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Methylmalonic acidemia without homocystinuria
Methylmalonic acidemia is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations resulting from decreased function of the mitochondrial enzyme methylmalonyl-CoA mutase.
ORPHA:293355Classification level: Group of disorders
- Methylmalonic aciduria without homocystinuria
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant or Autosomal recessive or X-linked dominant
- Age of onset: All ages
- ICD-10: E71.1
- OMIM: -
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Prevalence of methylmalonic acidemia has been estimated at 1/48,000 to 1/61,000 in North America, and at 1/26,000 in China (these values may include patients with methylmalonic acidemia with homocystinuria; see this term).
Clinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. Long-term consequences of the disorder include neurological damage due to metabolic stroke affecting the brain stem, and end stage renal failure. The disease can either be responsive or unresponsive to treatment with vitamin B12 (vitamin B12-responsive or unresponsive methylmalonic acidemia; see these terms). Patients with mut0 or cblB tend to be more severely affected than patients with cblA, cblDv2 or mut-.
Vitamin B12-responsive methylmalonic acidemia is caused by defects in the synthesis of adenosylcobalamin (AdoCbl) that result from genetic defects in cobalamin metabolism (cblA, cblB or cblD variant 2 [cblDv2]). Vitamin B12-unresponsive methylmalonic acidemia is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. cblA is caused by mutations in the MMAA gene (4q31.1-2), cblB by mutations in the MMAB gene (12q24.1), cblDv2 by mutations in the MMADHC gene (2q23.2), and mut0 and mut- by mutations in the MUT gene (6p21), and all are transmitted in an autosomal recessive manner. The previously reported cblH disorder is now known to be cblDv2.
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