title: Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type.
abstract: Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B(12). 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.
authors.affiliation: Genetics Medical Center, INSA, Oporto, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Nogueira
authors.forename: Chiara
authors.initials: C
authors.lastname: Aiello
authors.forename: Roberto
authors.initials: R
authors.lastname: Cerone
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Martins
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Caruso
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rizzo
authors.forename: Luísa
authors.initials: L
authors.lastname: Diogo
authors.forename: Elisa
authors.initials: E
authors.lastname: Leão
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.forename: Federica
authors.initials: F
authors.lastname: Deodato
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Schiaffino
authors.forename: Sara
authors.initials: S
authors.lastname: Boenzi
authors.forename: Olivier
authors.initials: O
authors.lastname: Danhaive
authors.forename: Clara
authors.initials: C
authors.lastname: Barbot
authors.forename: Sílvia
authors.initials: S
authors.lastname: Sequeira
authors.forename: Mattia
authors.initials: M
authors.lastname: Locatelli
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008764:Methylmalonic Acid / Q000652:urine; D010088:Oxidoreductases; D010641:Phenotype; D011174:Portugal
chemical_list: D002352:Carrier Proteins; D008764:Methylmalonic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases; D042965:Methylenetetrahydrofolate Reductase (NADPH2)