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

From INSERM U679 (ex U289) (H.A., N.R., C.V., G.D., A.G., M.R., A.B., O.D., E.L.G.), Neurology and Experimental Therapeutics, La Pitié-Salpêtrière Hospital (H.A., N.R., C.V., G.D., A.G., M.R., A.B., O.D., E.L.G.), Pierre and Marie Curie University (P6) (H.A., N.R., C.V., G.D., A.G., M.R., A.B., O.D., E.L.G.), Faculty of Medicine, Laboratory of Neurogenetics (A.B., E.L.G.), Department of Genetics, Cytogenetics, and Embryology, La Pitié-Salpêtrière Hospital, AP-HP, Centre de référence sur les pathologies neuromusculaires Paris-Est (O.D.), Institute of Myology, and Laboratory of Neuropathology "Escourolle" (O.D.), La Pitié-Salpêtrière Hospital, Paris, AFM-Généthon Evry (D.G.), and Department and Laboratory of Neurology, CHU Dupuytren, Limoges, France; Neuromuscular Center (A.G.-F., M.L.), Departments of Neurology and Pathology, Radboud University, Nijmegen Medical Center, the Netherlands; Department of Human Genetics (J.M.V., J.S., C.S.), Aachen University of Technology, Germany; Department of Neurology (S.N., M.T.), CHU Mustapha, and Laboratory of Molecular Biology (T.H.), Institut Pasteur d'Algérie, Algiers, Algeria; and Laboratory of Neurogenetics (A.B.) and Department of Neurophysiology (N.B.), Hospital of Specialties, Rabat, Morocco.

Address correspondence and reprint requests to Dr. H. Azzedine, INSERM U679 (ex U289), Hôpital de la Pitié-Salpêtrière, 47, Bd de l'Hôpital, 75651 Paris Cedex 13, France; e-mail: azzedine{at}ccr.jussieu.fr

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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the August 22 issue to find the title link for this article.

Supported by the Association Française contre les Myopathies, the Assistance Publique des Hôpitaux de Paris, the Institut National de la Santé et de la Recherche Médicale, and the GIS-Maladies rares. H.A., N.R., C.V., T.H., A.B.., O.D., M.T., and E.L. are members of the "French GIS-Maladies rares research network on autosomal recessive forms of CMT" supported by the GIS-Maladies rares.

Disclosure: The authors report no conflicts of interest.

Received October 31, 2005.

Accepted in final form April 24, 2006.

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