Four novel connexin 32 mutations in X-linked Charcot–Marie–Tooth disease. Phenotypic variability and central nervous system involvement

Karadima, Georgia; Raftopoulou, Maria; Floroskufi, Paraskewi; Karletidi, Karolina-Maria; Πάνας, Μάριος

doi:10.1016/j.jns.2014.04.007

Cited by 16 publications

(23 citation statements)

References 16 publications

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“…Dysarthria and hemiparesis were the main symptoms of our patients, and other similar symptoms have been occasionally reported in other countries. [313233343536] CNS symptoms developed after peripheral neuropathy symptoms in some patients in the present study, which has also been reported in previous studies. [3236] Brain MRIs showed abnormal transient lesions involving bilateral white matter in all patients.…”

Section: Discussionsupporting

confidence: 91%

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

Lyu

Jin

et al. 2017

Chinese Medical Journal

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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.

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Section: Discussionsupporting

confidence: 91%

“…However, the involvement of the corpus callosum which was frequently reported did not appear in all cases in the present study. [3437] The isolated involvement of the centrum semiovale, internal capsule, and the periventricular area appeared in the present study as well as in other reports. [3839]…”

Section: Discussionsupporting

confidence: 88%

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

Lyu

Jin

et al. 2017

Chinese Medical Journal

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“…men at all stages of the disease. CNS involvement is a typical and common manifestation in CMT1X patients; however, only one patient had demyelination of white matter and paroxysmal dysphasia in our cohort (31). Hearing impairment is another typical feature in CMT1X patients with several GJB1 mutations, and we found five patients with hearing loss in our cohort (32).…”

Section: Discussionmentioning

confidence: 57%

“…Codons 22 and 164 are the most commonly affected codons in our study and are considered as mutation hot spots. CNS involvement is a typical and common manifestation in CMT1X patients; however, only one patient had demyelination of white matter and paroxysmal dysphasia in our cohort (31). The age-at-onset ranged from 6 to 50 in females and from 2.5 to 42 in males.…”

Section: Discussionmentioning

confidence: 68%

Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families

Liu

et al. 2017

Clinical Genetics

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The aim of this study is to explore the phenotypic and genotypic features of X-linked Charcot-Marie-Tooth (CMT) disease in the mainland of China and to study the cellular effects of six novel Gap junction protein beta-1 variants. We identified 25 missense and 1 non-sense mutations of GJB1 in 31 unrelated families out of 226 CMT families. The frequency of GJB1 mutations was 13.7% of the total and 65% of intermediate CMT. Six novel GJB1 variants (c.5A>G, c.8G>A, c.242T>C, c.269T>C, c.317T>C and c.434T>G) were detected in six unrelated intermediate CMT families. Fluorescence revealed that HeLa cells transfected with EGFP-GJB1-V74M, EGFP-GJB1-L81P or EGFP-GJB1-L90P had diffuse endoplasmic reticulum staining, HeLa cells transfected with EGFP-GJB1-L106P had diffuse intracellular staining, and HeLa cells transfected with EGFP-GJB1-N2S had cytoplasmic and nuclear staining. The distribution of Cx32 in HeLa cells transfected with EGFP-GJB1-F145C was similar to that of those transfected with wild-type (WT). These six variants resulted in a higher percentage of apoptosis than did WT as detected by flow cytometry and Hoechst staining. In conclusion, mutation screening should be first performed in intermediate CMT patients, especially those with additional features. The novel GJB1 variants c.5A>G, c.8G>A, c.242T>C and c.269T>C are considered pathogenic, and c.317T>C and c.434T>G are classified as probably pathogenic.

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“…In total, 70 patients with mutations in GJB1 have been identified since 1997 with Sanger sequencing 19. These patients have originated from 32 families harbouring 22 different GJB1 mutations.…”

Section: Methodsmentioning

confidence: 99%

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association

Breza

Velonakis

Tzartos

et al. 2018

J Neurol Neurosurg Psychiatry

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Four novel connexin 32 mutations in X-linked Charcot–Marie–Tooth disease. Phenotypic variability and central nervous system involvement

Cited by 16 publications

References 16 publications

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

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

Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association

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