Methylmalonic acidemia with homocystinuria

Methylmalonic acidemia with homocystinuria (MMA-HC) is a rare inherited metabolic disorder characterized by the simultaneous accumulation of methylmalonic acid and homocysteine in the blood and urine. It results from defects in the intracellular metabolism of cobalamin (vitamin B12), which serves as a cofactor for two critical enzymes: methylmalonyl-CoA mutase (involved in organic acid metabolism) and methionine synthase (involved in homocysteine remethylation). Several complementation groups have been identified, including cblC (the most common form, caused by mutations in the MMACHC gene), cblD (MMADHC gene), cblF (LMBRD1 gene), cblJ (ABCD4 gene), and cblX (HCFC1 gene). The cblC type accounts for the vast majority of cases. The disease affects multiple body systems. Key clinical features include developmental delay, intellectual disability, failure to thrive, feeding difficulties, seizures, megaloblastic anemia, and visual impairment (including macular degeneration and retinopathy). Neurological involvement is prominent and may include hypotonia, lethargy, microcephaly, and progressive cognitive decline. Renal complications such as hemolytic uremic syndrome (HUS) can also occur. Early-onset forms typically present in the neonatal or infantile period with severe multisystem disease, while late-onset forms may present in childhood or adulthood with milder or more variable symptoms, including psychiatric manifestations, cognitive decline, and thromboembolic events. Treatment involves intramuscular hydroxocobalamin (vitamin B12) injections, oral betaine supplementation to help lower homocysteine levels, carnitine supplementation, and dietary protein restriction. Early diagnosis through newborn screening and prompt initiation of treatment can improve outcomes, though many patients, particularly those with early-onset cblC disease, continue to experience significant developmental and neurological challenges despite therapy. Long-term multidisciplinary follow-up involving metabolic specialists, neurologists, ophthalmologists, and nephrologists is essential.

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