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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. of VTE at a young age), should also include assays of:Protein C activity;Antithrombin activity;Protein S activity or free protein S antigen.Note: In an evaluation for thrombophilia: (1) Measurement of plasma concentration of homocysteine is no longer recommended because no data support the use of vitamin supplementation or modification of the duration of anticoagulation in individuals with hyperhomocysteinemia and a history of VTE ; (2) there is no clinical rationale for DNA testing for MTHFR variants; and (3) routine measurement of factor VIII and other clotting factor levels is not recommended; however, such testing may be useful in certain instances Treatment of ManifestationsThe management of thrombosis in individuals with prothrombin-related thrombophilia depends on the clinical circumstances.The first acute thrombosis should be treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux (a pentasaccharide) . Low molecular-weight heparins and fondapar | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. MTHFR variants; and (3) routine measurement of factor VIII and other clotting factor levels is not recommended; however, such testing may be useful in certain instances Treatment of ManifestationsThe management of thrombosis in individuals with prothrombin-related thrombophilia depends on the clinical circumstances.The first acute thrombosis should be treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux (a pentasaccharide) . Low molecular-weight heparins and fondaparinux have largely replaced unfractionated heparin because of their many advantages .Oral administration of warfarin is started concurrently with LMWH or fondaparinux (except during pregnancy) and monitored with the international-normalized ratio (INR). A target INR of 2.5 (therapeutic range: 2.0-3.0) provides effective anticoagulation, even in F2 20210G>A homozygotes.Rivaroxaban, a direct factor Xa inhibitor, is also approved for | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. -weight heparins and fondaparinux have largely replaced unfractionated heparin because of their many advantages .Oral administration of warfarin is started concurrently with LMWH or fondaparinux (except during pregnancy) and monitored with the international-normalized ratio (INR). A target INR of 2.5 (therapeutic range: 2.0-3.0) provides effective anticoagulation, even in F2 20210G>A homozygotes.Rivaroxaban, a direct factor Xa inhibitor, is also approved for the treatment of acute DVT and PE and secondary prevention of recurrent VTE.Note: LMWH and warfarin are both safe in women who are breast-feeding. Rivaroxaban is contraindicated during pregnancy and breast-feeding because animal studies showed reproductive toxicity, and evidence that the drug crosses the placenta and is secreted in milk .The duration of oral anticoagulation therapy should be based on an individualized assessment of the risks of VTE recurrence and anticoagulant-related bleeding. Approximately 30% of individuals with VTE | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. factor Xa inhibitor, is also approved for the treatment of acute DVT and PE and secondary prevention of recurrent VTE.Note: LMWH and warfarin are both safe in women who are breast-feeding. Rivaroxaban is contraindicated during pregnancy and breast-feeding because animal studies showed reproductive toxicity, and evidence that the drug crosses the placenta and is secreted in milk .The duration of oral anticoagulation therapy should be based on an individualized assessment of the risks of VTE recurrence and anticoagulant-related bleeding. Approximately 30% of individuals with VTE experience recurrent thrombosis within the subsequent five years . Recurrence risk is determined by the clinical circumstances of the first event (provoked or unprovoked), adequacy of early treatment, and individual risk factors (see Clinical Description, Recurrent Thrombosis, Risk for recurrent thrombosis in adult 20210G>A heterozygotes.20210G>A heterozygosity is generally not an indication for long-term anticoagulation in the absence of other risk factors. The presence of a | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. . Approximately 30% of individuals with VTE experience recurrent thrombosis within the subsequent five years . Recurrence risk is determined by the clinical circumstances of the first event (provoked or unprovoked), adequacy of early treatment, and individual risk factors (see Clinical Description, Recurrent Thrombosis, Risk for recurrent thrombosis in adult 20210G>A heterozygotes.20210G>A heterozygosity is generally not an indication for long-term anticoagulation in the absence of other risk factors. The presence of a hereditary thrombophilia was not a factor determining the duration of anticoagulation in the 2012 American College of Chest Physicians Guidelines on Antithrombotic Therapy and Prevention of Thrombosis based on evidence that inherited thrombophilic disorders are not major determinants of VTE recurrence risk (full text). Other clinical guidelines and expert opinion also conclude that identification of 20210G>A heterozygosity should not affect clinical decision making . See Published Guidelines / Consensus Statements.Anticoagulation for at least three months is recommended for persons | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. other risk factors. The presence of a hereditary thrombophilia was not a factor determining the duration of anticoagulation in the 2012 American College of Chest Physicians Guidelines on Antithrombotic Therapy and Prevention of Thrombosis based on evidence that inherited thrombophilic disorders are not major determinants of VTE recurrence risk (full text). Other clinical guidelines and expert opinion also conclude that identification of 20210G>A heterozygosity should not affect clinical decision making . See Published Guidelines / Consensus Statements.Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor .Long-term oral anticoagulation is recommended for individuals with a first or recurrent unprovoked (i.e., idiopathic) VTE and no risk factors for bleeding with good anticoagulation monitoring . The decision should be based on an assessment of potential risks and benefits regardless of 20210G>A status . Long-term anticoagulation is considered in selected individuals homozygous for the 20210 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor .Long-term oral anticoagulation is recommended for individuals with a first or recurrent unprovoked (i.e., idiopathic) VTE and no risk factors for bleeding with good anticoagulation monitoring . The decision should be based on an assessment of potential risks and benefits regardless of 20210G>A status . Long-term anticoagulation is considered in selected individuals homozygous for the 20210G>A allele or with multiple inherited or acquired thrombophilic disorders . In these individuals at higher risk for recurrence, the potential benefits of long-term anticoagulation may outweigh the bleeding risks.LMWH, fondaparinux, warfarin, and rivaroxaban are the primary antithrombotic agents used for the acute and long-term treatment of VTE. Several direct thrombin inhibitors (lepirudin, argatroban, and dabigatran), and apixaban, a | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. in selected individuals homozygous for the 20210G>A allele or with multiple inherited or acquired thrombophilic disorders . In these individuals at higher risk for recurrence, the potential benefits of long-term anticoagulation may outweigh the bleeding risks.LMWH, fondaparinux, warfarin, and rivaroxaban are the primary antithrombotic agents used for the acute and long-term treatment of VTE. Several direct thrombin inhibitors (lepirudin, argatroban, and dabigatran), and apixaban, a direct factor Xa inhibitor, are approved for use in specific circumstances .Graduated compression stockings should be worn for at least two years following an acute DVT.Treatment of thrombosis in children. Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that a 20210G>A allele should influence decisions about the intensity or duration of anticoagulation in children . British guidelines for antithrombotic therapy in children do not consider inherited thrombophilia as | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. ), and apixaban, a direct factor Xa inhibitor, are approved for use in specific circumstances .Graduated compression stockings should be worn for at least two years following an acute DVT.Treatment of thrombosis in children. Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that a 20210G>A allele should influence decisions about the intensity or duration of anticoagulation in children . British guidelines for antithrombotic therapy in children do not consider inherited thrombophilia as a determinant of either the intensity or duration of therapy.Children with a first VTE should receive initial treatment with either unfractionated heparin (UFH) or LMWH for at least five days. LMWH is favored over warfarin for continued therapy, especially in very young children and those with complex medical problems. Recommendations on the duration of antithrombotic therapy are based on the nature of the thrombotic event (e.g., spontaneous or provoked) (see Published Guidelines / Consensus Statements). | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. children do not consider inherited thrombophilia as a determinant of either the intensity or duration of therapy.Children with a first VTE should receive initial treatment with either unfractionated heparin (UFH) or LMWH for at least five days. LMWH is favored over warfarin for continued therapy, especially in very young children and those with complex medical problems. Recommendations on the duration of antithrombotic therapy are based on the nature of the thrombotic event (e.g., spontaneous or provoked) (see Published Guidelines / Consensus Statements).Anticoagulation is recommended:For at least three months after a VTE provoked by a clinical risk factor that has resolved.Beyond three months until the risk factor has resolved in children with ongoing but potentially reversible risk factors.For six to 12 months after a first idiopathic (unprovoked) VTE.Indefinitely for those with recurrent idiopathic VTEExpert opinion emphasizes the importance of a careful risk/benefit assessment in each individual .Consensus guidelines are also available for | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. see Published Guidelines / Consensus Statements).Anticoagulation is recommended:For at least three months after a VTE provoked by a clinical risk factor that has resolved.Beyond three months until the risk factor has resolved in children with ongoing but potentially reversible risk factors.For six to 12 months after a first idiopathic (unprovoked) VTE.Indefinitely for those with recurrent idiopathic VTEExpert opinion emphasizes the importance of a careful risk/benefit assessment in each individual .Consensus guidelines are also available for management of stroke in infants and children (full text).Prevention of Primary ManifestationsIn the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes, since the 1%-3% yearly risk for major bleeding from warfarin is greater than the estimated (<1%) yearly risk for thrombosis .Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. individual .Consensus guidelines are also available for management of stroke in infants and children (full text).Prevention of Primary ManifestationsIn the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes, since the 1%-3% yearly risk for major bleeding from warfarin is greater than the estimated (<1%) yearly risk for thrombosis .Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the 2012 American College of Chest Physicians consensus guidelines (full text).SurveillanceIndividuals receiving long-term anticoagulation require periodic reevaluation | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the 2012 American College of Chest Physicians consensus guidelines (full text).SurveillanceIndividuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the bleeding risk.Selected 20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. (See Prevention of Primary Manifestations.)Agents/Circumstances to AvoidF2 20210G>A heterozygotes:With a history of VTE should avoid estrogen contraception and HRT; asymptomatic women should be counseled on | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the bleeding risk.Selected 20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. (See Prevention of Primary Manifestations.)Agents/Circumstances to AvoidF2 20210G>A heterozygotes:With a history of VTE should avoid estrogen contraception and HRT; asymptomatic women should be counseled on the risks of estrogen-containing contraception and HRT and should consider alternative forms of contraception and strategies for control of menopausal symptoms.Who are asymptomatic and elect to use oral contraceptives should avoid formulations with third-generation and other progestins with a higher thrombotic risk;Who elect short-term hormone replacement therapy for severe menopausal symptoms should use low-dose transdermal preparations, which have a lower thrombotic risk than oral formulations .F2 20210G>A homozygous women with or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. ; asymptomatic women should be counseled on the risks of estrogen-containing contraception and HRT and should consider alternative forms of contraception and strategies for control of menopausal symptoms.Who are asymptomatic and elect to use oral contraceptives should avoid formulations with third-generation and other progestins with a higher thrombotic risk;Who elect short-term hormone replacement therapy for severe menopausal symptoms should use low-dose transdermal preparations, which have a lower thrombotic risk than oral formulations .F2 20210G>A homozygous women with or without prior VTE should avoid estrogen-containing contraception and HRT.Evaluation of Relatives at RiskThe genetic status of asymptomatic at-risk family members can be established using molecular genetic testing. However, as there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis .Clarification of 20210G>A allele status may be useful in: | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. >A homozygous women with or without prior VTE should avoid estrogen-containing contraception and HRT.Evaluation of Relatives at RiskThe genetic status of asymptomatic at-risk family members can be established using molecular genetic testing. However, as there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis .Clarification of 20210G>A allele status may be useful in:Asymptomatic adult family members of probands with one or two known 20210G>A alleles, especially those with a strong family history of VTE at a young age;Asymptomatic female family members of probands with known prothrombin-related thrombophilia who are pregnant or considering estrogen contraception or pregnancy.There is no clinical evidence to support testing asymptomatic children with a family history of thrombosis and/or inherited thrombophilia. Guidelines suggest delaying testing until children are able to understand the implications | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. A allele status may be useful in:Asymptomatic adult family members of probands with one or two known 20210G>A alleles, especially those with a strong family history of VTE at a young age;Asymptomatic female family members of probands with known prothrombin-related thrombophilia who are pregnant or considering estrogen contraception or pregnancy.There is no clinical evidence to support testing asymptomatic children with a family history of thrombosis and/or inherited thrombophilia. Guidelines suggest delaying testing until children are able to understand the implications of the results and (optimally) can give informed consent for testing .See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementNo consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals ; see Published Guidelines / Consensus Statements. LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. All women with inherited thrombophilia should undergo individualized risk assessment. Decisions about anticoagulation | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. until children are able to understand the implications of the results and (optimally) can give informed consent for testing .See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementNo consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals ; see Published Guidelines / Consensus Statements. LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. All women with inherited thrombophilia should undergo individualized risk assessment. Decisions about anticoagulation should be based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis .Prophylactic anticoagulation during pregnancy:Is recommended for all women:With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation .Heterozygous for the 20210G>A allele with a prior pregnancy or estrogen-related thrombosis | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. undergo individualized risk assessment. Decisions about anticoagulation should be based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis .Prophylactic anticoagulation during pregnancy:Is recommended for all women:With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation .Heterozygous for the 20210G>A allele with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence .Should be considered for:Asymptomatic women doubly heterozygous for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) ;Asymptomatic homozygous women with a family history of thrombosis .Is not routinely recommended in asymptomatic heterozygous women with no history of thrombosis or other risk factors. These women should be counseled about potential thrombotic complications during pregnancy and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence .Should be considered for:Asymptomatic women doubly heterozygous for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) ;Asymptomatic homozygous women with a family history of thrombosis .Is not routinely recommended in asymptomatic heterozygous women with no history of thrombosis or other risk factors. These women should be counseled about potential thrombotic complications during pregnancy and the postpartum period .In two large prospective studies, low-risk asymptomatic women with thrombophilia (including 20210G>A heterozygosity) did not receive LMWH during pregnancy in the absence of additional risk factors. All women received a course of postpartum anticoagulation. The low incidence of antepartum VTE in both studies (0% and 0.34%) suggested that anticoagulation may be safely withheld during pregnancy in low-risk 20210G> | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. ed about potential thrombotic complications during pregnancy and the postpartum period .In two large prospective studies, low-risk asymptomatic women with thrombophilia (including 20210G>A heterozygosity) did not receive LMWH during pregnancy in the absence of additional risk factors. All women received a course of postpartum anticoagulation. The low incidence of antepartum VTE in both studies (0% and 0.34%) suggested that anticoagulation may be safely withheld during pregnancy in low-risk 20210G>A heterozygotes who do not have other risk factors .A six-week course of postpartum prophylactic anticoagulation is recommended for:Heterozygous women with a positive family history of VTE or other additional risk factors;All asymptomatic homozygous women;All women with a prior history of VTE .Prevention of pregnancy loss. It is still unkown if prophylactic antithrombotic therapy improves pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss. The available evidence consists of predominantly uncontrolled trials, observational | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. -risk 20210G>A heterozygotes who do not have other risk factors .A six-week course of postpartum prophylactic anticoagulation is recommended for:Heterozygous women with a positive family history of VTE or other additional risk factors;All asymptomatic homozygous women;All women with a prior history of VTE .Prevention of pregnancy loss. It is still unkown if prophylactic antithrombotic therapy improves pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss. The available evidence consists of predominantly uncontrolled trials, observational studies, and a few randomized trials with important methodologic limitations. There are no prospective randomized trials that include an untreated control group that confirms the benefit of LMWH for preventing pregnancy loss in women with inherited thrombophilia. Of note, the ALIFE2 study, a multicenter randomized trial of LMWH versus standard surveillance in women with inherited thrombophilia and a history of recurrent miscarriage, began recruitment in December 2012 (www.trialregister.nl, NTR 3361). | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. evidence consists of predominantly uncontrolled trials, observational studies, and a few randomized trials with important methodologic limitations. There are no prospective randomized trials that include an untreated control group that confirms the benefit of LMWH for preventing pregnancy loss in women with inherited thrombophilia. Of note, the ALIFE2 study, a multicenter randomized trial of LMWH versus standard surveillance in women with inherited thrombophilia and a history of recurrent miscarriage, began recruitment in December 2012 (www.trialregister.nl, NTR 3361).Current consensus guidelines and expert opinion recommend against the use of antithrombotic therapy in women with inherited thrombophilia and unexplained recurrent pregnancy loss outside of clinical trials because of the absence of high quality evidence confirming benefit .Studies suggesting that prophylactic anticoagulation improves pregnancy outcome:The results of several observational studies suggested that prophylactic antithrombotic therapy may improve pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss .A recent study of women with a history of unexplained pregnancy loss compared the frequency of obstetric complications | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. .nl, NTR 3361).Current consensus guidelines and expert opinion recommend against the use of antithrombotic therapy in women with inherited thrombophilia and unexplained recurrent pregnancy loss outside of clinical trials because of the absence of high quality evidence confirming benefit .Studies suggesting that prophylactic anticoagulation improves pregnancy outcome:The results of several observational studies suggested that prophylactic antithrombotic therapy may improve pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss .A recent study of women with a history of unexplained pregnancy loss compared the frequency of obstetric complications in women with factor V Leiden or 20210G>A alleles and women without thrombophilia. Women