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.

Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations.

Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years. We detected 15 distinct IGHMBP2 mutations among 8 typical AR-CMT2S families in our cohort of 178 Chinese CMT2 families using Sanger sequencing and next-generation sequencing (NGS), making IGHMBP2 mutations the most frequent cause of AR-CMT2 in our cohort. From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported. One third of identified mutations represented presumed loss-of-function variants (nonsense, frameshift and splicing), while two-thirds were missense changes which clustered in the helicase and ATPase domains. The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%). The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%). Molecular structural model analysis of 26 missense IGHMBP2 mutations using PyMOL software revealed that six mutations were close to the RNA-binding channel, eight mutations were in or close to the nucleotide-binding pocket. Based on available limited clinical information, it seems possible that missense changes located in or close to these motifs might be linked to a more severe clinical outcome. In conclusion, IGHMBP2 mutation screening should recommended for early-onset, moderately or severely affected, and sporadic or AR-CMT2 patients. A tiny minority of patients were relatively late onset and mild affected, which should be given more attention in genetic diagnosis and treatment. While our preliminary analysis suggests a potential link between the localization of missense mutations and clinical presentation, definition of genotype-phenotype relationships will require harmonized clinical information from a larger series of patients.