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

Abstract

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) = CMAP^ADM/CMAP^APB and split-hand index (SHI) = (CMAP^APB × CMAP^FDI)/CMAP^ADM. 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.

Keywords: CMTX1; Charcot–Marie–tooth disease; split hand.

FIGURE 1

Clinical split hand syndrome in a patient with CMTX1. A male patient (patient 17, see Table 2) with CMTX1 while abducting fingers, showing a thenar‐to‐hypothenar gradient of atrophy and weakness, with the ADM (MRC R/L = 4−/3) muscle being relatively spared as compared to FDI (MRC R/L = 1/1). ADM, Abductor digiti minimi muscle; FDI, First dorsal interosseous; L, left; R, right.

FIGURE 2

Overview of SHS presence in our CMTX1 cohort. n, number; SHS, Split hand syndrome. *Neurophysiological evaluation not available.

FIGURE 3

Correlation between ADM/APBr and SHI with disease duration and severity. CMTES, CMT‐Examination‐Score; SHI, Split hand index; rs, Spearman's rho correlation. Red dotted lines identify ADM/APBr and SHI pathological cut‐off of > 1.7 and < 5.2, respectively, which were deemed highly specific for ALS.

FIGURE 4

Hand muscles MRI in CMTX1 patients. Normal APB, FDI, and ADM muscles signal and trophism in patient 8 (A, Axial Dixon T1w, water image). Severe atrophy of APB and FDI with relative sparing of ADM (B, Axial Dixon T1w, water image), and signs of active denervation in APB (C, axial STIR) in patient 13. STIR hyperintensity in APB (D) and FDI (E) but not ADM (E), reflecting dissociated active denervation, on the coronal plane in patient 6. APB – arrowhead; FDI – open arrow; ADM – arrow. ADM, abductor digiti minimi; APB, abductor pollicis brevis; FDI, first dorsal interosseous.

FIGURE 5

Assessment of the specificity of SHS for CMTX1 among CMTs through ADM/APBr. ADM, abductor digiti minimi; APB, abductor pollicis brevis; CMAP, Compound muscle action potential; CTS, carpal tunnel syndrome; HNPP, Hereditary Neuropathy with Liability to Pressure Palsies.