Mutation analysis and prenatal diagnosis for three families affected by isolated methylmalonic aciduria

Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous disorder caused mainly by deficiency of methylmalonyl-CoA mutase. In the present study, we analyzed MUT gene mutations in 3 Chinese couples with a birth history of isolated MMA. We also provided prenatal diagnoses for the detected mutation. Exons and exon-intron boundaries of the MUT gene were analyzed by polymerase chain reaction and direct sequencing. Prenatal genetic diagnoses were performed by chorionic villus sampling after the genotypes of parents were determined. Six heterozygous mutations in the MUT gene were identified in the 3 families, including c.1880A>G (p.H627R) and IVS9-1G>A for family 1, c.1741C>T (p.R581X) and c.729insTT (p.D244fX39) for family 2, and c.616C>T (p.Q206X) and c.1280G>A (p.G427D) for family 3. Among these, c.616C>T (p.Q206X), c.1280G>A (p.G427D), IVS9-1G>A, and c.1741C>T (p.R581X) were novel mutations. These mutations were not detected in 100 normal controls. The fetus in pedigree 3 was free of the mutations carried by the parents, while the fetuses in pedigrees 1 and 2 were heterozygous mutation carriers. All 3 families decided to continue with their pregnancies and the neonates did not show any symptoms of MMA after birth. Our results indicated that mutations in the MUT gene are the primary cause of isolated MMA, and that most mutations were novel. For families with early-onset isolated MMA, direct sequencing of the MUT gene is crucial for genetic counseling, prenatal diagnosis, and identification of carriers.