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

Chikashi Yano1, Masahiro Ando1, Yujiro Higuchi2

  • 1Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima, Japan.

Journal of Neurology
|June 29, 2026
PubMed
Abstract

Insights

PMP22 point mutations cause earlier onset and more severe polyneuropathies than duplications in Japanese patients. This highlights the diverse clinical spectrum of PMP22-related inherited neuropathies.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • PMP22 gene mutations are linked to various inherited peripheral neuropathies, including Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP).
  • While PMP22 duplications and deletions are common causes, PMP22 point mutations are rare and their clinical spectrum in Japanese populations remains undercharacterized.
  • Understanding these rare mutations is crucial for accurate diagnosis and management of inherited neuropathies.

Purpose of the Study:

  • To investigate and compare the genetic, clinical, and electrophysiological features of Japanese patients with PMP22 point mutations versus PMP22 duplications.
  • To characterize novel PMP22 variants and their association with specific neuropathy types.
  • To elucidate the full clinical spectrum of PMP22-related neuropathies.

Main Methods:

  • A multicenter study involving 3352 Japanese patients with suspected inherited peripheral neuropathies from 1995 to 2024.
  • Genetic analysis including fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, gene panel sequencing, and whole-exome analysis.
  • Retrospective collection and analysis of clinical and electrophysiological data from patient medical records.

Main Results:

  • Thirty patients with PMP22 point mutations and 57 with PMP22 duplications were identified, with 24 distinct point mutations found, including four novel variants.
  • PMP22 point mutations were associated with earlier disease onset (mean age 0 vs. 35 years), less frequent family history (14.3% vs. 61.7%), and reduced ambulation compared to duplications.
  • Patients with point mutations showed more frequent undetectable upper limb compound muscle action potentials (18/25 vs. 1/50).

Conclusions:

  • PMP22 point mutations lead to polyneuropathies with significantly earlier onset and more severe clinical manifestations than PMP22 duplications.
  • The findings underscore the broad and variable clinical spectrum associated with PMP22 gene alterations.
  • This study provides critical insights into the characteristics of PMP22 point mutations in Japanese patients, aiding in diagnosis and understanding of inherited neuropathies.
Keywords:
Charcot–Marie–Tooth diseaseDemyelinating neuropathyHereditary neuropathy with liability to pressure palsiesPMP22

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