Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype

• Published in: Journal of medical genetics Vol. 48; no. 9; pp. 602 - 605
• Main Authors: Alfares, Ahmed, Nunez, Laura Dempsey, Al-Thihli, Khalid, Mitchell, John, Melançon, Serge, Anastasio, Natascia, Ha, Kevin C H, Majewski, Jacek, Rosenblatt, David S, Braverman, Nancy
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.09.2011; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Alleles; Amino Acid Metabolism, Inborn Errors - genetics; Asymptomatic; Base Sequence; Biological and medical sciences; Carboxy-Lyases - deficiency; Carboxy-Lyases - genetics; Chromatography; Clinical geneticscombined malonic and methylmalonic aciduria; Coenzyme A Ligases - genetics; combined malonic and methylmalonic aciduria; Creatinine; endocrinology; Enzymes; Exome; exome capture; Families & family life; fatty acid synthase; Fibroblasts; Genetic Association Studies; genetic screening/counselling; genetics; Genomes; Humans; Infant; Malonates - urine; malonic aciduria; Malonyl Coenzyme A; malonyl-coenzyme A decarboxylase; Medical sciences; Metabolic diseases; metabolic disorders; Metabolism, Inborn Errors - genetics; Methylmalonic Acid - urine; methylmalonic aciduria; molecular genetics; Molecular Sequence Data; Mutation; Parents & parenting; Patients; Pedigree; Phenotype; Plasma; Sequence Analysis, DNA; Spectrum analysis; Urine; Canada; United States > US; Quebec Canada; Human; Phenotype; Gene; Nucleotide sequence; Aciduria; Genetics; Patient; Mutation; Genetic determinism; Sequencing
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2011-100230

BackgroundCombined Malonic and Methylmalonic Aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterised by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). Nearly all reported cases are caused by malonyl-CoA decarboxylase (MCD) deficiency. Most patients have metabolic acidosis, developmental delay, seizures and cardiomyopathy. CMAMMA was also described in symptomatic patients with normal MCD activity, suggesting heterogeneity in this disorder.Methods and resultsWe identified two probands with a non-classical CMAMMA variant through the Quebec newborn urine screening program. While they share the biochemical phenotype of elevated MA and MMA, the MMA excretion was higher than MA, the clinical courses were benign, MYLCD gene sequencing was normal and MCD activity, measured in one proband, was normal. Using exome sequencing in the single consanguineous proband, we identified a homozygous missense allele in the ACSF3 gene, encoding an Acyl-CoA Synthetase (ACS) with unknown substrate and function. The second proband was homozygous for a different ACSF3 missense allele. Both substitutions were in conserved residues and were identified in less than 0.5% of their respective ethnic control populations.ConclusionThese results suggest that ACSF3 is a candidate gene for non-classical CMAMMA observed in our patients and document the value of exome sequencing of a limited number of patients for the identification of novel disease genes.