Asymptomatic methylmalonic acidemia in a homozygous MUT mutation (p.P86L)

Deficiency in methylmalonyl-coenzyme A mutase (MCM) is associated with accumulation of methylmalonic acid (MMA) and clinical outcomes that include early death and neurological impairment. Reported here are two unrelated patients with a homozygous p.P86L mutation in the MUT gene, which encodes MCM, diagnosed following newborn screening. This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. Both in vitro and in vivo testing did not find a response to supplemental hydroxocobalamin. After discontinuation of hydroxocobalamin in one patient, serum MMA level remained elevated but stable, while urine MMA increased. Both patients have remained asymptomatic with normal development. The observed homozygous p.P86L mutation in the N-terminal extended segment may yield reduced MCM activity and is refractory to hydroxocobalamin supplementation, while not inducing a metabolically unstable phenotype. These genotype–phenotype associations further enhance the understanding of methylmalonic acidemia, which will continue to improve patient care.