Isolated methylmalonic acidemia/aciduria is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut(0) enzymatic subtype or mut(-) enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD variant 2 type), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes demonstrate periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death. In the infantile/non-B12-responsive phenotype, the most common form, infants are normal at birth but develop lethargy, vomiting, dehydration, hepatomegaly, hypotonia, and encephalopathy. An intermediate B12-responsive phenotype can occasionally present in neonates, but usually presents in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia are associated with increased, albeit mild, urinary excretion of methylmalonate; however, it is uncertain if some of these individuals will develop symptoms. Major secondary complications of methylmalonic acidemia include developmental delay (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia involvement); disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Definitive diagnosis of isolated methylmalonic acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific enzymatic subtype of methylmalonic acidemia requires studies on vitamin B12 responsiveness, (14)C propionate incorporation assays, complementation analysis, and cobalamin distribution assays. As an alternative or complement to the cellular biochemical studies, the finding of two distinct mutations in one of the genes associated with methylmalonic acidemia, with confirmation of carrier status in the parents, can definitely establish the diagnosis. Molecular genetic testing of MUT, MMAA, MMAB, MCEE, and MMADHC, the genes known to be associated with isolated methylmalonic acidemia, is available on a clinical basis.
Isolated methylmalonic acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing using molecular genetic techniques is possible in families in which the disease-causing mutations are known. Prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis), and by molecular genetic testing in those families in which the disease-causing mutations are known.