with a thrombophilic disorder with a prior fetal loss after ten weeks’ gestation who received enoxaparin during their next pregnancy had a significantly lower rate of fetal loss and severe preeclampsia and a higher rate of live births compared to women without a thrombophilic disorder with the same obstetric history who did not receive prophylaxis .A prospective randomized trial compared prophylactic-dose enoxaparin and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. pregnancy loss compared the frequency of obstetric complications in women with factor V Leiden or 20210G>A alleles and women without thrombophilia. Women with a thrombophilic disorder with a prior fetal loss after ten weeks’ gestation who received enoxaparin during their next pregnancy had a significantly lower rate of fetal loss and severe preeclampsia and a higher rate of live births compared to women without a thrombophilic disorder with the same obstetric history who did not receive prophylaxis .A prospective randomized trial compared prophylactic-dose enoxaparin and low-dose aspirin in women heterozygous for 20210G>A, factor V Leiden, or protein S deficiency, and a history of a single unexplained fetal loss after ten weeks’ gestation. Enoxaparin prophylaxis was associated with a significantly higher live birth rate of 86% compared to 29% with aspirin. However, there were methodologic problems with this study and the results have not been confirmed in other trials.Studies suggesting that prophylactic anticoagulation does not improve pregnancy | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. randomized trial compared prophylactic-dose enoxaparin and low-dose aspirin in women heterozygous for 20210G>A, factor V Leiden, or protein S deficiency, and a history of a single unexplained fetal loss after ten weeks’ gestation. Enoxaparin prophylaxis was associated with a significantly higher live birth rate of 86% compared to 29% with aspirin. However, there were methodologic problems with this study and the results have not been confirmed in other trials.Studies suggesting that prophylactic anticoagulation does not improve pregnancy outcome:Several studies found no benefit with LMWH on pregnancy outcome in women with inherited thrombophilia .Two recent randomized trials compared the efficacy of LMWH and aspirin to no antithrombotic therapy or placebo in women with unexplained recurrent pregnancy loss. Combined LMWH and low-dose aspirin did not increase the live birth rate in either study . Because only a small proportion of the study populations had inherited thrombophilia (3.5% and 15.7%), subgroup analyses were insufficiently | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. suggesting that prophylactic anticoagulation does not improve pregnancy outcome:Several studies found no benefit with LMWH on pregnancy outcome in women with inherited thrombophilia .Two recent randomized trials compared the efficacy of LMWH and aspirin to no antithrombotic therapy or placebo in women with unexplained recurrent pregnancy loss. Combined LMWH and low-dose aspirin did not increase the live birth rate in either study . Because only a small proportion of the study populations had inherited thrombophilia (3.5% and 15.7%), subgroup analyses were insufficiently powered to assess the effect of antithrombotic therapy.In the recent Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) multinational randomized trial, antepartum prophylactic LMWH did not reduce the incidence of pregnancy loss or placenta-mediated complications in pregnant women with thrombophilia (22% with a 20210G>A allele) who are at high risk for these complications .Other pregnancy complications. Data supporting the benefit of antithrombotic therapy in women with inherited thrombophilia and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. %), subgroup analyses were insufficiently powered to assess the effect of antithrombotic therapy.In the recent Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) multinational randomized trial, antepartum prophylactic LMWH did not reduce the incidence of pregnancy loss or placenta-mediated complications in pregnant women with thrombophilia (22% with a 20210G>A allele) who are at high risk for these complications .Other pregnancy complications. Data supporting the benefit of antithrombotic therapy in women with inherited thrombophilia and other pregnancy complications are considerably more limited and also conflicting . There is insufficient evidence that LMWH (with or without aspirin) reduces the risk for preeclampsia, placental abruption, or other obstetric complications in women with or without inherited thrombophilia. Current guidelines recommend against antithrombotic prophylaxis for women with inherited thrombophilia and a history of pregnancy complications .Therapies Under InvestigationSeveral new oral anticoagulants (which have not been specifically studied in individuals with inherited thrombophilia) are alternatives to warfarin in | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. therapy in women with inherited thrombophilia and other pregnancy complications are considerably more limited and also conflicting . There is insufficient evidence that LMWH (with or without aspirin) reduces the risk for preeclampsia, placental abruption, or other obstetric complications in women with or without inherited thrombophilia. Current guidelines recommend against antithrombotic prophylaxis for women with inherited thrombophilia and a history of pregnancy complications .Therapies Under InvestigationSeveral new oral anticoagulants (which have not been specifically studied in individuals with inherited thrombophilia) are alternatives to warfarin in specific clinical settings.Dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (two new factor Xa inhibitors) are approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation .Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1148/ | m1y45qR | Prothrombin-Related Thrombophilia | C1867596 | 31,754 | prothrombin-related thrombophilia. thrombophilia) are alternatives to warfarin in specific clinical settings.Dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (two new factor Xa inhibitors) are approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation .Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. Sinus pericraniiSpecialtyVascular surgery
Sinus pericranii (SP) is a rare disorder characterized by a congenital (or occasionally, acquired) epicranial venous malformation of the scalp. Sinus pericranii is an abnormal communication between the intracranial and extracranial venous drainage pathways. Treatment of this condition has mainly been recommended for aesthetic reasons and prevention of bleeding.
Contents
1 Signs and symptoms
2 Cause
3 Mechanism
4 Diagnosis
5 Treatment
6 See also
7 References
Signs and symptoms
Sinus pericranii typically present as soft palpable masses along midline skull, which may fluctuate in size depending on body positioning. Classically, these lesions are not associated with color change of the overlying skin, such as with other vascular lesions such as hemangioma.
Cause
The nature of this malformation remains unclear. Congenital, spontaneous, and acquired origins are accepted. The hypothesis of a spontaneous origin in the current case of SP is supported by no evidence of associated anomalies, such as cerebral aneurysmal venous malformations, systemic angio | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. symptoms
Sinus pericranii typically present as soft palpable masses along midline skull, which may fluctuate in size depending on body positioning. Classically, these lesions are not associated with color change of the overlying skin, such as with other vascular lesions such as hemangioma.
Cause
The nature of this malformation remains unclear. Congenital, spontaneous, and acquired origins are accepted. The hypothesis of a spontaneous origin in the current case of SP is supported by no evidence of associated anomalies, such as cerebral aneurysmal venous malformations, systemic angiomas, venous angioma dural malformation, internal cerebral vein aneurysm, and cavernous hemangiomas.
Mechanism
Sinus pericranii is a venous anomaly where a communication between the intracranial dural sinuses and dilated epicranial venous structures exists. That venous anomaly is a collection of nonmuscular venous blood vessels adhering tightly to the outer surface of the skull and directly communicating with intracranial venous sinuses through diploic veins. The venous collections receive blood from and drain into the intracranial venous sinuses. The varicosities | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. cerebral aneurysmal venous malformations, systemic angiomas, venous angioma dural malformation, internal cerebral vein aneurysm, and cavernous hemangiomas.
Mechanism
Sinus pericranii is a venous anomaly where a communication between the intracranial dural sinuses and dilated epicranial venous structures exists. That venous anomaly is a collection of nonmuscular venous blood vessels adhering tightly to the outer surface of the skull and directly communicating with intracranial venous sinuses through diploic veins. The venous collections receive blood from and drain into the intracranial venous sinuses. The varicosities are intimately associated with the periosteum, are distensible, and vary in size when changes in intracranial pressure occur.
Diagnosis
This section is empty. You can help by adding to it. (April 2017)
Treatment
The surgical treatment involves the resection of the extracranial venous package and ligation of the emissary communicating vein. In some cases of SP, surgical excision is performed for cosmetic reasons. The endovascular technique has been described by transvenous approach combined with direct | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. intracranial venous sinuses. The varicosities are intimately associated with the periosteum, are distensible, and vary in size when changes in intracranial pressure occur.
Diagnosis
This section is empty. You can help by adding to it. (April 2017)
Treatment
The surgical treatment involves the resection of the extracranial venous package and ligation of the emissary communicating vein. In some cases of SP, surgical excision is performed for cosmetic reasons. The endovascular technique has been described by transvenous approach combined with direct puncture and the recently endovascular embolization with Onyx.
See also
Mondor's disease
List of cutaneous conditions
References
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] |
wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. transvenous approach combined with direct puncture and the recently endovascular embolization with Onyx.
See also
Mondor's disease
List of cutaneous conditions
References
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-ws-icon a{background:linear-gradient(transparent,transparent),url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output . | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. center/12px no-repeat}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-maint{display:none;color:#33aa33;margin-left:0.3em}.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-pars | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. mw-parser-output .cs1-maint{display:none;color:#33aa33;margin-left:0.3em}.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007) | [
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. 2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 886. ISBN 978-1-4160-2999-1.
