Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease

Abstract

Background:X-linked Charcot-Marie-Tooth type 1 (CMT1X) disease is one of the most common forms of inherited neuropathy caused by mutations in the gap junction beta-1 protein (GJB1) gene (also known as connexin 32). This study presented the clinical and genetic features of a series of Chinese patients with GJB1 gene mutations.Methods:A total of 22 patients from unrelated families, who were referred to Department of Neurology, Peking University First Hospital from January 2005 to January 2016, were identified with GJB1 mutations. Their clinical records and laboratory findings were retrospectively collected and reviewed. Mutations in the GJB1 gene were analyzed by targeted next-generation sequencing (NGS). Nucleotide alternations were confirmed with Sanger sequencing.Results:The CMT1X patients predominantly showed distal muscle weakness of lower limbs with mild sensory disturbance. The mean age of onset was 15.6 ± 8.7 years (ranging from 1 year to 42 years). The sudden onset of cerebral symptoms appeared in four patients (18.2%); two were initial symptoms. One case had constant central nervous system (CNS) signs. There were 19 different heterozygous mutations, including 15 known mutations and four novel mutations (c.115G>T, c.380T>A, c.263C>A, and c.818_819insGGGCT). Among the 22 Chinese patients with CMT1X, the frequency of the GJB1 mutation was 4.5% in transmembrane domain 1 (TM1), 4.5% in TM2, 22.7% in TM3, 9.1% in TM4, 4.5% in extracellular 1 (EC1), 27.3% in EC2, 9.1% in intracellular loop, 13.6% in the N-terminal domain, and 4.5% in the C-terminal domain. CMT1X with CNS impairment appeared in five (22.7%) of these patients.Conclusions:This study indicated that CNS impairment was not rare in Chinese CMT1X patients. Mutations in the EC2 domain of the GJB1 gene were hotspot in Chinese CMT1X patients.

A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

“…We found CMAPs and SNAPs were not evocable or showed low amplitudes, with axonal degeneration and regenerating clusters in sural nerve biopsy，indicating axonal impairment. MCV of the left median nerve was moderately slow, which was consistent with CMTX1, caused by GJB1 mutations . The sural nerve biopsy also revealed onion bulbs, indicating remyelination.…”

“…The clinical phenotype and disease progression vary . In addition to time‐course‐dependent neuropathies, there are several types of CMT with additional phenotypic features, such as leucoencephalopathy in CMTX1 with GJB1 mutations, focal segmental glomerulosclerosis in dominant‐inherited intermediate CMT with INF2 mutations, and optic atrophy in CMT with C12orf65 mutations …”

An 8‐generation family with X‐linked Charcot–Marie–Tooth: Confirmation Of the pathogenicity Of a 3′ untranslated region mutation in GJB1 and its clinical features

“…Results of EDx studies are also variable, typically showing normal or mildly slow motor nerve conduction velocity and sometimes low CMAP. These characteristics are similar to the CMT syndrome associated with other mutations in GJB1 . Variability of manifestations in carrier females is presumably the result of random X inactivation, although Siskind et al .…”

“…3 More than 400 mutations in GJB1 have been reported, the overwhelming majority of which are missense mutations. [4][5][6] Recently, Tomaselli et al reported a variant (c.*15C>T) in the 3 0 untranslated region mutation (UTR) of GJB1 in 2 small nuclear families. 7 We evaluated a large family with this 3 0 UTR mutation in which we confirmed its pathogenicity and for which we provide details of clinical manifestations.…”

“…This X‐linked pattern, the second most common type of CMT, is usually caused by mutations in the GJB1 gene encoding a gap junction protein (connexin‐32) . More than 400 mutations in GJB1 have been reported, the overwhelming majority of which are missense mutations . Recently, Tomaselli et al .…”