Combined Malonic and Methylmalonic Aciduria (CMAMMA): Exome Sequencing Reveals Mutations in the ACSF3 gene in Patients with a Non-classical Phenotype

Exome sequencing is a novel tool to find new candidate disease genes. In this report we studied two probands with the biochemical phenotype of combined elevated malonic acid (MA) and methylmalonic acid (MMA). Unlike most patients with this biochemical abnormality, our patients were asymptomatic, did not have identifiable mutations in MYLCD and had a different biochemical profile, with MMA being higher than MA. In both, we identified novel missense alleles in conserved residues in ACSF3, a predicted mitochondrial protein and member of the family of Acyl-coA synthetases (ACSs) with unknown substrate and function. We suggest that this is a nonessential ACS involved in MA and MMA metabolism. Although functional assays are needed to prove that these defects cause the biochemical disturbance in these patients, this study is another example of the power of this new sequencing technique. By bringing a candidate gene to the forefront, new biochemical pathways can be investigated. (By Nancy Braverman, MS, MD, http://jmg.bmj.com/cgi/content/abstract/jmedgenet-2011-100230v1?papetoc)