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

Abstract

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.

Two Novel Myelin Protein Zero Mutations in a Group of Chinese Patients

“…The clinical manifestations of MPZ mutations varied among the enrolled families. We also found mild elevations in serum CK levels in some patients and a normal CSF protein level in the CMT1B patient (patient 2) ( 7 ).…”

“…We identified six MPZ mutations in six probands which were verified by Sanger sequencing, these included four known mutations [c.103G>T (p.D35Y), c.233C>T (p.S78L), c.293G>A (p.R98H), and c.449-1G>T], ( 7 , 8 ) a novel frameshift variant c.79delG (p. A27fs) in patient 2, and a novel intronic splice site variant (c.67+4A>G) in patient 1 and his father ( Figure 1A ). Both variants were absent from the controls (1,000 Genomes, gnomAD, dbSNP, and 8,000 healthy Chinese controls).…”

“…Fifty-four different mutations in the MPZ have been reported in Japanese individuals ( 1 , 7 , 23 – 26 ) and 23 mutations in Korean individuals ( 27 , 28 ). Among them, only six identical mutations (D35Y, S78L, R98C, R98H, T124M, K130R) were found in both Chinese and Japanese patients, ( 7 ) and five identical mutations (S78L, R98C, T124M, P132A, c.449- 1G>T) were found in both Chinese and Korean families ( Figure 1C ) ( 27 , 28 ). T124M in MPZ could be found in 8–17% of Japanese CMT families, but only in 3% of Chinese families.…”

“…The early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotypes reflect axonal degeneration without antecedent demyelination (8). Previous studies have shown that the spectra and frequencies of MPZ mutations in Caucasian and Japanese cohorts are different (7). Several studies have reported Chinese patients with MPZ mutations, but it is currently unknown whether there are differences in the spectra of MPZ mutations between Chinese and other ethnicities (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…Almost 300 mutations in MPZ have been identified ( 7 ). The early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotypes reflect axonal degeneration without antecedent demyelination ( 8 ).…”