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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.

ABSTRACT: INTRODUCTION:Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3' untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS:Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX. RESULTS:There were 22 affected males and 19 symptomatic females, including an 83-year-old woman followed for 40 years. Electrophysiological studies showed a primarily axonal neuropathy. The c.*15C>T mutation in the GJB1 3' UTR was identified in 4 branches of the family with a log of odds (LOD) of 4.91. This created a BstE II enzyme recognition site that enabled detection by restriction digestion. DISCUSSION:The c.*15C>T mutation in the GJB1 3' UTR segregates with CMTX1 in 8 generations. Penetrance in males and females is essentially complete. A straightforward genetic method to detect this mutation is described. Muscle Nerve 57: 859-862, 2018.

SUBMITTER: Chen DH

PROVIDER: S-EPMC5910283 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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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.

Chen Dong-Hui DH Ma Maxwell M Scavina Mena M Blue Elizabeth E Wolff John J Karna Prasanthi P Dorschner Michael O MO Raskind Wendy H WH Bird Thomas D TD

Muscle & nerve 20171228 5

<h4>Introduction</h4>Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3' untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot-Marie-Tooth disease (CMTX).<h4>Methods</h4>Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX.<h4>Results</h4>There were 22 affected males and 19 ...[more]

PMID: 29236290

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Project description:Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Project description:Background: Electrophysiological examination plays an important role in the diagnosis of X-linked Charcot-Marie-Tooth disease (CMTX1) with transient central nervous system deficits. However, the electrophysiological features are seldom reported. Methods: We reviewed and analyzed published reports to determine the electrophysiological features of CMTX1 patients with transient central nervous system deficits. Results: A total of 21 CMTX1 patients with transient central nervous system deficits were found in 17 published case reports/series. The age of onset ranged from 0.5 to 18 years (mean 12.02 ± 0.78 years). All patients were male. Recurrent episodes of central nervous system deficits were reported in all 21 cases and resolved in periods ranging from several minutes to 3 days. All 20 patients who had MRIs at presentation had bilaterally symmetrical abnormal T2/Diffusion signals in the white matter without enhancement of gadolinium. All subsequent MRIs showed improvement or were within normal limits. The median motor nerve conduction velocity (MNCV), motor latencies, and compound muscle action potential (CMAP) amplitude were the most commonly measurable electrophysiological parameters (85.7%). All cases that had MNCV at presentation had slower and significantly decreased MNCV compared with the normal value (34.1 ± 1.10 m/s vs. 46.8±2.05 m/s, P < 0.0001; 95% CI, -17.4 to -7.92). The average variations of MNCV in median nerve, ulnar nerve, peroneal nerve, and tibial nerve were 22.0 ± 5.96%, 27.6 ± 11.9%, 25.9 ± 4.36%, and 27.3 ± 4.30%, respectively. All cases with measured sensory nerve conduction velocity (SNCV) at presentation had slower and significantly decreased SNCV compared with the normal value (35.3 ± 1.33 m/s vs. 47.7 ± 2.40 m/s, P < 0.001; 95% CI -18.2 to -6.46). The average variations of SNCV in median nerve, ulnar nerve, and sural nerve were 19.9 ± 8.24%, 25.2 ± 7.75%, and 23.2 ± 3.95%, respectively. Conclusion: This case series serves as a reminder that electrophysiological examination should be included in the diagnosis of recurrent and episodic neurological deficit with white matter lesions. Median MNCV is a sensitive and valuable parameter to support the diagnosis of CMTX1 with transient central nervous system deficits.

Dataset Information

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.

Publications

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.

Similar Datasets

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