How T118M peripheral myelin protein 22 predisposes humans to Charcot-Marie-Tooth disease.

Data from gnomAD indicate that a missense mutation encoding the T118M variation in human peripheral myelin protein 22 (PMP22) is found in roughly one of every 75 genomes of western European lineage (1:120 in the overall human population). It is unusual among PMP22 variants that cause Charcot-Marie-Tooth (CMT) disease in that it is not 100% penetrant. Here, we conducted cellular and biophysical studies to determine why T118M PMP22 predisposes humans to CMT, but with only incomplete penetrance. We found that T118M PMP22 is prone to mistraffic but differs even from the WT protein in that increased expression levels do not result in a reduction in trafficking efficiency. Moreover, the T118M mutant exhibits a reduced tendency to form large intracellular aggregates relative to other disease mutants and even WT PMP22. NMR spectroscopy revealed that the structure and dynamics of T118M PMP22 resembled those of WT. These results show that the main consequence of T118M PMP22 in WT/T118M heterozygous individuals is a reduction in surface-trafficked PMP22, unaccompanied by formation of toxic intracellular aggregates. This explains the incomplete disease penetrance and the mild neuropathy observed for WT/T118M CMT cases. We also analyzed BioVU, a biobank linked to deidentified electronic medical records, and found a statistically robust association of the T118M mutation with the occurrence of long and/or repeated episodes of carpal tunnel syndrome. Collectively, our results illuminate the cellular effects of the T118M PMP22 variation leading to CMT disease and indicate a second disorder for which it is a risk factor.

Distinctive patterns of sonographic nerve enlargement in Charcot-Marie-Tooth type 1A and hereditary neuropathy with pressure palsies.

OBJECTIVE: The extent of sonomorphologic differences of peripheral nerves between CMT and HNPP is unknown. METHODS: We recruited 9 patients with CMT-1A and 9 with HNPP. Patients underwent a standardized sonographic protocol, which evaluated nerve size and vascularization. We quantitatively assessed fascicle size and echogenicity. RESULTS: All 18 patients demonstrated nerve enlargement, but no increased vascularization. HNPP demonstrated larger nerves at sites of entrapment (median nerve at the carpal tunnel p=0.049, ulnar nerve at the sulcus p<0.001), greater swelling ratios of median (p<0.001), ulnar (p=0.017) and fibular nerve (p=0.005) than CMT-1A. CMT-1A revealed larger nerves proximal to sites of entrapment (median and fibular nerve, brachial plexus p<0.001). Nerve fascicles where larger (p<0.001) and more hypo-echogenic in CMT-1A. Nerve, fascicle size nor echogenicity correlated with age, gender or MRC sum-score. CONCLUSIONS: Ultrasonography of nerves reveals specific phenotypes differentiating CMT-1A from HNPP. In CMT-1A enlargement of nerves and fascicles is multifocal among multiple nerves, whereas in HNPP nerve enlargement is restricted to sites of entrapment. SIGNIFICANCE: Our findings of specific sonomorphological phenotypes, differentiating CMT-1A from HNPP, may help to improve our pathophysiological insights in CMT and HNPP.