Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type

Célia Nogueira, Chiara Aiello, Roberto Cerone, Esmeralda Martins, Ubaldo Caruso, Isabella Moroni, Cristiano Rizzo, Luísa Diogo, Elisa Leão, Fernando Kok, Federica Deodato, Maria Cristina Schiaffino, Sara Boenzi, Olivier Danhaive, Clara Barbot, Sílvia Sequeira, Mattia Locatelli, Filippo M. Santorelli, Graziella Uziel, Laura VilarinhoCarlo Dionisi-Vici

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)475-480
Number of pages6
JournalMolecular Genetics and Metabolism
Issue number4
Publication statusPublished - Apr 2008


  • cblC
  • Methylmalonic aciduria and homocystinuria
  • Vitamin B

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism


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