low levels of NADPH and a depletion of an antioxidant known as glutathione, which is necessary to protect the cell's hemoglobin and its cell wall (red cell membrane) from highly reactive oxygen radicals (oxidative stress). Normally, the amount of NADPH, although reduced, is adequate for the health of a red blood cell. However, this reduction in NADPH makes red blood cells more susceptible to destruction from oxidative stress than other cells, resulting in their premature break down when in the presence of triggering factors. G6PD is a housecleaning enzyme that is expressed in all cells of the body. However, the body can compensate for the effects of G6PD deficiency in cells other than red blood cells.More than 400 different mutations have been found in individuals with G6PD deficiency. Mutations, with the exception of the G6PD A mutation, are associated with more or less enzyme deficiency, but never with complete enzyme deficiency, which is not compatible with life. The disorder has been classified into variants based upon the degree of deficiency and associated clinical symptoms.In many cases, a mutation occurs as a new (sporadic or de novo) mutation, which means that in these cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will have the mutation. In cases with a family history, the G6PD gene mutation is inherited in an X-linked manner.X-linked disorders are conditions caused by an abnormal gene on the X chromosome. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. The G6PD gene is located on the long arm (q) of the X chromosome (Xq28).X-linked disorders affect males and females differently. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Females have two X chromosomes. Whether females with a mutation of G6PD gene develop glucose-6-phosphate deficiency depends on a normal process known as random X-chromosome inactivation. Because females have two X chromosomes, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome. This is known as random X-chromosome inactivation. Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some instances, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, they may have sufficient G6PD enzyme activity as to avoid developing symptoms even in the presence of triggering factors. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females are similar to affected males and can develop symptoms (e.g. hemolysis) associated with G6PD deficiency when in the presence of triggering factors.Daughters of female carriers of an X-linked disorder have a 50% chance be carriers themselves, whereas boys have a 50% chance of being affected.Some females, known as homozygotes, have a mutation in the G6PD gene on both X chromosomes and can develop symptoms in the presence of triggering factors depending upon the specific mutation present. Homozygous females are extremely rare.As stated previously, several different environmental factors can trigger an episode of acute hemolytic anemia in individuals who are GP6D-deficient. Such factors include certain drugs, eating fava beans, and certain bacterial and viral infections.Hemolytic anemia episodes can result from exposure to certain drugs. Among the many that have been cited as causative agents are: acetanilid, cotrimoxazole, dapsone, doxorubicin, furazolidone, methylene blue, moxifloxacin, nalidixic acid, naphthalene, niridazole, nitrofuratoin, norfloxacin, pamaquine, pentaquine, phenazopyridine, phenylhydrazine, primaquine, rasburicase, sulfacetamide, sulfanilamide, sulfapyridine, thiazolesulfone, toluidine blue, and trinitrotoluene. The exact degree of susceptibility to a drug varies from one person to another. Other drugs have been suggested as best avoided by individuals with G6PD deficiency; however, determining which additional drugs convey a specific risk of a hemolytic anemia episode is unclear.One drug of particular note is primaquine, an antimalarial drug that is the only drug that can eradicate dormant forms (hypnozoites) of the malarial-causing parasite, Plasmodium vivax. This is essential in preventing endogenous (“from within”) recurrence of malaria (as opposed to reinfection from becoming exposed to malaria again). Because of its importance in treating malaria, primaquine is probably the drug that has caused the most cases of acute hemolytic anemia in G6PD-deficient people. The World Health Organization has developed recommendations to prevent relapse of P. vivax. Primaquine is given whenever needed to people who have tested G6PD normal, and not given (or given only under medical/health worker surveillance) to those have tested G6PD-deficient. More information on this is available here:http://www.who.int/malaria/mpac/mpac_sep13_erg_g6pd_testing.pdf The geographic distribution of G6PD deficiency correlates strongly with the distribution of malaria. This has led researchers to speculate that the G6PD gene mutation conveys protection from malaria in these regions. Additional evidence exists that seems to confirm this theory and several studies have indicated that G6PD deficiency is malaria protective, especially against severe malaria. The specific manner how G6PD deficiency protects against malaria is not fully understood. It is possible that this protective quality is linked to the inability of malaria to grow efficiently in G6PD-deficient cells.Acute hemolytic anemia in G6PD-deficient people can develop after eating fava beans. This is known as favism. It was once thought that favism was an allergic reaction and that the condition could occur from inhalation of pollen. However, researchers have identified the chemicals, known as vicine and convicine, found within fava beans that trigger acute hemolytic anemia episodes in G6PD-deficient people. These chemicals occur in high concentrations within fava beans, but do not occur in other types of beans. Most individuals with G6PD deficiency do not develop symptoms after eating fava beans and individuals who do develop symptoms will not always do so. This suggests that additional factors such as mutations in other genes (e.g. modifier genes) may be necessary to develop favism.Episodes of acute hemolytic anemia may also result in some affected individuals when exposed to infectious diseases. Care must be taken to know what drugs can cause acute hemolytic anemia in G6PD-deficient people before they be given to the patient. However, there is significant confusion in the medical literature in this regard. Some drugs are considered dangerous because they were given to G6PD-deficient individuals whose symptoms were caused by the preexisting infection, yet misattributed to the drug.As described in the medical literature, some G6PD-deficient individuals are at a higher risk of widespread infection of the blood (sepsis) following severe trauma. | Causes of Glucose-6-Phosphate Dehydrogenase Deficiency. G6PD deficiency is caused by an alteration (mutation) in the G6PD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In people with G6PD deficiency, the gene mutation and resultant enzyme deficiency is not sufficient by itself to cause symptoms. The development of symptoms requires the specific interaction of an alteration in the G6PD gene in combination with a specific environmental factor.The G6PD gene contains instructions for creating (encoding) an enzyme known as glucose-6-phosphate dehydrogenase. As part of a chemical reaction, this enzyme brings about (catalyzes) the coenzyme NADPH, which protects cells from oxidative damage. A mutation in the G6PD gene results in low levels of functional glucose-6-phosphate dehydrogenase, which in turn leads to low levels of NADPH and a depletion of an antioxidant known as glutathione, which is necessary to protect the cell's hemoglobin and its cell wall (red cell membrane) from highly reactive oxygen radicals (oxidative stress). Normally, the amount of NADPH, although reduced, is adequate for the health of a red blood cell. However, this reduction in NADPH makes red blood cells more susceptible to destruction from oxidative stress than other cells, resulting in their premature break down when in the presence of triggering factors. G6PD is a housecleaning enzyme that is expressed in all cells of the body. However, the body can compensate for the effects of G6PD deficiency in cells other than red blood cells.More than 400 different mutations have been found in individuals with G6PD deficiency. Mutations, with the exception of the G6PD A mutation, are associated with more or less enzyme deficiency, but never with complete enzyme deficiency, which is not compatible with life. The disorder has been classified into variants based upon the degree of deficiency and associated clinical symptoms.In many cases, a mutation occurs as a new (sporadic or de novo) mutation, which means that in these cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will have the mutation. In cases with a family history, the G6PD gene mutation is inherited in an X-linked manner.X-linked disorders are conditions caused by an abnormal gene on the X chromosome. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. The G6PD gene is located on the long arm (q) of the X chromosome (Xq28).X-linked disorders affect males and females differently. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.Females have two X chromosomes. Whether females with a mutation of G6PD gene develop glucose-6-phosphate deficiency depends on a normal process known as random X-chromosome inactivation. Because females have two X chromosomes, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome. This is known as random X-chromosome inactivation. Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced.” This occurs randomly and generally happens as a 50-50 split. However, in some instances, females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells. In such cases, they may have sufficient G6PD enzyme activity as to avoid developing symptoms even in the presence of triggering factors. In other cases, females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells. In such cases, affected females are similar to affected males and can develop symptoms (e.g. hemolysis) associated with G6PD deficiency when in the presence of triggering factors.Daughters of female carriers of an X-linked disorder have a 50% chance be carriers themselves, whereas boys have a 50% chance of being affected.Some females, known as homozygotes, have a mutation in the G6PD gene on both X chromosomes and can develop symptoms in the presence of triggering factors depending upon the specific mutation present. Homozygous females are extremely rare.As stated previously, several different environmental factors can trigger an episode of acute hemolytic anemia in individuals who are GP6D-deficient. Such factors include certain drugs, eating fava beans, and certain bacterial and viral infections.Hemolytic anemia episodes can result from exposure to certain drugs. Among the many that have been cited as causative agents are: acetanilid, cotrimoxazole, dapsone, doxorubicin, furazolidone, methylene blue, moxifloxacin, nalidixic acid, naphthalene, niridazole, nitrofuratoin, norfloxacin, pamaquine, pentaquine, phenazopyridine, phenylhydrazine, primaquine, rasburicase, sulfacetamide, sulfanilamide, sulfapyridine, thiazolesulfone, toluidine blue, and trinitrotoluene. The exact degree of susceptibility to a drug varies from one person to another. Other drugs have been suggested as best avoided by individuals with G6PD deficiency; however, determining which additional drugs convey a specific risk of a hemolytic anemia episode is unclear.One drug of particular note is primaquine, an antimalarial drug that is the only drug that can eradicate dormant forms (hypnozoites) of the malarial-causing parasite, Plasmodium vivax. This is essential in preventing endogenous (“from within”) recurrence of malaria (as opposed to reinfection from becoming exposed to malaria again). Because of its importance in treating malaria, primaquine is probably the drug that has caused the most cases of acute hemolytic anemia in G6PD-deficient people. The World Health Organization has developed recommendations to prevent relapse of P. vivax. Primaquine is given whenever needed to people who have tested G6PD normal, and not given (or given only under medical/health worker surveillance) to those have tested G6PD-deficient. More information on this is available here:http://www.who.int/malaria/mpac/mpac_sep13_erg_g6pd_testing.pdf The geographic distribution of G6PD deficiency correlates strongly with the distribution of malaria. This has led researchers to speculate that the G6PD gene mutation conveys protection from malaria in these regions. Additional evidence exists that seems to confirm this theory and several studies have indicated that G6PD deficiency is malaria protective, especially against severe malaria. The specific manner how G6PD deficiency protects against malaria is not fully understood. It is possible that this protective quality is linked to the inability of malaria to grow efficiently in G6PD-deficient cells.Acute hemolytic anemia in G6PD-deficient people can develop after eating fava beans. This is known as favism. It was once thought that favism was an allergic reaction and that the condition could occur from inhalation of pollen. However, researchers have identified the chemicals, known as vicine and convicine, found within fava beans that trigger acute hemolytic anemia episodes in G6PD-deficient people. These chemicals occur in high concentrations within fava beans, but do not occur in other types of beans. Most individuals with G6PD deficiency do not develop symptoms after eating fava beans and individuals who do develop symptoms will not always do so. This suggests that additional factors such as mutations in other genes (e.g. modifier genes) may be necessary to develop favism.Episodes of acute hemolytic anemia may also result in some affected individuals when exposed to infectious diseases. Care must be taken to know what drugs can cause acute hemolytic anemia in G6PD-deficient people before they be given to the patient. However, there is significant confusion in the medical literature in this regard. Some drugs are considered dangerous because they were given to G6PD-deficient individuals whose symptoms were caused by the preexisting infection, yet misattributed to the drug.As described in the medical literature, some G6PD-deficient individuals are at a higher risk of widespread infection of the blood (sepsis) following severe trauma. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_3 | Affects of Glucose-6-Phosphate Dehydrogenase Deficiency | G6PD deficiency is one of the most common forms of enzyme deficiency and is believed to affect more than 400 million people worldwide. Although the prevalence is high, the vast majority of people remain clinically asymptomatic throughout their lives. Many medical sources state that the disorder is more common in males, but this is not accurate. Females who have an altered G6PD gene on one X chromosome (heterozygous females) are more common than males with an altered G6PD gene. Because of random X-chromosome inactivation (described in the ‘Causes’ section above), it is more likely that males will develop full blown G6PD deficiency than will females, but females can develop a similar disease expression as seen in males. Females with a G6PD mutation on both of their X chromosomes (homozygous females) have been reported in the medical literature, but are very rare.G6PD deficiency affects individuals of all races and ethnic backgrounds. The highest prevalence rates are found in Africa, the Middle East, certain parts of the Mediterranean, and certain areas in Asia. In these regions, the rate ranges from 5% to 30% of the population. The severity of G6PD deficiency can vary based upon specific racial groups. The severe form of the disorders occurs more often in the Mediterranean population.In the United States, the incidence is much higher among the African-American population than in other sectors. The frequency of a carrier state in which one partner carries a normal gene and the other carries an abnormal variant is as high as 24%. About 10%-14% of African-American males are affected. For example, two common variants occur in many African-American males. Approximately 20 to 25 percent have the near normal G6PD variant called “A+”, while about 10 to 13 percent have another variant called “A-”. Another relatively common G6PD variant is found particularly among individuals of Sephardic Jewish or Sardinian descent. In addition, another somewhat common variant is present among some individuals of southern Chinese descent. | Affects of Glucose-6-Phosphate Dehydrogenase Deficiency. G6PD deficiency is one of the most common forms of enzyme deficiency and is believed to affect more than 400 million people worldwide. Although the prevalence is high, the vast majority of people remain clinically asymptomatic throughout their lives. Many medical sources state that the disorder is more common in males, but this is not accurate. Females who have an altered G6PD gene on one X chromosome (heterozygous females) are more common than males with an altered G6PD gene. Because of random X-chromosome inactivation (described in the ‘Causes’ section above), it is more likely that males will develop full blown G6PD deficiency than will females, but females can develop a similar disease expression as seen in males. Females with a G6PD mutation on both of their X chromosomes (homozygous females) have been reported in the medical literature, but are very rare.G6PD deficiency affects individuals of all races and ethnic backgrounds. The highest prevalence rates are found in Africa, the Middle East, certain parts of the Mediterranean, and certain areas in Asia. In these regions, the rate ranges from 5% to 30% of the population. The severity of G6PD deficiency can vary based upon specific racial groups. The severe form of the disorders occurs more often in the Mediterranean population.In the United States, the incidence is much higher among the African-American population than in other sectors. The frequency of a carrier state in which one partner carries a normal gene and the other carries an abnormal variant is as high as 24%. About 10%-14% of African-American males are affected. For example, two common variants occur in many African-American males. Approximately 20 to 25 percent have the near normal G6PD variant called “A+”, while about 10 to 13 percent have another variant called “A-”. Another relatively common G6PD variant is found particularly among individuals of Sephardic Jewish or Sardinian descent. In addition, another somewhat common variant is present among some individuals of southern Chinese descent. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_4 | Related disorders of Glucose-6-Phosphate Dehydrogenase Deficiency | Symptoms of the following disorders can be similar to those of G6PD deficiency. Comparisons may be useful for a differential diagnosis.There are several disorders that are characterized by anemia due to the premature destructions of red blood cells (hemolytic anemia). These disorders include acquired autoimmune hemolytic anemia, pyruvate kinase deficiency, cold antibody hemolytic anemia, warm antibody hemolytic anemia, hereditary spherocytosis, and sickle cell anemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Glucose-6-Phosphate Dehydrogenase Deficiency. Symptoms of the following disorders can be similar to those of G6PD deficiency. Comparisons may be useful for a differential diagnosis.There are several disorders that are characterized by anemia due to the premature destructions of red blood cells (hemolytic anemia). These disorders include acquired autoimmune hemolytic anemia, pyruvate kinase deficiency, cold antibody hemolytic anemia, warm antibody hemolytic anemia, hereditary spherocytosis, and sickle cell anemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_5 | Diagnosis of Glucose-6-Phosphate Dehydrogenase Deficiency | A diagnosis is based upon the identification of characteristic physical findings and symptoms, a thorough clinical evaluation, a detailed patient history, and/or specialized tests. If a person experiences symptoms, e.g. blood in the urine, and spontaneously reports eating fava beans and comes from an area or a population where G6PD deficiency is common, suspicion of the disorder should be high.If doctors suspect a person is G6PD-deficient, they will conduct a variety of blood tests to confirm a diagnosis and rule out other conditions that cause similar conditions. The diagnosis depends upon demonstrating decreased activity of the G6PD enzyme through either a quantitative assay or a screening test such as fluorescent spot test Molecular genetic testing can detect mutations in the specific gene known to cause G6PD, but is available only as diagnostic service at specialized laboratories. | Diagnosis of Glucose-6-Phosphate Dehydrogenase Deficiency. A diagnosis is based upon the identification of characteristic physical findings and symptoms, a thorough clinical evaluation, a detailed patient history, and/or specialized tests. If a person experiences symptoms, e.g. blood in the urine, and spontaneously reports eating fava beans and comes from an area or a population where G6PD deficiency is common, suspicion of the disorder should be high.If doctors suspect a person is G6PD-deficient, they will conduct a variety of blood tests to confirm a diagnosis and rule out other conditions that cause similar conditions. The diagnosis depends upon demonstrating decreased activity of the G6PD enzyme through either a quantitative assay or a screening test such as fluorescent spot test Molecular genetic testing can detect mutations in the specific gene known to cause G6PD, but is available only as diagnostic service at specialized laboratories. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_518_6 | Therapies of Glucose-6-Phosphate Dehydrogenase Deficiency | Treatment
Most affected individuals do not require treatment. G6PD deficiency is often best managed by preventative measures. Individuals should be screened for the G6PD defect before being treated with certain drugs such as certain antibiotics, antimalarials and other medications known to trigger hemolysis in G6PD-deficient individuals. In individuals who are G6PD-deficient, hemolytic anemia from fava beans or from known drugs should not occur because exposure can be avoided.If an episode of hemolytic anemia is due to the use of a certain medication, the causative drug should be discontinued under a physician's supervision. If such an episode is due to an underlying infection, appropriate steps should be taken to treat the infection in question.Some adults may need short-term treatment with fluids to prevent hemodynamic shock (in which there is inadequate supply of blood to the organs) or, in severe cases where the rate of hemolysis is very rapid, even blood transfusions. Blood transfusions are more likely to be indicated in children than adults, and in children with favism can prove life-saving. Neonatal jaundice is treated by placing the infant under special lights (bili lights) that alleviate the jaundice. In more severe cases, an exchange transfusion may be necessary. This procedure involves removing an affected infant’s blood and replacing it with fresh donor blood or plasma.Genetic counseling may be of benefit for patients and their families. | Therapies of Glucose-6-Phosphate Dehydrogenase Deficiency. Treatment
