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Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4).

Authors
  • Piscosquito, Giuseppe1
  • Saveri, Paola1
  • Magri, Stefania2
  • Ciano, Claudia3
  • Gandioli, Claudia4
  • Morbin, Michela5
  • Bella, Daniela D2
  • Moroni, Isabella4
  • Taroni, Franco2
  • Pareyson, Davide1
  • 1 Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy. , (Italy)
  • 2 Unit of Genetics of Neurodegenerative and Metabolic Disease, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy. , (Italy)
  • 3 Neurophysiopathology and Epilepsy Centre, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy. , (Italy)
  • 4 Division of Child Neurology, Department of Pediatric Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy. , (Italy)
  • 5 Division of Neurology and Neuropathology; Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy. , (Italy)
Type
Published Article
Journal
Journal of the peripheral nervous system : JPNS
Publication Date
September 2016
Volume
21
Issue
3
Pages
142–149
Identifiers
DOI: 10.1111/jns.12175
PMID: 27231023
Source
Medline
Keywords
License
Unknown

Abstract

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type.

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