Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E

Chiara Pisciotta, Yunhong Bai, Kathryn M. Brennan, Xingyao Wu, Tiffany Grider, Shawna Feely, Suola Wang, Steven Moore, Carly Siskind, Michael Gonzalez, Stephan L Zuchner, Michael E. Shy

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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.

Original languageEnglish (US)
Pages (from-to)228-234
Number of pages7
JournalNeurology
Volume85
Issue number3
DOIs
StatePublished - Jul 21 2015

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Intermediate Filaments
Nerve Fibers
Skin
Biopsy
Electron Microscopy
Tubulin
Fluorescence Microscopy
Axons
Western Blotting
Sodium Channels
Neural Conduction
Indirect Fluorescent Antibody Technique
Myelin Sheath
Cytoskeleton
Action Potentials
Fluorescent Antibody Technique
Type 2E Charcot-Marie-Tooth disease
Mutation
Proteins

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Pisciotta, C., Bai, Y., Brennan, K. M., Wu, X., Grider, T., Feely, S., ... Shy, M. E. (2015). Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. Neurology, 85(3), 228-234. https://doi.org/10.1212/WNL.0000000000001773

Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. / Pisciotta, Chiara; Bai, Yunhong; Brennan, Kathryn M.; Wu, Xingyao; Grider, Tiffany; Feely, Shawna; Wang, Suola; Moore, Steven; Siskind, Carly; Gonzalez, Michael; Zuchner, Stephan L; Shy, Michael E.

In: Neurology, Vol. 85, No. 3, 21.07.2015, p. 228-234.

Research output: Contribution to journalArticle

Pisciotta, C, Bai, Y, Brennan, KM, Wu, X, Grider, T, Feely, S, Wang, S, Moore, S, Siskind, C, Gonzalez, M, Zuchner, SL & Shy, ME 2015, 'Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E', Neurology, vol. 85, no. 3, pp. 228-234. https://doi.org/10.1212/WNL.0000000000001773
Pisciotta C, Bai Y, Brennan KM, Wu X, Grider T, Feely S et al. Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. Neurology. 2015 Jul 21;85(3):228-234. https://doi.org/10.1212/WNL.0000000000001773
Pisciotta, Chiara ; Bai, Yunhong ; Brennan, Kathryn M. ; Wu, Xingyao ; Grider, Tiffany ; Feely, Shawna ; Wang, Suola ; Moore, Steven ; Siskind, Carly ; Gonzalez, Michael ; Zuchner, Stephan L ; Shy, Michael E. / Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. In: Neurology. 2015 ; Vol. 85, No. 3. pp. 228-234.
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AU - Grider, Tiffany

AU - Feely, Shawna

AU - Wang, Suola

AU - Moore, Steven

AU - Siskind, Carly

AU - Gonzalez, Michael

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