Genetic spectrum and clinical features of PMP22 point mutations in Japanese Charcot-Marie-Tooth disease.

PMP22 duplications cause Charcot-Marie-Tooth disease (CMT), whereas PMP22 deletion results in hereditary neuropathy with liability to pressure palsies (HNPP). Although PMP22 point mutations can cause a spectrum of neuropathies, including hereditary motor and sensory neuropathy (HMSN) I, congenital hypomyelinating neuropathy, HMSN III, and HNPP, they are rare, and their features in Japanese patients have not been well characterized. Therefore, we compared the genetic, clinical, and electrophysiological characteristics of patients with PMP22 point mutations. This multicenter study enrolled 3352 Japanese patients clinically suspected of having inherited peripheral neuropathies/CMT who underwent fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, gene panel sequencing, or whole-exome analysis between 1995 and 2024. Clinical and electrophysiological data were obtained from patients' medical records. The study enrolled 30 patients with PMP22 point mutations and 57 patients with PMP22 duplications. Among the point mutation cases, 24 distinct variants were detected, including four novel variants (p.T23K, p.R95Sfs*16, p.M111R, and p.P144R). Two splice-site variants (c.78 + 3G > T and c.79-2A > G) were associated with HNPP, whereas the others were associated with polyneuropathy. Compared with patients with PMP22 duplications, those with point mutations experienced earlier disease onset (0 vs. 35.0 years), were less likely to have a family history (14.3% vs. 61.7%), and were less frequently ambulatory (12/28 vs. 50/54). Upper limb compound muscle action potentials were more frequently undetectable in patients with point mutations (18/25 vs. 1/50). PMP22 point mutations-associated polyneuropathies were characterized by earlier disease onset and more severe effects than duplications, highlighting the broad clinical spectrum of PMP22-related neuropathies.