title: Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease.
abstract: OBJECTIVE
  Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date.
  
  
  OBJECTIVE
  To assess the variability of disease severity in a large cohort of children and adolescents with CMT.
  
  
  METHODS
  A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015.
  
  
  METHODS
  Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected).
  
  
  RESULTS
  Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity.
  
  
  CONCLUSIONS
  These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.
authors.affiliation: University of Sydney & Children's Hospital at Westmead, Sydney Australia.
authors.forename: Kayla M D
authors.initials: KM
authors.lastname: Cornett
authors.affiliation: University of Sydney & Children's Hospital at Westmead, Sydney Australia.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.affiliation: University of Sydney & Children's Hospital at Westmead, Sydney Australia.
authors.forename: Paula
authors.initials: P
authors.lastname: Bray
authors.affiliation: University of Sydney & Children's Hospital at Westmead, Sydney Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Halaki
authors.affiliation: Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Rosemary R
authors.initials: RR
authors.lastname: Shy
authors.affiliation: Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania4Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Sabrina W
authors.initials: SW
authors.lastname: Yum
authors.affiliation: Neuromucsular Program, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Timothy
authors.initials: T
authors.lastname: Estilow
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Foscan
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pagliano
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Carlo Besta Neurological Institute, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology, Queen Square, London, England.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laurá
authors.affiliation: University College London Institute of Child Health & Great Ormond Street Hospital, London, England.
authors.forename: Trupti
authors.initials: T
authors.lastname: Bhandari
authors.affiliation: University College London Institute of Child Health & Great Ormond Street Hospital, London, England.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology, Queen Square, London, England.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: Neuromuscular Program, Division of Neurology, Nemours Children's Hospital, Orlando, Florida.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finkel
authors.affiliation: Department of Neurology, University of Rochester, Rochester, New York.
authors.forename: Janet
authors.initials: J
authors.lastname: Sowden
authors.affiliation: Department of Neurology, University of Rochester, Rochester, New York.
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Eichinger
authors.affiliation: Department of Neurology, University of Rochester, Rochester, New York.
authors.forename: David N
authors.initials: DN
authors.lastname: Herrmann
authors.affiliation: Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.affiliation: University of Sydney & Children's Hospital at Westmead, Sydney Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: Burns
mesh_terms: D000293:Adolescent; D001315:Australia; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D010641:Phenotype; D012189:Retrospective Studies; D012720:Severity of Illness Index; D006113:United Kingdom; D014481:United States; D055815:Young Adult