Split Hand Syndrome in Charcot–Marie–Tooth Disease Type X1 (CMTX1): A Clinical, Neurophysiological, and Radiological Study

Background: Split hand syndrome (SHS) is a hand atrophy pattern characterized by predominant wasting in the thenar muscles (abductor pollicis brevis-APB, first dorsal interosseous-FDI), with relative sparing of the hypothenar (abductor digiti minimi-ADM). SHS was also reported in CMTX1, but eventually attributed to median-ulnar dissociated involvement. We investigated the presence and specificity of SHS in CMTX1. Methods: We gathered clinical/neurophysiological/radiological information in CMTX1 and non-CMTX1 patients, including disease severity (CMT Examination Score-CMTES) and compound muscle amplitude potential (CMAP) of APB/FDI/ADM. We obtained ADM/APB ratio (ADM/APBr) = CMAPADM/CMAPAPB and split-hand index (SHI) = (CMAPAPB × CMAPFDI)/CMAPADM. Eight patients underwent 3T MRI of the hand muscles. We defined SHS based on three criteria: clinical, neurophysiological, and radiological, with at least one criterion required for SHS diagnosis. Through ADM/APBr > 1.7, we assessed the specificity of SHS for CMTX1 among the Italian CMT Registry cohort, encompassing 750 clinically well-characterized patients. Results: We evaluated 22 CMTX1 (age 41.3 ± 12.2) and 40 non-CMTX1 (49.2 ± 14.9). 50% (vs. 3% of non-CMTX1, p < 0.001) and 64% (vs. 0%, p < 0.001) of CMTX1 had clinical and neurophysiological SHS, respectively. In CMTX1, SHS was independent from gender and hand dominance. Both ADM/APBr and SHI correlated with disease duration (rs = 0.77, p < 0.001; rs = -0.65, p = 0.022, respectively), and CMTES (rs = 0.56, p = 0.006; rs = -0.62, p < 0.001, respectively). 3/8 CMTX1 had radiological SHS. Within the Italian CMT Registry cohort, ADM/APBr > 1.7 yielded a specificity of 74% for CMTX1 females among I-CMT/CMT2, and 85% for CMTX1 males among CMT1/I-CMT. Discussion: Up to 59% of CMTX1 patients develop thenar-hypothenar (rather than median-ulnar) SHS. MRI is a novel approach to detect this dissociated denervation pattern. ADM/APBr > 1.7 may be useful to address GJB1 testing in males.