Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in theMPZgene

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.

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

“…However, our proband for the Thr65Asp mutation was a 13‐year‐old girl who could not walk independently until 19 months of age, was unable to run after 5 years of age and had median motor nerve conduction velocities of 6 meters/sec. Alternatively, the proband for the Arg227Ser mutation was a 44‐year‐old man who walked by a year, was a fast runner as a child playing on his varsity football team in high school, who did not develop symptoms until 40 years of age and had median MNCV of 32 met/sec 1. We also identified no correlation between UPR activation and disease severity, as measured by the CMTNS (Fig.…”

“…Clinical investigators in the INC had evaluated and reported on these patients and their respective symptoms, signs and physiology 1. We report our findings in the present manuscript.…”

“…Ser63del MPZ4 and Arg98Cys MPZ5 activate the UPR in mice and cause CMT1B 1. We therefore investigated whether these mutations would activate the UPR in our RT4 cell lines.…”

“…To determine which CMT1B mutations cause UPR activation, we generated cDNA constructs for each of the 46 disease causing mutations evaluated by members of the INC. We selected these mutations because we had characterized and reported the clinical phenotype for 103 patients bearing these mutations in our clinics 1. We then transfected the respective constructs into the RT4 reporter cell line and compared the luciferase levels to transfections with those from wild‐type MPZ as we had done with Ser63del and Arg98Cys MPZ.…”

“…We next investigated whether UPR activity correlated with clinical phenotype based on our previous clinical evaluation of patients with the 46 different mutations 1. We identified similar percentages of UPR activation for mutations associated with infantile, childhood or adult onset forms of CMT1B (Fig.…”