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Jean L. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Mutations in the Molybdenum Cofactor biosynthetic genes MOCS1, MOCS2, and GEPH.
Human mutation, 2003Co-Authors: Jochen Reiss, Jean L. JohnsonAbstract:Molybdenum Cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of Molybdenum Cofactor deficiency are inherited as autosomal recessive traits. The Cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during Cofactor assembly for insertion of Molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in Molybdenum Cofactor-deficient patients and their relatives.
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Prenatal diagnosis of Molybdenum Cofactor deficiency and isolated sulfite oxidase deficiency
Prenatal diagnosis, 2003Co-Authors: Jean L. JohnsonAbstract:Molybdenum Cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity. The deficiencies can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue. In those families in which the specific defects have been identified, diagnosis can be achieved by mutation analysis or linkage studies directed at affected genes. These include MOCS1, MOCS2 or GEPH, in cases of Molybdenum Cofactor deficiency, or SUOX in patients with isolated sulfite oxidase deficiency.
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prenatal diagnosis of Molybdenum Cofactor deficiency and isolated sulfite oxidase deficiency
Prenatal Diagnosis, 2003Co-Authors: Jean L. JohnsonAbstract:Molybdenum Cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity. The deficiencies can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue. In those families in which the specific defects have been identified, diagnosis can be achieved by mutation analysis or linkage studies directed at affected genes. These include MOCS1, MOCS2 or GEPH, in cases of Molybdenum Cofactor deficiency, or SUOX in patients with isolated sulfite oxidase deficiency. Copyright © 2002 John Wiley & Sons, Ltd.
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Molybdopterin synthase mutations in a mild case of Molybdenum Cofactor deficiency.
American journal of medical genetics, 2001Co-Authors: Jean L. Johnson, K. V. Rajagopalan, Katharine E Coyne, Johan L.k. Van Hove, Mark T Mackay, James Pitt, Avihu BonehAbstract:Molybdenum Cofactor deficiency is a rare inborn error of metabolism with generally severe symptoms, most often including neonatal seizures and severe developmental delay. We describe a patient with an unusually mild form of the disease. Two mutations in MOCS2A (Molybdenum Cofactor synthesis enzyme 2A) were identified: a single base change, 16C > T, that predicts a Q6X substitution on one allele and a 19G > T transversion that predicts a valine to phenylalanine substitution, V7F, on the second. It is postulated that the milder clinical symptoms result from a low level of residual molybdopterin synthase activity derived from the 19G > T allele.
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ahomocysteinemia in Molybdenum Cofactor deficiency
Neurology, 1998Co-Authors: William D Graf, O E Oleinik, R M Jack, A H Weiss, Jean L. JohnsonAbstract:We report an infant with Molybdenum Cofactor deficiency (MCD) and a unique clinical presentation of hemiplegia, hypotonia, dystonia, and bilateral basal ganglia changes. Biochemistry revealed absent serum homocysteine, low concentrations of plasma cystine, high levels of urinary S-sulfocysteine and sulfite, and high levels of oxypurines in serum and urine. The depletion of cysteine and cystine through reaction with sulfite suggests that other thiols and thiol-dependent proteins may be similarly depleted. Ahomocysteinemia may be a clue to the mechanism of cytotoxicity in MCD.
Markus Ries - One of the best experts on this subject based on the ideXlab platform.
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Ultra-orphan diseases: a quantitative analysis of the natural history of Molybdenum Cofactor deficiency
Genetics in Medicine, 2015Co-Authors: Konstantin Mechler, William K. Mountford, Georg F. Hoffmann, Markus RiesAbstract:Genet Med 17 12, 965–970. Purpose: Experimental treatment with substrate replacement was successfully performed in single cases with Molybdenum Cofactor deficiency type A. The objective of this study was to quantitate the yet undefined natural history in untreated patients to ultimately benefit knowledge in experimental treatments in the future. Methods: Systematic analysis of published cases with Molybdenum Cofactor deficiency. The main outcome measures were survival, initial cardinal disease features at onset, and diagnostic delay. Results: The median survival for the overall population was 36 months. Initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (26%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. The median age at onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days. Conclusion: Molybdenum Cofactor deficiency has its onset during the neonatal period and infancy. There is considerable diagnostic delay. Although seizures were the most frequent initial cardinal sign, Molybdenum Cofactor deficiency should be considered as a differential diagnosis in patients presenting with hypotonia, developmental delay, or feeding difficulties. The survival data will inform further natural-history and therapeutic studies.
