SCIENTIFIC BACKGROUND

MMUT

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 developmental disabilities, among other symptoms, which can occur from the first weeks of life.

 

Vitamin B12-resistant MMA 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, substitution with vitamin B12 does not usually improve the symptoms of the disease (vitamin B12-independent form). Disease due to partial enzyme deficiency (mut-) is usually milder than that due to 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 a form with an alimentary cause without a severe genetic vitamin B12 deficiency.

 

References

Manoli et al. 2016, Isolated Methylmalonic Aciduria, Gene Reviews

GENES

MMUT

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