Skin biopsies in myelin-related neuropathies: bringing molecular pathology to the bedside

Abstract

Skin biopsy is a minimally invasive procedure and has been used in the evaluation of non-myelinated, but not myelinated nerve fibres, in sensory neuropathies. We therefore evaluated myelinated nerves in skin biopsies from normal controls and patients with Charcot-Marie-Tooth (CMT) disease caused by mutations in myelin proteins. Light microscopy, electron microscopy and immunohistochemistry routinely identified myelinated dermal nerves in glabrous skin that appeared similar to myelinated fibres in sural and sciatic nerve. Myelin abnormalities were observed in all patients with CMT. Moreover, skin biopsies detected potential pathogenic abnormalities in the axolemmal molecular architecture previously undetected in human neuropathies. Finally, myelin gene expression at both mRNA and protein levels was evaluated by real-time PCR and immunoelectron microscopy. Peripheral myelin protein 22 (PMP22) was increased in CMT1A (PMP22 duplication) and decreased in patients with hereditary neuropathy with liability to pressure palsies (PMP22 deletion). Taken together, our data suggest that skin biopsy may in certain circumstances replace the more invasive sural nerve biopsy in the morphological and molecular evaluation of inherited and other demyelinating neuropathies.

Caveats in the Established Understanding of CMT1A

“…The latter group would be incompatible with the increased dosage of PMP22 being the cause of the disease. This finding was replicated in two separated publications by different experimenters in our lab 3, 4. The fluctuation of PMP22 was not seen for another compact myelin protein–myelin basic protein (MBP).…”

“…While the ascorbic acid trial failed to improve the disease of CMT1A, materials derived from the trials have been instrumental to several important neurobiological issues. Along with our published studies,3, 4 these have raised several critical concerns in the established understanding of CMT1A.…”

“…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.…”

“…Skin biopsy has its limitations, including a difference of gene expression profile from that in human sural nerves 4. However, with proper controls, important information has still been obtained via this approach.…”