Here, we report the structural evidence of cerebral white matter abnormalities in Charcot-Marie-Tooth (CMT) patients and the relationship between these abnormalities and clinical disability. Brain diffusion tensor imaging (DTI) was performed in CMT patients with demyelinating (CMT1A/CMT1E), axonal (CMT2A/CMT2E), or intermediate (CMTX1/DI-CMT) peripheral neuropathy. Although all patients had normal brain magnetic resonance imaging, all genetic subgroups except CMT1A had abnormal DTI findings indicative of significant cerebral white matter abnormalities: decreased fractional anisotropy and axial diffusivity, and increased radial diffusivity. DTI abnormalities were correlated with clinical disability, suggesting that there is comorbidity of central nervous system damage with peripheral neuropathy in CMT patients. ANN NEUROL 2017;81:147-151.

The objective of the study was to investigate the disease-causing mutation in an autosomal dominant Charcot-Marie-Tooth disease type 2 family and examine the clinical and histopathological evaluation. We enrolled a family of Korean origin with axonal Charcot-Marie-Tooth disease neuropathy (FC305; 13 males, six females) and applied genome-wide linkage analysis. Whole exome sequencing was performed for two patients. In addition, sural nerve biopsies were obtained from two patients. Through whole exome sequencing, we identified an average of 20,336 coding variants from two patients. We also found evidence of linkage mapped to chromosome 11p11-11q13.3 (LOD score of 3.6). Among these variants in the linkage region, we detected a novel p.S90W mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, after filtering 31 Korean control exomes. Our p.S90W patients had frequent sensory disturbances, pyramidal tract signs, and predominant right thenar muscle atrophy in comparison with reported p.S90L patients. The phenotypic spectra were wide and demonstrated intrafamilial variability. Two patients with different clinical features underwent sural nerve biopsies; the myelinated fiber densities were increased slightly in both patients, which differed from two previous case reports of BSCL2 mutations (p.S90L and p.N88S). This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation.

Background and PurposeCharcot-Marie-Tooth disease (CMT) type 1A (CMT1A) is the demyelinating form of CMT that is significantly associated with PMP22 duplication. Some studies have found that the disease-related disabilities of these patients are correlated with their compound muscle action potentials (CMAPs), while others have suggested that they are related to the nerve conduction velocities. In the present study, we investigated the correlations between the disease-related disabilities and the electrophysiological values in a large cohort of Korean CMT1A patients.MethodsWe analyzed 167 CMT1A patients of Korean origin with PMP22 duplication using clinical and electrophysiological assessments, including the CMT neuropathy score and the functional disability scale.ResultsClinical motor disabilities were significantly correlated with the CMAPs but not the motor nerve conduction velocities (MNCVs). Moreover, the observed sensory impairments matched the corresponding reductions in the sensory nerve action potentials (SNAPs) but not with slowing of the sensory nerve conduction velocities (SNCVs). In addition, CMAPs were strongly correlated with the disease duration but not with the age at onset. The terminal latency index did not differ between CMT1A patients and healthy controls.ConclusionsIn CMT1A patients, disease-related disabilities such as muscle wasting and sensory impairment were strongly correlated with CMAPs and SNAPs but not with the MNCVs or SNCVs. Therefore, we suggest that the clinical disabilities of CMT patients are determined by the extent of axonal dysfunction.

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