Most affected individuals do not require treatment. G6PD deficiency is often best managed by preventative measures. Individuals should be screened for the G6PD defect before being treated with certain drugs such as certain antibiotics, antimalarials and other medications known to trigger hemolysis in G6PD-deficient individuals. In individuals who are G6PD-deficient, hemolytic anemia from fava beans or from known drugs should not occur because exposure can be avoided.If an episode of hemolytic anemia is due to the use of a certain medication, the causative drug should be discontinued under a physician's supervision. If such an episode is due to an underlying infection, appropriate steps should be taken to treat the infection in question.Some adults may need short-term treatment with fluids to prevent hemodynamic shock (in which there is inadequate supply of blood to the organs) or, in severe cases where the rate of hemolysis is very rapid, even blood transfusions. Blood transfusions are more likely to be indicated in children than adults, and in children with favism can prove life-saving. Neonatal jaundice is treated by placing the infant under special lights (bili lights) that alleviate the jaundice. In more severe cases, an exchange transfusion may be necessary. This procedure involves removing an affected infant’s blood and replacing it with fresh donor blood or plasma.Genetic counseling may be of benefit for patients and their families. | 518 | Glucose-6-Phosphate Dehydrogenase Deficiency |
nord_519_0 | Overview of Glucose-Galactose Malabsorption | SummaryGlucose-galactose malabsorption (GGM) is an inherited metabolic disorder. It is caused by the small intestines not being able to absorb and use glucose and galactose (simple sugars). Glucose and galactose have very similar chemical structures. The same protein carries both sugars into the intestines. The intestines absorb the simple sugars which are used throughout the body. The gene for GGM makes this enzyme work properly. When this gene is changed (mutated), the enzyme cannot bring the simple sugars into the small intestines, causing GGM. | Overview of Glucose-Galactose Malabsorption. SummaryGlucose-galactose malabsorption (GGM) is an inherited metabolic disorder. It is caused by the small intestines not being able to absorb and use glucose and galactose (simple sugars). Glucose and galactose have very similar chemical structures. The same protein carries both sugars into the intestines. The intestines absorb the simple sugars which are used throughout the body. The gene for GGM makes this enzyme work properly. When this gene is changed (mutated), the enzyme cannot bring the simple sugars into the small intestines, causing GGM. | 519 | Glucose-Galactose Malabsorption |
nord_519_1 | Symptoms of Glucose-Galactose Malabsorption | Symptoms usually begin in the first days of life, when a newborn drinks milk. Milk is broken down into simple sugars. Symptoms include severe diarrhea which can lead to life-threatening dehydration and difficulties gaining weight. The diarrhea and dehydration are fatal if left untreated. Once symptoms are managed, affected children typically have a normal lifespan. The symptoms may become less severe as patients age, which can allow for some sugars to be introduced back into their diet. Children with GGM can have infrequent diarrhea when eating high sugar foods. Mild amounts of sugar in the urine (glucosuria) of an affected child may be a warning that kidney stones are developing. In adults, symptoms of GGM may include bloating, nausea, diarrhea, abdominal cramps, rumbling sounds caused by gas in the intestine and frequent urination. | Symptoms of Glucose-Galactose Malabsorption. Symptoms usually begin in the first days of life, when a newborn drinks milk. Milk is broken down into simple sugars. Symptoms include severe diarrhea which can lead to life-threatening dehydration and difficulties gaining weight. The diarrhea and dehydration are fatal if left untreated. Once symptoms are managed, affected children typically have a normal lifespan. The symptoms may become less severe as patients age, which can allow for some sugars to be introduced back into their diet. Children with GGM can have infrequent diarrhea when eating high sugar foods. Mild amounts of sugar in the urine (glucosuria) of an affected child may be a warning that kidney stones are developing. In adults, symptoms of GGM may include bloating, nausea, diarrhea, abdominal cramps, rumbling sounds caused by gas in the intestine and frequent urination. | 519 | Glucose-Galactose Malabsorption |
nord_519_2 | Causes of Glucose-Galactose Malabsorption | Normally, the SCL5A1 gene creates a protein that transports glucose and galactose into the intestines and kidneys. These simple sugars are used throughout the body and removed through urination. When the gene is not working, the sugars are not transported and absorbed properly. There is nowhere for the glucose and galactose to go except into the stool. These sugars draw large amounts of water out of the body and into the stool, leading to watery (osmotic) diarrhea. GGM is a recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass on the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Glucose-Galactose Malabsorption. Normally, the SCL5A1 gene creates a protein that transports glucose and galactose into the intestines and kidneys. These simple sugars are used throughout the body and removed through urination. When the gene is not working, the sugars are not transported and absorbed properly. There is nowhere for the glucose and galactose to go except into the stool. These sugars draw large amounts of water out of the body and into the stool, leading to watery (osmotic) diarrhea. GGM is a recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass on the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 519 | Glucose-Galactose Malabsorption |
nord_519_3 | Affects of Glucose-Galactose Malabsorption | GGM is an extremely rare disorder. There are around 300 cases worldwide. It appears to be more common in females. Most cases are seen in families where the parents are related by blood because they are more likely to carry the same harmful gene change. | Affects of Glucose-Galactose Malabsorption. GGM is an extremely rare disorder. There are around 300 cases worldwide. It appears to be more common in females. Most cases are seen in families where the parents are related by blood because they are more likely to carry the same harmful gene change. | 519 | Glucose-Galactose Malabsorption |
nord_519_4 | Related disorders of Glucose-Galactose Malabsorption | The following disorders may appear with similar symptoms to GGM. Irritable bowel syndrome is a condition involving irritation of the small intestine which leads to diarrhea or constipation. Symptoms include abdominal pain, unpredictable bowel movements, variation in stool consistency, bloating, passing gas (flatulence), nausea, headache, fatigue, depression, anxiety and difficulty concentrating. Lactose intolerance is a condition characterized by an inability to break down the sugar in milk (lactose). The unabsorbed lactose remains in the intestine, causing symptoms of diarrhea, bloating, cramping pain, nausea and flatulence. People with this disorder must avoid milk and milk products, but can eat other sugars. Crohn’s disease is a chronic inflammatory condition which affects the large intestine. Symptoms may include chronic diarrhea, abdominal pain, fever and weight loss. (For more information on this disorder, choose “Pediatric Crohn’s disease” as your search term in the Rare Disease Database.) Galactosemia is an inherited condition in which galactose cannot be converted to glucose. Symptoms in children may include vomiting, lack of appetite, cataracts, jaundice and neurological problems. (For more information on this disorder, choose “galactosemia” as your search term in the Rare Disease Database.) | Related disorders of Glucose-Galactose Malabsorption. The following disorders may appear with similar symptoms to GGM. Irritable bowel syndrome is a condition involving irritation of the small intestine which leads to diarrhea or constipation. Symptoms include abdominal pain, unpredictable bowel movements, variation in stool consistency, bloating, passing gas (flatulence), nausea, headache, fatigue, depression, anxiety and difficulty concentrating. Lactose intolerance is a condition characterized by an inability to break down the sugar in milk (lactose). The unabsorbed lactose remains in the intestine, causing symptoms of diarrhea, bloating, cramping pain, nausea and flatulence. People with this disorder must avoid milk and milk products, but can eat other sugars. Crohn’s disease is a chronic inflammatory condition which affects the large intestine. Symptoms may include chronic diarrhea, abdominal pain, fever and weight loss. (For more information on this disorder, choose “Pediatric Crohn’s disease” as your search term in the Rare Disease Database.) Galactosemia is an inherited condition in which galactose cannot be converted to glucose. Symptoms in children may include vomiting, lack of appetite, cataracts, jaundice and neurological problems. (For more information on this disorder, choose “galactosemia” as your search term in the Rare Disease Database.) | 519 | Glucose-Galactose Malabsorption |
nord_519_5 | Diagnosis of Glucose-Galactose Malabsorption | GGM can be diagnosed by testing the SLC5A1 gene to look for harmful changes. Diagnosis may also be confirmed through restricting dietary sugars (glucose, galactose, sucrose and lactose) to see if the symptoms stop. Genetic testing is replacing the “glucose hydrogen breath test” which is now less frequently used. | Diagnosis of Glucose-Galactose Malabsorption. GGM can be diagnosed by testing the SLC5A1 gene to look for harmful changes. Diagnosis may also be confirmed through restricting dietary sugars (glucose, galactose, sucrose and lactose) to see if the symptoms stop. Genetic testing is replacing the “glucose hydrogen breath test” which is now less frequently used. | 519 | Glucose-Galactose Malabsorption |
nord_519_6 | Therapies of Glucose-Galactose Malabsorption | Treatment
Treatment involves avoiding milk, milk products, and foods with glucose and galactose. Patients will need to follow a low glucose and low galactose diet. Fructose, a different simple sugar, can be used as a substitute for glucose and galactose. Some individuals may eventually be able to introduce these foods back into their diet, however, others may need to follow these restrictions for life. It is recommended that patients with GGM speak to a nutritionist familiar with the condition to identify a low or glucose-galactose-free diet and to see if gradual reintroduction is tolerated. | Therapies of Glucose-Galactose Malabsorption. Treatment
Treatment involves avoiding milk, milk products, and foods with glucose and galactose. Patients will need to follow a low glucose and low galactose diet. Fructose, a different simple sugar, can be used as a substitute for glucose and galactose. Some individuals may eventually be able to introduce these foods back into their diet, however, others may need to follow these restrictions for life. It is recommended that patients with GGM speak to a nutritionist familiar with the condition to identify a low or glucose-galactose-free diet and to see if gradual reintroduction is tolerated. | 519 | Glucose-Galactose Malabsorption |
nord_520_0 | Overview of Glutaric Aciduria Type I | Summary
Glutaric aciduria type I (GA1) is a rare hereditary metabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). It is in the group of disorders known as cerebral organic acidemias. Individuals with this condition have deficiency or absence of GCDH enzyme that is involved in the lysine metabolism. GCDH deficiency results in increased concentrations of potentially neurotoxic metabolites, glutaric acid (GA), 3-hydroxy glutaric acid (3-OH-GA) and glutaconic acid within body tissues, especially within the brain, and also non-toxic glutarylcarnitine (C5DC). Two biochemical subtypes have been defined, high (HE) and low excretors (LE), depending on residual enzyme activity and the amount of GA in the urine. Newborns may show unspecific clinical signs like enlarged head circumference (macrocephaly) or decreased muscle tone (hypotonia). Without treatment, most affected children develop an acute encephalopathic crisis (AEC) following episodes of fever or other catabolic conditions resulting in bilateral striatal injury and consequently, dystonic movement disorder (MD), within the first three years of life. Single acute-onset events have been reported up to the age of six years. Besides acute-onset, individuals with insidious-onset type of striatal injury without an apparent crisis have also been described. Sometimes babies with GA1 have been mistaken to have been abused because they may present with subdural hemorrhages (SDH). Since early diagnosis and treatment dramatically improve outcome and prognosis, GA1 has been included in the newborn screening (NBS) panel in a constantly growing number of countries worldwide which is essential for early intervention. Importantly, some low excretor patients may be missed by newborn screening due to normal C5DC concentrations.Introduction
For 80-90% of people with GA1, motor symptom development is preventable, but this requires early diagnosis by NBS and metabolic treatment according to guideline recommendations from birth on. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, tryptophane-reduced and arginine-fortified amino acid supplement and oral carnitine supplementation as well as intermittent emergency treatment during episodes that are likely to induce catabolism, such as fever. If treatment is delayed or inadequate, motor symptoms begin to manifest acutely or insidiously during infancy or early childhood (before the age of 6) and are often highly variable. | Overview of Glutaric Aciduria Type I. Summary
Glutaric aciduria type I (GA1) is a rare hereditary metabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). It is in the group of disorders known as cerebral organic acidemias. Individuals with this condition have deficiency or absence of GCDH enzyme that is involved in the lysine metabolism. GCDH deficiency results in increased concentrations of potentially neurotoxic metabolites, glutaric acid (GA), 3-hydroxy glutaric acid (3-OH-GA) and glutaconic acid within body tissues, especially within the brain, and also non-toxic glutarylcarnitine (C5DC). Two biochemical subtypes have been defined, high (HE) and low excretors (LE), depending on residual enzyme activity and the amount of GA in the urine. Newborns may show unspecific clinical signs like enlarged head circumference (macrocephaly) or decreased muscle tone (hypotonia). Without treatment, most affected children develop an acute encephalopathic crisis (AEC) following episodes of fever or other catabolic conditions resulting in bilateral striatal injury and consequently, dystonic movement disorder (MD), within the first three years of life. Single acute-onset events have been reported up to the age of six years. Besides acute-onset, individuals with insidious-onset type of striatal injury without an apparent crisis have also been described. Sometimes babies with GA1 have been mistaken to have been abused because they may present with subdural hemorrhages (SDH). Since early diagnosis and treatment dramatically improve outcome and prognosis, GA1 has been included in the newborn screening (NBS) panel in a constantly growing number of countries worldwide which is essential for early intervention. Importantly, some low excretor patients may be missed by newborn screening due to normal C5DC concentrations.Introduction
For 80-90% of people with GA1, motor symptom development is preventable, but this requires early diagnosis by NBS and metabolic treatment according to guideline recommendations from birth on. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, tryptophane-reduced and arginine-fortified amino acid supplement and oral carnitine supplementation as well as intermittent emergency treatment during episodes that are likely to induce catabolism, such as fever. If treatment is delayed or inadequate, motor symptoms begin to manifest acutely or insidiously during infancy or early childhood (before the age of 6) and are often highly variable. | 520 | Glutaric Aciduria Type I |
nord_520_1 | Symptoms of Glutaric Aciduria Type I | Babies with GA1 are born healthy and may only have unspecific signs like macrocephaly or muscular hypotonia at birth. Macrocephaly is one of the earliest signs of GA1 so newborns with an enlarged head circumference should be evaluated for GA1. Especially during the age of 3 months to 3 years, most affected untreated babies develop an acute encephalopathic crisis which is triggered by catabolic conditions such as febrile infections, febrile reactions to vaccinations or surgery. These crises result in striatal injury and a complex, mostly dystonic, irreversible and severe movement disorder which is associated with high morbidity and mortality. These babies can experience several symptoms resembling those of cerebral palsy, such as frequently assuming odd positions due to disordered muscle tone (dystonia), involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs. Controlling the movement of hands, arms, feet, legs, head and neck may become very hard and muscle spasms may occur. Repeated stress on the body (such as infection and fever) can cause symptoms to worsen, but in some children, brain damage will occur without a triggering fever. Clinical early signs suggesting an “acute encephalopathic crisis” may comprise:• Irritability
• Jitteriness
• Nausea, vomiting, diarrhea
• Hypotonia (low muscle tone)
• Poor appetite or difficulty feeding
• Lack of energy/sleepy
• Muscle weaknessPossible irreversible neurologic symptoms of an acute encephalopathic crisis are:• Dyskinesia-disorder of involuntary muscle movements
• Dystonia – fixed abnormal postures due to abnormally increased muscle tone
• Orofacial dyskinesia
• Choreoathetosis—irregular migrating contractions, twisting, writhing
• Abnormality of eye movement- nystagmus (involuntary shaking of the eyes)
• Cognitive impairment (highly variable and not seen in many patients)
• Developmental regression
• Opisthotonus- full body spasms
• ComaBesides acute-onset, individuals with insidious onset type of striatal injury have been reported in up to 50% of symptomatic patients in NBS cohorts, primarily associated with deviations from dietary treatment recommendations. These patients show a milder degree of dystonic MD and a characteristic striatal injury pattern restricted to the dorsolateral putamen.
After age 6 years, a new onset of striatal injury has not been reported.Besides striatal pathology, all GA1 patients additionally may develop numerous extrastriatal MRI abnormalities, such as frontotemporal hypoplasia, widening of anterior temporal CSF spaces and the Sylvian fissure or white matter abnormalities.Although HE and LE patients have the same risk for developing striatal injury, HE patients show increased frequency of extra-striatal abnormalities, higher intracerebral concentrations of GA and 3-OHGA, larger head circumference, increased SDH and a poorer cognitive outcome.Some patients have been diagnosed in adolescence or adulthood (late-onset) with unspecific neurologic symptoms, such as polyneuropathy, incontinence, headache, dementia, tremor or epilepsy, without striatal injury.GA1 is associated with an increased risk of developing traumatic or incidental SDH and hygroma. SDH manifests mostly during the first 3 years of life, with a peak in late infancy and affecting primarily HE patients, usually associated with additional characteristic neuroradiologic abnormalities on MRI. In recent years, other neurologic disease manifestations have been reported such as chronic kidney disease in adolescent and adult patients. | Symptoms of Glutaric Aciduria Type I. Babies with GA1 are born healthy and may only have unspecific signs like macrocephaly or muscular hypotonia at birth. Macrocephaly is one of the earliest signs of GA1 so newborns with an enlarged head circumference should be evaluated for GA1. Especially during the age of 3 months to 3 years, most affected untreated babies develop an acute encephalopathic crisis which is triggered by catabolic conditions such as febrile infections, febrile reactions to vaccinations or surgery. These crises result in striatal injury and a complex, mostly dystonic, irreversible and severe movement disorder which is associated with high morbidity and mortality. These babies can experience several symptoms resembling those of cerebral palsy, such as frequently assuming odd positions due to disordered muscle tone (dystonia), involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs. Controlling the movement of hands, arms, feet, legs, head and neck may become very hard and muscle spasms may occur. Repeated stress on the body (such as infection and fever) can cause symptoms to worsen, but in some children, brain damage will occur without a triggering fever. Clinical early signs suggesting an “acute encephalopathic crisis” may comprise:• Irritability
• Jitteriness
• Nausea, vomiting, diarrhea
• Hypotonia (low muscle tone)
• Poor appetite or difficulty feeding
• Lack of energy/sleepy
• Muscle weaknessPossible irreversible neurologic symptoms of an acute encephalopathic crisis are:• Dyskinesia-disorder of involuntary muscle movements
• Dystonia – fixed abnormal postures due to abnormally increased muscle tone
• Orofacial dyskinesia
• Choreoathetosis—irregular migrating contractions, twisting, writhing
• Abnormality of eye movement- nystagmus (involuntary shaking of the eyes)
• Cognitive impairment (highly variable and not seen in many patients)
• Developmental regression
• Opisthotonus- full body spasms
• ComaBesides acute-onset, individuals with insidious onset type of striatal injury have been reported in up to 50% of symptomatic patients in NBS cohorts, primarily associated with deviations from dietary treatment recommendations. These patients show a milder degree of dystonic MD and a characteristic striatal injury pattern restricted to the dorsolateral putamen.
