Three novel and six common mutations in 11 patients with methylmalonic acidemia

Background: Patients with a defect in methylmalonyl-coenzyme A mutase (MCM) are classified as having methylmalonic acidemia, which is divided into two subclasses: mut0 and mut−. Fifty-five disease-causing mutations have been identified. Although most are private mutations, only three (E117X, G717V, and N219Y) are reportedly common in Japanese, Black, and Caucasian populations, respectively. Here we identified mutations in 11 Japanese patients with MCM deficiency. Methods: Mutational analysis was performed in 11 unrelated Japanese patients with MCM deficiency using polymerase chain reaction and direct sequencing. Results: Three novel (L494X, R727X, and 449_461del) and six previously reported (R93H, E117X, N219Y, R369H, G648D and IVS2 + 5G>A) mutations were identified. The L494X mutation was found in three unrelated patients, and the R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations occurred more than once. Two of the patients were classified as mut− phenotype because of residual [14C]-propionate incorporation in the presence of a high concentration of hydroxocobalamin. The two mut− patients were heterozygous for the G648D mutation and presented with lethargy and metabolic acidosis after 2 years of life. Their psychomotor development has been documented as normal. The patients with the R727X or 449_461del mutations clinically exhibited mut0 phenotype. Two patients with mut0 phenotype died in infancy. One presented early in the neonatal period; the other was symptomatic in the late infantile period. Conclusions: The L494X, R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations are found in more than two unrelated families in the Japanese population. The short-term outcome was generally poor in patients with mut0, and therefore alternative treatments should be considered.