^ Vasc Endovascular Surg. 2011 Jan;45(1):103-5
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. seph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 886. ISBN 978-1-4160-2999-1.
^ Vasc Endovascular Surg. 2011 Jan;45(1):103-5
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. content: false
Complications:
CPU time usage: 0.184 seconds
Real time usage: 0.277 seconds
Preprocessor visited node count: 469/1000000
Post‐expand include size: 6049/2097152 bytes
Template argument size: 254/2097152 bytes
Highest expansion depth: 8/40
Expensive parser function count: 2/500
Unstrip recursion depth: 1/20
Unstrip post‐expand size: 3446/5000000 bytes
Lua time usage: 0.111/10.000 seconds
Lua memory usage: 3295909/52428800 bytes
Number of Wikibase entities loaded: 0/400
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. 3446/5000000 bytes
Lua time usage: 0.111/10.000 seconds
Lua memory usage: 3295909/52428800 bytes
Number of Wikibase entities loaded: 0/400
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Transclusion expansion time report (%,ms,calls,template)
100.00% 258.320 1 -total
44.71% 115.500 1 Template:Infobox_medical_condition_(new)
37.35% 96.472 1 Template:Infobox
36.10% 93.252 1 Template:Reflist
33.16% 85.660 1 Template:Cite_book
18.20% 47.002 1 Template:Empty_section
16.05% 41.466 1 Template:Ambox
2.57% 6.645 3 Template:Main_other
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. medical_condition_(new)
37.35% 96.472 1 Template:Infobox
36.10% 93.252 1 Template:Reflist
33.16% 85.660 1 Template:Cite_book
18.20% 47.002 1 Template:Empty_section
16.05% 41.466 1 Template:Ambox
2.57% 6.645 3 Template:Main_other
1.27% 3.275 1 Template:Template_other
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wikipedia | https://en.wikipedia.org/wiki/Sinus_pericranii | 25YoxNK | Sinus pericranii | C0266494 | 31,755 | sinus pericranii. 1 Template:Template_other
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-3 (MTDPS3) is caused by homozygous or compound heterozygous mutation in the DGUOK gene (601465) on chromosome 2p13.Biallelic mutation in the DGUOK gene can also cause adult-onset PEOB4 (617070).
Description
Mitochondrial DNA depletion syndrome-3 is a severe autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (Mandel et al., 2001). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Clinical Features
Boustany et al. (1983) reported a patient who died at age 9 | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (Mandel et al., 2001). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Clinical Features
Boustany et al. (1983) reported a patient who died at age 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement. Liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. A second cousin, related through the maternal grandfather, had a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. In an addendum, the | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). et al. (1983) reported a patient who died at age 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement. Liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. A second cousin, related through the maternal grandfather, had a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. In an addendum, the authors noted that another family member presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. In tissue samples from the patient reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA involving liver (12% of control values). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). oplegia, and severe lactic acidosis. In an addendum, the authors noted that another family member presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. In tissue samples from the patient reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA involving liver (12% of control values). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. Mazziotta et al. (1992) reported a 3-month-old | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. Mazziotta et al. (1992) reported a 3-month-old girl who presented with frequent vomiting and hypotonia. She had severe metabolic acidosis, hepatomegaly, and rapidly progressive fatal liver failure with death at age 4 months. Mitochondrial DNA was 90% depleted in liver and activity of mitochondrial-encoded respiratory chain enzymes were markedly decreased. Bodnar et al. (1993) studied fibroblasts from a patient described by Leonard et al. (1991). The fourth child of healthy, unrelated parents | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). a et al. (1992) reported a 3-month-old girl who presented with frequent vomiting and hypotonia. She had severe metabolic acidosis, hepatomegaly, and rapidly progressive fatal liver failure with death at age 4 months. Mitochondrial DNA was 90% depleted in liver and activity of mitochondrial-encoded respiratory chain enzymes were markedly decreased. Bodnar et al. (1993) studied fibroblasts from a patient described by Leonard et al. (1991). The fourth child of healthy, unrelated parents and the product of an uncomplicated full-term pregnancy, the infant soon after birth developed progressive liver failure, widespread edema, hyponatremia, hypoalbuminemia, marked prolongation of clotting times, and lactic acidosis. He became progressively more hypotonic and unresponsive and died at 4 months of age. An older sister had a clinically similar illness and died at 4 months of age. One older brother was noted to be hypertonic and jittery on the | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). al. (1991). The fourth child of healthy, unrelated parents and the product of an uncomplicated full-term pregnancy, the infant soon after birth developed progressive liver failure, widespread edema, hyponatremia, hypoalbuminemia, marked prolongation of clotting times, and lactic acidosis. He became progressively more hypotonic and unresponsive and died at 4 months of age. An older sister had a clinically similar illness and died at 4 months of age. One older brother was noted to be hypertonic and jittery on the second day of life and died suddenly and unexpectedly at 4 weeks of age. Clinical presentation and family history were similar to those reported for cases of mtDNA depletion. Studies on cultured skin fibroblasts from patient 1 revealed a decrease in activities of the respiratory-chain enzymes and a quantitative decrease in mtDNA. It was also observed that the fibroblasts were dependent on uridine and pyruvate for growth, which is a well-characterized requirement for rho(0) cells | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). older brother was noted to be hypertonic and jittery on the second day of life and died suddenly and unexpectedly at 4 weeks of age. Clinical presentation and family history were similar to those reported for cases of mtDNA depletion. Studies on cultured skin fibroblasts from patient 1 revealed a decrease in activities of the respiratory-chain enzymes and a quantitative decrease in mtDNA. It was also observed that the fibroblasts were dependent on uridine and pyruvate for growth, which is a well-characterized requirement for rho(0) cells, which have been depleted of mtDNA by long-term exposure to low concentrations of ethidium bromide. This property of the patient's fibroblasts provided a selectable marker for experiments performed by Bodnar et al. (1993) because complementation of these metabolic requirements indicated the reconstitution of mitochondrial function. The nuclear genome of this patient was represented by enucleated fibroblasts and human-derived rho(0) cell lines. The resulting cybrids grew in | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). , which is a well-characterized requirement for rho(0) cells, which have been depleted of mtDNA by long-term exposure to low concentrations of ethidium bromide. This property of the patient's fibroblasts provided a selectable marker for experiments performed by Bodnar et al. (1993) because complementation of these metabolic requirements indicated the reconstitution of mitochondrial function. The nuclear genome of this patient was represented by enucleated fibroblasts and human-derived rho(0) cell lines. The resulting cybrids grew in medium lacking pyruvate and uridine, indicating restoration of respiratory chain function. Taanman et al. (1997) studied myoblast cell cultures from a patient with the mtDNA depletion syndrome and demonstrated complementation by normal nuclei. The patient presented at 8 weeks of age with hypotonia, poor visual fixation, and variable lactic acidemia. He died of progressive liver failure at the age of 7.5 months. Taanman et al. | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). derived rho(0) cell lines. The resulting cybrids grew in medium lacking pyruvate and uridine, indicating restoration of respiratory chain function. Taanman et al. (1997) studied myoblast cell cultures from a patient with the mtDNA depletion syndrome and demonstrated complementation by normal nuclei. The patient presented at 8 weeks of age with hypotonia, poor visual fixation, and variable lactic acidemia. He died of progressive liver failure at the age of 7.5 months. Taanman et al. (1997) stated that the mitochondrial DNA depletion syndrome had been documented in 29 children. Blake et al. (1999) reported 2 sibs with the disorder. In the proband, they used immunocytochemical techniques to demonstrate that the disorder was expressed in amniotic fluid cells. The proband, the second child in the family, was well at birth but developed hypoglycemia during the first 24 hours of life. Later, she developed lactic acidemia with | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). the age of 7.5 months. Taanman et al. (1997) stated that the mitochondrial DNA depletion syndrome had been documented in 29 children. Blake et al. (1999) reported 2 sibs with the disorder. In the proband, they used immunocytochemical techniques to demonstrate that the disorder was expressed in amniotic fluid cells. The proband, the second child in the family, was well at birth but developed hypoglycemia during the first 24 hours of life. Later, she developed lactic acidemia with progressive liver failure. Liver biopsy showed micronodular cirrhosis with proliferation of bile ducts and abundant neutral fat and bile pigment in hepatocytes. The activity of cytochrome c oxidase was severely depleted in liver. Assay of phosphoenolpyruvate carboxykinase (PEPCK; 