CMT 1A: Shortened internodal length of dermal myelinated nerve fibres

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Shortened internodal length of dermal myelinated nerve fibres in

Charcot–Marie-Tooth disease type 1A

http://brain.oxfordjournals.org/cgi/content/abstract/awp274

A. Saporta1, Istvan Katona1, A. 1, Stacey Masse1, E.

Shy1,2 and Jun Li3

1 Department of Neurology, Wayne State University, Detroit 48201, USA 2

Department of Molecular Medicine and Genetics, Wayne State University, Detroit

48201, USA 3 Department of Neurology, Vanderbilt University, Nashville 37232,

USA

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.

Key Words: CMT1A; internodal length; Schwann cell; skin biopsy;

Charcot–Marie-Tooth disease

Abbreviations: Caspr, contactin-associated protein; CIDP, chronic inflammatory

demyelinating polyradiculoneuropathy; CMT1A, Charcot–Marie-Tooth disease type

1A; MBP, myelin basic protein; PGP, protein gene product; PMP22, peripheral

myelin protein 22 gene