Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease

J Child Neurol. 2016 Aug;31(9):1127-37. doi: 10.1177/0883073816643402. Epub 2016 Apr 19.


Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins.

Keywords: FARS2; mitochondrial tRNA synthetase; progressive myoclonus epilepsy.

Publication types

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

MeSH terms

  • Adolescent
  • Drug Resistant Epilepsy / diagnostic imaging
  • Drug Resistant Epilepsy / genetics*
  • Drug Resistant Epilepsy / pathology
  • Drug Resistant Epilepsy / physiopathology
  • Epilepsies, Myoclonic / diagnostic imaging
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / pathology
  • Epilepsies, Myoclonic / physiopathology
  • Fatal Outcome
  • Female
  • Heterozygote*
  • Humans
  • Mitochondrial Proteins / genetics*
  • Mutation*
  • Phenotype
  • Phenylalanine-tRNA Ligase / genetics*


  • Mitochondrial Proteins
  • FARS2 protein, human
  • Phenylalanine-tRNA Ligase