Analyzing histopathological features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis

Arch Neurol. 2010 Dec;67(12):1498-505. doi: 10.1001/archneurol.2010.303.


Background: Charcot-Marie-Tooth (CMT) neuropathies are very heterogeneous disorders from both a clinical and genetic point of view. The CMT genes identified so far encode different proteins that are variably involved in regulating Schwann cells and/or axonal functions. However, the function of most of these proteins still remains to be elucidated.

Objective: To characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of CMT neuropathy.

Design: A cohort of 131 unrelated patients were screened for mutations in 12 genes responsible for CMT neuropathies. Demyelinating, axonal, and intermediate forms of CMT neuropathy were initially distinguished as usual on the basis of electrophysiological criteria and clinical evaluation. A sural nerve biopsy was also performed for selected cases. Accordingly, patients underwent first-level analysis of the genes most frequently mutated in each clinical form of CMT neuropathy.

Results: Although our cohort had a particularly high percentage of cases of rare axonal and intermediate CMT neuropathies, we found mutations in 40% of patients. Among identified changes, 7 represented new mutations occurring in the MPZ, GJB1, EGR2, MFN2, NEFL, and HSBP1/HSP27 genes. Histopathological analysis performed in selected cases revealed morphological features, which correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism.

Conclusion: Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Charcot-Marie-Tooth Disease / complications
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology*
  • Child
  • Cohort Studies
  • Connexins / genetics
  • DNA Mutational Analysis
  • Demyelinating Diseases / complications
  • Demyelinating Diseases / genetics*
  • Demyelinating Diseases / pathology*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Female
  • GTP Phosphohydrolases
  • HSP27 Heat-Shock Proteins / genetics
  • Heat-Shock Proteins
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Molecular Chaperones
  • Mutation / genetics
  • Phosphoproteins / genetics
  • Retrospective Studies
  • Sural Nerve / pathology
  • Transcription Factors / genetics
  • Young Adult


  • Connexins
  • Ether-A-Go-Go Potassium Channels
  • HSP27 Heat-Shock Proteins
  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • KCNH6 protein, human
  • MPZL1 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • NSMF protein, human
  • Phosphoproteins
  • Transcription Factors
  • connexin 32
  • GTP Phosphohydrolases
  • MFN2 protein, human