Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia

Abstract

Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous organic acid disorder caused by either deficiency of the enzyme methylmalonyl-CoA mutase (MCM), or a defect in the biosynthesis of its cofactor, adenosyl-cobalamin (AdoCbl). Herein, we report and review the genotypes and phenotypes of 14 Thai patients with isolated MMA. Between 1997 and 2011, we identified 6 . mut patients, 2 . cblA patients, and 6 . cblB patients. The . mut and . cblB patients had relatively severe phenotypes compared to relatively mild phenotypes of the . cblA patients. The . MUT and . MMAB genotypes were also correlated to the severity of the phenotypes. Three mutations in the . MUT gene: c.788G > T (p.G263V), c.809_812dupGGGC (p.D272Gfs*2), and c.1426C > T (p.Q476*); one mutation in the . MMAA gene: c.292A > G (p.R98G); and three mutations in the . MMAB gene: c.682delG (p.A228Pfs*2), c.435delC (p.F145Lfs*69), and c.585-1G > A, have not been previously reported. RT-PCR analysis of a common intron 6 polymorphism (c.520-159C > T) of the . MMAB gene revealed that it correlates to deep intronic exonization leading to premature termination of the open reading frame. This could decrease the ATP:cobalamin adenosyltransferase (ATR) activity resulting in abnormal phenotypes if found in a compound heterozygous state with a null mutation. We confirm the genotype-phenotype correlation of isolated MMA in the study population, and identified a new molecular basis of the . cblB disorder. © 2012 Elsevier Inc.