Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia.
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.
Division of Medical Genetics, Department of Pediatrics, Mahidol University, Bangkok, Thailand. nithiwat_v@hotmail.com
Nithiwat
N
Vatanavicharn
Voraratt
V
Champattanachai
Somporn
S
Liammongkolkul
Phannee
P
Sawangareetrakul
Siriporn
S
Keeratichamroen
James R
JR
Ketudat Cairns
Chantragan
C
Srisomsap
Achara
A
Sathienkijkanchai
Vorasuk
V
Shotelersuk
Mahattana
M
Kamolsilp
Duangrurdee
D
Wattanasirichaigoon
Jisnuson
J
Svasti
Pornswan
P
Wasant
D000293:Adolescent; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D044466:Asian People; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic
C497512:MMAA protein, human; D033681:Mitochondrial Membrane Transport Proteins; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D008765:Methylmalonyl-CoA Mutase