After age 6 years, a new onset of striatal injury has not been reported.Besides striatal pathology, all GA1 patients additionally may develop numerous extrastriatal MRI abnormalities, such as frontotemporal hypoplasia, widening of anterior temporal CSF spaces and the Sylvian fissure or white matter abnormalities.Although HE and LE patients have the same risk for developing striatal injury, HE patients show increased frequency of extra-striatal abnormalities, higher intracerebral concentrations of GA and 3-OHGA, larger head circumference, increased SDH and a poorer cognitive outcome.Some patients have been diagnosed in adolescence or adulthood (late-onset) with unspecific neurologic symptoms, such as polyneuropathy, incontinence, headache, dementia, tremor or epilepsy, without striatal injury.GA1 is associated with an increased risk of developing traumatic or incidental SDH and hygroma. SDH manifests mostly during the first 3 years of life, with a peak in late infancy and affecting primarily HE patients, usually associated with additional characteristic neuroradiologic abnormalities on MRI. In recent years, other neurologic disease manifestations have been reported such as chronic kidney disease in adolescent and adult patients. | 520 | Glutaric Aciduria Type I |
nord_520_2 | Causes of Glutaric Aciduria Type I | GA1 is caused by pathogenic variants in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase or GCDH. This enzyme is responsible for metabolizing the amino acids lysine, hydroxylysine and tryptophan. Pathogenic variants in GCDH prevent production of the enzyme resulting in abnormal levels of glutaric, 3-hydroxyglutaric and (to a lesser extent) glutaconic acids These products accumulate and cause damage to an area of the brain called the basal ganglia that regulates motor movement.GA1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | Causes of Glutaric Aciduria Type I. GA1 is caused by pathogenic variants in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase or GCDH. This enzyme is responsible for metabolizing the amino acids lysine, hydroxylysine and tryptophan. Pathogenic variants in GCDH prevent production of the enzyme resulting in abnormal levels of glutaric, 3-hydroxyglutaric and (to a lesser extent) glutaconic acids These products accumulate and cause damage to an area of the brain called the basal ganglia that regulates motor movement.GA1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. | 520 | Glutaric Aciduria Type I |
nord_520_3 | Affects of Glutaric Aciduria Type I | GA1 is a rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 patients with this type of organic aciduria in the United States. GA1 occurs in approximately 1 of every 100,000 births. Five genetic isolates are known with a high carrier frequency (up to 1:10) and incidence (up to 1:250 newborns): the Old Order Amish Community in Lancaster County, Pennsylvania, United States, the Oji-Cree First Nations in Manitoba and Western Ontario, Canada, the Irish Travelers in the Republic of Ireland and United Kingdom, the Lumbee in North Carolina, United States and the Xhosa in South Africa. | Affects of Glutaric Aciduria Type I. GA1 is a rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 patients with this type of organic aciduria in the United States. GA1 occurs in approximately 1 of every 100,000 births. Five genetic isolates are known with a high carrier frequency (up to 1:10) and incidence (up to 1:250 newborns): the Old Order Amish Community in Lancaster County, Pennsylvania, United States, the Oji-Cree First Nations in Manitoba and Western Ontario, Canada, the Irish Travelers in the Republic of Ireland and United Kingdom, the Lumbee in North Carolina, United States and the Xhosa in South Africa. | 520 | Glutaric Aciduria Type I |
nord_520_4 | Related disorders of Glutaric Aciduria Type I | There are many rare disorders caused by enzyme deficiencies, so misdiagnosis is common for a GA1 patient. Differential diagnosis includes encephalitis, Reye’s syndrome, familial infantile bilateral striatal necrosis, familial megalocephaly, post encephalitic parkinsonism, dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury. Increased levels of 3‐OH‐GA, typical in GA1 patients, have been found in patients with short‐chain 3‐hydroxyacyl CoA dehydrogenase (SCAD) deficiency, patients with renal insufficiency, in patients with disorders of long‐chain fatty acid oxidation and mitochondrial disorders, and in ketotic patients.Glutaric aciduria type II is a totally different disease and belongs to the group of fatty acid oxidation disorders. These are metabolic disorders characterized by a lack of the enzymes needed to break down fats, resulting in delayed mental and physical development. Two forms of this disorder occur during different stages of life.1) Glutaric aciduria IIA (GA IIA) is the neonatal form of glutaricaciduria II. This form of glutaric aciduria II is a very rare, X-linked hereditary disorder characterized by large amounts of glutaric and other acids in blood and urine. The disorder is caused by dysfunction of the electron-transferring flavoprotein in the mitochondria.2) Glutarica aciduria IIB (GA IIB; ethylmalonic adipicaciduria) is the adult form of glutaricaciduria II. This milder form of the disorder is inherited in an autosomal recessive pattern. Acidity of the body tissues (metabolic acidosis), and a low blood sugar level (hypoglycemia) without an elevated level of ketones in body tissues (ketosis), occur during adulthood. Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme multiple acyl-CoA dehydrogenase. (For more information on this disorder, choose “glutaric aciduria II” as your search term in the Rare Disease Database.)Glutaric aciduria III is an autosomal recessive genetic condition characterized by accumulation or excretion of glutaric acid and caused by pathogenic variants in the C7ORF10 gene. Symptoms vary and some individuals show no symptoms. | Related disorders of Glutaric Aciduria Type I. There are many rare disorders caused by enzyme deficiencies, so misdiagnosis is common for a GA1 patient. Differential diagnosis includes encephalitis, Reye’s syndrome, familial infantile bilateral striatal necrosis, familial megalocephaly, post encephalitic parkinsonism, dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury. Increased levels of 3‐OH‐GA, typical in GA1 patients, have been found in patients with short‐chain 3‐hydroxyacyl CoA dehydrogenase (SCAD) deficiency, patients with renal insufficiency, in patients with disorders of long‐chain fatty acid oxidation and mitochondrial disorders, and in ketotic patients.Glutaric aciduria type II is a totally different disease and belongs to the group of fatty acid oxidation disorders. These are metabolic disorders characterized by a lack of the enzymes needed to break down fats, resulting in delayed mental and physical development. Two forms of this disorder occur during different stages of life.1) Glutaric aciduria IIA (GA IIA) is the neonatal form of glutaricaciduria II. This form of glutaric aciduria II is a very rare, X-linked hereditary disorder characterized by large amounts of glutaric and other acids in blood and urine. The disorder is caused by dysfunction of the electron-transferring flavoprotein in the mitochondria.2) Glutarica aciduria IIB (GA IIB; ethylmalonic adipicaciduria) is the adult form of glutaricaciduria II. This milder form of the disorder is inherited in an autosomal recessive pattern. Acidity of the body tissues (metabolic acidosis), and a low blood sugar level (hypoglycemia) without an elevated level of ketones in body tissues (ketosis), occur during adulthood. Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme multiple acyl-CoA dehydrogenase. (For more information on this disorder, choose “glutaric aciduria II” as your search term in the Rare Disease Database.)Glutaric aciduria III is an autosomal recessive genetic condition characterized by accumulation or excretion of glutaric acid and caused by pathogenic variants in the C7ORF10 gene. Symptoms vary and some individuals show no symptoms. | 520 | Glutaric Aciduria Type I |
nord_520_5 | Diagnosis of Glutaric Aciduria Type I | GA1 Is diagnosed by the characteristic metabolites GA, 3-OH-GA, glutaconic acid and glutarylcarnitine (C5DC) detected in body fluids (urine, plasma, CSF) and tissues using gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS). As neonatal diagnosis and start of treatment significantly improves neurologic outcome, GA1 has been included in MS/MS based NBS disease panels in many countries worldwide.Abnormal newborn screening results should be confirmed by quantitative analysis of GA and 3-OH-GA in urine and/or blood with GC/MS, variant analysis of the GCDH gene and/or GCDH enzyme analysis in leukocytes or fibroblasts. The diagnosis is confirmed by significantly reduced enzyme activity and/or detection of two disease-causing GCDH gene variants. | Diagnosis of Glutaric Aciduria Type I. GA1 Is diagnosed by the characteristic metabolites GA, 3-OH-GA, glutaconic acid and glutarylcarnitine (C5DC) detected in body fluids (urine, plasma, CSF) and tissues using gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS). As neonatal diagnosis and start of treatment significantly improves neurologic outcome, GA1 has been included in MS/MS based NBS disease panels in many countries worldwide.Abnormal newborn screening results should be confirmed by quantitative analysis of GA and 3-OH-GA in urine and/or blood with GC/MS, variant analysis of the GCDH gene and/or GCDH enzyme analysis in leukocytes or fibroblasts. The diagnosis is confirmed by significantly reduced enzyme activity and/or detection of two disease-causing GCDH gene variants. | 520 | Glutaric Aciduria Type I |
nord_520_6 | Therapies of Glutaric Aciduria Type I | Metabolic treatment
Following the guideline-recommended treatment is associated with the best neurological outcome. Evidence-based treatment recommendations have been developed since 2003, resulting in a first guideline publication in 2007 and three revisions since then, the last in 2022.Today, GA1 is considered to be a treatable condition. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, trytophane-reduced, amino acid mixture, oral supplementation of L-carnitine and an intensified emergency treatment during episodes of intercurrent illness or surgical interventions. It has been recommended by an international guideline group for all patients up to 6 years. Children with GA1 can develop normally if a thorough treatment plan is followed properly, but treatment must begin from a very early age (from the newborn period before symptoms occur and onwards). If not promptly and properly treated, GA1 will typically cause serious, irreversible, neurologic damage that can permanently affect control of voluntary muscle movement and can severely impact life and shorten life expectancy, especially if damage occurs before the age of 6. The long-term outcome is still incompletely understood. Neurologic disease or extracerebral manifestations like chronic kidney disease may occur in adulthood and variable extrastriatal MRI changes may progress after age 6 years. Therefore, protein control using natural protein with a low lysine content and avoidance of lysine-rich food is advisable after age 6 years.Genetic counseling is recommended for families of children with GA1. | Therapies of Glutaric Aciduria Type I. Metabolic treatment
Following the guideline-recommended treatment is associated with the best neurological outcome. Evidence-based treatment recommendations have been developed since 2003, resulting in a first guideline publication in 2007 and three revisions since then, the last in 2022.Today, GA1 is considered to be a treatable condition. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, trytophane-reduced, amino acid mixture, oral supplementation of L-carnitine and an intensified emergency treatment during episodes of intercurrent illness or surgical interventions. It has been recommended by an international guideline group for all patients up to 6 years. Children with GA1 can develop normally if a thorough treatment plan is followed properly, but treatment must begin from a very early age (from the newborn period before symptoms occur and onwards). If not promptly and properly treated, GA1 will typically cause serious, irreversible, neurologic damage that can permanently affect control of voluntary muscle movement and can severely impact life and shorten life expectancy, especially if damage occurs before the age of 6. The long-term outcome is still incompletely understood. Neurologic disease or extracerebral manifestations like chronic kidney disease may occur in adulthood and variable extrastriatal MRI changes may progress after age 6 years. Therefore, protein control using natural protein with a low lysine content and avoidance of lysine-rich food is advisable after age 6 years.Genetic counseling is recommended for families of children with GA1. | 520 | Glutaric Aciduria Type I |
nord_521_0 | Overview of Glutaric Aciduria Type II | Glutaric aciduria type II (GAII) is one of the conditions termed organic acidemias. Individuals with these conditions have a deficiency or absence of an enzyme that prevents the breakdown of certain chemicals (proteins and fats) in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient in GAII are electron transfer flavoprotein (ETF) and ETF-dehydrogenase (ETFDH). The severity of GAll varies widely among affected individuals. A complete enzyme deficiency causes a severe form of the disorder termed neonatal GAll that is associated with a short life span and, sometimes, with specific physical birth defects. Individuals with this form may be born with physical abnormalities including brain malformations, enlarged liver, kidney malformations, unusual facial features, and genital abnormalities. They may also emit an odor resembling sweaty feet. The less severe form of the disorder is termed late onset GAll, which may appear in infancy, childhood, or even adulthood. Most often, GAll first appears in infancy or early childhood as a sudden episode of a metabolic crisis, that can cause weakness, behavior changes (such as poor feeding and decreased activity) nausea, vomiting and low blood sugar (hypoglycemia). GAII is an autosomal recessive genetic disorder caused by mutations in the ETFA, ETFB, or ETFDH genes. Treatment varies depending on the severity and symptoms but often includes a low fat, low protein, and high carbohydrate diet. | Overview of Glutaric Aciduria Type II. Glutaric aciduria type II (GAII) is one of the conditions termed organic acidemias. Individuals with these conditions have a deficiency or absence of an enzyme that prevents the breakdown of certain chemicals (proteins and fats) in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient in GAII are electron transfer flavoprotein (ETF) and ETF-dehydrogenase (ETFDH). The severity of GAll varies widely among affected individuals. A complete enzyme deficiency causes a severe form of the disorder termed neonatal GAll that is associated with a short life span and, sometimes, with specific physical birth defects. Individuals with this form may be born with physical abnormalities including brain malformations, enlarged liver, kidney malformations, unusual facial features, and genital abnormalities. They may also emit an odor resembling sweaty feet. The less severe form of the disorder is termed late onset GAll, which may appear in infancy, childhood, or even adulthood. Most often, GAll first appears in infancy or early childhood as a sudden episode of a metabolic crisis, that can cause weakness, behavior changes (such as poor feeding and decreased activity) nausea, vomiting and low blood sugar (hypoglycemia). GAII is an autosomal recessive genetic disorder caused by mutations in the ETFA, ETFB, or ETFDH genes. Treatment varies depending on the severity and symptoms but often includes a low fat, low protein, and high carbohydrate diet. | 521 | Glutaric Aciduria Type II |
nord_521_1 | Symptoms of Glutaric Aciduria Type II | Signs and symptoms of GAII vary greatly depending on the age of onset and severity of the condition in each affected individual. There are three main subtypes of GAII: the neonatal form with congenital anomalies, the neonatal form without congenital anomalies, and the late onset form. Newborns with the neonatal (first 4 weeks of life) form without congenital anomalies may have severe hypoglycemia, respiratory distress, low muscle tone, an odor of sweaty feet, liver (hepatomegaly), heart (cardiomyopathy) and kidney abnormalities.In addition to these symptoms, neonates having GAII with congenital anomalies may also present with an abnormally large head (macrocephaly), high forehead, flat nasal bridge, malformed ears, genital abnormalities, brain malformations, enlarged weak heart (cardiomyopathy), fluid-filled renal cysts, and unusual facial features. Complete enzyme deficiency found in severely affected patients with the neonatal form is not compatible with life beyond the first few days/weeks of life.Symptoms present in patients with the late onset form of GAII generally appear in childhood to adulthood, are less severe and highly variable. Muscle weakness is the most common symptom of this late onset form and individuals may have intermittent vomiting and hypoglycemia. Some of these patients may respond very well to high dose oral riboflavin treatment. | Symptoms of Glutaric Aciduria Type II. Signs and symptoms of GAII vary greatly depending on the age of onset and severity of the condition in each affected individual. There are three main subtypes of GAII: the neonatal form with congenital anomalies, the neonatal form without congenital anomalies, and the late onset form. Newborns with the neonatal (first 4 weeks of life) form without congenital anomalies may have severe hypoglycemia, respiratory distress, low muscle tone, an odor of sweaty feet, liver (hepatomegaly), heart (cardiomyopathy) and kidney abnormalities.In addition to these symptoms, neonates having GAII with congenital anomalies may also present with an abnormally large head (macrocephaly), high forehead, flat nasal bridge, malformed ears, genital abnormalities, brain malformations, enlarged weak heart (cardiomyopathy), fluid-filled renal cysts, and unusual facial features. Complete enzyme deficiency found in severely affected patients with the neonatal form is not compatible with life beyond the first few days/weeks of life.Symptoms present in patients with the late onset form of GAII generally appear in childhood to adulthood, are less severe and highly variable. Muscle weakness is the most common symptom of this late onset form and individuals may have intermittent vomiting and hypoglycemia. Some of these patients may respond very well to high dose oral riboflavin treatment. | 521 | Glutaric Aciduria Type II |
nord_521_2 | Causes of Glutaric Aciduria Type II | Glutaric aciduria type II is an autosomal recessive disease caused by changes (mutations) in the ETF-A (subunit alpha), ETF-B (subunit beta) or ETFDH genes. The mutations result in deficient or complete absence of activity of multiple acyl-CoA dehydrogenase (MADD) enzymes needed to break down fats and proteins that the body uses for energy. This results in the accumulation of several organic acids in the blood and urine. Mutations in ETFA and ETFB generally cause the neonatal forms of this disorder and the ETFDH gene mutation is found in many late onset forms of GAII. Dysfunction of either ETF or ETFDH flavoproteins leads to compromised fatty acid oxidation and amino acid degradation that alters energy production as well as production of other molecules needed for fuel storage and use. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Glutaric Aciduria Type II. Glutaric aciduria type II is an autosomal recessive disease caused by changes (mutations) in the ETF-A (subunit alpha), ETF-B (subunit beta) or ETFDH genes. The mutations result in deficient or complete absence of activity of multiple acyl-CoA dehydrogenase (MADD) enzymes needed to break down fats and proteins that the body uses for energy. This results in the accumulation of several organic acids in the blood and urine. Mutations in ETFA and ETFB generally cause the neonatal forms of this disorder and the ETFDH gene mutation is found in many late onset forms of GAII. Dysfunction of either ETF or ETFDH flavoproteins leads to compromised fatty acid oxidation and amino acid degradation that alters energy production as well as production of other molecules needed for fuel storage and use. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 521 | Glutaric Aciduria Type II |
nord_521_3 | Affects of Glutaric Aciduria Type II | Prevalence is estimated to be 1/200,000 and GAll affects both males and females. Prevalence in ethnicities is not known. | Affects of Glutaric Aciduria Type II. Prevalence is estimated to be 1/200,000 and GAll affects both males and females. Prevalence in ethnicities is not known. | 521 | Glutaric Aciduria Type II |
nord_521_4 | Related disorders of Glutaric Aciduria Type II | Glutaric aciduria type I is a rare hereditary metabolic disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. Patients are usually well at birth but present during early infancy/childhood with an acute event of vomiting, seizures & reduced consciousness often in association with an infection such as a bad cold or gastroenteritis. The patient may have involuntary movements of the trunk and limbs (dystonia or athetosis), and intellectual disability may occur. (For more information on this disorder, choose “glutaric aciduria I” as your search term in the Rare Disease Database.)Gluraric aciduria type III is a rare metabolic disorder characterized by isolated abnormally high levels of glutaric acid excreted from the body. GAIII is an autosomal recessive disorder caused by mutations in the succinyl-CoA:glutarate-CoA transferase (SUGCT) gene, and has no distinct phenotype as symptoms widely vary and some patients remain asymptomatic. Medium chain acyl-CoA dehydrogenase deficiency (MCAD) is a rare metabolic disorder characterized by a deficiency of the medium chain acyl-CoA dehydrogenase enzyme. This enzyme is needed in the breakdown (metabolism) of fats. Low blood sugar (hypoglycemia), lack of energy (lethargy), drowsiness, seizures, coma & eventually death in association with fatty changes in the liver, can occur usually in association with infection and reduced intake of energy. During hypoglycemic periods, tests usually show increased amounts of dicarboxylic acids, hexanoylglycine & suberylglycine in the urine. Blood acylcarnitines show increased octanoyl carnitine (C8) & an increased ratio (>2) of C8/C10 acylcarnitines. However diagnosed patients are easily treated by careful management with an excellent long term prognosis. | Related disorders of Glutaric Aciduria Type II. Glutaric aciduria type I is a rare hereditary metabolic disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. Patients are usually well at birth but present during early infancy/childhood with an acute event of vomiting, seizures & reduced consciousness often in association with an infection such as a bad cold or gastroenteritis. The patient may have involuntary movements of the trunk and limbs (dystonia or athetosis), and intellectual disability may occur. (For more information on this disorder, choose “glutaric aciduria I” as your search term in the Rare Disease Database.)Gluraric aciduria type III is a rare metabolic disorder characterized by isolated abnormally high levels of glutaric acid excreted from the body. GAIII is an autosomal recessive disorder caused by mutations in the succinyl-CoA:glutarate-CoA transferase (SUGCT) gene, and has no distinct phenotype as symptoms widely vary and some patients remain asymptomatic. Medium chain acyl-CoA dehydrogenase deficiency (MCAD) is a rare metabolic disorder characterized by a deficiency of the medium chain acyl-CoA dehydrogenase enzyme. This enzyme is needed in the breakdown (metabolism) of fats. Low blood sugar (hypoglycemia), lack of energy (lethargy), drowsiness, seizures, coma & eventually death in association with fatty changes in the liver, can occur usually in association with infection and reduced intake of energy. During hypoglycemic periods, tests usually show increased amounts of dicarboxylic acids, hexanoylglycine & suberylglycine in the urine. Blood acylcarnitines show increased octanoyl carnitine (C8) & an increased ratio (>2) of C8/C10 acylcarnitines. However diagnosed patients are easily treated by careful management with an excellent long term prognosis. | 521 | Glutaric Aciduria Type II |
nord_521_5 | Diagnosis of Glutaric Aciduria Type II | The diagnosis of GAll begins with examining urine organic acids. The characteristic pattern for glutaric aciduria is an elevation of a range of organic acids which may include glutaric, lactic, ethylmalonic, isovaleric, adipic,butyric, isobutyric, suberic & sebacic acids with a number of characteristic acylglycines. Blood acylcarnitine analysis by tandem mass spectrometry will show increases in a wide range of acylcarnitines from C4-C18. Some mildly affected individuals may not have an abnormal pattern of urine organic acids except when they are ill. Diagnosis of GAll can also be made by demonstrating reduced fatty acid oxidation in cultured fibroblasts obtained from a skin biopsy or by molecular genetic testing. | Diagnosis of Glutaric Aciduria Type II. The diagnosis of GAll begins with examining urine organic acids. The characteristic pattern for glutaric aciduria is an elevation of a range of organic acids which may include glutaric, lactic, ethylmalonic, isovaleric, adipic,butyric, isobutyric, suberic & sebacic acids with a number of characteristic acylglycines. Blood acylcarnitine analysis by tandem mass spectrometry will show increases in a wide range of acylcarnitines from C4-C18. Some mildly affected individuals may not have an abnormal pattern of urine organic acids except when they are ill. Diagnosis of GAll can also be made by demonstrating reduced fatty acid oxidation in cultured fibroblasts obtained from a skin biopsy or by molecular genetic testing. | 521 | Glutaric Aciduria Type II |