614168) in liver mitochondria revealed evidence of reduced mitochondrial PEPCK activity, but PEPCK activity measured in amniotic fluid cells and fibroblasts was within normal limits. The patient died of progressive liver failure | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). first 24 hours of life. Later, she developed lactic acidemia with progressive liver failure. Liver biopsy showed micronodular cirrhosis with proliferation of bile ducts and abundant neutral fat and bile pigment in hepatocytes. The activity of cytochrome c oxidase was severely depleted in liver. Assay of phosphoenolpyruvate carboxykinase (PEPCK; 614168) in liver mitochondria revealed evidence of reduced mitochondrial PEPCK activity, but PEPCK activity measured in amniotic fluid cells and fibroblasts was within normal limits. The patient died of progressive liver failure at the age of 6 months. Skeletal muscle obtained at postmortem showed relatively uniform fibers with no evidence of ragged-red fibers. There was an excess of coarse lipid droplets in many muscle fibers. Cytochrome c oxidase activity was normal and present in all fibers. The patient's elder brother was well at birth but very soon developed symptoms compatible with liver failure. Blood lactate was variably increased. The child died at the age of | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). and fibroblasts was within normal limits. The patient died of progressive liver failure at the age of 6 months. Skeletal muscle obtained at postmortem showed relatively uniform fibers with no evidence of ragged-red fibers. There was an excess of coarse lipid droplets in many muscle fibers. Cytochrome c oxidase activity was normal and present in all fibers. The patient's elder brother was well at birth but very soon developed symptoms compatible with liver failure. Blood lactate was variably increased. The child died at the age of 7 weeks of progressive liver failure. Mandel et al. (2001) reported 19 affected members from 3 unrelated Israeli-Druze families with the hepatocerebral form of mtDNA depletion syndrome. Affected individuals presented between birth and 6 months of age with hepatic failure, severe failure to thrive, oscillating eye movements, and neurologic abnormalities, accompanied by lactic acidosis, hypoglycemia, and markedly elevated amounts of alpha-fetoprotein in plasma. | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). Blood lactate was variably increased. The child died at the age of 7 weeks of progressive liver failure. Mandel et al. (2001) reported 19 affected members from 3 unrelated Israeli-Druze families with the hepatocerebral form of mtDNA depletion syndrome. Affected individuals presented between birth and 6 months of age with hepatic failure, severe failure to thrive, oscillating eye movements, and neurologic abnormalities, accompanied by lactic acidosis, hypoglycemia, and markedly elevated amounts of alpha-fetoprotein in plasma. Death usually occurred before 1 year of age. Enzymatic activities of the mitochondrial respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, and IV) were reduced to various extents, whereas complex II enzymatic activity, which is encoded solely by nuclear genes, was normal. Muscle tissue from 7 affected patients showed normal histology and respiratory chain complex activities. Mancuso et al. (2005) reported 2 sibs and 1 unrelated patient | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). , hypoglycemia, and markedly elevated amounts of alpha-fetoprotein in plasma. Death usually occurred before 1 year of age. Enzymatic activities of the mitochondrial respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, and IV) were reduced to various extents, whereas complex II enzymatic activity, which is encoded solely by nuclear genes, was normal. Muscle tissue from 7 affected patients showed normal histology and respiratory chain complex activities. Mancuso et al. (2005) reported 2 sibs and 1 unrelated patient with hepatocerebral DNA depletion syndrome caused by mutations in the DGUOK gene. Common features included poor feeding, vomiting, failure to thrive, hypothermia, metabolic acidosis, and hypoglycemia in the neonatal period. Signs of overt liver failure developed in the first months of life with ascites, jaundice, hepatomegaly, abnormal liver function tests, hyperbilirubinemia, and coagulopathy. Liver biopsy of 2 patients showed severe micronodular cirrhosis, marked | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). et al. (2005) reported 2 sibs and 1 unrelated patient with hepatocerebral DNA depletion syndrome caused by mutations in the DGUOK gene. Common features included poor feeding, vomiting, failure to thrive, hypothermia, metabolic acidosis, and hypoglycemia in the neonatal period. Signs of overt liver failure developed in the first months of life with ascites, jaundice, hepatomegaly, abnormal liver function tests, hyperbilirubinemia, and coagulopathy. Liver biopsy of 2 patients showed severe micronodular cirrhosis, marked cholestasis, steatosis, hepatocellular loss, and fibrosis. Ultrastructural examination in 1 patient showed excessive and abnormal mitochondria. Liver specimens showed 84 to 90% mtDNA depletion. All patients showed variable encephalopathic signs including nystagmus, cerebral atrophy, microcephaly, hypotonia, and in 1 patient, optic dysplasia. Although 1 patient underwent liver transplantation, all 3 died by 5 months of age. Clinical Variability
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). coagulopathy. Liver biopsy of 2 patients showed severe micronodular cirrhosis, marked cholestasis, steatosis, hepatocellular loss, and fibrosis. Ultrastructural examination in 1 patient showed excessive and abnormal mitochondria. Liver specimens showed 84 to 90% mtDNA depletion. All patients showed variable encephalopathic signs including nystagmus, cerebral atrophy, microcephaly, hypotonia, and in 1 patient, optic dysplasia. Although 1 patient underwent liver transplantation, all 3 died by 5 months of age. Clinical Variability
Ducluzeau et al. (1999) described the case of a 28-month-old French boy who presented with a transient liver cholestasis, beginning at the age of 2 months, complicated by progressive fibrosis due to liver mtDNA depletion but without extrahepatic involvement. Lactate levels and lactate/pyruvate ratio were elevated. On the third liver biopsy, micronodular cirrhosis was fully established. Mitochondrial enzyme analyses and Southern blots were abnormal in liver, but normal in skin and skeletal muscle. Duc | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). of age. Clinical Variability
Ducluzeau et al. (1999) described the case of a 28-month-old French boy who presented with a transient liver cholestasis, beginning at the age of 2 months, complicated by progressive fibrosis due to liver mtDNA depletion but without extrahepatic involvement. Lactate levels and lactate/pyruvate ratio were elevated. On the third liver biopsy, micronodular cirrhosis was fully established. Mitochondrial enzyme analyses and Southern blots were abnormal in liver, but normal in skin and skeletal muscle. Ducluzeau et al. (2002) reported clinical follow-up of the patient reported by Ducluzeau et al. (1999), who was 6 years old at the time of the second report. At about 32 months of age, the patient's liver tests began to improve spontaneously, and this was associated with an increase in clotting factors, a dramatic decrease of liver fibrosis and normal appearance of hepatocytes on biopsy, | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). were abnormal in liver, but normal in skin and skeletal muscle. Ducluzeau et al. (2002) reported clinical follow-up of the patient reported by Ducluzeau et al. (1999), who was 6 years old at the time of the second report. At about 32 months of age, the patient's liver tests began to improve spontaneously, and this was associated with an increase in clotting factors, a dramatic decrease of liver fibrosis and normal appearance of hepatocytes on biopsy, an increase in liver mtDNA content, and almost complete restoration of respiratory chain complex activities containing mtDNA-encoded subunits. He showed normal psychomotor development at age 46 months. Ducluzeau et al. (2002) suggested that the most probable hypotheses for such a highly unusual recovery of mtDNA level include somatic mosaicism for a mutation in the nuclear genome or spontaneous reversion to normal of one of the putative mutations. In the patient reported by Duclu | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). a dramatic decrease of liver fibrosis and normal appearance of hepatocytes on biopsy, an increase in liver mtDNA content, and almost complete restoration of respiratory chain complex activities containing mtDNA-encoded subunits. He showed normal psychomotor development at age 46 months. Ducluzeau et al. (2002) suggested that the most probable hypotheses for such a highly unusual recovery of mtDNA level include somatic mosaicism for a mutation in the nuclear genome or spontaneous reversion to normal of one of the putative mutations. In the patient reported by Ducluzeau et al. (1999), Mousson de Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene (N46S, 601465.0008 and L266R, 601465.0009). In vitro studies showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient.
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). of one of the putative mutations. In the patient reported by Ducluzeau et al. (1999), Mousson de Camaret et al. (2007) identified compound heterozygous missense mutations in the DGUOK gene (N46S, 601465.0008 and L266R, 601465.0009). In vitro studies showed that these mutations retained 10 to 14% residual enzymatic activity, which likely contributed to the unusual phenotypic reversal in this patient.
Inheritance
Moraes et al. (1991) found no evidence of maternal inheritance, and suggested that mtDNA depletion may be inherited as an autosomal recessive disorder. Alternatively, they also suggested that this phenotype may be the result of a dominant nuclear mutation expressed only when combined with a certain mitochondrial genotype. Mazziotta et al. (1992) suggested that it is an autosomal dominant trait with incomplete penetrance. All 29 patients reviewed by Taa | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). , which likely contributed to the unusual phenotypic reversal in this patient.
