Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type.
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.
Nogueira
Célia
C
Genetics Medical Center, INSA, Oporto, Portugal.
Aiello
Chiara
C
Cerone
Roberto
R
Martins
Esmeralda
E
Caruso
Ubaldo
U
Moroni
Isabella
I
Rizzo
Cristiano
C
Diogo
Luísa
L
Leão
Elisa
E
Kok
Fernando
F
Deodato
Federica
F
Schiaffino
Maria Cristina
MC
Boenzi
Sara
S
Danhaive
Olivier
O
Barbot
Clara
C
Sequeira
Sílvia
S
Locatelli
Mattia
M
Santorelli
Filippo M
FM
Uziel
Graziella
G
Vilarinho
Laura
L
Dionisi-Vici
Carlo
C
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
D002352:Carrier Proteins; D008764:Methylmalonic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases; D042965:Methylenetetrahydrofolate Reductase (NADPH2)