nord_521_6 | Therapies of Glutaric Aciduria Type II | TreatmentThe goal of treatment is to support development by regular monitoring & avoidance of acute life-threatening events through careful medical management & dietary control. However, children who have repeated metabolic crises may develop life-long learning & other health problems. Where necessary, treatment should be continued throughout life & this will apply to most patients. Glutaric aciduria type II is treated with a high carbohydrate, low protein and low fat diet. It is recommended that affected individuals eat often to avoid low blood sugar. Dietary supplementation with riboflavin, carnitine & other supplements may be helpful. It is important to have an emergency regimen ready & to alert the patient’s doctor if they should become ill, as illness can trigger a metabolic crisis. | Therapies of Glutaric Aciduria Type II. TreatmentThe goal of treatment is to support development by regular monitoring & avoidance of acute life-threatening events through careful medical management & dietary control. However, children who have repeated metabolic crises may develop life-long learning & other health problems. Where necessary, treatment should be continued throughout life & this will apply to most patients. Glutaric aciduria type II is treated with a high carbohydrate, low protein and low fat diet. It is recommended that affected individuals eat often to avoid low blood sugar. Dietary supplementation with riboflavin, carnitine & other supplements may be helpful. It is important to have an emergency regimen ready & to alert the patient’s doctor if they should become ill, as illness can trigger a metabolic crisis. | 521 | Glutaric Aciduria Type II |
nord_522_0 | Overview of Glutathione Synthetase Deficiency | Glutathione synthetase deficiency is an extremely rare disorder characterized by a deficiency of the enzyme glutathione synthetase. This enzyme is part of the chemical process by which the body creates glutathione, a protein molecule that plays a role in many cell processes. Glutathione synthetase deficiency is often classified as mild, moderate or severe. Consequently, the specific symptoms and severity can vary greatly from one person to another. Generally, the mild form only affects red blood cells (erythrocytes). The severe form is widespread (generalized) affecting many types of cells of the body. The moderate form falls in between these two extremes. Glutathione synthetase deficiency is caused by alterations (mutations) in the GSS gene and is inherited in an autosomal recessive manner.The generalized form is also known as 5-oxoprolinuria or pyroglutamic aciduria because extremely high levels of 5-oxoproline, an amino acid derivative, can be detected in the urine. However, 5-oxoprolinuria can occur as part of several different disorders or due to several environmental factors. | Overview of Glutathione Synthetase Deficiency. Glutathione synthetase deficiency is an extremely rare disorder characterized by a deficiency of the enzyme glutathione synthetase. This enzyme is part of the chemical process by which the body creates glutathione, a protein molecule that plays a role in many cell processes. Glutathione synthetase deficiency is often classified as mild, moderate or severe. Consequently, the specific symptoms and severity can vary greatly from one person to another. Generally, the mild form only affects red blood cells (erythrocytes). The severe form is widespread (generalized) affecting many types of cells of the body. The moderate form falls in between these two extremes. Glutathione synthetase deficiency is caused by alterations (mutations) in the GSS gene and is inherited in an autosomal recessive manner.The generalized form is also known as 5-oxoprolinuria or pyroglutamic aciduria because extremely high levels of 5-oxoproline, an amino acid derivative, can be detected in the urine. However, 5-oxoprolinuria can occur as part of several different disorders or due to several environmental factors. | 522 | Glutathione Synthetase Deficiency |
nord_522_1 | Symptoms of Glutathione Synthetase Deficiency | Glutathione synthetase deficiency may be best thought of as a spectrum of disease ranging from mild to moderate to severe expression of the disorder. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that each individual is unique. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The mild form of glutathione synthetase deficiency is characterized by the premature breakdown of red blood cells (hemolytic anemia). Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In affected individuals, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. The severity of the anemia is determined by the length of time that the red blood cells survive and by the rate at which the bone marrow continues to create new red blood cell production.The primary role of red blood cells is to delivery oxygen throughout the body. Hemolytic anemia can be associated with fatigue, pale skin color, lightheadedness, irregular heartbeats, and shortness of breath. Hemolytic anemia is usually the only symptom associated with the mild form of glutathione synthetase deficiency, although some individuals may have an abnormally enlarged spleen (splenomegaly).The moderate form may be associated with mild to moderate hemolytic anemia. Affected infants may also have severe metabolic acidosis caused by an accumulation of 5-oxoproline. Metabolic acidosis is a condition in which the chemical balance of the body is off and the body fluids contain too much acid.The symptoms and signs of the severe form of glutathione synthetase deficiency can vary greatly from one person to another. Affected infants experience mild to moderate hemolytic anemia and metabolic acidosis in the newborn period. These infants may experience progressive cerebral and cerebellar degeneration. Affected infants may develop progressive neurological symptoms including impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation), varying degrees of intellectual disability, seizures, impaired coordination of voluntary movements (ataxia), tremors that occur when attempting to make deliberate actions (intention tremor), and increased muscle tone and stiffness of muscles (spasticity). Some infants develop recurrent bacterial infections. Severe metabolic acidosis and bacterial infections can potentially cause life-threatening complications such as widespread infection of the blood (sepsis).Chronic and progressive disorders of vision known as retinal dystrophies have been reported in adults with glutathione synthetase deficiency. | Symptoms of Glutathione Synthetase Deficiency. Glutathione synthetase deficiency may be best thought of as a spectrum of disease ranging from mild to moderate to severe expression of the disorder. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that each individual is unique. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.The mild form of glutathione synthetase deficiency is characterized by the premature breakdown of red blood cells (hemolytic anemia). Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In affected individuals, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. The severity of the anemia is determined by the length of time that the red blood cells survive and by the rate at which the bone marrow continues to create new red blood cell production.The primary role of red blood cells is to delivery oxygen throughout the body. Hemolytic anemia can be associated with fatigue, pale skin color, lightheadedness, irregular heartbeats, and shortness of breath. Hemolytic anemia is usually the only symptom associated with the mild form of glutathione synthetase deficiency, although some individuals may have an abnormally enlarged spleen (splenomegaly).The moderate form may be associated with mild to moderate hemolytic anemia. Affected infants may also have severe metabolic acidosis caused by an accumulation of 5-oxoproline. Metabolic acidosis is a condition in which the chemical balance of the body is off and the body fluids contain too much acid.The symptoms and signs of the severe form of glutathione synthetase deficiency can vary greatly from one person to another. Affected infants experience mild to moderate hemolytic anemia and metabolic acidosis in the newborn period. These infants may experience progressive cerebral and cerebellar degeneration. Affected infants may develop progressive neurological symptoms including impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation), varying degrees of intellectual disability, seizures, impaired coordination of voluntary movements (ataxia), tremors that occur when attempting to make deliberate actions (intention tremor), and increased muscle tone and stiffness of muscles (spasticity). Some infants develop recurrent bacterial infections. Severe metabolic acidosis and bacterial infections can potentially cause life-threatening complications such as widespread infection of the blood (sepsis).Chronic and progressive disorders of vision known as retinal dystrophies have been reported in adults with glutathione synthetase deficiency. | 522 | Glutathione Synthetase Deficiency |
nord_522_2 | Causes of Glutathione Synthetase Deficiency | Glutathione synthetase deficiency is caused by alterations in the GSS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The GSS gene contains instructions for making the enzyme glutathione synthetase. This enzyme is required for the body to create the small protein molecule glutathione. An alteration in the GSS gene leads to deficiency of or glutathione synthetase, which, in turn, leads to a lack of glutathione, which is a peptide molecule that plays a crucial role in many cellular processes. Cellular processes are activities that go on inside of a cell that are vital for proper health and development.The GSS alterations that cause glutathione synthetase deficiency are inherited in an autosomal recessive manner. Most such genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Researchers believe that certain factors, in addition to alterations in the GSS gene, influence the severity of glutathione synthetase deficiency. This includes genetic and environmental factors. Modifier genes, unlike the GSS gene, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes and/or environment factors associated with glutathione synthetase deficiency and their exact role in the development of the disorder. | Causes of Glutathione Synthetase Deficiency. Glutathione synthetase deficiency is caused by alterations in the GSS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.The GSS gene contains instructions for making the enzyme glutathione synthetase. This enzyme is required for the body to create the small protein molecule glutathione. An alteration in the GSS gene leads to deficiency of or glutathione synthetase, which, in turn, leads to a lack of glutathione, which is a peptide molecule that plays a crucial role in many cellular processes. Cellular processes are activities that go on inside of a cell that are vital for proper health and development.The GSS alterations that cause glutathione synthetase deficiency are inherited in an autosomal recessive manner. Most such genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.Researchers believe that certain factors, in addition to alterations in the GSS gene, influence the severity of glutathione synthetase deficiency. This includes genetic and environmental factors. Modifier genes, unlike the GSS gene, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes and/or environment factors associated with glutathione synthetase deficiency and their exact role in the development of the disorder. | 522 | Glutathione Synthetase Deficiency |
nord_522_3 | Affects of Glutathione Synthetase Deficiency | Glutathione synthetase deficiency affects males and females in equal numbers. More than 70 individuals from 50 families have been described in the medical literature. The exact incidence and prevalence are unknown. Because individuals may be misdiagnosed or go undiagnosed, determining the true frequency in the general population is difficult. | Affects of Glutathione Synthetase Deficiency. Glutathione synthetase deficiency affects males and females in equal numbers. More than 70 individuals from 50 families have been described in the medical literature. The exact incidence and prevalence are unknown. Because individuals may be misdiagnosed or go undiagnosed, determining the true frequency in the general population is difficult. | 522 | Glutathione Synthetase Deficiency |
nord_522_4 | Related disorders of Glutathione Synthetase Deficiency | Symptoms of the following disorders may be similar to those of glutathione synthetase deficiency. Comparisons may be useful for a differential diagnosis:There are numerous other conditions that cause elevated levels of 5-oxoproline in the urine (5-oxoprolinuria) including severe burns, Stevens-Johnson syndrome, nephropathic cystinosis, and various inborn errors of metabolism including 5-oxoprolinase deficiency, urea cycle disorders, tyrosinemia and homocystinuria. In some individuals, the use of certain drugs may cause 5-oxoprolinuria. Such drugs include paracetamol, vigabatrin, and certain antibiotics. Hemolytic anemia can occur in many different conditions including other disorders of glutathione metabolism including gamma-glutamylcysteine synthetase deficiency and glucose-6-phosphate dehydrogenase deficiency. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | Related disorders of Glutathione Synthetase Deficiency. Symptoms of the following disorders may be similar to those of glutathione synthetase deficiency. Comparisons may be useful for a differential diagnosis:There are numerous other conditions that cause elevated levels of 5-oxoproline in the urine (5-oxoprolinuria) including severe burns, Stevens-Johnson syndrome, nephropathic cystinosis, and various inborn errors of metabolism including 5-oxoprolinase deficiency, urea cycle disorders, tyrosinemia and homocystinuria. In some individuals, the use of certain drugs may cause 5-oxoprolinuria. Such drugs include paracetamol, vigabatrin, and certain antibiotics. Hemolytic anemia can occur in many different conditions including other disorders of glutathione metabolism including gamma-glutamylcysteine synthetase deficiency and glucose-6-phosphate dehydrogenase deficiency. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.) | 522 | Glutathione Synthetase Deficiency |
nord_522_5 | Diagnosis of Glutathione Synthetase Deficiency | A diagnosis of glutathione synthetase deficiency is based upon identification of characteristic findings, a detailed patient and family history, and a variety of specialized tests.Enzyme assays are tests that determine the activity of enzymes in certain cells of the body. These tests can demonstrate decreased activity of the enzyme glutathione synthetase in red blood cells (erythrocytes) or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Tests that demonstrate low levels of glutathione in red blood cells or cultured fibroblasts can also be used to support a diagnosis.High levels of 5-oxoproline in the urine can be demonstrated through a procedure known as gas chromatography-mass spectrometry (GC-MS). In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. Complex sample preparation and a lengthy analysis time make GC-MS testing a time-consuming technique.Molecular genetic testing can confirm a diagnosis of glutathione synthetase deficiency. Molecular genetic testing can detect mutations in the GSS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.In families with a known history of glutathione synthetase deficiency, a diagnosis may be obtained before birth (antenatal diagnosis). If the specific gene mutation in the family is known, then a sample of tissue taken from the placenta (chorionic villi sampling) can be studied to detect the mutation. Antenatal diagnosis is also possible through the analysis of amniotic fluid for elevated levels of 5-oxoproline or through demonstrating reduced glutathione synthetase activity in fetal cells taken from the amniotic fluid (amniocytes) or in placenta tissue. | Diagnosis of Glutathione Synthetase Deficiency. A diagnosis of glutathione synthetase deficiency is based upon identification of characteristic findings, a detailed patient and family history, and a variety of specialized tests.Enzyme assays are tests that determine the activity of enzymes in certain cells of the body. These tests can demonstrate decreased activity of the enzyme glutathione synthetase in red blood cells (erythrocytes) or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Tests that demonstrate low levels of glutathione in red blood cells or cultured fibroblasts can also be used to support a diagnosis.High levels of 5-oxoproline in the urine can be demonstrated through a procedure known as gas chromatography-mass spectrometry (GC-MS). In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. Complex sample preparation and a lengthy analysis time make GC-MS testing a time-consuming technique.Molecular genetic testing can confirm a diagnosis of glutathione synthetase deficiency. Molecular genetic testing can detect mutations in the GSS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.In families with a known history of glutathione synthetase deficiency, a diagnosis may be obtained before birth (antenatal diagnosis). If the specific gene mutation in the family is known, then a sample of tissue taken from the placenta (chorionic villi sampling) can be studied to detect the mutation. Antenatal diagnosis is also possible through the analysis of amniotic fluid for elevated levels of 5-oxoproline or through demonstrating reduced glutathione synthetase activity in fetal cells taken from the amniotic fluid (amniocytes) or in placenta tissue. | 522 | Glutathione Synthetase Deficiency |
nord_522_6 | Therapies of Glutathione Synthetase Deficiency | The treatment of glutathione synthetase deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment will include sodium bicarbonate to correct the metabolic acidosis. Initially, this may require parenteral (e.g. intravenous) therapy. Eventually, affected individuals can be treated with sodium bicarbonate or citrate, delivered through the mouth (orally). Supplemental therapy with vitamins E and C, which have antioxidant properties, may also be given.Drugs that precipitate hemolysis in glucose-6-phosphate dehydrogenase deficiency should be avoided. (For more information on this disorder and such drugs, choose “glucose 6 phosphate dehydrogenase deficiency” as your search term in the NORD Rare Disease Database.)Genetic counseling should be offered to affected individuals and their families. | Therapies of Glutathione Synthetase Deficiency. The treatment of glutathione synthetase deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment will include sodium bicarbonate to correct the metabolic acidosis. Initially, this may require parenteral (e.g. intravenous) therapy. Eventually, affected individuals can be treated with sodium bicarbonate or citrate, delivered through the mouth (orally). Supplemental therapy with vitamins E and C, which have antioxidant properties, may also be given.Drugs that precipitate hemolysis in glucose-6-phosphate dehydrogenase deficiency should be avoided. (For more information on this disorder and such drugs, choose “glucose 6 phosphate dehydrogenase deficiency” as your search term in the NORD Rare Disease Database.)Genetic counseling should be offered to affected individuals and their families. | 522 | Glutathione Synthetase Deficiency |
nord_523_0 | Overview of Glycogen Storage Disease Type 7 | SummaryGlycogen storage diseases are a group of diseases where the body’s form of stored energy (glycogen) cannot be broken down into smaller pieces of sugars (glucose) for the body to use. People with glycogen storage disease type 7 (GSD7) usually have symptoms during childhood, but some people may have symptoms beginning as infants or later as adults. GSD7 symptoms areGSD7 is caused by harmful changes (mutations) in the gene for muscle phosphofructokinase (PFKM) that leads to lowered activity (deficiency) in the phosphofructokinase enzyme, the protein that breaks down glycogen to glucose. The lack of this enzyme leads to a decreased amount of energy available to muscles during exercise. GSD7 is passed down in families in an autosomal recessive pattern of inheritance.There is no specific cure or treatment for GSD7, but people with GSD7 are recommended to avoid heavy exercise and avoid eating meals with high amounts of carbohydrates.IntroductionGSD7 was first described by Tarui et al. in 1965 in three Japanese siblings. The siblings were easily tired and were not able to keep pace with other people. They had muscle weakness and stiffness in muscles used in heavy exercise. | Overview of Glycogen Storage Disease Type 7. SummaryGlycogen storage diseases are a group of diseases where the body’s form of stored energy (glycogen) cannot be broken down into smaller pieces of sugars (glucose) for the body to use. People with glycogen storage disease type 7 (GSD7) usually have symptoms during childhood, but some people may have symptoms beginning as infants or later as adults. GSD7 symptoms areGSD7 is caused by harmful changes (mutations) in the gene for muscle phosphofructokinase (PFKM) that leads to lowered activity (deficiency) in the phosphofructokinase enzyme, the protein that breaks down glycogen to glucose. The lack of this enzyme leads to a decreased amount of energy available to muscles during exercise. GSD7 is passed down in families in an autosomal recessive pattern of inheritance.There is no specific cure or treatment for GSD7, but people with GSD7 are recommended to avoid heavy exercise and avoid eating meals with high amounts of carbohydrates.IntroductionGSD7 was first described by Tarui et al. in 1965 in three Japanese siblings. The siblings were easily tired and were not able to keep pace with other people. They had muscle weakness and stiffness in muscles used in heavy exercise. | 523 | Glycogen Storage Disease Type 7 |
nord_523_1 | Symptoms of Glycogen Storage Disease Type 7 | There are four types of GSD7:Childhood (Classic) GSD7
This is the most common form of GSD7 and usually begins in childhood with symptoms including:Other symptoms can include:Symptoms usually go away after rest.Infant GSD7
This rare type of GSD7 occurs in babies. Symptoms include:Late-onset (adult) GSD7
This form of GSD7 happens in adults who experience only muscle weakness and pain. They may have some muscle weakness and tiredness in childhood.Hemolytic GSD7
People with hemolytic GSD7 do not have muscle symptoms but have anemia due to break down of red blood cells. | Symptoms of Glycogen Storage Disease Type 7. There are four types of GSD7:Childhood (Classic) GSD7
This is the most common form of GSD7 and usually begins in childhood with symptoms including:Other symptoms can include:Symptoms usually go away after rest.Infant GSD7
This rare type of GSD7 occurs in babies. Symptoms include:Late-onset (adult) GSD7
This form of GSD7 happens in adults who experience only muscle weakness and pain. They may have some muscle weakness and tiredness in childhood.Hemolytic GSD7
People with hemolytic GSD7 do not have muscle symptoms but have anemia due to break down of red blood cells. | 523 | Glycogen Storage Disease Type 7 |
nord_523_2 | Causes of Glycogen Storage Disease Type 7 | GSD7 is caused by harmful changes (mutations) in the gene for muscle phosphofructokinase (PFKM). This leads to problems with the function of phosphofructokinase enzyme, the protein that breaks down glycogen to glucose. This lowered enzyme activity results in a decreased amount of energy for muscles to use during exercise. This leads to muscle pain and cramps. GSD7 is inherited in an autosomal recessive manner. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but will usually not show symptoms. The chance for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The chance to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Glycogen Storage Disease Type 7. GSD7 is caused by harmful changes (mutations) in the gene for muscle phosphofructokinase (PFKM). This leads to problems with the function of phosphofructokinase enzyme, the protein that breaks down glycogen to glucose. This lowered enzyme activity results in a decreased amount of energy for muscles to use during exercise. This leads to muscle pain and cramps. GSD7 is inherited in an autosomal recessive manner. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but will usually not show symptoms. The chance for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The chance to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 523 | Glycogen Storage Disease Type 7 |
nord_523_3 | Affects of Glycogen Storage Disease Type 7 | GSD7 is a rare disease that is seen more often in individuals of Japanese and Ashkenazi (Eastern European) Jewish ancestry. GSD7 affects males and females in equal numbers. The condition is estimated to occur is less than 1/1,000,000 people. | Affects of Glycogen Storage Disease Type 7. GSD7 is a rare disease that is seen more often in individuals of Japanese and Ashkenazi (Eastern European) Jewish ancestry. GSD7 affects males and females in equal numbers. The condition is estimated to occur is less than 1/1,000,000 people. | 523 | Glycogen Storage Disease Type 7 |