Inheritance
Moraes et al. (1991) found no evidence of maternal inheritance, and suggested that mtDNA depletion may be inherited as an autosomal recessive disorder. Alternatively, they also suggested that this phenotype may be the result of a dominant nuclear mutation expressed only when combined with a certain mitochondrial genotype. Mazziotta et al. (1992) suggested that it is an autosomal dominant trait with incomplete penetrance. All 29 patients reviewed by Taanman et al. (1997) were born to clinically normal parents, and family histories were compatible with autosomal recessive inheritance in all but 1 pedigree, where the pattern of inheritance could be explained by autosomal dominant transmission with incomplete penetrance (Mazziotta et al., 1992). Whether recessive or dominant, the autosomal inheritance supported the involvement of a nuclear-encoded factor. Complementation with nuclear DNA from a normal cell line ( | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). an autosomal dominant trait with incomplete penetrance. All 29 patients reviewed by Taanman et al. (1997) were born to clinically normal parents, and family histories were compatible with autosomal recessive inheritance in all but 1 pedigree, where the pattern of inheritance could be explained by autosomal dominant transmission with incomplete penetrance (Mazziotta et al., 1992). Whether recessive or dominant, the autosomal inheritance supported the involvement of a nuclear-encoded factor. Complementation with nuclear DNA from a normal cell line (Bodnar et al., 1993) indicated involvement of the nuclear genome. Douglas et al. (2011) reported a patient, born of unrelated Mexican parents, with classic hepatocerebral mtDNA depletion syndrome due to an apparently homozygous mutation in the DGUOK gene. However, analysis of parental DNA showed that only the father carried the mutation in the heterozygous state. Analysis of patient tissue ruled out gene deletion, and SNP array | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). -encoded factor. Complementation with nuclear DNA from a normal cell line (Bodnar et al., 1993) indicated involvement of the nuclear genome. Douglas et al. (2011) reported a patient, born of unrelated Mexican parents, with classic hepatocerebral mtDNA depletion syndrome due to an apparently homozygous mutation in the DGUOK gene. However, analysis of parental DNA showed that only the father carried the mutation in the heterozygous state. Analysis of patient tissue ruled out gene deletion, and SNP array analysis showed only paternal inheritance of informative markers and no inheritance of maternal alleles. There was copy-neutral absence of heterozygosity across the entire chromosome 2, consistent with uniparental isodisomy for the DGUOK gene. The findings had implications for genetic counseling.
Mapping
Mandel et al. (2001) used homozygosity mapping in 3 kindreds of Druze origin segregating for the hepatocerebral mtDNA depletion syndrome | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). state. Analysis of patient tissue ruled out gene deletion, and SNP array analysis showed only paternal inheritance of informative markers and no inheritance of maternal alleles. There was copy-neutral absence of heterozygosity across the entire chromosome 2, consistent with uniparental isodisomy for the DGUOK gene. The findings had implications for genetic counseling.
Mapping
Mandel et al. (2001) used homozygosity mapping in 3 kindreds of Druze origin segregating for the hepatocerebral mtDNA depletion syndrome and mapped the disorder to a region of 6.1 cM on chromosome 2p13.
Molecular Genetics
In 3 Israeli-Druze kindreds with hepatocerebral mtDNA depletion syndrome-3, Mandel et al. (2001) identified a 1-bp deletion in the DGUOK gene (204delA; 601465.0001) that segregated with the disease. Western blot analysis failed to detect deoxyguanosine kinase protein | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). Druze origin segregating for the hepatocerebral mtDNA depletion syndrome and mapped the disorder to a region of 6.1 cM on chromosome 2p13.
Molecular Genetics
In 3 Israeli-Druze kindreds with hepatocerebral mtDNA depletion syndrome-3, Mandel et al. (2001) identified a 1-bp deletion in the DGUOK gene (204delA; 601465.0001) that segregated with the disease. Western blot analysis failed to detect deoxyguanosine kinase protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by deoxyguanosine kinase and thymidine kinase-2. The association of mtDNA depletion with mutated DGUOK suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools. In 3 (14%) of 21 patients with hepatocerebral mtDNA depletion syndrome-3, Salviat | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). with the disease. Western blot analysis failed to detect deoxyguanosine kinase protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by deoxyguanosine kinase and thymidine kinase-2. The association of mtDNA depletion with mutated DGUOK suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools. In 3 (14%) of 21 patients with hepatocerebral mtDNA depletion syndrome-3, Salviati et al. (2002) identified mutations in the DGUOK gene (601465.0003-601465.0006). The findings suggested that other genes may also be responsible for mitochondrial depletion in the liver. Tadiboyina et al. (2005) reported 3 patients with the hepatocerebral form of mtDNA depletion syndrome together with cystathioninuria. All 3 children were homozygous for a D255 | [
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omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). 21 patients with hepatocerebral mtDNA depletion syndrome-3, Salviati et al. (2002) identified mutations in the DGUOK gene (601465.0003-601465.0006). The findings suggested that other genes may also be responsible for mitochondrial depletion in the liver. Tadiboyina et al. (2005) reported 3 patients with the hepatocerebral form of mtDNA depletion syndrome together with cystathioninuria. All 3 children were homozygous for a D255Y mutation (601465.0007) in the DGUOK gene but had no mutations in the cystathionine gamma-lyase gene (CTH; 607657), indicating that the hepatocerebral form of mtDNA depletion syndrome might be associated with secondary cystathioninuria.
INHERITANCE
- Autosomal recessive
GROWTH
Other
- Poor growth
- Failure to thrive
HEAD & NECK
Head
- Microcephaly (less common)
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). cystathioninuria. All 3 children were homozygous for a D255Y mutation (601465.0007) in the DGUOK gene but had no mutations in the cystathionine gamma-lyase gene (CTH; 607657), indicating that the hepatocerebral form of mtDNA depletion syndrome might be associated with secondary cystathioninuria.
INHERITANCE
- Autosomal recessive
GROWTH
Other
- Poor growth
- Failure to thrive
HEAD & NECK
Head
- Microcephaly (less common)
Eyes
- Nystagmus
- Disconjugate eye movements
- Optic dysplasia
ABDOMEN
External Features
- Ascites
- Portal hypertension
Liver
- Hepatomegaly
- Abnormal liver function tests
- Liver tissue shows 80 to 99% depletion of mitochondrial DNA (mtDNA) with decreased activities of mitochondrial-encoded respiratory chain complexes
- Biopsy shows micronodular cirrhosis
- Cholestasis
- Steatosis
- Jaundice
- Hepatocellular loss
- Hepatocellular necrosis
- Periportal fibrosis
- Pseudoacinar formation
- Electron microscopy shows increased | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). ive
HEAD & NECK
Head
- Microcephaly (less common)
Eyes
- Nystagmus
- Disconjugate eye movements
- Optic dysplasia
ABDOMEN
External Features
- Ascites
- Portal hypertension
Liver
- Hepatomegaly
- Abnormal liver function tests
- Liver tissue shows 80 to 99% depletion of mitochondrial DNA (mtDNA) with decreased activities of mitochondrial-encoded respiratory chain complexes
- Biopsy shows micronodular cirrhosis
- Cholestasis
- Steatosis
- Jaundice
- Hepatocellular loss
- Hepatocellular necrosis
- Periportal fibrosis
- Pseudoacinar formation
- Electron microscopy shows increased and abnormal mitochondria
- Hepatic failure
Spleen
- Splenomegaly
Gastrointestinal
- Poor feeding
- Vomiting
SKIN, NAILS, & HAIR
Skin
- Jaundice
NEUROLOGIC
Central Nervous System
- Encephalopathy
- Nystagmus
- Hypotonia
- Hyperreflexia
- Seizures
- Cerebral atrophy
Peripheral Nervous System
- Peripheral neuropathy
METABOLIC FEATURES
- Hypoglycemia
- Hypothermia
- Lactic acidosis
HEMATOLOGY
- Coagulopathy due to hepatic failure
- Thrombocytopenia
LABORATORY ABNORMALITIES
- Hyperbilirubinemia
- Abnormal liver function tests
- Hypoalbuminemia
- Generalized amino | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). - Periportal fibrosis
- Pseudoacinar formation
- Electron microscopy shows increased and abnormal mitochondria
- Hepatic failure
Spleen
- Splenomegaly
Gastrointestinal
- Poor feeding
- Vomiting
SKIN, NAILS, & HAIR
Skin
- Jaundice
NEUROLOGIC
Central Nervous System
- Encephalopathy
- Nystagmus
- Hypotonia
- Hyperreflexia
- Seizures
- Cerebral atrophy
Peripheral Nervous System
- Peripheral neuropathy
METABOLIC FEATURES
- Hypoglycemia
- Hypothermia
- Lactic acidosis
HEMATOLOGY
- Coagulopathy due to hepatic failure
- Thrombocytopenia
LABORATORY ABNORMALITIES
- Hyperbilirubinemia
- Abnormal liver function tests
- Hypoalbuminemia
- Generalized aminoaciduria
MISCELLANEOUS
- Onset as neonate
- Hepatic failure develops in first months of life
- Most patients die of hepatic failure by 9 months of age
MOLECULAR BASIS
- Caused by mutation in the nuclear-encoded mitochondrial deoxyguanosine kinase gene (DGUOK,
601465.0001
).
