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

doi:10.1016/j.ymgme.2007.11.005

Molecular Genetics and Metabolism

Volume 93, Issue 4, April 2008, Pages 475-480

https://doi.org/10.1016/j.ymgme.2007.11.005 Get rights and content

Abstract

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.

Section snippets

Patients and methods

Over the past years our centers have been collecting clinical information and biological materials (cultured skin fibroblasts, blood, serum, urine, post-mortem tissue, DNA) from patients suspected of having an inborn error of metabolism. Patients in this study were selected after sharing and matching our databases. The diagnosis of cblC defect was based on the identification of urinary and circulating metabolites and, whenever possible, confirmed with fibroblast studies [6]. Patients were

Results

A total of 28 boys and 13 girls were identified (M/F ratio 2:1) in 24 Italian and 17 Portuguese kindred, two of which were of Brazilian origin. No multiple affected cases were found in our families. Median age at onset was 3 months (range 6 days–25 years), age at diagnosis ranged between 0 and 25 years.

As shown in Table 1, 36 patients (25M, 11F) presented the landmark description of cblC defect within the first year of life (EO) and five (3M, 2F) showed the disease later in life (LO).

Discussion

The recent identification of the gene mutated in cblC defect [4] allowed the recognition of apparent phenotype–genotype correlations as well as the association of mutations with specific ethnicities as outlined in a large French-Canadian study [10]. This new information proves immediately useful for carrier-status detection in families where mutations are known, and in setting up initial screening programs in molecular diagnostic laboratories.

Our study in 41 southern European individuals with

Acknowledgments

This work was supported in parts from grants of the Italian Ministry of Health, the Istituto Superiore di Sanità (to FMS and CDV), and a research scholarship to CN. CA is a fellow of the Bambino Gesù-Roma Tre University PhD program.

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¹: These authors contributed equally and share the first authorship.

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

Abstract

Section snippets

Patients and methods

Results

Discussion

Acknowledgments

Clin. Chim. Acta

Am. J. Clin. Nutr.

Genet. Med.

Biochem. Biophys. Res. Commun.

Mol. Genet. Metab.

Methylmalonic and propionic aciduria

Am. J. Med. Genet. C.

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