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Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype
  1. Ahmed Alfares1,2,
  2. Laura Dempsey Nunez2,
  3. Khalid Al-Thihli1,2,
  4. John Mitchell3,
  5. Serge Melançon1,2,
  6. Natascia Anastasio2,
  7. Kevin C H Ha2,
  8. Jacek Majewski1,2,
  9. David S Rosenblatt1,2,3,
  10. Nancy Braverman2,3,4
  1. 1Department of Medical Genetics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada
  2. 2Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  3. 3Department of Paediatrics, McGill University, Montreal, Quebec, Canada
  4. 4McGill University–Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
  1. Correspondence to Dr Nancy Braverman, McGill University–Montreal Children's Hospital Research Institute, 4060 Ste-Catherine West, PT-406.2, Montreal, QC H3Z 2Z3, Canada; nancy.braverman{at}mcgill.ca

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 results We 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.

  • Clinical geneticscombined malonic and methylmalonic aciduria
  • combined malonic and methylmalonic aciduria
  • endocrinology
  • exome capture
  • fatty acid synthase
  • genetics
  • malonic aciduria
  • malonyl-coenzyme A decarboxylase
  • metabolic disorders
  • methylmalonic aciduria
  • genetic screening/counselling
  • molecular genetics

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Footnotes

  • Funding Funding was received from the Montreal Children's Hospital Research Institute (NB), from the Canadian Institutes for Health Research (DSR and JM) and a Canada Research Chair (JM). DSR and NB are members of the Research Institute of the McGill University Health Centre, which is supported in part by the Fonds de la Recherche en Santé (Quebec).

  • Competing interests None.

  • Ethics approval Ethics approval was obtained from Montreal Children's Hospital and MUHC.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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