nord_523_4 | Related disorders of Glycogen Storage Disease Type 7 | Glycogen storage disease type 5 (McArdle disease or GSD5) is an inherited or genetic glycogen storage disease. In GSD5, symptoms are caused by a missing muscle enzyme called myophosphorylase. This enzyme is needed for the breakdown of glycogen (the body’s form of stored energy) into sugar (glucose) in muscle. Autosomal recessive GSD5 symptoms can start in childhood or in adulthood. There is also a much rarer autosomal dominant form of GSD5. Symptoms of GSD5 are exercise intolerance, muscle cramping and dark, reddish brown-colored urine (myoglobinuria) Pompe disease is an inherited metabolic disorder caused by the complete or partial deficiency of the enzyme acid alpha-glucosidase (also known as lysosomal alpha-glucosidase or acid maltase). This enzyme deficiency causes extra amounts of glycogen to build up in the lysosomes, where cells store waste, in many types of cells, but mostly in muscle cells. This causes damage to the cell that leads to muscle weakness and/or breathing difficulty. Pompe disease is also classified as glycogen storage disease type 2 (GSD2). Glycogen storage disease type 3 (Forbes disease or GSD3) is a glycogen storage disorder that is inherited as an autosomal recessive disorder. Symptoms are caused by missing enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes extra amounts of an abnormal glycogen to be stored in the liver, muscles and sometimes the heart. For more information on the above disorders, choose “glycogen storage disease type V”, “Pompe” and “glycogen storage disease type III” as your search terms in the Rare Disease Database. | Related disorders of Glycogen Storage Disease Type 7. Glycogen storage disease type 5 (McArdle disease or GSD5) is an inherited or genetic glycogen storage disease. In GSD5, symptoms are caused by a missing muscle enzyme called myophosphorylase. This enzyme is needed for the breakdown of glycogen (the body’s form of stored energy) into sugar (glucose) in muscle. Autosomal recessive GSD5 symptoms can start in childhood or in adulthood. There is also a much rarer autosomal dominant form of GSD5. Symptoms of GSD5 are exercise intolerance, muscle cramping and dark, reddish brown-colored urine (myoglobinuria) Pompe disease is an inherited metabolic disorder caused by the complete or partial deficiency of the enzyme acid alpha-glucosidase (also known as lysosomal alpha-glucosidase or acid maltase). This enzyme deficiency causes extra amounts of glycogen to build up in the lysosomes, where cells store waste, in many types of cells, but mostly in muscle cells. This causes damage to the cell that leads to muscle weakness and/or breathing difficulty. Pompe disease is also classified as glycogen storage disease type 2 (GSD2). Glycogen storage disease type 3 (Forbes disease or GSD3) is a glycogen storage disorder that is inherited as an autosomal recessive disorder. Symptoms are caused by missing enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes extra amounts of an abnormal glycogen to be stored in the liver, muscles and sometimes the heart. For more information on the above disorders, choose “glycogen storage disease type V”, “Pompe” and “glycogen storage disease type III” as your search terms in the Rare Disease Database. | 523 | Glycogen Storage Disease Type 7 |
nord_523_5 | Diagnosis of Glycogen Storage Disease Type 7 | GSD7 is diagnosed by measuring the amount of the phosphofructokinase enzyme in a sample of muscle tissue taken from a muscle biopsy. It can also be diagnosed by measuring the phosphofructokinase enzyme level in red blood cells. Lab tests after exercise can also show high levels of other proteins in the blood including creatinine kinase, lactate dehydrogenase, and aspartate transaminase. Molecular genetic testing from a blood test can confirm changes in the PFKM gene. The diagnosis of GDS7 is supported by high levels of ammonia and low levels of lactate in muscle biopsy or in blood removed from the forearm before and after exercise (forearm exercise test). | Diagnosis of Glycogen Storage Disease Type 7. GSD7 is diagnosed by measuring the amount of the phosphofructokinase enzyme in a sample of muscle tissue taken from a muscle biopsy. It can also be diagnosed by measuring the phosphofructokinase enzyme level in red blood cells. Lab tests after exercise can also show high levels of other proteins in the blood including creatinine kinase, lactate dehydrogenase, and aspartate transaminase. Molecular genetic testing from a blood test can confirm changes in the PFKM gene. The diagnosis of GDS7 is supported by high levels of ammonia and low levels of lactate in muscle biopsy or in blood removed from the forearm before and after exercise (forearm exercise test). | 523 | Glycogen Storage Disease Type 7 |
nord_523_6 | Therapies of Glycogen Storage Disease Type 7 | Treatment
Heavy exercise should be avoided to prevent muscle pain and cramps. Eating simple sugars (carbohydrates) should also be avoided because this can make the exercise intolerance worse. Eating high amounts of protein during exercise may prevent symptoms. Genetic counseling is recommended for individuals with GSD7 and their families. | Therapies of Glycogen Storage Disease Type 7. Treatment
Heavy exercise should be avoided to prevent muscle pain and cramps. Eating simple sugars (carbohydrates) should also be avoided because this can make the exercise intolerance worse. Eating high amounts of protein during exercise may prevent symptoms. Genetic counseling is recommended for individuals with GSD7 and their families. | 523 | Glycogen Storage Disease Type 7 |
nord_524_0 | Overview of Glycogen Storage Disease Type I | Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I (GSDI) is characterized by accumulation of excessive glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature. GSDI is associated with abnormalities (mutations) in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood. The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides. | Overview of Glycogen Storage Disease Type I. Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I (GSDI) is characterized by accumulation of excessive glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature. GSDI is associated with abnormalities (mutations) in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood. The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides. | 524 | Glycogen Storage Disease Type I |
nord_524_1 | Symptoms of Glycogen Storage Disease Type I | The primary symptom of GSDI in infancy is a low blood sugar level (hypoglycemia). Symptoms of GSDI usually begin at three to four months of age and include enlargement of the liver (hepatomegaly), kidney (nephromegaly), elevated levels of lactate, uric acid and lipids (both total lipids and triglycerides), and possible seizures caused due to repeated episodes of hypoglycemia. Continued low blood sugar can lead to delayed growth and development and muscle weakness. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen.High lipid levels can lead to the formation of fatty skin growths called xanthomas. Other conditions that can be associated with untreated GSD1 include; osteoporosis, delayed puberty, gout (arthritis caused by accumulation of uric acid), kidney disease, pulmonary hypertension (high blood pressure in the arteries that supply the lungs), hepatic adenoma (benign liver tumors), polycystic ovaries in females, an inflammation of the pancreas (pancreatitis), diarrhea and changes in brain function due to repeated episodes of hypoglycemia.Impaired platelet function can lead to a bleeding tendency with frequent nose bleeds (epistaxis). In general GSD type Ib patients have similar clinical manifestations as type Ia patients, but in addition to the above mentioned manifestations, GSDIb is also associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers.Early diagnosis and effective treatment can result in normal growth and puberty and many affected individuals live into adulthood and enjoy normal life activities. Many female patients have had successful pregnancies and childbirth. | Symptoms of Glycogen Storage Disease Type I. The primary symptom of GSDI in infancy is a low blood sugar level (hypoglycemia). Symptoms of GSDI usually begin at three to four months of age and include enlargement of the liver (hepatomegaly), kidney (nephromegaly), elevated levels of lactate, uric acid and lipids (both total lipids and triglycerides), and possible seizures caused due to repeated episodes of hypoglycemia. Continued low blood sugar can lead to delayed growth and development and muscle weakness. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen.High lipid levels can lead to the formation of fatty skin growths called xanthomas. Other conditions that can be associated with untreated GSD1 include; osteoporosis, delayed puberty, gout (arthritis caused by accumulation of uric acid), kidney disease, pulmonary hypertension (high blood pressure in the arteries that supply the lungs), hepatic adenoma (benign liver tumors), polycystic ovaries in females, an inflammation of the pancreas (pancreatitis), diarrhea and changes in brain function due to repeated episodes of hypoglycemia.Impaired platelet function can lead to a bleeding tendency with frequent nose bleeds (epistaxis). In general GSD type Ib patients have similar clinical manifestations as type Ia patients, but in addition to the above mentioned manifestations, GSDIb is also associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers.Early diagnosis and effective treatment can result in normal growth and puberty and many affected individuals live into adulthood and enjoy normal life activities. Many female patients have had successful pregnancies and childbirth. | 524 | Glycogen Storage Disease Type I |
nord_524_2 | Causes of Glycogen Storage Disease Type I | Type I glycogen storage disease is associated with abnormalities in two genes. Mutations in the G6PC gene result in a deficiency in the glucose-6-phosphatase (G6Pase) enzyme and account for approximately 80% of GSDI. This type of GSDI is termed glycogen storage disease type Ia. Mutations in the SLC37A4 gene result in a deficiency in the glucose-6-phosphatase translocase enzyme (transporter deficiency) and account for approximately 20% of GSDI. This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues.Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | Causes of Glycogen Storage Disease Type I. Type I glycogen storage disease is associated with abnormalities in two genes. Mutations in the G6PC gene result in a deficiency in the glucose-6-phosphatase (G6Pase) enzyme and account for approximately 80% of GSDI. This type of GSDI is termed glycogen storage disease type Ia. Mutations in the SLC37A4 gene result in a deficiency in the glucose-6-phosphatase translocase enzyme (transporter deficiency) and account for approximately 20% of GSDI. This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues.Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. | 524 | Glycogen Storage Disease Type I |
nord_524_3 | Affects of Glycogen Storage Disease Type I | Type I glycogen storage disease occurs in approximately 1 in 100,000 births. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20,000. This condition affects males and females in equal numbers in any given population group. | Affects of Glycogen Storage Disease Type I. Type I glycogen storage disease occurs in approximately 1 in 100,000 births. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20,000. This condition affects males and females in equal numbers in any given population group. | 524 | Glycogen Storage Disease Type I |
nord_524_4 | Related disorders of Glycogen Storage Disease Type I | Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:Forbes or Cori disease (GSD-III) is one of several glycogen storage disorders that are inherited as autosomal recessive traits. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes excessive amounts of an abnormally digested glycogen (the stored form of energy that comes from carbohydrates) to be deposited in the liver, muscles and, in some cases, the heart. Symptoms become evident during the first years of life with hepatomegaly and/or myopathy, and elevated liver enzymes. In the first few months some symptoms may overlap with GSDI (elevated lipids, hepatomegaly, low glucose).Andersen disease (GSD-IV) also known as glycogen storage disease type IV; This GSD is also inherited as an autosomal recessive trait. It is caused by deficient activity of the glycogen-branching enzyme (GBE), resulting in accumulation of abnormally formed glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first few years of life. Such features typically include failure to grow and gaining weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly).Hers disease (GSD-VI) is also called glycogen storage disease type VI. It usually has milder symptoms than most other types of glycogen storage diseases. It is caused by a deficiency of the enzyme liver phosphorylase. Hers disease is characterized by enlargement of the liver (hepatomegaly), moderately low blood sugar (hypoglycemia), elevated levels of acetone and other ketone bodies in the blood (ketosis), and moderate growth retardation. Symptoms are not always evident during childhood, and children are usually able to lead normal lives. However, in some instances, symptoms may be severe.Glycogen storage disease IX is caused due to deficiency of phosphorylase kinase enzyme (PK enzyme deficiency). It can be inherited as an X-linked genetic disorder caused by a deficiency of the enzyme liver phosphorylase kinase (mainly PHKA2 gene) or it can be inherited as an autosomal recessive form (caused due to PHKG2 and PHKB genes) causing liver and/or muscle disease. The disorder is characterized by slightly low blood sugar (hypoglycemia). Excess amounts of glycogen (the stored form of energy that comes from carbohydrates) are deposited in the liver, causing enlargement of the liver (hepatomegaly).For more information on the above disorders, choose “Forbes,” “Anderson,” “Hers,” and “glycogen storage disease IX” as your search terms in the Rare Disease Database.
Hereditary Fructose intolerance (HFI) is an autosomal recessive genetic condition that causes an inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). This is due to a deficiency of activity of the enzyme fructose-1-phosphate aldolase (Aldolase B), resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Fructose and sucrose are naturally occurring sugars that are used as sweeteners in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults. (For more information about this condition, choose “fructose” as your search term in the Rare Disease Database.) | Related disorders of Glycogen Storage Disease Type I. Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:Forbes or Cori disease (GSD-III) is one of several glycogen storage disorders that are inherited as autosomal recessive traits. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes excessive amounts of an abnormally digested glycogen (the stored form of energy that comes from carbohydrates) to be deposited in the liver, muscles and, in some cases, the heart. Symptoms become evident during the first years of life with hepatomegaly and/or myopathy, and elevated liver enzymes. In the first few months some symptoms may overlap with GSDI (elevated lipids, hepatomegaly, low glucose).Andersen disease (GSD-IV) also known as glycogen storage disease type IV; This GSD is also inherited as an autosomal recessive trait. It is caused by deficient activity of the glycogen-branching enzyme (GBE), resulting in accumulation of abnormally formed glycogen in the liver, muscle, and/or other tissues. In most affected individuals, symptoms and findings become evident in the first few years of life. Such features typically include failure to grow and gaining weight at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly).Hers disease (GSD-VI) is also called glycogen storage disease type VI. It usually has milder symptoms than most other types of glycogen storage diseases. It is caused by a deficiency of the enzyme liver phosphorylase. Hers disease is characterized by enlargement of the liver (hepatomegaly), moderately low blood sugar (hypoglycemia), elevated levels of acetone and other ketone bodies in the blood (ketosis), and moderate growth retardation. Symptoms are not always evident during childhood, and children are usually able to lead normal lives. However, in some instances, symptoms may be severe.Glycogen storage disease IX is caused due to deficiency of phosphorylase kinase enzyme (PK enzyme deficiency). It can be inherited as an X-linked genetic disorder caused by a deficiency of the enzyme liver phosphorylase kinase (mainly PHKA2 gene) or it can be inherited as an autosomal recessive form (caused due to PHKG2 and PHKB genes) causing liver and/or muscle disease. The disorder is characterized by slightly low blood sugar (hypoglycemia). Excess amounts of glycogen (the stored form of energy that comes from carbohydrates) are deposited in the liver, causing enlargement of the liver (hepatomegaly).For more information on the above disorders, choose “Forbes,” “Anderson,” “Hers,” and “glycogen storage disease IX” as your search terms in the Rare Disease Database.
Hereditary Fructose intolerance (HFI) is an autosomal recessive genetic condition that causes an inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol and brown sugar). This is due to a deficiency of activity of the enzyme fructose-1-phosphate aldolase (Aldolase B), resulting in an accumulation of fructose-1-phosphate in the liver, kidney, and small intestine. Fructose and sucrose are naturally occurring sugars that are used as sweeteners in many foods, including many baby foods. This disorder can be life threatening in infants and ranges from mild to severe in older children and adults. (For more information about this condition, choose “fructose” as your search term in the Rare Disease Database.) | 524 | Glycogen Storage Disease Type I |
nord_524_5 | Diagnosis of Glycogen Storage Disease Type I | GSD type I is diagnosed by laboratory tests that indicate abnormal levels of glucose, lactate, uric acid, triglycerides and cholesterol. Molecular genetic testing for the G6PC and SLC37A4 genes is available to confirm a diagnosis. Molecular genetic testing can also be used for carrier testing and prenatal diagnosis. Liver biopsy can also be used to prove specific enzyme deficiency for GSD Ia. | Diagnosis of Glycogen Storage Disease Type I. GSD type I is diagnosed by laboratory tests that indicate abnormal levels of glucose, lactate, uric acid, triglycerides and cholesterol. Molecular genetic testing for the G6PC and SLC37A4 genes is available to confirm a diagnosis. Molecular genetic testing can also be used for carrier testing and prenatal diagnosis. Liver biopsy can also be used to prove specific enzyme deficiency for GSD Ia. | 524 | Glycogen Storage Disease Type I |
nord_524_6 | Therapies of Glycogen Storage Disease Type I | Treatment
GSDI is treated with a special diet in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development. Frequent small servings of carbohydrates must be maintained during the day and night throughout the life. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose. Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years. Medications maybe prescribed to lower lipid levels and prevent and/or treat kidney disease. Human granulocyte colony stimulating factor (GCSF) may be used to treat recurrent infections in GSD type Ib patients. Liver tumors (adenomas) can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current (radiofrequency ablation). Kidney and/or liver transplantation are sometimes considered if other therapies are unsuccessful or where liver adenomas keep growing.Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.Genetic counseling is recommended for affected individuals and their families. | Therapies of Glycogen Storage Disease Type I. Treatment
GSDI is treated with a special diet in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development. Frequent small servings of carbohydrates must be maintained during the day and night throughout the life. Calcium, vitamin D and iron supplements maybe recommended to avoid deficits. Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose. Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years. Medications maybe prescribed to lower lipid levels and prevent and/or treat kidney disease. Human granulocyte colony stimulating factor (GCSF) may be used to treat recurrent infections in GSD type Ib patients. Liver tumors (adenomas) can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current (radiofrequency ablation). Kidney and/or liver transplantation are sometimes considered if other therapies are unsuccessful or where liver adenomas keep growing.Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.Genetic counseling is recommended for affected individuals and their families. | 524 | Glycogen Storage Disease Type I |
nord_525_0 | Overview of Glycogen Storage Disease Type III | SummaryThe human diet contains 3 macronutrients that can be stored by the body as energy: carbohydrates (as the natural carbohydrate polymer glycogen, in mainly the liver and muscle), protein (as muscle, the natural protein source of the body) and fat (in organs and fat tissue). There are at least 13 glycogen storage disease (GSD) subtypes, in which the energy stored as glycogen cannot be adequately produced or broken down. The liver GSD subtypes cause fasting intolerance (types 0, Ia, Ib, III, VI, IX and XI) or liver failure (type IV), with or without muscle symptoms. The fasting induced low blood glucose concentrations decrease the energy supply by the liver to organs like the brain.The ketotic GSD subtypes 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia. In these patients, the breakdown of glycogen (glycogenolysis) is defective. Their fasting intolerance is considered relatively mild compared to GSD type I patients, in whom both glycogenolysis and the generation of glucose from non-carbohydrate substances (gluconeogenesis) are impaired.IntroductionThe first patient with GSD type III (GSD-III) was described in 1928 by the Dutch pediatrician Simon van Creveld. He described a 7-year-old boy with marked enlarged liver, obesity and small genitals. The fasting blood glucose concentration appeared to be very low, and concentrations of ketone bodies in urine were high. Based on additional investigations in the patient, Dr Van Creveld concluded that the body increasingly burned fat, resulted from “insufficient mobilization of glycogen”. | Overview of Glycogen Storage Disease Type III. SummaryThe human diet contains 3 macronutrients that can be stored by the body as energy: carbohydrates (as the natural carbohydrate polymer glycogen, in mainly the liver and muscle), protein (as muscle, the natural protein source of the body) and fat (in organs and fat tissue). There are at least 13 glycogen storage disease (GSD) subtypes, in which the energy stored as glycogen cannot be adequately produced or broken down. The liver GSD subtypes cause fasting intolerance (types 0, Ia, Ib, III, VI, IX and XI) or liver failure (type IV), with or without muscle symptoms. The fasting induced low blood glucose concentrations decrease the energy supply by the liver to organs like the brain.The ketotic GSD subtypes 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia. In these patients, the breakdown of glycogen (glycogenolysis) is defective. Their fasting intolerance is considered relatively mild compared to GSD type I patients, in whom both glycogenolysis and the generation of glucose from non-carbohydrate substances (gluconeogenesis) are impaired.IntroductionThe first patient with GSD type III (GSD-III) was described in 1928 by the Dutch pediatrician Simon van Creveld. He described a 7-year-old boy with marked enlarged liver, obesity and small genitals. The fasting blood glucose concentration appeared to be very low, and concentrations of ketone bodies in urine were high. Based on additional investigations in the patient, Dr Van Creveld concluded that the body increasingly burned fat, resulted from “insufficient mobilization of glycogen”. | 525 | Glycogen Storage Disease Type III |
nord_525_1 | Symptoms of Glycogen Storage Disease Type III | The median age at the first clinical presentations is in the first year of life. Most common presenting symptoms are enlarged liver (hepatomegaly) (98%), low blood sugar (hypoglycemia) (53%), failure to thrive (49%) and recurrent illness and/or infections (17%). Symptoms and signs of GSD-III, at least during the first 4 to 6 years of life, may be indistinguishable from GSD type I. The amount of glycogen in the liver and muscles is abnormally high, the liver is enlarged, and the abdomen protrudes. The muscles tend to be flaccid or weak.A typical child with GSD-III has short stature, low blood sugar after fasting that does not respond to the hormone glucagon, and an elevated level of fatty substances in the blood, known as hyperlipidemia. Hypoglycemia is usually associated with increased ketone bodies, and ketonemia can precede hypoglycemia, reflecting activation of burning fat stores. Patients with GSD-III may also have difficulty fighting infections, and may experience unusually frequent nosebleeds. Enlarged heart muscle (cardiac hypertrophy) is common in individuals with GSD-IIIa and can already appear in early childhood. However, in most children, heart function remains within normal limits. Children with GSD-III often grow slowly during childhood and puberty may be delayed, but their adult height is usually normal. Most signs and symptoms improve significantly with adequate dietary management.In adulthood, the liver manifestations of the disease usually subside, but progression to liver scarring (cirrhosis) and malignancy (carcinoma) may occur. Despite dietary management, muscle disease can get worse. As the cohort of adult GSD-III patients is still relatively young and small, the course of the disease over time is incompletely described.Some affected individuals may have virtually no symptoms (asymptomatic) other than a protruding abdomen and an enlarged liver in childhood. These patients tend to lose these few symptoms during adolescence when their liver decreases progressively in size.ClassificationThere are four subtypes of GSD-III:GSD-IIIa is the most common type, affecting 85%, and affects both the liver and (cardiac and/or skeletal) muscles.GSD-IIIb affects about 15% of individuals and only affects the liver. AGL molecular testing can display mutations specific to GSD-IIIb.GSD-IIIc is extremely rare and believed to be caused by loss of activity of the glucosidase active site of the glycogen debranching enzyme.GSD-IIId is extremely rare and believed to be caused by loss of activity of the transferase active site of the glycogen debranching enzyme. | Symptoms of Glycogen Storage Disease Type III. The median age at the first clinical presentations is in the first year of life. Most common presenting symptoms are enlarged liver (hepatomegaly) (98%), low blood sugar (hypoglycemia) (53%), failure to thrive (49%) and recurrent illness and/or infections (17%). Symptoms and signs of GSD-III, at least during the first 4 to 6 years of life, may be indistinguishable from GSD type I. The amount of glycogen in the liver and muscles is abnormally high, the liver is enlarged, and the abdomen protrudes. The muscles tend to be flaccid or weak.A typical child with GSD-III has short stature, low blood sugar after fasting that does not respond to the hormone glucagon, and an elevated level of fatty substances in the blood, known as hyperlipidemia. Hypoglycemia is usually associated with increased ketone bodies, and ketonemia can precede hypoglycemia, reflecting activation of burning fat stores. Patients with GSD-III may also have difficulty fighting infections, and may experience unusually frequent nosebleeds. Enlarged heart muscle (cardiac hypertrophy) is common in individuals with GSD-IIIa and can already appear in early childhood. However, in most children, heart function remains within normal limits. Children with GSD-III often grow slowly during childhood and puberty may be delayed, but their adult height is usually normal. Most signs and symptoms improve significantly with adequate dietary management.In adulthood, the liver manifestations of the disease usually subside, but progression to liver scarring (cirrhosis) and malignancy (carcinoma) may occur. Despite dietary management, muscle disease can get worse. As the cohort of adult GSD-III patients is still relatively young and small, the course of the disease over time is incompletely described.Some affected individuals may have virtually no symptoms (asymptomatic) other than a protruding abdomen and an enlarged liver in childhood. These patients tend to lose these few symptoms during adolescence when their liver decreases progressively in size.ClassificationThere are four subtypes of GSD-III:GSD-IIIa is the most common type, affecting 85%, and affects both the liver and (cardiac and/or skeletal) muscles.GSD-IIIb affects about 15% of individuals and only affects the liver. AGL molecular testing can display mutations specific to GSD-IIIb.GSD-IIIc is extremely rare and believed to be caused by loss of activity of the glucosidase active site of the glycogen debranching enzyme.GSD-IIId is extremely rare and believed to be caused by loss of activity of the transferase active site of the glycogen debranching enzyme. | 525 | Glycogen Storage Disease Type III |
