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

Abstract

Background Combined 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. Conclusion These 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.

The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency

“…Although the relative contributions of each of these potential sources of mitochondrial malonate remains to be determined, our model describes the roles for ACSF3 and MLYCD in regulating mitochondrial malonate concentrations. Consistent with our model, mutations in human ACSF3 or MLYCD result in toxic accumulation of malonate and systemic metabolic acidosis (Alfares et al, 2011; Sloan et al, 2011). …”

“…The severe malonic and methylmalonic aciduria characteristic of MLYCD deficiency is also accompanied by developmental delay, seizure disorders, hypoglycemia, and cardiomyopathy. Recently, patients that presented with combined malonic and methylmalonic aciduria without mutations in MLYCD were found to have nonsynonymous mutations in the ACSF3 gene (Alfares et al, 2011; Sloan et al, 2011). The similarities in the phenotypes of MLYCD and ACSF3 deficiencies suggest that they exist in the same biochemical pathway.…”

Late onset of symptoms in an atypical patient with the cblJ inborn error of vitamin B12 metabolism: Diagnosis and novel mutation revealed by exome sequencing

“…We therefore turned to exome sequencing to identify the gene affected in this patient. This procedure has proven to be an effective tool for disease gene identification in rare autosomal recessive disorders with limited number of affected individuals [12]. In this case, gene identification by exome sequencing was successful with a single patient.…”

“…(3) The annotation of variants was performed by ANNOVAR [11] for the type of mutations, presence in dbSNP132, minor allele frequency in the 1000 Genomes project, EVS (Exome variant server), SIFT, Polyphen-2 and PHASTCONS scores. (4) Novel variants were defined as those having an allele frequency of less than 0.05 in the 1000 Genomes Project and predicted to be non-synonymous substitutions caused by missense and nonsense single-nucleotide polymorphisms (SNP), splice-site SNPs, and frame shift changes due to indels [12]. Candidate genes containing either a homozygous or two potentially compound heterozygous variants were selected for further study and were manually examined using IGV [13].…”

Methylmalonic and propionic acidemias: clinical management update

“…Defects in other genes within the propionate catabolism pathway or mitochondrial disorders may also result in excretion of methylmalonic acid in the urine [89, 90]. These disorders are rarer than classical isolated MMA, often manifest other biochemically diagnostic markers in urine or plasma to suggest the diagnosis, and will not be addressed further in this review.…”