Genotype–phenotype characteristics and baseline natural history of Chinese myelin protein zero gene related neuropathy patients

Background and purpose The aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials. Method Clinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected. Results Nineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile‐onset group included 12 families, the childhood‐onset group consisted of two families and the adult‐onset group included nine families. The Charcot–Marie–Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early‐onset Charcot–Marie–Tooth disease type 1B (CMT1B) or Dejerine–Sottas syndrome. Nonsense‐mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile‐onset CMT1B or Dejerine–Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood‐onset CMT1 phenotype. Conclusion Four novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile‐onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.