▲ Close | [
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] |
omim | https://www.omim.org/entry/251880 | yn9glgZ | MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE) | C5191055 | 31,756 | mitochondrial dna depletion syndrome 3 (hepatocerebral type). irubinemia
- Abnormal liver function tests
- Hypoalbuminemia
- Generalized aminoaciduria
MISCELLANEOUS
- Onset as neonate
- Hepatic failure develops in first months of life
- Most patients die of hepatic failure by 9 months of age
MOLECULAR BASIS
- Caused by mutation in the nuclear-encoded mitochondrial deoxyguanosine kinase gene (DGUOK,
601465.0001
).
▲ Close | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency is caused by homozygous or compound heterozygous mutation in the nuclear-encoded SDHA gene (600857) on chromosome 5p, the nuclear-encoded SDHAF1 gene (612848) on chromosome 19q, or the nuclear-encoded SDHD gene (602690) on chromosome 11q23.Complex II, also known as succinate dehydrogenase (EC 1.3.5.1), is part of the mitochondrial respiratory chain.
Description
Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. .5.1), is part of the mitochondrial respiratory chain.
Description
Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).
Clinical Features
Riggs et al. (1984) described 2 sibs with deficiency of complex II. A 7-year-old boy and his 9-year-old sister had progressive encephalomyopathy with dementia, myoclonic seizures, and short stature. A muscle biopsy showed mitochondrial aggregates and excessive lipid droplets in muscle | [
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] |
omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).
Clinical Features
Riggs et al. (1984) described 2 sibs with deficiency of complex II. A 7-year-old boy and his 9-year-old sister had progressive encephalomyopathy with dementia, myoclonic seizures, and short stature. A muscle biopsy showed mitochondrial aggregates and excessive lipid droplets in muscle fibers. In muscle mitochondria, the activity of succinate cytochrome c reductase was deficient. The activities of NADH-cytochrome c reductase and cytochrome oxidase were normal. The defect was thought to lie somewhere between succinate dehydrogenase and coenzyme Q10 in complex II. Rivner et al. (1989) reported a 25-year-old woman with Kearns-Sayre syndrome (530000) and isolated complex II deficiency. She had short stature, complete external ophthalmoplegia | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. aggregates and excessive lipid droplets in muscle fibers. In muscle mitochondria, the activity of succinate cytochrome c reductase was deficient. The activities of NADH-cytochrome c reductase and cytochrome oxidase were normal. The defect was thought to lie somewhere between succinate dehydrogenase and coenzyme Q10 in complex II. Rivner et al. (1989) reported a 25-year-old woman with Kearns-Sayre syndrome (530000) and isolated complex II deficiency. She had short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects. Muscle biopsy showed ragged-red fibers and increased number of mitochondria with abnormal structure and paracrystalline inclusions. A patient with complex II deficiency reported by Rustin et al. (1993) had isolated hypertrophic cardiomyopathy. Reichmann and Angelini (1994) reported 2 brothers with hypertrophic cardiopathy and skeletal muscle myopathy associated with complex II deficiency. Bourgeois et al. (1992 | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects. Muscle biopsy showed ragged-red fibers and increased number of mitochondria with abnormal structure and paracrystalline inclusions. A patient with complex II deficiency reported by Rustin et al. (1993) had isolated hypertrophic cardiomyopathy. Reichmann and Angelini (1994) reported 2 brothers with hypertrophic cardiopathy and skeletal muscle myopathy associated with complex II deficiency. Bourgeois et al. (1992) reported 2 sisters with a degenerative neurologic disorder presenting clinically as a leukodystrophy. Brain imaging showed symmetric foci of necrosis in the substantia nigra and basal ganglia typical of Leigh syndrome (256000). Mitochondria isolated from skeletal muscle, fibroblasts, and lymphocytes showed complex II deficiency. The heart was not involved in these sisters.Arpa et al. (1994) reviewed 10 previously published cases of succinate dehydrogenase deficiency and reported another case. Their patient was a 22 | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. urgeois et al. (1992) reported 2 sisters with a degenerative neurologic disorder presenting clinically as a leukodystrophy. Brain imaging showed symmetric foci of necrosis in the substantia nigra and basal ganglia typical of Leigh syndrome (256000). Mitochondria isolated from skeletal muscle, fibroblasts, and lymphocytes showed complex II deficiency. The heart was not involved in these sisters.Arpa et al. (1994) reviewed 10 previously published cases of succinate dehydrogenase deficiency and reported another case. Their patient was a 22-year-old woman, the daughter of consanguineous parents, with generalized muscle weakness and easy fatigability. She had mild proximal muscle weakness with distal wasting and an elevation of creatine kinase. Histopathologically, there were no ragged-red fibers, but there was a mild excess of neutral lipids and subsarcolemmal granular accumulations. Enzymatic analysis of isolated muscle mitochondria showed mild diminution of all respiratory complexes, most markedly of succinate-cytochrome c reductase. Free carnitine | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. case. Their patient was a 22-year-old woman, the daughter of consanguineous parents, with generalized muscle weakness and easy fatigability. She had mild proximal muscle weakness with distal wasting and an elevation of creatine kinase. Histopathologically, there were no ragged-red fibers, but there was a mild excess of neutral lipids and subsarcolemmal granular accumulations. Enzymatic analysis of isolated muscle mitochondria showed mild diminution of all respiratory complexes, most markedly of succinate-cytochrome c reductase. Free carnitine was also reduced. Brockmann et al. (2002) reported 3 patients, 2 Turkish sibs and an unrelated Norwegian boy, with isolated complex II deficiency with decreased activities of succinate dehydrogenase and succinate:cytochrome c oxidoreductase. The patients presented in infancy and very early childhood with neurologic symptoms, including loss of motor skills and spastic paresis, and leukoencephalopathy on MRI. Proton MRS showed strongly elevated concentrations of succinate in white matter and CSF. Ghezzi et | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. -cytochrome c reductase. Free carnitine was also reduced. Brockmann et al. (2002) reported 3 patients, 2 Turkish sibs and an unrelated Norwegian boy, with isolated complex II deficiency with decreased activities of succinate dehydrogenase and succinate:cytochrome c oxidoreductase. The patients presented in infancy and very early childhood with neurologic symptoms, including loss of motor skills and spastic paresis, and leukoencephalopathy on MRI. Proton MRS showed strongly elevated concentrations of succinate in white matter and CSF. Ghezzi et al. (2009) provided follow-up of the consanguineous Turkish family reported by Brockmann et al. (2002) and an Italian family reported by Bugiani et al. (2006). The 3 Italian patients originated from a small village in Lombardy, Italy. Two of the patients were clearly related and the other was believed to be related. Onset of the disorder became apparent in the first year of life, manifest as acute psychomotor | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. CSF. Ghezzi et al. (2009) provided follow-up of the consanguineous Turkish family reported by Brockmann et al. (2002) and an Italian family reported by Bugiani et al. (2006). The 3 Italian patients originated from a small village in Lombardy, Italy. Two of the patients were clearly related and the other was believed to be related. Onset of the disorder became apparent in the first year of life, manifest as acute psychomotor regression and poor growth with lack of speech development. All patients developed severe spastic quadriplegia with partial loss of postural control and dystonia. Brain imaging studies showed leukoencephalopathy with sparing of the peripheral U-fibers and basal ganglia and increased lactate and succinate. Lactate and pyruvate were variably elevated in blood. Most had relative stabilization of their clinical conditions, with survival beyond the first decade of life in several cases, although growth was consistently and severely impaired. Biochemical analysis | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. of life, manifest as acute psychomotor regression and poor growth with lack of speech development. All patients developed severe spastic quadriplegia with partial loss of postural control and dystonia. Brain imaging studies showed leukoencephalopathy with sparing of the peripheral U-fibers and basal ganglia and increased lactate and succinate. Lactate and pyruvate were variably elevated in blood. Most had relative stabilization of their clinical conditions, with survival beyond the first decade of life in several cases, although growth was consistently and severely impaired. Biochemical analysis of mitochondrial respiratory chain complexes in muscle and fibroblasts showed 20 to 30% residual activity of SDH and succinate-CoQ reductase (SCoQR) and decreased protein levels. Alston et al. (2012) reported a boy who presented at 3 months of age with symptoms of dilated cardiomyopathy after a normal neonatal period. He later showed delayed motor development with hypertonia, hyperreflexia, and joint contractures. Speech was delayed. Brain MRI at age 2.5 | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. consistently and severely impaired. Biochemical analysis of mitochondrial respiratory chain complexes in muscle and