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ultra orphan diseases a quantitative analysis of the natural history of Molybdenum Cofactor deficiency
Genetics in Medicine, 2015Co-Authors: Konstantin Mechler, William K. Mountford, Georg F. Hoffmann, Markus RiesAbstract:Ultra-orphan diseases: a quantitative analysis of the natural history of Molybdenum Cofactor deficiency
Brahim Tabarki - One of the best experts on this subject based on the ideXlab platform.
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pyridoxine dependent epilepsy with elevated urinary alpha amino adipic semialdehyde in Molybdenum Cofactor deficiency
Pediatrics, 2012Co-Authors: E A Struijs, B Nota, A Bakkali, Al S Shahwan, G S Salomons, Brahim TabarkiAbstract:α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin ( ALDH7A1 ) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in Molybdenum Cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B 6 ), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for Molybdenum Cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS 2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with Molybdenum Cofactor or sulfite oxidase deficiencies.
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Pyridoxine-dependent epilepsy with elevated urinary α-amino adipic semialdehyde in Molybdenum Cofactor deficiency.
Pediatrics, 2012Co-Authors: B Nota, A Bakkali, G S Salomons, Saad Al Shahwan, Brahim TabarkiAbstract:α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in Molybdenum Cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for Molybdenum Cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with Molybdenum Cofactor or sulfite oxidase deficiencies.
Jochen Reiss - One of the best experts on this subject based on the ideXlab platform.
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Molybdenum Cofactor and sulfite oxidase deficiency
Journal of Postgenomics Drug & Biomarker Development, 2016Co-Authors: Jochen ReissAbstract:A universal Molybdenum-containing Cofactor is necessary for the activity of all eukaryotic molybdoenzymes. In humans four such enzymes are known: Sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase and a mitochondrial amidoxime reducing component. Of these, sulfite oxidase is the most important and clinically relevant one. Mutations in the genes MOCS1, MOCS2 or GPHN - all encoding Cofactor biosynthesis proteins - lead to Molybdenum Cofactor deficiency type A, B or C, respectively. All three types plus mutations in the SUOX gene responsible for isolated sulfite oxidase deficiency lead to progressive neurological disease which untreated in most cases leads to death in early childhood. Currently, only for type A of the Cofactor deficiency an experimental treatment is available.
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Molybdenum Cofactor deficiency mutations in gphn mocs1 and mocs2
Human Mutation, 2011Co-Authors: Jochen Reiss, Rita HahnewaldAbstract:All Molybdenum-containing enzymes other than the bacterial nitrogenase share an identical Molybdenum Cofactor (MoCo), which is synthesized via a conserved pathway in all organisms and therefore also is called “universal Molybdenum Cofactor.” In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase, and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo pathway enzymes abrogate the activities of all molybdoenzymes and result in the “combined” form of MoCo deficiency, which is clinically very similar to isolated sulfite oxidase deficiency, caused by mutations in the gene for the corresponding apoenzyme. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death in most cases. The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency), MOCS2 (type B deficiency), with one reported in GPHN. For type A deficiency an effective substitution therapy has been described recently. Hum Mutat 32:10–18, 2011. © 2010 Wiley-Liss, Inc.
