Analyzing Histopathological Features of Rare CMT Neuropathies to Unravel Their P

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Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to

Unravel Their Pathogenesis

http://archneur.ama-assn.org/cgi/content/abstract/67/12/1498?view=short & fp=1498 & \

vol=67 & lookupType

Sara Benedetti, PhD; Stefano Carlo Previtali, MD, PhD; Silvia Coviello, PhD;

Marina Scarlato, MD, PhD; Federica Cerri, MD; Emanuela Di Pierri, BS; Lara

Piantoni, BS; Ivana Spiga, PhD; Raffaella Fazio, MD; Nilo Riva, MD; Grazia

Natali Sora, MD; Patrizia Dacci, MD; Chiara Malaguti, MD; betta

Munerati, MD; Luigi Edoardo Grimaldi, MD; Giovanna Marrosu, MD;

Maurizio De Pellegrin, MD; Maurizio Ferrari, MD; Giancarlo Comi, MD; Angelo

Quattrini, MD; Alessandra Bolino, PhD

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.