Periaxin Mutations in CMT

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1: Ann Neurol 2002 Jun;51(6):709-15

Periaxin mutations cause a broad spectrum of demyelinating neuropathies.

Takashima H, Boerkoel CF, De Jonghe P, Ceuterick C,

JJ, Voit T, Schroder JM, A, Brophy PJ, Timmerman V,

Lupski JR.

Departments of Molecular and Human Genetics

ABSTRACT:

Previous studies have demonstrated that apparent loss-of-function

mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas

neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this

report, we extend the associated phenotypes with the identification of

two additional families with novel periaxin gene mutations (C715X and

R82fsX96) and provide detailed neuropathology.

Each patient had marked sensory involvement; two siblings with a

homozygous C715X

mutation had much worse sensory impairment than motor impairment.

Despite early disease onset, these siblings with the C715X mutation had

relatively slow disease progression and adult motor impairment typical

of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a

patient with the homozygous R82fsX96 mutation had a disease course

consistent with Dejerine-Sottas neuropathy. The

neuropathology of patients in both families was remarkable for

demyelination, onion bulb and occasional tomacula formation with focal

myelin thickening, abnormalities of the paranodal myelin loops, and

focal absence of paranodal septate-like junctions between the terminal

loops and axon.

Our study indicates a prominent sensory neuropathy resulting from

periaxin gene mutations and suggests a role for the carboxyl terminal

domain of the periaxin protein.