Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

Abstract

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

Keywords: CMT1B; MPZ; demyelination; myelin, neuropathy.

Mutations in the gene encoding Myelin Protein Zero (MPZ) are the second most common cause of Charcot-Marie-Tooth disease type 1. Sanmaneechai et al. present cross-sectional data from 103 patients with MPZ mutations, recruited by an international collaborative group. The analyses reveal genotype-phenotype correlations, and establish baseline data for clinical trials.

Figure 1

CMTNS at initial visit in 81 patients with CMT caused by mutations in the MPZ gene.

Figure 2

Correlation between age of symptom onset and ulnar motor NCV (MNCV) in 76 patients with CMT caused by mutations in the MPZ gene.

Figure 3

Mutations in the MPZ gene associated with inherited neuropathies. Adhesive interface, 4-fold interface and head-to-head interface, marked with colour to the border of circle, refer to amino acid residues deemed essential for cis and trans adhesion between adjacent myelin wraps. The numbering system for MPZ mutations includes the 29 amino acid leader peptide cleaved before insertion in the myelin sheath. Mutations demonstrated by adding the letter represent amino acid change, arrows represent frameshift mutation and line represent nonsense mutation. Mutations causing early onset phenotype are filled or noted with red colour, while those causing childhood onset phenotype are in green, and those causing late onset phenotype are in blue (updated from Shy et al., 2004).