RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia

Eur J Paediatr Neurol. 2016 May;20(3):412-7. doi: 10.1016/j.ejpn.2016.02.012. Epub 2016 Mar 2.


Introduction: Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly.

Methods: We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy.

Results: Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2. This gene has been previously described as the cause of pontocerebellar hypoplasia type 6.

Conclusion: We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia.

Keywords: Epileptic encephalopathy; Mitochondrial; Pontocerebellar hypoplasia; RARS2.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Arginine-tRNA Ligase / genetics*
  • Child, Preschool
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Epilepsy / physiopathology
  • Fatal Outcome
  • Female
  • Humans
  • Male
  • Siblings


  • Arginine-tRNA Ligase
  • RARS2 protein, human