CMT 4C: Phenotype due to SH3TC2 mutations + possible predisposition to inflamma

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Neuromuscul Disord. 2009 Mar 7.

The phenotype of Charcot-Marie-Tooth disease type 4C due to SH3TC2 mutations and

possible predisposition to an inflammatory neuropathy.

Houlden H, M, Ginsberg L, Jungbluth H, Robb SA, Blake J, S, King

RH, Reilly MM.

Department of Molecular Neurosciences and The MRC Centre for Neuromuscular

diseases, The National Hospital for Neurology and Neurosurgery, The Institute of

Neurology, Queen Square, London, WC1N 3BG, England, UK.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited

peripheral motor and sensory neuropathies. The locus responsible for CMT4C was

previously assigned to the chromosome 5q23 region by homozygosity mapping and

mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly

in families around the Mediterranean basin but also frequently in European

Gypsies. No English families have been reported to date.

To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2

mutations we screened 23 English autosomal recessive (AR) demyelinating CMT

families. Five families with AR demyelinating CMT and SH3TC2 mutations were

identified, four families were homozygous for the R954X mutation and the fifth

family was compound heterozygous for the R954X and E657K mutations.

There was significant clinical variation between these families with some cases

presenting with a severe childhood onset neuropathy with respiratory and cranial

nerve involvement, compared to other families with mild scoliosis and foot

deformity.

Characteristic sural nerve neuropathology was seen in three families with

frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming

basal lamina onion bulbs and abnormally long and attenuated Schwann cell

processes. One patient homozygous for the R954X mutation had a 20-year history

of an inflammatory neuropathy that was superimposed onto the hereditary form,

indicating that structural alterations to the SH3TC2 gene could possibly

predispose to peripheral nerve inflammation.