Journal article
Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene
Brain (London, England : 1878), Vol.138(Pt 11), pp.3180-3192
11/2015
DOI: 10.1093/brain/awv241
PMCID: PMC4643641
PMID: 26310628
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.
Details
- Title: Subtitle
- Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene
- Creators
- Oranee Sanmaneechai - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA 2 Division of Neurology, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand oranee141@gmail.comShawna Feely - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USASteven S Scherer - 3 The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USADavid N Herrmann - 4 Department of Neurology, University of Rochester Medical Center, Rochester, NY, USAJoshua Burns - 5 Arthritis and Musculoskeletal Research Group, University of Sydney / Paediatric Gait Analysis Service of NSW, Children's Hospital at Westmead, Sydney / Neuromuscular Research Group, Murdoch Childrens Research Institute, Melbourne, AustraliaFrancesco Muntoni - 6 University College London Institute of Child Health and Great Ormond Street Hospital, London, UKJun Li - 7 Department of Neurology, Vanderbilt University, Nashville, TN, USACarly E Siskind - 8 Department of Neurology, Stanford University, Stanford, CA, USAJohn W Day - 8 Department of Neurology, Stanford University, Stanford, CA, USAMatilde Laura - 9 MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UKCharlotte J Sumner - 10 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USAThomas E Lloyd - 10 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USASindhu Ramchandren - 11 Department of Neurology, University of Michigan, Ann Arbor, MI, USARosemary R Shy - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USATiffany Grider - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USAChelsea Bacon - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USARichard S Finkel - 12 Nemours Children's Hospital, Orlando, FL, USASabrina W Yum - 3 The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 13 Neuromuscular Program, Children's Hospital of Philadelphia, Philadelphia, PA, USAIsabella Moroni - 14 Departments of Child Neurology, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, ItalyGiuseppe Piscosquito - 15 Departments of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, ItalyDavide Pareyson - 15 Departments of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, ItalyMary M Reilly - 9 MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UKMichael E Shy - 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.138(Pt 11), pp.3180-3192
- Publisher
- England
- DOI
- 10.1093/brain/awv241
- PMID
- 26310628
- PMCID
- PMC4643641
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- R01 NS082563 / NINDS NIH HHS MR/K000608/1 / Medical Research Council K23 NS072279 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS
- Language
- English
- Date published
- 11/2015
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984013205102771
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