Late-onset cobalamin C defect with a rare MMACHC c.457 C > T variant: a case report and literature review

Cobalamin C (cblC) defect, also referred to as combined methylmalonic acidemia and homocystinuria, is the most common inborn error of intracellular cobalamin metabolism. Late-onset cblC defect often presents with atypical and heterogeneous manifestations, particularly neuropsychiatric symptoms, which may lead to misdiagnosis and delayed treatment.

We report a 13-year-old girl with late-onset cblC defect who presented with progressive cognitive impairment, psychiatric and behavioral abnormalities, and motor dysfunction. Because of these atypical manifestations, she was initially misdiagnosed with autoimmune encephalitis. Laboratory evaluation showed markedly elevated plasma total homocysteine, decreased methionine, mildly increased propionylcarnitine with elevated C3/C2 and C3/C0 ratios, and markedly increased urinary methylmalonic acid and methylcitrate. Genetic testing identified compound heterozygous pathogenic variants in the MMACHC gene: c.482G > A (p.Arg161Gln, maternally inherited) and c.457 C > T (p.Arg153Ter), the latter being rarely reported in China. Following treatment with hydroxocobalamin, folate, betaine, and L-carnitine, the patient showed marked biochemical improvement and partial clinical recovery, although residual cognitive impairment and gait disturbance persisted.

This case expands the genotypic spectrum of cblC defect in China and highlights the importance of metabolic screening and genetic testing in children and adolescents with otherwise unexplained neuropsychiatric manifestations. Early recognition and targeted treatment are crucial for improving long-term neurological outcomes.