title: Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes.
abstract: BACKGROUND
  Most mutations in the myelin protein zero gene (MPZ) typically cause a severe demyelinating/dysmyelinating neuropathy that begins in infancy or an adult-onset axonal neuropathy. Axonal degeneration in the late-onset H10P mutation may be caused by the disruption of axoglial interaction.
  
  
  OBJECTIVE
  To evaluate sural nerve biopsy samples from a patient with early-onset Charcot-Marie-Tooth disease type 1B caused by an arg69-to-cys (R69C) mutation.
  
  
  METHODS
  Biopsies of sural nerves were performed 20 years apart in a patient with an R69C mutation (early onset). In addition, peripheral nerves were obtained from autopsy material from a patient with a T95M mutation (late onset). These nerves were analyzed using light microscopy of semithin sections, teased nerve fiber immunohistochemical analysis, electron microscopy, and immunologic electron microscopy.
  
  
  METHODS
  Pathological changes in sural nerve.
  
  
  RESULTS
  Both R69C biopsy samples showed prominent demyelination and onion bulb formation, unlike the late-onset T95M mutation, which showed primarily axonal degeneration with no onion bulbs. The sural biopsy sample obtained 20 years earlier from the R69C patient showed minimal difference from the present sample, consistent with the lack of clinical progression during the 2 decades. Teased fiber immunohistochemical analysis of R69C revealed voltage-gated sodium channel subtype 1.8 expressions at the nodes of Ranvier around the areas of segmental demyelination. Internodal length in all R69C nerve fibers was invariably short (>94% of all internodes are <150 mum).
  
  
  CONCLUSIONS
  Morphologic abnormalities in this early-onset R69C neuropathy were severe in childhood but progressed very slowly after adolescence. The switch to voltage-gated sodium channel subtype 1.8 expression at the nodes may provide clues into the pathogenesis of this case of early-onset neuropathy, and the short internodes may contribute to the extremely slowed conduction velocities in this case (<10 m/s).
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Bai
authors.forename: Emilia
authors.initials: E
authors.lastname: Ianokova
authors.forename: Qin
authors.initials: Q
authors.lastname: Pu
authors.forename: Khaled
authors.initials: K
authors.lastname: Ghandour
authors.forename: Rock
authors.initials: R
authors.lastname: Levinson
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-de Groote
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D018993:Myelin P0 Protein / Q000235:genetics*; D009186:Myelin Sheath / Q000502:physiology*; D009412:Nerve Fibers / Q000473:pathology; D013497:Sural Nerve / Q000473:pathology; D014459:Ulnar Nerve / Q000473:pathology
chemical_list: D007473:Ion Channels; D018993:Myelin P0 Protein