title: Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.
abstract: OBJECTIVE
  To identify the underlying genetic cause of a congenital neuropathy in a 5-year-old boy as part of a cohort of 32 patients from 23 families with genetically unresolved neuropathies.
  
  
  METHODS
  We used autozygosity mapping coupled with next-generation sequencing to investigate a consanguineous family from Lebanon with 1 affected and 2 healthy children. Variants were investigated for segregation in the family by Sanger sequencing. A splice site mutation was further evaluated on the messenger RNA level by quantitative reverse transcription PCR. Subsequently, a larger cohort was specifically screened for receptor expression-enhancing protein 1 (REEP1) gene mutations.
  
  
  RESULTS
  We detected a homozygous splice donor mutation in REEP1 (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912) that cosegregated with the phenotype in the family, leading to complete skipping of exon 4 and a premature stop codon. The phenotype of the patient is similar to spinal muscular atrophy with respiratory distress type 1 (SMARD1) with additional distal arthrogryposis and involvement of the upper motor neuron manifested by pronounced hyperreflexia.
  
  
  CONCLUSIONS
  To date, only dominant REEP1 mutations have been reported to be associated with a slowly progressive hereditary spastic paraplegia. The findings from our patient expand the phenotypical spectrum and the mode of inheritance of REEP1-associated disorders. Recessive mutations in REEP1 should be considered in the molecular genetic workup of patients with a neuromuscular disorder resembling SMARD1, especially if additional signs of upper motor neuron involvement and distal arthrogryposis are present.
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schottmann
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Seifert
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Morales-Gonzalez
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Gill
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: von Au
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children's Hospital Berlin (A.v.M.), Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke