title: Analyzing histopathological features of rare charcot-marie-tooth neuropathies to unravel their pathogenesis.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.
authors.affiliation: San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.forename: Stefano Carlo
authors.initials: SC
authors.lastname: Previtali
authors.forename: Silvia
authors.initials: S
authors.lastname: Coviello
authors.forename: Marina
authors.initials: M
authors.lastname: Scarlato
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Emanuela
authors.initials: E
authors.lastname: Di Pierri
authors.forename: Lara
authors.initials: L
authors.lastname: Piantoni
authors.forename: Ivana
authors.initials: I
authors.lastname: Spiga
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fazio
authors.forename: Nilo
authors.initials: N
authors.lastname: Riva
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Natali Sora
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dacci
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Malaguti
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Munerati
authors.forename: Luigi Maria Edoardo
authors.initials: LM
authors.lastname: Grimaldi
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Maurizio
authors.initials: M
authors.lastname: De Pellegrin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ferrari
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D002648:Child; D015331:Cohort Studies; D017630:Connexins / Q000235:genetics; D004252:DNA Mutational Analysis; D003711:Demyelinating Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics; D006360:Heat-Shock Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D012189:Retrospective Studies; D013497:Sural Nerve / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D051638:Ether-A-Go-Go Potassium Channels; D020558:GTP Phosphohydrolases; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D010750:Phosphoproteins; D014157:Transcription Factors; D000097002:Gap Junction beta-1 Protein; C057725:HSPB1 protein, human; C092509:KCNH6 protein, human; C115628:MPZL1 protein, human; C411985:NSMF protein, human; C470018:MFN2 protein, human