title: Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4).
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.
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Piscosquito
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Saveri
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Magri
authors.affiliation: Neurophysiopathology and Epilepsy Centre, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ciano
authors.affiliation: Division of Child Neurology, Department of Pediatric Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gandioli
authors.affiliation: Division of Neurology and Neuropathology; Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Bella
authors.affiliation: Division of Child Neurology, Department of Pediatric Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Disease, Department of Diagnostics and Applied Technology, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Taroni
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, "C. Besta" Neurological Institute, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003711:Demyelinating Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D055724:Electrophysiological Phenomena / Q000502:physiology; D005260:Female; D005820:Genetic Testing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C488620:SH3TC2 protein, human
keywords: CMT type 4C; Charcot-Marie-Tooth disease; SH3TC2 gene; hereditary motor sensory neuropathy; recessive demyelinating CMT