title: 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.
authors: 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.com.
authors: Oranee
authors: O
authors: Sanmaneechai
authors: 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA.
authors: Shawna
authors: S
authors: Feely
authors: 3 The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Steven S
authors: SS
authors: Scherer
authors: 4 Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
authors: David N
authors: DN
authors: Herrmann
authors: 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, Australia.
authors: Joshua
authors: J
authors: Burns
authors: 6 University College London Institute of Child Health and Great Ormond Street Hospital, London, UK.
authors: Francesco
authors: F
authors: Muntoni
authors: 7 Department of Neurology, Vanderbilt University, Nashville, TN, USA.
authors: Jun
authors: J
authors: Li
authors: 8 Department of Neurology, Stanford University, Stanford, CA, USA.
authors: Carly E
authors: CE
authors: Siskind
authors: 8 Department of Neurology, Stanford University, Stanford, CA, USA.
authors: John W
authors: JW
authors: Day
authors: 9 MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UK.
authors: Matilde
authors: M
authors: Laura
authors: 10 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Charlotte J
authors: CJ
authors: Sumner
authors: 10 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Thomas E
authors: TE
authors: Lloyd
authors: 11 Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors: Sindhu
authors: S
authors: Ramchandren
authors: 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA.
authors: Rosemary R
authors: RR
authors: Shy
authors: 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA.
authors: Tiffany
authors: T
authors: Grider
authors: 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA.
authors: Chelsea
authors: C
authors: Bacon
authors: 12 Nemours Children's Hospital, Orlando, FL, USA.
authors: Richard S
authors: RS
authors: Finkel
authors: 3 The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 13 Neuromuscular Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Sabrina W
authors: SW
authors: Yum
authors: 14 Departments of Child Neurology, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors: Isabella
authors: I
authors: Moroni
authors: 15 Departments of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors: Giuseppe
authors: G
authors: Piscosquito
authors: 15 Departments of Clinical Neurosciences, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors: Davide
authors: D
authors: Pareyson
authors: 9 MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UK.
authors: Mary M
authors: MM
authors: Reilly
authors: 1 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA, USA.
authors: Michael E
authors: ME
authors: Shy
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003711:Demyelinating Diseases / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005838:Genotype; D034381:Hearing Loss / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D051346:Mobility Limitation; D018993:Myelin P0 Protein / Q000235:genetics*; D009431:Neural Conduction; D010641:Phenotype; D012600:Scoliosis / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C560547:MPZ protein, human; D018993:Myelin P0 Protein
keywords: CMT1B; MPZ; demyelination; myelin, neuropathy