Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A

Mario da Cunha Saporta, Istvan Katona, Richard A. Lewis, Stacey Masse, Michael E. Shy, Jun Li

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.

Original languageEnglish (US)
Pages (from-to)3263-3273
Number of pages11
JournalBrain
Volume132
Issue number12
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Fingerprint

Charcot-Marie-Tooth Disease
Myelinated Nerve Fibers
Skin
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Demyelinating Diseases
Biopsy
Mitochondria
Chromosome Duplication
Myelin Proteins
Mechanoreceptors
Electron Microscopy
Immunohistochemistry

Keywords

  • Charcot-Marie-Tooth disease
  • CMT1A
  • Internodal length
  • Schwann cell
  • Skin biopsy

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. / da Cunha Saporta, Mario; Katona, Istvan; Lewis, Richard A.; Masse, Stacey; Shy, Michael E.; Li, Jun.

In: Brain, Vol. 132, No. 12, 01.12.2009, p. 3263-3273.

Research output: Contribution to journalArticle

da Cunha Saporta, Mario ; Katona, Istvan ; Lewis, Richard A. ; Masse, Stacey ; Shy, Michael E. ; Li, Jun. / Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. In: Brain. 2009 ; Vol. 132, No. 12. pp. 3263-3273.
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abstract = "Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.",
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