nord_525_2 | Causes of Glycogen Storage Disease Type III | GSD-III is an inborn error of metabolism caused by mutations in the AGL gene that is located on chromosome 1p21. The AGL gene is responsible for the production of the debranching enzyme.Glycogen is stored in the liver and muscles for future energy needs. Glycogen can then be converted into sugar (glucose). Glucose is used as a readily available source of energy during fasting or exercise. The debranching enzyme has two active (catalytic) sites called amylo-1,6-glucosidase and 4-alpha-glucanotransferase. Both sites on the enzyme are together with the phosphorylase and phosphorylase kinase enzymes (impaired in GSD types VI and IX, respectively) responsible for breaking down glycogen to raise the blood sugar concentration. Without normal debranching enzyme function, two changes take place. If glycogen can only be broken down partially, an insufficient amount of energy/glucose can be produced. The structure that is left, resembling a molecule called a “limit dextrin”, is excessively stored in liver, and (skeletal and cardiac) muscle tissues.Inheritance/geneticsGSD-III is a genetic disorder characterized by variable liver, cardiac muscle and skeletal muscle abnormalities. Symptoms are associated with abnormalities in the AGL gene, causing deficiency of the glycogen debranching enzyme. GSD-III is inherited as an autosomal recessive trait.Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.All individuals carry mutations/variants in ± 4-5 genes. Parents who are close relatives (consanguineous) or who originate from closed communities have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Glycogen Storage Disease Type III. GSD-III is an inborn error of metabolism caused by mutations in the AGL gene that is located on chromosome 1p21. The AGL gene is responsible for the production of the debranching enzyme.Glycogen is stored in the liver and muscles for future energy needs. Glycogen can then be converted into sugar (glucose). Glucose is used as a readily available source of energy during fasting or exercise. The debranching enzyme has two active (catalytic) sites called amylo-1,6-glucosidase and 4-alpha-glucanotransferase. Both sites on the enzyme are together with the phosphorylase and phosphorylase kinase enzymes (impaired in GSD types VI and IX, respectively) responsible for breaking down glycogen to raise the blood sugar concentration. Without normal debranching enzyme function, two changes take place. If glycogen can only be broken down partially, an insufficient amount of energy/glucose can be produced. The structure that is left, resembling a molecule called a “limit dextrin”, is excessively stored in liver, and (skeletal and cardiac) muscle tissues.Inheritance/geneticsGSD-III is a genetic disorder characterized by variable liver, cardiac muscle and skeletal muscle abnormalities. Symptoms are associated with abnormalities in the AGL gene, causing deficiency of the glycogen debranching enzyme. GSD-III is inherited as an autosomal recessive trait.Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.All individuals carry mutations/variants in ± 4-5 genes. Parents who are close relatives (consanguineous) or who originate from closed communities have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 525 | Glycogen Storage Disease Type III |
nord_525_3 | Affects of Glycogen Storage Disease Type III | All glycogen storage diseases together affect fewer than 1 in 40,000 persons in the United States. GSD-III has an incidence of about 1 in 100,000. The incidence of GSD-III is higher in North African Jews (± 1 in 5,400), Faroese (± 1 in 3,100) and the Inuit population in Nunavik, Canada (± 1 in 2,500). | Affects of Glycogen Storage Disease Type III. All glycogen storage diseases together affect fewer than 1 in 40,000 persons in the United States. GSD-III has an incidence of about 1 in 100,000. The incidence of GSD-III is higher in North African Jews (± 1 in 5,400), Faroese (± 1 in 3,100) and the Inuit population in Nunavik, Canada (± 1 in 2,500). | 525 | Glycogen Storage Disease Type III |
nord_525_4 | Related disorders of Glycogen Storage Disease Type III | The following diseases are similar to GSD-III. Comparisons may be useful for a differential diagnosis. Several GSD subtypes can be considered:GSD type 0 (GSD-0) is caused by the inability to store glycogen in the liver. This explains why the liver size is normal and the biochemical observation of postprandial hyperglycemia and increase of blood lactate concentrations.GSD type I (GSD-I), also known as von Gierke disease, is a more severe form of GSD. GSD-I is a hereditary metabolic disorder caused by an inborn lack of either the enzyme glucose-6-phosphatase or the enzyme glucose-6-phosphate translocase. These enzymes are needed to convert glucose-6-phosphate into glucose that the body uses for its energy needs. A deficiency of these enzymes causes abnormal deposits of glycogen in the liver and kidney cells. Unlike GSD-III, uric acid and lactic acid levels are elevated in GSD-I and hypoglycemia and hypertriglyceridemia (high triglycerides) are more severe.GSD type IV (GSD-IV), also known as Andersen disease, is characterized by scarring of the liver (cirrhosis) which may lead to liver failure. GSD-IV is an autosomal recessive genetic disorder caused by mutations in the GBE1 gene that provides instructions for making the glycogen branching enzyme. Deficient activity of the glycogen branching enzyme leads to a generalized accumulation of structurally abnormal glycogen.GSD type VI (GSD-VI), also known as Hers disease, is a relatively mild hepatic form of glycogen storage disease. The disorder is caused by mutations in the PYGL gene that provides instructions for making an enzyme called liver glycogen phosphorylase. Deficient activity of this enzyme leads to enlargement of the liver, moderately low blood sugar (hypoglycemia), elevated levels of ketone bodies in the blood (ketosis), and growth retardation. Symptoms are not always evident during childhood.GSD type IX (GSD-IX) affecting the liver can be inherited via both X-linked (caused by PHKA2 mutations) and autosomal recessive (caused by mutations in PHKAB or PHKG2) inheritance. The mutations cause a deficiency of the enzyme liver phosphorylase kinase. The disorder is characterized by slightly low blood sugar (hypoglycemia) during fasting. Excess amounts of glycogen are deposited in the liver, causing enlargement of the liver. Untreated patients may present with failure to thrive and hypotonia, but can remain undiagnosed, like GSD-0 and GSD-VI patients.Patients with fructose-1,6-bisphosphatase deficiency present with fasting associated hypoglycemia, hepatomegaly and increased blood concentrations of liver enzymes. In contrast with GSD-III patients, blood lactate concentrations increase upon fasting.Patients with certain lysosomal storage diseases (like Niemann Pick type B and Gaucher disease) may present with hepatomegaly, stunted growth and hyperlipidemia. In contrast with GSD-III patients, fasting intolerance is absent.For more information on the above disorders, search the Rare Disease Database. | Related disorders of Glycogen Storage Disease Type III. The following diseases are similar to GSD-III. Comparisons may be useful for a differential diagnosis. Several GSD subtypes can be considered:GSD type 0 (GSD-0) is caused by the inability to store glycogen in the liver. This explains why the liver size is normal and the biochemical observation of postprandial hyperglycemia and increase of blood lactate concentrations.GSD type I (GSD-I), also known as von Gierke disease, is a more severe form of GSD. GSD-I is a hereditary metabolic disorder caused by an inborn lack of either the enzyme glucose-6-phosphatase or the enzyme glucose-6-phosphate translocase. These enzymes are needed to convert glucose-6-phosphate into glucose that the body uses for its energy needs. A deficiency of these enzymes causes abnormal deposits of glycogen in the liver and kidney cells. Unlike GSD-III, uric acid and lactic acid levels are elevated in GSD-I and hypoglycemia and hypertriglyceridemia (high triglycerides) are more severe.GSD type IV (GSD-IV), also known as Andersen disease, is characterized by scarring of the liver (cirrhosis) which may lead to liver failure. GSD-IV is an autosomal recessive genetic disorder caused by mutations in the GBE1 gene that provides instructions for making the glycogen branching enzyme. Deficient activity of the glycogen branching enzyme leads to a generalized accumulation of structurally abnormal glycogen.GSD type VI (GSD-VI), also known as Hers disease, is a relatively mild hepatic form of glycogen storage disease. The disorder is caused by mutations in the PYGL gene that provides instructions for making an enzyme called liver glycogen phosphorylase. Deficient activity of this enzyme leads to enlargement of the liver, moderately low blood sugar (hypoglycemia), elevated levels of ketone bodies in the blood (ketosis), and growth retardation. Symptoms are not always evident during childhood.GSD type IX (GSD-IX) affecting the liver can be inherited via both X-linked (caused by PHKA2 mutations) and autosomal recessive (caused by mutations in PHKAB or PHKG2) inheritance. The mutations cause a deficiency of the enzyme liver phosphorylase kinase. The disorder is characterized by slightly low blood sugar (hypoglycemia) during fasting. Excess amounts of glycogen are deposited in the liver, causing enlargement of the liver. Untreated patients may present with failure to thrive and hypotonia, but can remain undiagnosed, like GSD-0 and GSD-VI patients.Patients with fructose-1,6-bisphosphatase deficiency present with fasting associated hypoglycemia, hepatomegaly and increased blood concentrations of liver enzymes. In contrast with GSD-III patients, blood lactate concentrations increase upon fasting.Patients with certain lysosomal storage diseases (like Niemann Pick type B and Gaucher disease) may present with hepatomegaly, stunted growth and hyperlipidemia. In contrast with GSD-III patients, fasting intolerance is absent.For more information on the above disorders, search the Rare Disease Database. | 525 | Glycogen Storage Disease Type III |
nord_525_5 | Diagnosis of Glycogen Storage Disease Type III | An enlarged liver and low blood sugar with high levels of ketones, transaminases, lipids and creatine kinase is indicative of GSD-III. Uric acid and fasting lactic acid levels are usually normal. In GSD-IIIb creatine kinase can be normal. Molecular genetic testing for mutations in the AGL gene can be used to confirm the diagnosis. Nowadays, liver and muscle biopsies are uncommon. In many countries besides the United States, studies in blood cells and skin fibroblasts are clinically available to confirm GDE deficiency. | Diagnosis of Glycogen Storage Disease Type III. An enlarged liver and low blood sugar with high levels of ketones, transaminases, lipids and creatine kinase is indicative of GSD-III. Uric acid and fasting lactic acid levels are usually normal. In GSD-IIIb creatine kinase can be normal. Molecular genetic testing for mutations in the AGL gene can be used to confirm the diagnosis. Nowadays, liver and muscle biopsies are uncommon. In many countries besides the United States, studies in blood cells and skin fibroblasts are clinically available to confirm GDE deficiency. | 525 | Glycogen Storage Disease Type III |
nord_525_6 | Therapies of Glycogen Storage Disease Type III | TreatmentDietary management is the cornerstone.Liver transplantation is indicated only for patients with severe hepatic cirrhosis, liver dysfunction and /or liver cancer (hepatocellular carcinoma).Clinical Testing and Follow-UpEmergency letters should be provided and shared care with local physicians should be organized. Liver ultrasound and baseline heart tests (electrocardiogram and echocardiograms) are usually recommended to determine the medical needs for individual patients based on the severity of the condition.Genetic counseling is recommended for families of children with glycogen storage diseases. | Therapies of Glycogen Storage Disease Type III. TreatmentDietary management is the cornerstone.Liver transplantation is indicated only for patients with severe hepatic cirrhosis, liver dysfunction and /or liver cancer (hepatocellular carcinoma).Clinical Testing and Follow-UpEmergency letters should be provided and shared care with local physicians should be organized. Liver ultrasound and baseline heart tests (electrocardiogram and echocardiograms) are usually recommended to determine the medical needs for individual patients based on the severity of the condition.Genetic counseling is recommended for families of children with glycogen storage diseases. | 525 | Glycogen Storage Disease Type III |
nord_526_0 | Overview of Glycogen Storage Disease Type IX | SummaryGlycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by a deficiency of the enzyme phosphorylase kinase. This enzyme is necessary to break down (metabolize) a type of complex sugar known as glycogen. Normally, glycogen is metabolized into a simple sugar known as glucose. Glucose is one of the main sources of energy for the body. When there is excess glycogen, it is stored in the body, primarily in the liver and muscles and, when the body needs more energy, is eventually converted into glucose. Because individuals with GSD-IX cannot properly break down glycogen, excess amounts accumulate in the liver, muscles, or both. GSD-IX is sometimes categorized into a liver form (caused by phosphorylase kinase deficiency in the liver, or liver and muscle) and muscle form, which is rare and is caused by phosphorylase kinase deficiency in the muscle only.Common symptoms of the liver form include abnormal enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting, and growth delays. The specific symptoms that develop and the overall severity of GSD-IX can vary greatly from one individual to another, even among individuals with the same subtype. The liver form of GSD-IX is inherited in either an X-linked or autosomal recessive manner and can be caused by a mutation in one of three different genes. Mutations in only one gene have been found in individuals with the muscle form. This form is rare and is inherited in an X-linked manner.IntroductionGSD-IX is part of a larger group of disorders in which the body cannot metabolize glycogen into glucose (glycogen storage diseases). The underlying cause is different for each glycogen storage disease. GSD-IX was first described in the medical literature in 1966 by Dr. Hug, et al. They reported on a young girl with phosphorylase kinase deficiency of the liver that was consistent with autosomal recessive inheritance. Later on, similar individuals were described in the medical literature whose cases were more consistent with X-linked inheritance. This second group of individuals was originally classified as having glycogen storage disease type VIII. However, the X-linked form is now classified as a subtype of GSD-IX since the disorder involves the same enzyme complex as the autosomal recessive forms. The classification of GSD-VIII is no longer used (obsolete). | Overview of Glycogen Storage Disease Type IX. SummaryGlycogen storage disease type IX (GSD-IX) is a group of at least four disorders characterized by a deficiency of the enzyme phosphorylase kinase. This enzyme is necessary to break down (metabolize) a type of complex sugar known as glycogen. Normally, glycogen is metabolized into a simple sugar known as glucose. Glucose is one of the main sources of energy for the body. When there is excess glycogen, it is stored in the body, primarily in the liver and muscles and, when the body needs more energy, is eventually converted into glucose. Because individuals with GSD-IX cannot properly break down glycogen, excess amounts accumulate in the liver, muscles, or both. GSD-IX is sometimes categorized into a liver form (caused by phosphorylase kinase deficiency in the liver, or liver and muscle) and muscle form, which is rare and is caused by phosphorylase kinase deficiency in the muscle only.Common symptoms of the liver form include abnormal enlargement of the liver (hepatomegaly), unusually low levels of blood glucose (hypoglycemia), increase in blood ketones, which are byproducts generated when the body burns fats for energy (hyperketosis) during fasting, and growth delays. The specific symptoms that develop and the overall severity of GSD-IX can vary greatly from one individual to another, even among individuals with the same subtype. The liver form of GSD-IX is inherited in either an X-linked or autosomal recessive manner and can be caused by a mutation in one of three different genes. Mutations in only one gene have been found in individuals with the muscle form. This form is rare and is inherited in an X-linked manner.IntroductionGSD-IX is part of a larger group of disorders in which the body cannot metabolize glycogen into glucose (glycogen storage diseases). The underlying cause is different for each glycogen storage disease. GSD-IX was first described in the medical literature in 1966 by Dr. Hug, et al. They reported on a young girl with phosphorylase kinase deficiency of the liver that was consistent with autosomal recessive inheritance. Later on, similar individuals were described in the medical literature whose cases were more consistent with X-linked inheritance. This second group of individuals was originally classified as having glycogen storage disease type VIII. However, the X-linked form is now classified as a subtype of GSD-IX since the disorder involves the same enzyme complex as the autosomal recessive forms. The classification of GSD-VIII is no longer used (obsolete). | 526 | Glycogen Storage Disease Type IX |
nord_526_1 | Symptoms of Glycogen Storage Disease Type IX | GSD-IX is caused by deficiency of the enzyme phosphorylase kinase. The specific symptoms present, severity and prognosis can vary depending upon the subtype and the areas of the body affected. The symptoms and severity can vary even among individuals with the same mutation. In addition, some subtypes have only been reported in a handful of individuals, which prevents physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Individuals with the liver form of GSD-IX have a wide range of clinical symptoms ranging from less severe to more severe hepatic manifestations of the disease. Natural history studies are necessary to understand completely the long-term course and prognosis of GSD IX. Glycogen Storage Disease Type IXa
GSD-IXa is the most common subtype of GSD IX, and is caused by the deficiency of phosphorylase kinase in the liver. It accounts for approximately 75% of affected individuals and is also known as X-linked liver glycogenesis or PHKA2-related phosphorylase kinase deficiency. Affected individuals often develop an enlarged liver (hepatomegaly), low blood glucose levels (hypoglycemia) and high levels of blood ketones during fasting, and growth delays. Some children have delays in motor development. Hypoglycemia can develop after fasting overnight, after shorter periods of fasting, or if food intake is reduced during illness. Symptoms of hypoglycemia include shakiness, irritability, unexplained fatigue, headache, pale skin, and rapid heartbeat. Hypoglycemia can result in the body burning fat for energy in which causes high levels of ketones in the body (hyperketosis). Hyperketotic hypoglycemia can be associated with nausea and vomiting. Although hypoglycemia can be considered mild symptoms could be masked because of the body’s ability to lower levels of blood glucose than in unaffected individuals. Hypoglycemia can also be very severe and may recur. Growth delays can be pronounced during childhood, but most children show catch-up growth and ultimately reach a normal adult height. Diminished muscle tone (hypotonia) and muscle weakness may also be seen during early childhood. Puberty may be delayed. Increased levels of different lipids such as cholesterol (hypercholesterolemia) and triglycerides (hypertriglyceridemia) may be seen in blood of some affected individuals.Although GSD-IXa has, historically, been considered a benign (mild) disorder, this notion is being currently dispelled with reports of patients with severe symptoms. It is being increasingly recognized that there is a broad range in the severity of symptoms. Some people have few or no problems with hypoglycemia while others have severe and recurrent hypoglycemia. There have been reports in the medical literature of cases in which scar tissue has developed within the liver (fibrosis) and, in some children may develop irreversible scarring of the liver (cirrhosis).Glycogen Storage Disease Type IXb
This subtype of the disorder is characterized by phosphorylase kinase deficiency of the liver and the muscle. It is also known as PHKB-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa. Children with GSD-IXb can develop an enlarged liver (hepatomegaly), hypoglycemia, diminished muscle tone (hypotonia), muscle weakness, and growth delays that can result in childhood short stature. Despite the deficiency of PhK in muscle as well as liver, muscle weakness is not always reported in people with this subtype.Glycogen Storage Disease Type IXc
This subtype of GSD-IX is characterized by phosphorylase kinase deficiency of the liver. It is also known as PHKG2-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa and GSD-IXb, but tend to be severe. Like GSD IXa and GSD-IXb, this form of the disorder is characterized by an enlarged liver, hypoglycemia, hypotonia and delays in motor development in some children, and growth delays in childhood. Most individuals attain a normal adult height.. Some children may develop recurrent episodes of low blood glucose levels (hypoglycemia). This can result in the body burning fat for energy resulting in high levels of ketones in the body (hyperketosis). Hyperketotic hypoglycemia may only occur after prolonged fasting, such as overnight or during an illness if food intake is reduced, and can be associated with nausea and vomiting. Benign tumors of the liver, also known as hepatic adenomas may be seen in some individuals. Affected individuals may present with a wide range of disease symptoms. Understanding of this disease continues to evolve as more cases come to light.In some cases of GSD-IXc, more serious complications can occur such as the development scar tissue (fibrosis) within the liver as well as degeneration, inflammation and scarring of the liver (cirrhosis). The risk of these complications appears to be greater in GSD-IXc than in other forms of the disorder. Liver transplantation may be needed for survival in some patients who have severe liver damage.Glycogen Storage Disease Type IXd
This extremely rare form of the disorder is characterized by phosphorylase kinase deficiency of the muscle. The liver is not affected. Affected individuals may develop progressive muscle weakness, muscle degeneration (atrophy), muscle cramps, abnormal muscle pain (myalgia) that occurs following exercise (exercise-induced muscle pain), abnormal muscle stiffness following exercise and rust colored urine due to excretion of myoglobin, a muscle protein (myoglobinuria). In general, affected individuals cannot exercise at normally accepted levels (exercise intolerance). The onset of symptoms can occur in childhood or adulthood; most patients have adult onset. Notably, some individuals with phosphorylase kinase deficiency in muscle do not have any obvious symptoms. This form is also known as PHKA1-related phosphorylase kinase deficiency. | Symptoms of Glycogen Storage Disease Type IX. GSD-IX is caused by deficiency of the enzyme phosphorylase kinase. The specific symptoms present, severity and prognosis can vary depending upon the subtype and the areas of the body affected. The symptoms and severity can vary even among individuals with the same mutation. In addition, some subtypes have only been reported in a handful of individuals, which prevents physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Individuals with the liver form of GSD-IX have a wide range of clinical symptoms ranging from less severe to more severe hepatic manifestations of the disease. Natural history studies are necessary to understand completely the long-term course and prognosis of GSD IX. Glycogen Storage Disease Type IXa
