Spine deformities in CMT 4C caused by SH3TC2 gene mutations

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Neurology. 2006 Aug 22;67(4):602-6.

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene

mutations.

Azzedine H, Ravise N, Verny C, Gabreels-Festen A, Lammens M, Grid D,

Vallat JM, Durosier G, Senderek J, Nouioua S, Hamadouche T, Bouhouche

A, Guilbot A, Stendel C, Ruberg M, Brice A, Birouk N, Dubourg O,

Tazir M, LeGuern E.

INSERM U679 (ex U289), Neurology and Experimental Therapeutics, La

Pitie-Salpetriere Hospital, Paris, France.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous

group of inherited peripheral motor and sensory neuropathies with

several modes of inheritance: autosomal dominant, X-linked, and

autosomal recessive (AR) CMT. A locus responsible for the

demyelinating form of ARCMT was assigned to the 5q23-q33 region

(CMT4C) by homozygosity mapping. Recently, 11 mutations were

identified in the SH3TC2 (KIAA1985) gene in 12 families with

demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German

origin.

OBJECTIVE: To identify mutations in the SH3TC2 gene.

METHODS: The authors searched for SH3TC2 gene mutations in 10

consanguineous CMT families putatively linked to the CMT4C locus on

the basis of haplotype segregation and linkage analysis.

RESULTS: Ten families had mutations, eight of which were new and one,

R954X, recurrent. Six of the 10 mutations were in exon 11. Onset

occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot

deformities were found in almost all patients and were often

inaugural. The median motor nerve conduction velocity values (</=34

m/s) were not correlated with disease duration. The functional

disability score was </=3, indicating that the patients could walk

without help. Unexpectedly, typical giant axons were observed on

biopsies from a large Algerian family.

CONCLUSIONS: Charcot-Marie-Tooth type 4C (CMT4C) is less severe than

other autosomal recessive (AR) CMT. Intrafamilial variability is

important, making phenotype-genotype correlations difficult, but

spine deformities are clearly a hallmark of CMT4C. In the presence of

scoliosis, a neurologic examination is recommended. Giant axons on

biopsies are also suggestive of CMT4C. For genetic analysis, the

R954X mutation should be looked for before systematic sequencing of

exon 11.