title: Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E.
abstract: OBJECTIVE
  To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E).
  
  
  METHODS
  A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis.
  
  
  RESULTS
  The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and α-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of α-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E.
  
  
  CONCLUSIONS
  Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E.
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL. chiara.pisciotta@gmail.com.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pisciotta
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Bai
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Brennan
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Xingyao
authors.initials: X
authors.lastname: Wu
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Grider
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Shawna
authors.initials: S
authors.lastname: Feely
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Suola
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Steven
authors.initials: S
authors.lastname: Moore
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Carly
authors.initials: C
authors.lastname: Siskind
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: From the Departments of Neurology (C.P., Y.B., K.M.B., X.W., T.G., S.F., S.W., M.E.S.) and Pathology (S.M.), University of Iowa Hospitals and Clinics, Iowa City; Departments of Neurology (C.S.), Stanford University, CA; Dr. John T. Macdonald Foundation Department of Human Genetics (M.G., S.Z.), University of Miami Miller School of Medicine, FL.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D012867:Skin / Q000378:metabolism / Q000473:pathology