title: RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Child Development Center, Central District, Maccabi Health Services, Tel Aviv, Israel.
authors.forename: Daniella
authors.initials: D
authors.lastname: Nishri
authors.affiliation: Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Hadassa
authors.initials: H
authors.lastname: Goldberg-Stern
authors.affiliation: Pediatric Neurology Unit, Soroka Medical Center, Beer-Sheba, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Noyman
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Lubov
authors.initials: L
authors.lastname: Blumkin
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: dorlev@post.tau.ac.il.
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
mesh_terms: D017668:Age of Onset; D001126:Arginine-tRNA Ligase / Q000235:genetics*; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008297:Male; D035781:Siblings
chemical_list: D001126:Arginine-tRNA Ligase; C000604250:RARS2 protein, human
keywords: Epileptic encephalopathy; Mitochondrial; Pontocerebellar hypoplasia; RARS2