GSD-IXa is the most common subtype of GSD IX, and is caused by the deficiency of phosphorylase kinase in the liver. It accounts for approximately 75% of affected individuals and is also known as X-linked liver glycogenesis or PHKA2-related phosphorylase kinase deficiency. Affected individuals often develop an enlarged liver (hepatomegaly), low blood glucose levels (hypoglycemia) and high levels of blood ketones during fasting, and growth delays. Some children have delays in motor development. Hypoglycemia can develop after fasting overnight, after shorter periods of fasting, or if food intake is reduced during illness. Symptoms of hypoglycemia include shakiness, irritability, unexplained fatigue, headache, pale skin, and rapid heartbeat. Hypoglycemia can result in the body burning fat for energy in which causes high levels of ketones in the body (hyperketosis). Hyperketotic hypoglycemia can be associated with nausea and vomiting. Although hypoglycemia can be considered mild symptoms could be masked because of the body’s ability to lower levels of blood glucose than in unaffected individuals. Hypoglycemia can also be very severe and may recur. Growth delays can be pronounced during childhood, but most children show catch-up growth and ultimately reach a normal adult height. Diminished muscle tone (hypotonia) and muscle weakness may also be seen during early childhood. Puberty may be delayed. Increased levels of different lipids such as cholesterol (hypercholesterolemia) and triglycerides (hypertriglyceridemia) may be seen in blood of some affected individuals.Although GSD-IXa has, historically, been considered a benign (mild) disorder, this notion is being currently dispelled with reports of patients with severe symptoms. It is being increasingly recognized that there is a broad range in the severity of symptoms. Some people have few or no problems with hypoglycemia while others have severe and recurrent hypoglycemia. There have been reports in the medical literature of cases in which scar tissue has developed within the liver (fibrosis) and, in some children may develop irreversible scarring of the liver (cirrhosis).Glycogen Storage Disease Type IXb
This subtype of the disorder is characterized by phosphorylase kinase deficiency of the liver and the muscle. It is also known as PHKB-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa. Children with GSD-IXb can develop an enlarged liver (hepatomegaly), hypoglycemia, diminished muscle tone (hypotonia), muscle weakness, and growth delays that can result in childhood short stature. Despite the deficiency of PhK in muscle as well as liver, muscle weakness is not always reported in people with this subtype.Glycogen Storage Disease Type IXc
This subtype of GSD-IX is characterized by phosphorylase kinase deficiency of the liver. It is also known as PHKG2-related phosphorylase kinase deficiency. The symptoms are similar to those in people with GSD-IXa and GSD-IXb, but tend to be severe. Like GSD IXa and GSD-IXb, this form of the disorder is characterized by an enlarged liver, hypoglycemia, hypotonia and delays in motor development in some children, and growth delays in childhood. Most individuals attain a normal adult height.. Some children may develop recurrent episodes of low blood glucose levels (hypoglycemia). This can result in the body burning fat for energy resulting in high levels of ketones in the body (hyperketosis). Hyperketotic hypoglycemia may only occur after prolonged fasting, such as overnight or during an illness if food intake is reduced, and can be associated with nausea and vomiting. Benign tumors of the liver, also known as hepatic adenomas may be seen in some individuals. Affected individuals may present with a wide range of disease symptoms. Understanding of this disease continues to evolve as more cases come to light.In some cases of GSD-IXc, more serious complications can occur such as the development scar tissue (fibrosis) within the liver as well as degeneration, inflammation and scarring of the liver (cirrhosis). The risk of these complications appears to be greater in GSD-IXc than in other forms of the disorder. Liver transplantation may be needed for survival in some patients who have severe liver damage.Glycogen Storage Disease Type IXd
This extremely rare form of the disorder is characterized by phosphorylase kinase deficiency of the muscle. The liver is not affected. Affected individuals may develop progressive muscle weakness, muscle degeneration (atrophy), muscle cramps, abnormal muscle pain (myalgia) that occurs following exercise (exercise-induced muscle pain), abnormal muscle stiffness following exercise and rust colored urine due to excretion of myoglobin, a muscle protein (myoglobinuria). In general, affected individuals cannot exercise at normally accepted levels (exercise intolerance). The onset of symptoms can occur in childhood or adulthood; most patients have adult onset. Notably, some individuals with phosphorylase kinase deficiency in muscle do not have any obvious symptoms. This form is also known as PHKA1-related phosphorylase kinase deficiency. | 526 | Glycogen Storage Disease Type IX |
nord_526_2 | Causes of Glycogen Storage Disease Type IX | Glycogen storage disease type IX is caused by mutations in the PHKA1, the PHKA2, the PHKB, or the PHKG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation is present in a gene, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For GSD-IX, these mutations can be inherited in either an autosomal recessive or X-linked manner.Genetic diseases are determined by the combination of genes for a particular trait. Genes are packaged in the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an altered gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% (1 in 4) with each pregnancy. The risk to have a child who is a carrier like the parents is 50% (1 in 2) with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25% (1 in 4). The chance is the same for males and females.X-linked recessive genetic disorders are conditions caused by an altered gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This process, called “X-inactivation”, is random. In some cells of the body, one of the X chromosomes is inactivated, while in the remaining cells, the other X chromosome is inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder but may have symptoms if the X chromosome with the altered gene is the one that is active in a larger proportion of cells. Females who are carriers and have symptoms of an X-linked disorder are known as manifesting heterozygotes. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters. The daughters will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% (1 in 4) chance with each pregnancy to have a carrier daughter like themselves, a 25% (1 in 4) chance to have a non-carrier daughter, a 25% (1 in 4) chance to have a son affected with the disease, and a 25% (1 in 4) chance to have an unaffected son. In other words, if a female carrier is pregnant with a male child, there is a 50% (1 in 2) chance that the baby will have inherited the altered gene and will have GSD IX, and if the baby is female, there is a 50% (1 in 2) chance that she will be a carrier.Investigators have determined that glycogen storage disease type GSD-IXa is caused by mutations in the PHKA2 gene, which is located on the short arm (p) of the X chromosome (Xp22.13). This form of the disorder is inherited in an X-linked manner. Some individuals have a mutation in this gene that causes detectable phosphorylase kinase deficiency in laboratory tests (sometimes called X-linked glycogenesis type 1 or XLG1). Other individuals have a different mutation in this gene that presumably disrupts the function of phosphorylase kinase in the body, but results in normal activity of the enzyme in laboratory tests (sometimes called X-linked glycogenesis type 2 or XLG2).Investigators have determined that glycogen storage disease type IXb is caused by mutations in the PHKB gene, which is located on the long arm (q) of chromosome 16 (16q12.1). This form of the disorder is inherited in an autosomal recessive manner.Investigators have determined that glycogen storage disease type IXc is caused by mutations in the PHKG2 gene, which is located on the short arm (p) of chromosome 16 (16p11.2). This form of the disorder is inherited in an autosomal recessive manner.Investigators have determined that glycogen storage disease type IXd is caused by mutations in the PHKA1 gene, which is located on the long arm (q) of the X chromosome (Xq13.1-13.2). This form of the disorder is inherited in an X-linked manner.The enzyme phosphorylase kinase consists of four separate pieces called subunits. Each of the genes associated with GSD-IX contain instructions for creating (encoding) one of these subunits. A mutation in one of these genes results in a deficiency of functional levels of the associated protein product. An abnormality in any of these subunits results in phosphorylase kinase deficiency, although the specific symptoms may vary. For example, mutations in the PHKA1 gene result in a deficiency of the alpha subunit of phosphorylase kinase in muscle. This causes a deficiency of the enzyme in muscle, but not the liver. | Causes of Glycogen Storage Disease Type IX. Glycogen storage disease type IX is caused by mutations in the PHKA1, the PHKA2, the PHKB, or the PHKG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation is present in a gene, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For GSD-IX, these mutations can be inherited in either an autosomal recessive or X-linked manner.Genetic diseases are determined by the combination of genes for a particular trait. Genes are packaged in the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits an altered gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% (1 in 4) with each pregnancy. The risk to have a child who is a carrier like the parents is 50% (1 in 2) with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25% (1 in 4). The chance is the same for males and females.X-linked recessive genetic disorders are conditions caused by an altered gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This process, called “X-inactivation”, is random. In some cells of the body, one of the X chromosomes is inactivated, while in the remaining cells, the other X chromosome is inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder but may have symptoms if the X chromosome with the altered gene is the one that is active in a larger proportion of cells. Females who are carriers and have symptoms of an X-linked disorder are known as manifesting heterozygotes. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters. The daughters will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% (1 in 4) chance with each pregnancy to have a carrier daughter like themselves, a 25% (1 in 4) chance to have a non-carrier daughter, a 25% (1 in 4) chance to have a son affected with the disease, and a 25% (1 in 4) chance to have an unaffected son. In other words, if a female carrier is pregnant with a male child, there is a 50% (1 in 2) chance that the baby will have inherited the altered gene and will have GSD IX, and if the baby is female, there is a 50% (1 in 2) chance that she will be a carrier.Investigators have determined that glycogen storage disease type GSD-IXa is caused by mutations in the PHKA2 gene, which is located on the short arm (p) of the X chromosome (Xp22.13). This form of the disorder is inherited in an X-linked manner. Some individuals have a mutation in this gene that causes detectable phosphorylase kinase deficiency in laboratory tests (sometimes called X-linked glycogenesis type 1 or XLG1). Other individuals have a different mutation in this gene that presumably disrupts the function of phosphorylase kinase in the body, but results in normal activity of the enzyme in laboratory tests (sometimes called X-linked glycogenesis type 2 or XLG2).Investigators have determined that glycogen storage disease type IXb is caused by mutations in the PHKB gene, which is located on the long arm (q) of chromosome 16 (16q12.1). This form of the disorder is inherited in an autosomal recessive manner.Investigators have determined that glycogen storage disease type IXc is caused by mutations in the PHKG2 gene, which is located on the short arm (p) of chromosome 16 (16p11.2). This form of the disorder is inherited in an autosomal recessive manner.Investigators have determined that glycogen storage disease type IXd is caused by mutations in the PHKA1 gene, which is located on the long arm (q) of the X chromosome (Xq13.1-13.2). This form of the disorder is inherited in an X-linked manner.The enzyme phosphorylase kinase consists of four separate pieces called subunits. Each of the genes associated with GSD-IX contain instructions for creating (encoding) one of these subunits. A mutation in one of these genes results in a deficiency of functional levels of the associated protein product. An abnormality in any of these subunits results in phosphorylase kinase deficiency, although the specific symptoms may vary. For example, mutations in the PHKA1 gene result in a deficiency of the alpha subunit of phosphorylase kinase in muscle. This causes a deficiency of the enzyme in muscle, but not the liver. | 526 | Glycogen Storage Disease Type IX |
nord_526_3 | Affects of Glycogen Storage Disease Type IX | The autosomal recessive forms of glycogen storage disease IX affect males and females in equal numbers. The X-linked forms primarily affect males, although females can have symptoms, such as enlargement of the liver and, more rarely, females can have symptoms similar to those seen in males. GSD-IX types A, B and C are estimated to affect 1 in 100,000 individuals in the general population. These disorders account for approximately 25% of all glycogen storage disorders making GSD-IX one of the most common forms of these disorders. Because some affected individuals go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of GSD-IX in the general population. GSD-IXd is extremely rare and its prevalence is unknown. | Affects of Glycogen Storage Disease Type IX. The autosomal recessive forms of glycogen storage disease IX affect males and females in equal numbers. The X-linked forms primarily affect males, although females can have symptoms, such as enlargement of the liver and, more rarely, females can have symptoms similar to those seen in males. GSD-IX types A, B and C are estimated to affect 1 in 100,000 individuals in the general population. These disorders account for approximately 25% of all glycogen storage disorders making GSD-IX one of the most common forms of these disorders. Because some affected individuals go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of GSD-IX in the general population. GSD-IXd is extremely rare and its prevalence is unknown. | 526 | Glycogen Storage Disease Type IX |
nord_526_4 | Related disorders of Glycogen Storage Disease Type IX | Symptoms of the following disorders can be similar to those of glycogen storage disease type IX. Comparisons may be useful for a differential diagnosis.Hers disease, also known as glycogen storage disease type VI (GSD-VI), is a rare genetic disorder characterized by deficiency of the liver glycogen phosphorylase enzyme. This enzyme is activated by the liver enzyme, phosphorylase kinase that is deficient in GSD-IX. These disorders cannot be distinguished from associated symptoms, which are extremely similar. Enzymatic assay or molecular genetic testing can distinguish GSD-VI from GSD-IX. GSD-VI is caused by mutations in the PYGL gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Hers” as your search term in the Rare Disease Database.)Other glycogen storage diseases, such as GSD-III, can have symptoms and physical findings that are similar to those seen in individuals with the liver form of GSD-IX. In addition, certain mitochondrial myopathies and other metabolic diseases may have symptoms that are similar to the muscle form of GSD-IX. Such disorders include carnitine palmitoyltransferase II deficiency, very long chain Acyl CoA dehydrogenase (VCLAD) deficiency, and phosphoglycerate kinase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Isolated cases of cardiac phosphorylase kinase deficiency, which present as heart failure in infancy, have been reported. However it has come to light that this is primarily caused by a mutation in the PRKAG2 gene. The deficiency of phosphorylase kinase in this disorder seems to be a secondary effect Affected individuals develop disease or weakening of the heart muscle (cardiomyopathy) very early in life. | Related disorders of Glycogen Storage Disease Type IX. Symptoms of the following disorders can be similar to those of glycogen storage disease type IX. Comparisons may be useful for a differential diagnosis.Hers disease, also known as glycogen storage disease type VI (GSD-VI), is a rare genetic disorder characterized by deficiency of the liver glycogen phosphorylase enzyme. This enzyme is activated by the liver enzyme, phosphorylase kinase that is deficient in GSD-IX. These disorders cannot be distinguished from associated symptoms, which are extremely similar. Enzymatic assay or molecular genetic testing can distinguish GSD-VI from GSD-IX. GSD-VI is caused by mutations in the PYGL gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “Hers” as your search term in the Rare Disease Database.)Other glycogen storage diseases, such as GSD-III, can have symptoms and physical findings that are similar to those seen in individuals with the liver form of GSD-IX. In addition, certain mitochondrial myopathies and other metabolic diseases may have symptoms that are similar to the muscle form of GSD-IX. Such disorders include carnitine palmitoyltransferase II deficiency, very long chain Acyl CoA dehydrogenase (VCLAD) deficiency, and phosphoglycerate kinase deficiency. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Isolated cases of cardiac phosphorylase kinase deficiency, which present as heart failure in infancy, have been reported. However it has come to light that this is primarily caused by a mutation in the PRKAG2 gene. The deficiency of phosphorylase kinase in this disorder seems to be a secondary effect Affected individuals develop disease or weakening of the heart muscle (cardiomyopathy) very early in life. | 526 | Glycogen Storage Disease Type IX |
nord_526_5 | Diagnosis of Glycogen Storage Disease Type IX | A diagnosis of glycogen storage disease type IX is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
The diagnosis of the liver form of GSD-IX is often first suspected from symptoms, such as hepatomegaly and growth delay, and abnormalities on routine laboratory tests including elevated liver transaminases, and elevations of cholesterol and triglyceride levels. Some children may present with seizures caused by low glucose levels. However, these findings are nonspecific and more specialized enzyme and genetic tests are needed to diagnose GSD-IX. These tests include an enzyme assay that measures the activity of phosphorylase kinase in red blood cells (erythrocytes) or in liver tissue. However, normal phosphorylase kinase activity does not exclude a diagnosis (samples from some affected individuals have had normal activity when tested).Individuals with symptoms of muscle PhK activity can have elevated creatine kinase level in blood but the presentation is similar to many other muscle disorders, and measurement of phosphorylase kinase activity in a muscle sample is needed to further investigate the diagnosis.Molecular genetic testing can confirm a diagnosis of GSD-IX. Molecular genetic testing can detect mutations in specific genes known to cause GSD-IX but, like the enzyme test, is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis for at-risk pregnancies allows prior identification of risk in families with affected individuals. Evaluation of family members at risk may be done by carrier testing. | Diagnosis of Glycogen Storage Disease Type IX. A diagnosis of glycogen storage disease type IX is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.Clinical Testing and Workup
The diagnosis of the liver form of GSD-IX is often first suspected from symptoms, such as hepatomegaly and growth delay, and abnormalities on routine laboratory tests including elevated liver transaminases, and elevations of cholesterol and triglyceride levels. Some children may present with seizures caused by low glucose levels. However, these findings are nonspecific and more specialized enzyme and genetic tests are needed to diagnose GSD-IX. These tests include an enzyme assay that measures the activity of phosphorylase kinase in red blood cells (erythrocytes) or in liver tissue. However, normal phosphorylase kinase activity does not exclude a diagnosis (samples from some affected individuals have had normal activity when tested).Individuals with symptoms of muscle PhK activity can have elevated creatine kinase level in blood but the presentation is similar to many other muscle disorders, and measurement of phosphorylase kinase activity in a muscle sample is needed to further investigate the diagnosis.Molecular genetic testing can confirm a diagnosis of GSD-IX. Molecular genetic testing can detect mutations in specific genes known to cause GSD-IX but, like the enzyme test, is available only as a diagnostic service at specialized laboratories.Prenatal diagnosis for at-risk pregnancies allows prior identification of risk in families with affected individuals. Evaluation of family members at risk may be done by carrier testing. | 526 | Glycogen Storage Disease Type IX |
nord_526_6 | Therapies of Glycogen Storage Disease Type IX | TreatmentThe treatment of GSD-IX is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, liver specialists (hepatologists), pediatric gastroenterologists, nutritionists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.There are no dietary restrictions associated with GSD-IX, although ingestion of simple sugars should be limited. A high-protein, complex carbohydrate diet is recommended. Prolonged fasting should be avoided. Frequent, small meals that can be supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may need to have a bedtime snack or cornstarch to prevent nighttime development of hypoglycemia. Some individuals will only require cornstarch supplementation before bedtime. If hypoglycemia or ketosis develops, affected individuals can be treated with Polycose® (glucose polymer powder) or fruit juice. Some individuals may be unable to tolerate oral therapy with Polycose® or fruit juice and may require glucose to be delivered through an IV line. If the muscles are affected, physical therapy may be recommended. Vigorous exercise should be avoided and drugs that can damage muscle tissue (such as statins) should be taken after consultation with a physician.Monitoring of blood glucose and ketone levels periodically as well as during periods of stress is necessary. Follow-up of liver involvement may be done by checking liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and gamma glutaryl transferase (GGT) and abdominal ultrasound/MRI every 6-12 months or as clinically relevant.Prognosis is considered generally good for the X-linked and certain autosomal forms of the disease. However, at this time, more severe presentations such as liver fibrosis and cirrhosis are being reported, even in the X-linked form. Further research is needed to completely understand long-term complications of the disease progression into adulthood.If affected individuals require general anesthesia, precautions against malignant hyperthermia should be taken. Malignant hyperthermia is a disorder characterized by an abnormal and potentially life-threatening response to muscle relaxants and general anesthesia drugs. (For more information on this disorder, choose “malignant hyperthermia” as your search term in the Rare Disease Database.) | Therapies of Glycogen Storage Disease Type IX. TreatmentThe treatment of GSD-IX is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, liver specialists (hepatologists), pediatric gastroenterologists, nutritionists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.There are no dietary restrictions associated with GSD-IX, although ingestion of simple sugars should be limited. A high-protein, complex carbohydrate diet is recommended. Prolonged fasting should be avoided. Frequent, small meals that can be supplemented with uncooked cornstarch are recommended to avoid hypoglycemia. Some individuals may need to have a bedtime snack or cornstarch to prevent nighttime development of hypoglycemia. Some individuals will only require cornstarch supplementation before bedtime. If hypoglycemia or ketosis develops, affected individuals can be treated with Polycose® (glucose polymer powder) or fruit juice. Some individuals may be unable to tolerate oral therapy with Polycose® or fruit juice and may require glucose to be delivered through an IV line. If the muscles are affected, physical therapy may be recommended. Vigorous exercise should be avoided and drugs that can damage muscle tissue (such as statins) should be taken after consultation with a physician.Monitoring of blood glucose and ketone levels periodically as well as during periods of stress is necessary. Follow-up of liver involvement may be done by checking liver enzyme levels such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and gamma glutaryl transferase (GGT) and abdominal ultrasound/MRI every 6-12 months or as clinically relevant.Prognosis is considered generally good for the X-linked and certain autosomal forms of the disease. However, at this time, more severe presentations such as liver fibrosis and cirrhosis are being reported, even in the X-linked form. Further research is needed to completely understand long-term complications of the disease progression into adulthood.If affected individuals require general anesthesia, precautions against malignant hyperthermia should be taken. Malignant hyperthermia is a disorder characterized by an abnormal and potentially life-threatening response to muscle relaxants and general anesthesia drugs. (For more information on this disorder, choose “malignant hyperthermia” as your search term in the Rare Disease Database.) | 526 | Glycogen Storage Disease Type IX |
