Cardiovascular Autonomic Neuropathy in Charcot–Marie–Tooth Disease: A Genotype-Stratified Study of PMP22 Duplication and GJB1 Mutation Carriers

Abstract

Background and Aims

Data on cardiovascular autonomic neuropathy (CAN) are sparse in Charcot–Marie–Tooth disease. We aimed to determine the prevalence of CAN in CMT1A and CMTX1 and its associations with neuropathy severity and heart rate variability (HRV), compared with age- and sex-matched controls.

Methods

Thirty-six CMT1A, 24 CMTX1 patients, and 62 controls underwent cardiovascular autonomic testing including the modified Ewing battery (Expiration: Inspiration ratio, 30:15 ratio, Valsalva ratio; complete in 41/62 controls), orthostatic blood pressure measurement, and HRV analysis from 10-min supine–standing recordings. Abnormality was defined using age-stratified 2.3rd-percentile cutoffs. CMT Neuropathy Score version 2 (CMTNSv2) and Survey of Autonomic Symptoms were recorded. Comparisons used Fisher's exact test and the Kruskal–Wallis test with Holm correction; HRV was age- and sex-adjusted.

Results

CAN was present in 30.6% of CMT1A and 33.3% of CMTX1, versus 10.0% of controls (p = 0.011). Definite CAN occurred only in CMT1A (11.1%), although the CMT1A–CMTX1 contrast was not significant (p = 0.14). The Valsalva ratio was lower in CMT1A than in CMTX1 (median 1.54 vs. 1.89, p = 0.001), with abnormal values confined to CMT1A (14.7%). After age and sex adjustment, vagal HRV was reduced in CMT1A but not CMTX1.

Interpretation

CAN affects approximately one-third of patients with CMT1A and CMTX1, roughly three times the control prevalence. Overall prevalence was similar in the two genotypes, but Valsalva impairment was confined to CMT1A, indicating that similar prevalence does not imply an identical pattern of involvement. Cardiovascular autonomic assessment warrants consideration in these patients, particularly perioperatively.