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Molybdenum Cofactor deficiency
Human Mutation, 2010Co-Authors: Jochen Reiss, Rita HahnewaldAbstract:All Molybdenum-containing enzymes other than the bacterial nitrogenase share an identical Molybdenum Cofactor (MoCo), which is synthesized via a conserved pathway in all organisms and therefore also is called "universal Molybdenum Cofactor". In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo pathway enzymes abrogate the activities of all molybdoenzymes and result in the "combined" form of MoCo deficiency (OMIM # 252150), which is clinically very similar to isolated sulfite oxidase deficiency (OMIM # 606887), caused by mutations in the gene for the corresponding apoenzyme. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death in most cases. The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency) and MOCS2 (type B deficiency). For type A deficiency an effective substitution therapy has been described recently.
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Molybdenum Cofactor deficiency: Mutations in GPHN, MOCS1, and MOCS2
Human mutation, 2010Co-Authors: Jochen Reiss, Rita HahnewaldAbstract:All Molybdenum-containing enzymes other than the bacterial nitrogenase share an identical Molybdenum Cofactor (MoCo), which is synthesized via a conserved pathway in all organisms and therefore also is called "universal Molybdenum Cofactor." In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase, and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo pathway enzymes abrogate the activities of all molybdoenzymes and result in the "combined" form of MoCo deficiency, which is clinically very similar to isolated sulfite oxidase deficiency, caused by mutations in the gene for the corresponding apoenzyme. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death in most cases. The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency), MOCS2 (type B deficiency), with one reported in GPHN. For type A deficiency an effective substitution therapy has been described recently.
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cranial ultrasound and chronological changes in Molybdenum Cofactor deficiency
Pediatric Radiology, 2007Co-Authors: Mercedes Serrano, Jochen Reiss, Isabel Lizarraga, Anna Paula Dias, Belen Perezduenas, M A Vilaseca, Rafael Artuch, Jaume Campistol, Angels GarciacazorlaAbstract:Molybdenum Cofactor is essential for the function of three human enzymes: sulphite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Molybdenum Cofactor deficiency is a rare autosomal recessively inherited disease. Disturbed development and damage to the brain may occur as a result of accumulation of toxic levels of sulphite. The CT and MRI findings include severe early brain abnormalities and have been widely reported, but the cranial US imaging findings have seldom been reported. We report a chronological series of cranial US images obtained from an affected infant that show the rapid development of cerebral atrophy, calcifications and white matter cysts. Our report supports the utility of cranial US, a noninvasive bed-side technique, in the detection and follow-up of these rapidly changing lesions.
Konstantin Mechler - One of the best experts on this subject based on the ideXlab platform.
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Ultra-orphan diseases: a quantitative analysis of the natural history of Molybdenum Cofactor deficiency
Genetics in Medicine, 2015Co-Authors: Konstantin Mechler, William K. Mountford, Georg F. Hoffmann, Markus RiesAbstract:Genet Med 17 12, 965–970. Purpose: Experimental treatment with substrate replacement was successfully performed in single cases with Molybdenum Cofactor deficiency type A. The objective of this study was to quantitate the yet undefined natural history in untreated patients to ultimately benefit knowledge in experimental treatments in the future. Methods: Systematic analysis of published cases with Molybdenum Cofactor deficiency. The main outcome measures were survival, initial cardinal disease features at onset, and diagnostic delay. Results: The median survival for the overall population was 36 months. Initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (26%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. The median age at onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days. Conclusion: Molybdenum Cofactor deficiency has its onset during the neonatal period and infancy. There is considerable diagnostic delay. Although seizures were the most frequent initial cardinal sign, Molybdenum Cofactor deficiency should be considered as a differential diagnosis in patients presenting with hypotonia, developmental delay, or feeding difficulties. The survival data will inform further natural-history and therapeutic studies.
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ultra orphan diseases a quantitative analysis of the natural history of Molybdenum Cofactor deficiency
Genetics in Medicine, 2015Co-Authors: Konstantin Mechler, William K. Mountford, Georg F. Hoffmann, Markus RiesAbstract:Ultra-orphan diseases: a quantitative analysis of the natural history of Molybdenum Cofactor deficiency