CMT 1B: Major myelin protein gene (P0) mutation causes a novel form of axonal

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J Comp Neurol. 2006 Jul 19;498(2):252-265

Major myelin protein gene (P0) mutation causes a novel form of axonal

degeneration.

Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A,

Krajewski KM, Garbern J, Kupsky WJ, Shy ME.

Department of Neurology, Wayne State University School of Medicine,

Detroit, Michigan 48201.

Mutations in the major peripheral nervous system (PNS) myelin

protein, myelin protein zero (MPZ), cause Charcot-Marie-Tooth Disease

type 1B (CMT1B), typically thought of as a demyelinating peripheral

neuropathy. Certain MPZ mutations, however, cause adult onset

neuropathy with minimal demyelination but pronounced axonal

degeneration. Mechanism(s) for this phenotype are unknown.

We performed an autopsy of a 73-year-old woman with a late-onset

neuropathy caused by an H10P MPZ mutation whose nerve conduction

studies suggested severe axonal loss but no demyelination. The

autopsy demonstrated axonal loss and reorganization of the molecular

architecture of the axolemma. Segmental demyelination was negligible.

In addition, we identified focal nerve enlargements containing MPZ

and ubiquitin either in the inner myelin intralaminar and/or

periaxonal space that separates axons from myelinating Schwann cells.

Taken together, these data confirmed that a mutation in MPZ can cause

axonal neuropathy, in the absence of segmental demyelination, thus

uncoupling the two pathological processes. More important, it also

provided potential molecular mechanisms as to how the axonal

degeneration occurred: either by disruption of glial-axon interaction

by protein aggregates or by alterations in the molecular architecture

of internodes and paranodes.

This report represents the first study in which the molecular basis

of axonal degeneration in the late-onset CMT1B has been explored in

human tissue.