TY - JOUR
T1 - Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type
AU - Nogueira, Célia
AU - Aiello, Chiara
AU - Cerone, Roberto
AU - Martins, Esmeralda
AU - Caruso, Ubaldo
AU - Moroni, Isabella
AU - Rizzo, Cristiano
AU - Diogo, Luísa
AU - Leão, Elisa
AU - Kok, Fernando
AU - Deodato, Federica
AU - Schiaffino, Maria Cristina
AU - Boenzi, Sara
AU - Danhaive, Olivier
AU - Barbot, Clara
AU - Sequeira, Sílvia
AU - Locatelli, Mattia
AU - Santorelli, Filippo M.
AU - Uziel, Graziella
AU - Vilarinho, Laura
AU - Dionisi-Vici, Carlo
PY - 2008/4
Y1 - 2008/4
N2 - Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B12. The recent identification of the disease gene, MMACHC, has permitted preliminary genotype-phenotype correlations. We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR-playing a key role in homocysteine remethylation pathway-could act as genetic modifier in cblC defect. We found that the c.271dupA (accounting for 55% of the MMACH alleles in our cohort) followed by c.394C > T (16%) and c.331C > T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T > C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect. This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C > T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children.
AB - Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B12. The recent identification of the disease gene, MMACHC, has permitted preliminary genotype-phenotype correlations. We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR-playing a key role in homocysteine remethylation pathway-could act as genetic modifier in cblC defect. We found that the c.271dupA (accounting for 55% of the MMACH alleles in our cohort) followed by c.394C > T (16%) and c.331C > T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T > C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect. This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C > T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children.
KW - cblC
KW - Methylmalonic aciduria and homocystinuria
KW - MMACHC
KW - MTHFR
KW - Vitamin B
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U2 - 10.1016/j.ymgme.2007.11.005
DO - 10.1016/j.ymgme.2007.11.005
M3 - Article
C2 - 18164228
AN - SCOPUS:40849138093
VL - 93
SP - 475
EP - 480
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 4
ER -