fibroblasts showed 20 to 30% residual activity of SDH and succinate-CoQ reductase (SCoQR) and decreased protein levels. Alston et al. (2012) reported a boy who presented at 3 months of age with symptoms of dilated cardiomyopathy after a normal neonatal period. He later showed delayed motor development with hypertonia, hyperreflexia, and joint contractures. Speech was delayed. Brain MRI at age 2.5 years showed cystic changes and abnormal symmetric signals in the central cerebral white matter, as well as abnormal signals in the corpus callosum, ventral pons, medulla, and throughout the majority of the gray matter of the spinal cord. Laboratory studies showed normal plasma lactate, but evidence of ketosis and increased urinary lactate and urinary tricarboxylic acid cycle metabolites. Skeletal muscle biopsy showed severe deficiency of mitochondrial complex II activity. Western blot analysis of patient fibroblasts showed decreased amounts of fully assembled complex II | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. Brain MRI at age 2.5 years showed cystic changes and abnormal symmetric signals in the central cerebral white matter, as well as abnormal signals in the corpus callosum, ventral pons, medulla, and throughout the majority of the gray matter of the spinal cord. Laboratory studies showed normal plasma lactate, but evidence of ketosis and increased urinary lactate and urinary tricarboxylic acid cycle metabolites. Skeletal muscle biopsy showed severe deficiency of mitochondrial complex II activity. Western blot analysis of patient fibroblasts showed decreased amounts of fully assembled complex II with almost complete absence of SDHA. Genetic analysis identified compound heterozygosity for 2 mutations in the SDHA gene (600857.0006 and 600857.0007). Jain-Ghai et al. (2013) reported a female infant, born of unrelated parents of Middle Eastern descent, with complex II deficiency. She was born at 28 weeks' gestation due to preeclampsia. Echocardiogram showed dilated cardiomyopathy and left ventricular noncompaction, and laboratory studies showed | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. decreased amounts of fully assembled complex II with almost complete absence of SDHA. Genetic analysis identified compound heterozygosity for 2 mutations in the SDHA gene (600857.0006 and 600857.0007). Jain-Ghai et al. (2013) reported a female infant, born of unrelated parents of Middle Eastern descent, with complex II deficiency. She was born at 28 weeks' gestation due to preeclampsia. Echocardiogram showed dilated cardiomyopathy and left ventricular noncompaction, and laboratory studies showed increased serum lactate. The patient later showed developmental delay, failure to thrive, and hypotonia. She died at age 13 months. Electron microscopic analysis of muscle biopsy showed mitochondria with a dense array of parallel cristae and matrix granules, isolated complex II deficiency, and low levels of SDHA protein (24%) compared to controls. However, genetic analysis did not reveal mutations in the SDHA, SDHAF1, or ISCU (611911) genes. | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. noncompaction, and laboratory studies showed increased serum lactate. The patient later showed developmental delay, failure to thrive, and hypotonia. She died at age 13 months. Electron microscopic analysis of muscle biopsy showed mitochondria with a dense array of parallel cristae and matrix granules, isolated complex II deficiency, and low levels of SDHA protein (24%) compared to controls. However, genetic analysis did not reveal mutations in the SDHA, SDHAF1, or ISCU (611911) genes. Jain-Ghai et al. (2013) postulated that this patient had a novel genetic defect. Jain-Ghai et al. (2013) reviewed 36 cases of complex II deficiency from the literature. The phenotype was highly variable: some patients had multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others had only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Neurologic findings, | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. (611911) genes. Jain-Ghai et al. (2013) postulated that this patient had a novel genetic defect. Jain-Ghai et al. (2013) reviewed 36 cases of complex II deficiency from the literature. The phenotype was highly variable: some patients had multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others had only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Neurologic findings, although variable, included developmental delay or regression following infection, hypotonia, hypertonia, and spasticity. Ophthalmologic features included ophthalmoplegia, retinopathy, nystagmus, optic atrophy, and blindness. Measurement of complex II activity in muscle was the most reliable means of diagnosis; however, there was no correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin had some clinical benefit. Jackson et al. (2014) reported a girl, | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. and normal cognition. Neurologic findings, although variable, included developmental delay or regression following infection, hypotonia, hypertonia, and spasticity. Ophthalmologic features included ophthalmoplegia, retinopathy, nystagmus, optic atrophy, and blindness. Measurement of complex II activity in muscle was the most reliable means of diagnosis; however, there was no correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin had some clinical benefit. Jackson et al. (2014) reported a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency. The patient showed developmental regression with reduced motor development at age 3 months of age after a respiratory infection. Thereafter, she showed severely delayed psychomotor development associated with hypotonia, nystagmus, secondary microcephaly, ataxia, dystonia, and deteriorating vision. Laboratory studies were normal, excluding severe catabolic episodes. After 4.5 years of age, she developed seizures and myoclonic | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. (2014) reported a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency. The patient showed developmental regression with reduced motor development at age 3 months of age after a respiratory infection. Thereafter, she showed severely delayed psychomotor development associated with hypotonia, nystagmus, secondary microcephaly, ataxia, dystonia, and deteriorating vision. Laboratory studies were normal, excluding severe catabolic episodes. After 4.5 years of age, she developed seizures and myoclonic movements. During an illness at age 7, the patient underwent laboratory studies that showed lactic acidosis, ketonuria, and Krebs cycle intermediates, suggesting a mitochondrial defect. Biochemical assays of skin fibroblasts and muscle homogenates indicated isolated mitochondrial complex II deficiency (5% residual activity) and defective oxygen consumption; immunoblotting showed impaired complex II assembly. Genetic analysis identified compound heterozygous mutation in the SDHD gene (602690.0029 and 602690.0030). | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. , she developed seizures and myoclonic movements. During an illness at age 7, the patient underwent laboratory studies that showed lactic acidosis, ketonuria, and Krebs cycle intermediates, suggesting a mitochondrial defect. Biochemical assays of skin fibroblasts and muscle homogenates indicated isolated mitochondrial complex II deficiency (5% residual activity) and defective oxygen consumption; immunoblotting showed impaired complex II assembly. Genetic analysis identified compound heterozygous mutation in the SDHD gene (602690.0029 and 602690.0030). Cellular complementation studies showed that the SDHD variants were unable to rescue the complex II assembly defect, whereas wildtype SDHD was able to rescue it. Alston et al. (2015) reported an infant, born of unrelated Irish parents, with fatal cardiomyopathy associated with mitochondrial complex II deficiency. The patient was noted prenatally to have dilated cardiomyopathy with mitral regurgitation and left ventricular systolic dysfunction. He died on the first day of life. Postmortem examination showed noncompaction of the | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. 2690.0030). Cellular complementation studies showed that the SDHD variants were unable to rescue the complex II assembly defect, whereas wildtype SDHD was able to rescue it. Alston et al. (2015) reported an infant, born of unrelated Irish parents, with fatal cardiomyopathy associated with mitochondrial complex II deficiency. The patient was noted prenatally to have dilated cardiomyopathy with mitral regurgitation and left ventricular systolic dysfunction. He died on the first day of life. Postmortem examination showed noncompaction of the hypertrophic left ventricle and an underdeveloped right ventricle. Genetic analysis identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031). Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in SDHD protein levels and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. Postmortem examination showed noncompaction of the hypertrophic left ventricle and an underdeveloped right ventricle. Genetic analysis identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031). Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in SDHD protein levels and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative growth defect, consistent with a loss of function.
Clinical Management
Bugiani et al. (2006) reported favorable results with oral riboflavin treatment in 2 Italian patients with complex II deficiency. The patients showed acute psychomotor regression in the first year of life, followed by rapidly progressive neurologic deterioration, spastic quadriparesis with dystonic posturing, and mental impairment. One patient was blind. Complex II deficiency was demonstrated in muscle and fibroblasts. Treatment with oral riboflavin resulted in stabilization | [
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