Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• The MPZ gene encodes myelin protein zero, crucial for peripheral nerve myelination.
• Mutations in MPZ are a known cause of inherited peripheral neuropathies, including Charcot-Marie-Tooth disease (CMT).
• Understanding genetic variations in MPZ is essential for diagnosing and managing CMT.

Purpose of the Study:

• To investigate the genetic landscape of MPZ variants in a Japanese cohort.
• To identify and characterize novel MPZ variants and assess their pathogenicity.
• To correlate MPZ variant genotypes with clinical phenotypes in CMT patients.

Main Methods:

• Retrospective analysis of 64 patients with reported MPZ variants and 21 patients with novel MPZ variants.
• Variant pathogenicity assessment using American College of Medical Genetics (ACMG) standards.
• Clinical data collection including age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein levels.

Main Results:

• Identified 64 patients with reported MPZ variants, noting distinct common variants compared to other populations.
• Discovered 11 novel pathogenic MPZ variants in 13 patients; 6 variants were classified as likely benign or of uncertain significance.
• Observed cranial nerve involvement in 20 patients, elevated serum CK in 8 of 30 patients, and elevated CSF protein in 18 of 30 patients.

Conclusions:

• The study highlights significant genetic diversity in MPZ variants among Japanese CMT patients.
• Novel pathogenic variants were identified, expanding the known spectrum of MPZ-related neuropathies.
• Clinical manifestations associated with MPZ variants, such as cranial nerve involvement and elevated CSF protein, were observed.