nord_527_0 | Overview of Glycogen Storage Disease Type V | Glycogen storage disease type V (GSD-V or McArdle disease) is the most common disorder of skeletal muscle carbohydrate metabolism and one of most frequent genetic myopathies (prevalence ~1:100000). Twelve different types of glycogen storage disease have been described (type 0, I-VII, IX, XI-XIII), which result from defects in glycogen synthesis and breakdown principally in the muscle and liver, although other tissues can also be affected. GSD-V is caused by the lack of the muscle glycogen phosphorylase (myophosphorylase) enzyme. Although symptoms typically begin during the first ten years of life, the age of diagnosis can vary significantly. The characteristic symptoms of GSD-V are exercise intolerance, myalgia (muscle pain), muscle stiffness and contractures, quick fatigue as well as hyperCKemia and myoglobinuria (dark, burgundy-colored urine due to the presence of myoglobin, a protein found in heart and muscles). These symptoms are usually caused by isometric or uninterrupted aerobic exercise. Currently, there is no cure for GSD-V. To manage GSD-V, medical professionals suggest that people affected avoid intense exercise and a completely inactive lifestyle, but do engage in consistent, reasonable aerobic exercise. | Overview of Glycogen Storage Disease Type V. Glycogen storage disease type V (GSD-V or McArdle disease) is the most common disorder of skeletal muscle carbohydrate metabolism and one of most frequent genetic myopathies (prevalence ~1:100000). Twelve different types of glycogen storage disease have been described (type 0, I-VII, IX, XI-XIII), which result from defects in glycogen synthesis and breakdown principally in the muscle and liver, although other tissues can also be affected. GSD-V is caused by the lack of the muscle glycogen phosphorylase (myophosphorylase) enzyme. Although symptoms typically begin during the first ten years of life, the age of diagnosis can vary significantly. The characteristic symptoms of GSD-V are exercise intolerance, myalgia (muscle pain), muscle stiffness and contractures, quick fatigue as well as hyperCKemia and myoglobinuria (dark, burgundy-colored urine due to the presence of myoglobin, a protein found in heart and muscles). These symptoms are usually caused by isometric or uninterrupted aerobic exercise. Currently, there is no cure for GSD-V. To manage GSD-V, medical professionals suggest that people affected avoid intense exercise and a completely inactive lifestyle, but do engage in consistent, reasonable aerobic exercise. | 527 | Glycogen Storage Disease Type V |
nord_527_1 | Symptoms of Glycogen Storage Disease Type V | GSD-V is characterized by exercise intolerance. This typically consists in acute crises of early fatigue and muscle stiffness and contractures, especially at the start of the exercise, that usually disappear if exercise is stopped or the intensity is reduced. Symptoms usually present within the first ten years of life, but there is a wide range of clinical onset and severity. Some GSD-V patients have mild symptoms while another form progresses quickly and is apparent shortly after the person is born. Progressively weak muscles, in some individuals, do not manifest until the age of sixty to seventy years old.Muscles of affected patients usually function normally while at rest or during moderate exercise. Only during strenuous exercise do severe muscle cramps occur. Exercising in the presence of severe pain results in muscle damage (rhabdomyolysis) and myoglobinuria in about 50% of those affected. The myoglobin protein can also damage the kidneys and lead to develop life-threatening kidney failure if not treated promptly.A unique feature of the disease is the so-called “second wind” phenomenon, which most patients refers to as the ability to resume dynamic, large mass exercise, if they take a brief rest upon the appearance of premature fatigue early in exercise. This “second wind” phenomenon is present in approximately ~90% of people with GSD-V.A severity scale has been developed to describe the variation in clinical features: | Symptoms of Glycogen Storage Disease Type V. GSD-V is characterized by exercise intolerance. This typically consists in acute crises of early fatigue and muscle stiffness and contractures, especially at the start of the exercise, that usually disappear if exercise is stopped or the intensity is reduced. Symptoms usually present within the first ten years of life, but there is a wide range of clinical onset and severity. Some GSD-V patients have mild symptoms while another form progresses quickly and is apparent shortly after the person is born. Progressively weak muscles, in some individuals, do not manifest until the age of sixty to seventy years old.Muscles of affected patients usually function normally while at rest or during moderate exercise. Only during strenuous exercise do severe muscle cramps occur. Exercising in the presence of severe pain results in muscle damage (rhabdomyolysis) and myoglobinuria in about 50% of those affected. The myoglobin protein can also damage the kidneys and lead to develop life-threatening kidney failure if not treated promptly.A unique feature of the disease is the so-called “second wind” phenomenon, which most patients refers to as the ability to resume dynamic, large mass exercise, if they take a brief rest upon the appearance of premature fatigue early in exercise. This “second wind” phenomenon is present in approximately ~90% of people with GSD-V.A severity scale has been developed to describe the variation in clinical features: | 527 | Glycogen Storage Disease Type V |
nord_527_2 | Causes of Glycogen Storage Disease Type V | GSD-V is caused by mutations in the PYGM (glycogen phosphorylase, muscle form) gene that codes for the myophosphorylase enzyme. The PYGM gene is located on chromosome 11 at 11q13.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait which are on the chromosomes received from an individual’s father and mother.GSD-V is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to each carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | Causes of Glycogen Storage Disease Type V. GSD-V is caused by mutations in the PYGM (glycogen phosphorylase, muscle form) gene that codes for the myophosphorylase enzyme. The PYGM gene is located on chromosome 11 at 11q13.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q13” refers to band 13 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait which are on the chromosomes received from an individual’s father and mother.GSD-V is an autosomal recessive genetic disorder. Autosomal recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to each carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. | 527 | Glycogen Storage Disease Type V |
nord_527_3 | Affects of Glycogen Storage Disease Type V | GSD-V is very rare with only a few hundred cases reported in the medical literature. Some researchers believe that it is probably under-diagnosed because of the mildness of the symptoms. The neonatal, early-onset and very late-onset forms are even rarer. The prevalence of GSD-V in the Dallas-Fort Worth, TX area has been estimated at 1:100,000 and the prevalence in Spain has been reported at 1:170,000. | Affects of Glycogen Storage Disease Type V. GSD-V is very rare with only a few hundred cases reported in the medical literature. Some researchers believe that it is probably under-diagnosed because of the mildness of the symptoms. The neonatal, early-onset and very late-onset forms are even rarer. The prevalence of GSD-V in the Dallas-Fort Worth, TX area has been estimated at 1:100,000 and the prevalence in Spain has been reported at 1:170,000. | 527 | Glycogen Storage Disease Type V |
nord_527_4 | Related disorders of Glycogen Storage Disease Type V | Symptoms of the following disorders can be similar to those of GSD-V. Comparisons may be useful for a differential diagnosis:Pompe Disease (GSD-II) is a rare multisystem genetic disorder that is characterized by absence or deficiency of the lysosomal enzyme alpha-glucosidase (GAA). The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Without treatment, progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. Pompe disease can also present in childhood, adolescence or adulthood, collectively known as late-onset Pompe disease. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. Initial symptoms of late-onset Pompe disease may be subtle and may go unrecognized for years. Pompe disease is inherited as an autosomal recessive trait.Forbes Disease (GSD-III; Cori disease) is another glycogen storage disease with autosomal recessive inheritance. Symptoms are caused by the lack of the glycogen debranching (amylo-1,6 glucosidase) enzyme. This enzyme deficiency causes excess amounts of glycogen derived from carbohydrates to be deposited in the liver, muscles, and heart. The nerves in the back of the legs and on the sides of the heel and foot (sural nerves) also tend to accumulate excess glycogen. The heart may be involved in some cases.Tarui Disease (GSD-VII) is another type of glycogen storage disease with autosomal recessive inheritance. Symptoms of this genetic metabolic disorder are caused by an inborn lack of the enzyme phosphofructokinase in muscle, and a partial deficiency of this enzyme in red blood cells. The deficiency prevents the breakdown of glucose into energy. Tarui Disease is characterized by pain and muscle cramps during muscle stress, but often to a less severe degree than in GSD-V.For more information on the above disorders, choose “Pompe,” “Forbes,” and “glycogen storage disease type VII” as your search terms in the Rare Disease Database.Other differential diagnoses of GSD-V include: mitochondrial myopathy; myodenylate deaminase deficiency type 1 (MADD); carnitine palmitoyl transferase II deficiency; glycogen storage disease type X (GSD-X); glycogen storage disease type XI (GSD-XI); phosphorylase b kinase deficiency; creatine phosphokinase, elevated serum; very long-chain acyl-CoA dehydrogenase deficiency (VLCADD); and mitochondrial trifunctional protein deficiency (MTPD). | Related disorders of Glycogen Storage Disease Type V. Symptoms of the following disorders can be similar to those of GSD-V. Comparisons may be useful for a differential diagnosis:Pompe Disease (GSD-II) is a rare multisystem genetic disorder that is characterized by absence or deficiency of the lysosomal enzyme alpha-glucosidase (GAA). The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Without treatment, progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. Pompe disease can also present in childhood, adolescence or adulthood, collectively known as late-onset Pompe disease. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. Initial symptoms of late-onset Pompe disease may be subtle and may go unrecognized for years. Pompe disease is inherited as an autosomal recessive trait.Forbes Disease (GSD-III; Cori disease) is another glycogen storage disease with autosomal recessive inheritance. Symptoms are caused by the lack of the glycogen debranching (amylo-1,6 glucosidase) enzyme. This enzyme deficiency causes excess amounts of glycogen derived from carbohydrates to be deposited in the liver, muscles, and heart. The nerves in the back of the legs and on the sides of the heel and foot (sural nerves) also tend to accumulate excess glycogen. The heart may be involved in some cases.Tarui Disease (GSD-VII) is another type of glycogen storage disease with autosomal recessive inheritance. Symptoms of this genetic metabolic disorder are caused by an inborn lack of the enzyme phosphofructokinase in muscle, and a partial deficiency of this enzyme in red blood cells. The deficiency prevents the breakdown of glucose into energy. Tarui Disease is characterized by pain and muscle cramps during muscle stress, but often to a less severe degree than in GSD-V.For more information on the above disorders, choose “Pompe,” “Forbes,” and “glycogen storage disease type VII” as your search terms in the Rare Disease Database.Other differential diagnoses of GSD-V include: mitochondrial myopathy; myodenylate deaminase deficiency type 1 (MADD); carnitine palmitoyl transferase II deficiency; glycogen storage disease type X (GSD-X); glycogen storage disease type XI (GSD-XI); phosphorylase b kinase deficiency; creatine phosphokinase, elevated serum; very long-chain acyl-CoA dehydrogenase deficiency (VLCADD); and mitochondrial trifunctional protein deficiency (MTPD). | 527 | Glycogen Storage Disease Type V |
nord_527_5 | Diagnosis of Glycogen Storage Disease Type V | Traditionally, diagnosis has been based on the inability of the patient to produce lactate during a forearm exercise test, lack of muscle glycogen phosphorylase on muscle biopsy (generally from vastus lateralis or biceps brachialis muscles), and more recently DNA studies to look for mutations in the PYGM gene. Additionally, the measure of plasma CK levels as well as the determination of the “second wind” phenomenon help to precisely provide a correct diagnosis. Currently, the diagnosis of GSD-V is mainly based on the molecular analysis of DNA obtained from blood samples. This is a minimally invasive method, and given the accumulated knowledge on the genetics of this disease in different populations, it can be highly targeted. Gene sequencing after PCR amplification is the most frequently utilized technique for screening the different PYGM mutations. | Diagnosis of Glycogen Storage Disease Type V. Traditionally, diagnosis has been based on the inability of the patient to produce lactate during a forearm exercise test, lack of muscle glycogen phosphorylase on muscle biopsy (generally from vastus lateralis or biceps brachialis muscles), and more recently DNA studies to look for mutations in the PYGM gene. Additionally, the measure of plasma CK levels as well as the determination of the “second wind” phenomenon help to precisely provide a correct diagnosis. Currently, the diagnosis of GSD-V is mainly based on the molecular analysis of DNA obtained from blood samples. This is a minimally invasive method, and given the accumulated knowledge on the genetics of this disease in different populations, it can be highly targeted. Gene sequencing after PCR amplification is the most frequently utilized technique for screening the different PYGM mutations. | 527 | Glycogen Storage Disease Type V |
nord_527_6 | Therapies of Glycogen Storage Disease Type V | TreatmentAt present there is no curative therapy for GSD-V, but several different therapeutic approaches have been utilized.Nutritional Supplements/Drugs No significant beneficial effects have been reported in GSD-V patients receiving branched chain aminoacids, depot glucagon, dantrolene sodium, verapamil, vitamin B6 or high-dose oral ribose. More controversial results have been obtained for creatine supplementation; low dose supplementation (60 mg/kg/day for 4 weeks) reduced muscle complaints in five of nine patients tested, but higher doses (150 mg/kg/day) actually increased exercise induced myalgia.However, a beneficial intervention for alleviating exercise intolerance symptoms and protecting the muscle from rhabdomyolysis consists of ensuring that sufficient blood glucose is constantly made available to patients during daytime. This can be achieved by adopting a diet with high proportion (65%) of complex carbohydrates (as those found in vegetables, fruit, cereals, pasta and rice) and low fat (20%). A different strategy could be the ingestion of simple carbohydrates before engaging in a strenuous exercise (75 g of sucrose 30-40 min pre-exercise).Exercise interventionsGSD-V patients adapt favorably to regular exercise, with a significant increase in VO2 peak after supervised aerobic exercise. In fact, it has been shown that physically active patients are much more likely to improve their clinical course over a four year period compared with their inactive peers. | Therapies of Glycogen Storage Disease Type V. TreatmentAt present there is no curative therapy for GSD-V, but several different therapeutic approaches have been utilized.Nutritional Supplements/Drugs No significant beneficial effects have been reported in GSD-V patients receiving branched chain aminoacids, depot glucagon, dantrolene sodium, verapamil, vitamin B6 or high-dose oral ribose. More controversial results have been obtained for creatine supplementation; low dose supplementation (60 mg/kg/day for 4 weeks) reduced muscle complaints in five of nine patients tested, but higher doses (150 mg/kg/day) actually increased exercise induced myalgia.However, a beneficial intervention for alleviating exercise intolerance symptoms and protecting the muscle from rhabdomyolysis consists of ensuring that sufficient blood glucose is constantly made available to patients during daytime. This can be achieved by adopting a diet with high proportion (65%) of complex carbohydrates (as those found in vegetables, fruit, cereals, pasta and rice) and low fat (20%). A different strategy could be the ingestion of simple carbohydrates before engaging in a strenuous exercise (75 g of sucrose 30-40 min pre-exercise).Exercise interventionsGSD-V patients adapt favorably to regular exercise, with a significant increase in VO2 peak after supervised aerobic exercise. In fact, it has been shown that physically active patients are much more likely to improve their clinical course over a four year period compared with their inactive peers. | 527 | Glycogen Storage Disease Type V |
nord_528_0 | Overview of Glycogen Storage Disease Type VI | Summary Glycogen storage disease type VI (GSD6) is a genetic condition in which the liver cannot process sugar properly. The liver is responsible for breaking down a type of sugar called glycogen. Glycogen is a carbohydrate that is stored in the liver and muscle and used for energy. When the liver cannot break down glycogen properly, excess amounts accumulate in the liver and this causes a buildup that is damaging to the body. Symptoms of the disease vary between individuals with GSD6. Most symptoms begin in infancy or childhood and include low blood sugar (hypoglycemia), an enlarged liver (hepatomegaly) and an increased amount of lactic acid in the blood (lactic acidosis). These symptoms are likely to occur when an individual does not eat for a long time. Symptoms tend to improve as people with this disease get older. Some individuals with GSD6 may not require any treatment. Standard therapy includes eating several meals that are high in carbohydrates. Uncooked cornstarch can be used to quickly improve blood sugar levels. GSD6 is caused by harmful changes (mutations) in the PYGL gene and this condition is inherited in an autosomal recessive manner.Introduction GSD6 is one of a group of several glycogen storage disorders that all impact the liver’s ability to process glycogen.Glycogen storage disease type VI was originally called Hers disease when Henry-Gery Hers first described it in 1959. Hers reported three children with an enlarged liver, mild hypoglycemia, and increased glycogen content in the liver. | Overview of Glycogen Storage Disease Type VI. Summary Glycogen storage disease type VI (GSD6) is a genetic condition in which the liver cannot process sugar properly. The liver is responsible for breaking down a type of sugar called glycogen. Glycogen is a carbohydrate that is stored in the liver and muscle and used for energy. When the liver cannot break down glycogen properly, excess amounts accumulate in the liver and this causes a buildup that is damaging to the body. Symptoms of the disease vary between individuals with GSD6. Most symptoms begin in infancy or childhood and include low blood sugar (hypoglycemia), an enlarged liver (hepatomegaly) and an increased amount of lactic acid in the blood (lactic acidosis). These symptoms are likely to occur when an individual does not eat for a long time. Symptoms tend to improve as people with this disease get older. Some individuals with GSD6 may not require any treatment. Standard therapy includes eating several meals that are high in carbohydrates. Uncooked cornstarch can be used to quickly improve blood sugar levels. GSD6 is caused by harmful changes (mutations) in the PYGL gene and this condition is inherited in an autosomal recessive manner.Introduction GSD6 is one of a group of several glycogen storage disorders that all impact the liver’s ability to process glycogen.Glycogen storage disease type VI was originally called Hers disease when Henry-Gery Hers first described it in 1959. Hers reported three children with an enlarged liver, mild hypoglycemia, and increased glycogen content in the liver. | 528 | Glycogen Storage Disease Type VI |
nord_528_1 | Symptoms of Glycogen Storage Disease Type VI | Symptoms vary from person to person, and people with GSD6 may not have all the symptoms listed. GSD6 is usually a relatively mild disorder, although rare cases with more severe symptoms have been reported. Symptoms of GSD6 usually begin in infancy or childhood and may include an enlarged liver (hepatomegaly), low blood sugar (hypoglycemia) or an increase in the amount of lactic acid in the blood (lactic acidosis). Hypoglycemia can also cause symptoms such as faintness, weakness, hunger and nervousness. If present, hypoglycemia is usually mild and occurs more often during an illness. The symptoms of the disease are especially likely to occur when an individual does not eat for a long time. Some children with GSD6 are shorter than average due to slow growth. They may also have muscle weakness (hypotonia). Intellectual development is usually normal. Although symptoms of GSD6 may not be present during childhood, it has been reported that liver enlargement can be noted, even if no other symptoms are present. Many of the symptoms of GSD6 tend to improve as children get older, and most adults do not have symptoms. Liver enlargement often disappears by puberty and final adult height is often average. Muscle strength and tone are usually normal by adulthood as well. In untreated individuals, growth delays and weakening of the bone (osteoporosis) are common. People with GSD6 may be at an increased risk of having liver cancer or an enlarged heart (cardiomyopathy) in late childhood and adulthood. | Symptoms of Glycogen Storage Disease Type VI. Symptoms vary from person to person, and people with GSD6 may not have all the symptoms listed. GSD6 is usually a relatively mild disorder, although rare cases with more severe symptoms have been reported. Symptoms of GSD6 usually begin in infancy or childhood and may include an enlarged liver (hepatomegaly), low blood sugar (hypoglycemia) or an increase in the amount of lactic acid in the blood (lactic acidosis). Hypoglycemia can also cause symptoms such as faintness, weakness, hunger and nervousness. If present, hypoglycemia is usually mild and occurs more often during an illness. The symptoms of the disease are especially likely to occur when an individual does not eat for a long time. Some children with GSD6 are shorter than average due to slow growth. They may also have muscle weakness (hypotonia). Intellectual development is usually normal. Although symptoms of GSD6 may not be present during childhood, it has been reported that liver enlargement can be noted, even if no other symptoms are present. Many of the symptoms of GSD6 tend to improve as children get older, and most adults do not have symptoms. Liver enlargement often disappears by puberty and final adult height is often average. Muscle strength and tone are usually normal by adulthood as well. In untreated individuals, growth delays and weakening of the bone (osteoporosis) are common. People with GSD6 may be at an increased risk of having liver cancer or an enlarged heart (cardiomyopathy) in late childhood and adulthood. | 528 | Glycogen Storage Disease Type VI |
nord_528_2 | Causes of Glycogen Storage Disease Type VI | GSD6 is caused by harmful changes (mutations) in the PYGL gene. This gene is responsible for telling the body how to make an enzyme called liver glycogen phosphorylase. This enzyme is responsible for breaking down glycogen. Glycogen is a form of energy that comes from carbohydrates and is stored in the liver. When the body needs more energy, glycogen in the liver is broken down by the PYGL gene product, glycogen phosphorylase. When there are mutations in the PYGL gene, there is not enough functioning glycogen phosphorylase to break down glycogen. Therefore, glycogen starts to build up in the liver cells, which causes an enlarged liver. This also means that the body does not get enough energy, which causes symptoms such as hypoglycemia and lactic acidosis. GSD6 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The chance for two carrier parents to both pass on the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The chance is the same for males and females. | Causes of Glycogen Storage Disease Type VI. GSD6 is caused by harmful changes (mutations) in the PYGL gene. This gene is responsible for telling the body how to make an enzyme called liver glycogen phosphorylase. This enzyme is responsible for breaking down glycogen. Glycogen is a form of energy that comes from carbohydrates and is stored in the liver. When the body needs more energy, glycogen in the liver is broken down by the PYGL gene product, glycogen phosphorylase. When there are mutations in the PYGL gene, there is not enough functioning glycogen phosphorylase to break down glycogen. Therefore, glycogen starts to build up in the liver cells, which causes an enlarged liver. This also means that the body does not get enough energy, which causes symptoms such as hypoglycemia and lactic acidosis. GSD6 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The chance for two carrier parents to both pass on the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The chance of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The chance is the same for males and females. | 528 | Glycogen Storage Disease Type VI |
nord_528_3 | Affects of Glycogen Storage Disease Type VI | Males and females are affected in equal numbers due to the autosomal recessive inheritance of GSD6. The incidence of all glycogen storage diseases is estimated to be between 1 in 20,000 and 1 in 25,000 persons in the United States. However, GSD6 is estimated to affect only 1 in 1,000,000 individuals in the general population. Because some affected individuals go undiagnosed or are misdiagnosed, it is difficult to determine the exact frequency of GSD6 in the general population. A higher occurrence of GSD6 has been seen in the Mennonite population, about 1 in 1,000 live births. There is a specific PYGL gene mutation that is present in about 3% of the Mennonite population which accounts for this higher incidence. | Affects of Glycogen Storage Disease Type VI. Males and females are affected in equal numbers due to the autosomal recessive inheritance of GSD6. The incidence of all glycogen storage diseases is estimated to be between 1 in 20,000 and 1 in 25,000 persons in the United States. However, GSD6 is estimated to affect only 1 in 1,000,000 individuals in the general population. Because some affected individuals go undiagnosed or are misdiagnosed, it is difficult to determine the exact frequency of GSD6 in the general population. A higher occurrence of GSD6 has been seen in the Mennonite population, about 1 in 1,000 live births. There is a specific PYGL gene mutation that is present in about 3% of the Mennonite population which accounts for this higher incidence. | 528 | Glycogen Storage Disease Type VI |
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