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.

Clinicaltrialsgov identifier: NCT01193075.

Figure 1. Amino acid sequence and reported GJB1 mutations

Schematic diagram showing the predicted amino acid sequence and all 420 reported GJB1 mutations (Inherited Neuropathies Consortium variant Browser [hihg.med.miami.edu/code/http/cmt/public_html/index.html#/]). Previously unreported mutations reported are shown in red.

Figure 2. Age, sex, and clinical characteristics of patients with CMTX1 in the cohort

(A) Frequency distribution of age and sex of patients with CMTX1 at the age they were first given a CMTNS in an Inherited Neuropathies Consortium clinic. (B) Clinical characteristics separated by sex of 160 patients with CMTX1. CMTX1 = X-linked form of Charcot-Marie-Tooth disease.

Figure 3. CMT examination score and CMT neuropathy score in male patients with CMTX1

(A) CMTES and CMTNS in male patients with CMTX1 grouped by age. The CMTES is based on history and neurologic examination; the CMTNS adds neurophysiology. Both CMTES and CMTNS increase with age in male patients with CMTX1 (p < 0.0005 for both CMTES and CMTNS, analysis of variance). (B) CMTES and CMTNS in female patients with CMTX1 grouped by age. There is an increase in CMTES (but not CMTNS) after the second decade (p < 0.03, analysis of variance). CMTES = Charcot-Marie-Tooth disease examination score; CMTNS = Charcot-Marie-Tooth disease neuropathy score; CMTX1 = X-linked form of Charcot-Marie-Tooth disease.

Figure 4. Nerve conduction studies in male and female patients with CMTX1 according to age

(A) Ulnar and median nerve CMAPs in males and females with CMTX1 by age. The data from individual patients are represented as single points. There is a correlation between the ulnar and median CMAP with age in males (p = 0.02, Spearman ρ = −0.4, and p = 0.002, Spearman ρ = −0.6, respectively) and ulnar CMAP with age in females (p = 0.002, Spearman ρ = −0.6). A correlation is not observed between median CMAP with age in females (p = 0.3, Spearman ρ = −0.2). (B) Ulnar and median motor NCVs in males and females with CMTX1 by age. The data from individual patients are represented as single points. Nerves that did not have a recordable response were excluded. A correlation is not observed between ulnar and median motor NCVs in males with age (p = 0.8 and 0.2, Spearman ρ = 0.04 and 0.30, respectively). A correlation is also not observed between ulnar and median motor NCVs in females with age (p = 0.7 and 0.4, Spearman ρ = 0.06 and 0.10, respectively). (C) Amplitude of the ulnar and radial SNAPs in males and females with CMTX1 by age. The data from individual patients are represented as single points. There is a correlation between the radial sensory SNAPs with age in males (p = 0.01, Spearman ρ = −0.4). A correlation is not observed between ulnar sensory SNAPs with age in males (p = 0.6, Spearman ρ = −0.1). A correlation is also not observed between ulnar and radial SNAPs with age in females (p = 0.8 and 0.9, Spearman ρ = 0.04 and 0.01, respectively). CMAP = compound muscle action potential; CMTX1 = X-linked form of Charcot-Marie-Tooth disease; MNCV = motor nerve conduction velocity; SNAP = sensory nerve action potential.