Molecular characteristics

iMMA refers to a heterogeneous group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to convert methylmalonyl-CoA into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix. IMMA is due to the deficiency of the methylmalonyl-CoA mutase (MCM) enzyme activity. MCM deficiency is caused either by a deficiency of the enzyme itself (mut forms, encoded by MMUT) or by diminished synthesis or availability of its cofactor 5’-deoxyadenosylcobalamin which is associated with cobalamin A, B or D deficiencies encoded by MMAA, MMAB or MMADHC, respectively. All the iMMA are transmitted in an autosomal recessive mode.

MMA associated with hyperhomocysteinuria is another group of disorder not discussed here.The diagnosis requires investigations including determination of organic acids in urine, amino acids in blood (plasma, drawn ideally after 3-4 hours fasting), urine, acylcarnitine profile in blood (dried blood or plasma) and total plasma homocysteine which is essential in order to differentiate the various types of MMA.

The complexity of inherited iMMA usually requires characterization of the underlying defect in cultured skin fibroblasts and/or lymphocytes and/or molecular genetic analysis. mut forms are often distinguish in complete mut0 enzymatic subtype (B12-unresponsive) deficiency or partial mut– enzymatic subtype (B12-responsive in vitro but rarely in vivo) deficiency. Most of cobalamin A and few cobalamin B are B12-responsive in vivo. mut° and cobalamin B deficient patients are considered severely affected regarding morbidity and mortality, whereas mut- and cobalamin A deficient patients are considered to present with a milder form of iMMA. Cobalamin D deficiency can either result in combined methylmalonic aciduria and homocystinuria (cblD-MMA/HC), in isolated homocystinuria (cblD-HC) or in isolated MMA (cblD-MMA). MMUT mutations are responsible for at least 50% of the iMMA. There is no frequent mutation and more than 350 mutations have been identified in MMUT.

Most of the patients have private mutations and are compound heterozygotes making difficult the evaluation of genotype-phenotype correlation.