title: eIF2B-related multisystem disorder in two sisters with atypical presentations.
abstract: BACKGROUND
  Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy.
  
  
  METHODS
  The index case had a history of hepatomegaly and intermittent vomiting after upper respiratory infection at 11 months of age. Her older brothers had died at an early age, one with similar symptoms and the other because of septic shock. Her older sister had similar presenting symptoms; she later suffered from both cataracts and primary amenorrhea, but showed neurological improvement. Her follow-up MRIs (at 21 years of age) revealed progressive diffuse brain atrophy with leukoencephalopathy, without cystic rarefaction. Whole-exome sequencing of the index case revealed the presence of the compound heterozygous variants, Val85Glu and Met226Lys in EIF2B2. The affected sister had the same compound heterozygous variants, and their unaffected parents were heterozygous carriers of each variant.
  
  
  CONCLUSIONS
  This study expanded the clinical and genetic spectrum of VWM with EIF2B2 variants. It would be better to consider VWM as an eIF2B-related multisystem disorder, not just as a neurological disorder, on the basis that this is a family of housekeeping genes that affect multiple organs.
authors.affiliation: Department of Pediatrics, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sangmoon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Byung Chan
authors.initials: BC
authors.lastname: Lim
authors.affiliation: Department of Pediatrics, SMG-SNU Boramae Medical Center, Seoul, South Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Ki Joong
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, South Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Cheon
authors.affiliation: Department of Radiology, Seoul National University College of Medicine, South Korea.
authors.forename: In-One
authors.initials: IO
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea. Electronic address: chaeped1@snu.ac.kr.
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Chae
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D010375:Pedigree; D035781:Siblings
chemical_list: D020717:Eukaryotic Initiation Factor-2B
keywords: Amenorrhea; Cataract; EIF2B2; Leukoencephalopathy; Vanishing white matter disease; Whole-exome sequencing