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

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.

Charcot-Marie-Tooth disease

“…Beginning with studies of glabrous 3 and hairy skin, 4 these biopsies have already provided pathogenic information in sensory nerves from patients with CMT1A, such as reduced Meissner corpuscles (MC) density, shortened internodal length, and abnormal paranodaljuxtaparanodal architecture. 5,6 In the present study, we extend these observations in a larger series of patients. We performed skin biopsies on 31 patients with 3 common CMT genotypes (i.e., PMP22 [CMT1A], MPZ [late-onset CMT1B], and GJB1 [CMTX1] genes) and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes.…”

Caveats in the Established Understanding of CMT1A

“…These observations are in line with the findings in humans with CMT1A. Dysmyelination was found in children with CMT1A,15, 16 but conduction velocities were stable for decades2 and segmental demyelination was minimal in the dermal myelinated nerve fibers of adult patients with CMT1A 19. However, there were undesirable features in the mouse model.…”

“…By human skin biopsies, mild hemiparanodal asymmetry was found in myelinated nerve fibers of CMT1A patients, implicating insidious de‐/remyelination 19. However, the de‐/remyelination process is unlikely primary or prevailing activity.…”

“…This leaves a group of myelinated nerve fibers that are relatively “homogenous” in their sizes with small diameters. Based on the observations by Erlanger and Gasser,17, 18 nerve fibers with similar sizes would produce similar conduction velocities and explain the uniform slowing.We have utilized human skin biopsies to examine segmental demyelination in patients with CMT1A 4, 19. Skin biopsy has its limitations, including a difference of gene expression profile from that in human sural nerves 4.…”

“…We have utilized human skin biopsies to examine segmental demyelination in patients with CMT1A 4, 19. Skin biopsy has its limitations, including a difference of gene expression profile from that in human sural nerves 4.…”