Vitamin B12-resistant methylmalonic aciduria (MMA) is a very rare autosomal recessive inherited metabolic disorder belonging to the group of organoacidopathies characterized by accumulation and increased renal excretion of methylmalonic acid. This usually results in recurrent ketoacidotic coma and/or hyperammonemia, episodes of vomiting, dehydration, muscle hypotonia, and later developmental disabilities, among other symptoms, already in the first weeks of life.
Vitamin B12-resistant methylmalonic aciduria is due to a deficiency of the mitochondrial vitamin B12-dependent enzyme methylmalonyl-CoA mutase, resulting in impaired degradation of methylmalonyl-CoA to succinyl-CoA. This results in accumulation of methylmalonyl-CoA, which is converted to methylmalonic acid by an alternative degradation pathway.
Pathogenic variants in the methylmalonyl-CoA mutase (MMUT) gene lead to partial (mut-) or complete (mut0) deficiency of the enzyme. In this form of the disease, a substitution with vitamin B12 usually does not have an ameliorating effect on the symptomatology of the disease (vitamin B12-independent form). The clinical picture of partial enzyme deficiency (mut-) is usually milder than in the case of complete loss of enzyme activity (mut0).
In addition to the vitamin B12-resistant form, several other forms of genetic methylmalonic aciduria are known. Furthermore, there is also an alimentary caused form without genetic background in severe vitamin B12 deficiency.
Manoli et al. 2016, Isolated Methylmalonic Aciduria, Gene Reviews