Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1)

Abstract

Objective:To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships.Methods:Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers.Results:We evaluated 87 males who had a mean age of 41 years (range 10–78 years) and 73 females who had a mean age of 46 years (range 15–84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity.Conclusions:In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1.ClinicalTrials.gov identifier:NCT01193075.

Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations

“…We also observed that male patients often had similar onset age and disease progression rate, whereas women patients had varied phenotypes from asymptomatic to relatively severe. This was consistent with the previous study (15,20) that found that approximately two thirds of female patients with GJB1 mutations had a mild phenotype, one third had a moderately severe phenotype that progressed with time, and only a small proportion of patients remained in a subclinical state. Although it is not fully understood, the skewed X inactivation may partly explain the variable phenotype in females (4,21) and has been documented in mice (22).…”

Genetic and phenotypic profile of 112 patients with X‐linked Charcot–Marie–Tooth disease type 1

“…Korea 68.3% (43/63) and China 83.9% (26/31) . Amongst these variants identified in our study, p.Arg22Gln was the most common variant (7/88), which is comparable to China but different from Korea (p.Val95Met, 6/63) and America (p.Arg15Gln, 11/120) .…”

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

“…Finally, based on recent studies suggesting that GJB1 promoter mutations may be a more common cause of CMTX than previously suspected, this study is limited by the absence of promoter screening 48. Notwithstanding the above limitations, it remains surprising that the association between CMTX and MS has not been previously noted in reports of larger cohorts of patients with CMTX 49. It is possible that the distinguishing factor is one of the current authors’ active interests in both CMT and inflammatory CNS demyelinating disease, a rare occurrence in our age of ever increasing subspecialising.…”