Phenotypic variability of childhood Charcot-Marie-Tooth disease

Kayla M D Cornett, Manoj P. Menezes, Paula Bray, Mark Halaki, Rosemary R. Shy, Sabrina W. Yum, Timothy Estilow, Isabella Moroni, Maria Foscan, Emanuela Pagliano, Davide Pareyson, Matilde Laurá, Trupti Bhandari, Francesco Muntoni, Mary M. Reilly, Richard S. Finkel, Janet Sowden, Katy J. Eichinger, David N. Herrmann, Michael E. ShyJoshua Burns, Steven Scherer, Stephan Züchner, Mario Saporta, Thomas Lloyd, Jun Li, Michael D. Weiss, Kenneth Fischbeck, John Day, Robert Baloh, Richard A. Lewis, Vera Fridman, Sindhu Ramchandren, David Walk, Nicholas Johnson, Gyula Acsadi, Jonathan Baets, Jeffery Krischer

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional studywas 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. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.

Original languageEnglish (US)
Pages (from-to)645-651
Number of pages7
JournalJAMA Neurology
Volume73
Issue number6
DOIs
StatePublished - Jun 2016

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Charcot-Marie-Tooth Disease
Pediatrics
Hand Strength
Ankle
Outcome Assessment (Health Care)
Italy
Foot
Hand
Genotype

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Cornett, K. M. D., Menezes, M. P., Bray, P., Halaki, M., Shy, R. R., Yum, S. W., ... Krischer, J. (2016). Phenotypic variability of childhood Charcot-Marie-Tooth disease. JAMA Neurology, 73(6), 645-651. https://doi.org/10.1001/jamaneurol.2016.0171

Phenotypic variability of childhood Charcot-Marie-Tooth disease. / Cornett, Kayla M D; Menezes, Manoj P.; Bray, Paula; Halaki, Mark; Shy, Rosemary R.; Yum, Sabrina W.; Estilow, Timothy; Moroni, Isabella; Foscan, Maria; Pagliano, Emanuela; Pareyson, Davide; Laurá, Matilde; Bhandari, Trupti; Muntoni, Francesco; Reilly, Mary M.; Finkel, Richard S.; Sowden, Janet; Eichinger, Katy J.; Herrmann, David N.; Shy, Michael E.; Burns, Joshua; Scherer, Steven; Züchner, Stephan; Saporta, Mario; Lloyd, Thomas; Li, Jun; Weiss, Michael D.; Fischbeck, Kenneth; Day, John; Baloh, Robert; Lewis, Richard A.; Fridman, Vera; Ramchandren, Sindhu; Walk, David; Johnson, Nicholas; Acsadi, Gyula; Baets, Jonathan; Krischer, Jeffery.

In: JAMA Neurology, Vol. 73, No. 6, 06.2016, p. 645-651.

Research output: Contribution to journalArticle

Cornett, KMD, Menezes, MP, Bray, P, Halaki, M, Shy, RR, Yum, SW, Estilow, T, Moroni, I, Foscan, M, Pagliano, E, Pareyson, D, Laurá, M, Bhandari, T, Muntoni, F, Reilly, MM, Finkel, RS, Sowden, J, Eichinger, KJ, Herrmann, DN, Shy, ME, Burns, J, Scherer, S, Züchner, S, Saporta, M, Lloyd, T, Li, J, Weiss, MD, Fischbeck, K, Day, J, Baloh, R, Lewis, RA, Fridman, V, Ramchandren, S, Walk, D, Johnson, N, Acsadi, G, Baets, J & Krischer, J 2016, 'Phenotypic variability of childhood Charcot-Marie-Tooth disease', JAMA Neurology, vol. 73, no. 6, pp. 645-651. https://doi.org/10.1001/jamaneurol.2016.0171
Cornett KMD, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW et al. Phenotypic variability of childhood Charcot-Marie-Tooth disease. JAMA Neurology. 2016 Jun;73(6):645-651. https://doi.org/10.1001/jamaneurol.2016.0171
Cornett, Kayla M D ; Menezes, Manoj P. ; Bray, Paula ; Halaki, Mark ; Shy, Rosemary R. ; Yum, Sabrina W. ; Estilow, Timothy ; Moroni, Isabella ; Foscan, Maria ; Pagliano, Emanuela ; Pareyson, Davide ; Laurá, Matilde ; Bhandari, Trupti ; Muntoni, Francesco ; Reilly, Mary M. ; Finkel, Richard S. ; Sowden, Janet ; Eichinger, Katy J. ; Herrmann, David N. ; Shy, Michael E. ; Burns, Joshua ; Scherer, Steven ; Züchner, Stephan ; Saporta, Mario ; Lloyd, Thomas ; Li, Jun ; Weiss, Michael D. ; Fischbeck, Kenneth ; Day, John ; Baloh, Robert ; Lewis, Richard A. ; Fridman, Vera ; Ramchandren, Sindhu ; Walk, David ; Johnson, Nicholas ; Acsadi, Gyula ; Baets, Jonathan ; Krischer, Jeffery. / Phenotypic variability of childhood Charcot-Marie-Tooth disease. In: JAMA Neurology. 2016 ; Vol. 73, No. 6. pp. 645-651.
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title = "Phenotypic variability of childhood Charcot-Marie-Tooth disease",
abstract = "IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional studywas 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. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.",
author = "Cornett, {Kayla M D} and Menezes, {Manoj P.} and Paula Bray and Mark Halaki and Shy, {Rosemary R.} and Yum, {Sabrina W.} and Timothy Estilow and Isabella Moroni and Maria Foscan and Emanuela Pagliano and Davide Pareyson and Matilde Laur{\'a} and Trupti Bhandari and Francesco Muntoni and Reilly, {Mary M.} and Finkel, {Richard S.} and Janet Sowden and Eichinger, {Katy J.} and Herrmann, {David N.} and Shy, {Michael E.} and Joshua Burns and Steven Scherer and Stephan Z{\"u}chner and Mario Saporta and Thomas Lloyd and Jun Li and Weiss, {Michael D.} and Kenneth Fischbeck and John Day and Robert Baloh and Lewis, {Richard A.} and Vera Fridman and Sindhu Ramchandren and David Walk and Nicholas Johnson and Gyula Acsadi and Jonathan Baets and Jeffery Krischer",
year = "2016",
month = "6",
doi = "10.1001/jamaneurol.2016.0171",
language = "English (US)",
volume = "73",
pages = "645--651",
journal = "JAMA Neurology",
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TY - JOUR

T1 - Phenotypic variability of childhood Charcot-Marie-Tooth disease

AU - Cornett, Kayla M D

AU - Menezes, Manoj P.

AU - Bray, Paula

AU - Halaki, Mark

AU - Shy, Rosemary R.

AU - Yum, Sabrina W.

AU - Estilow, Timothy

AU - Moroni, Isabella

AU - Foscan, Maria

AU - Pagliano, Emanuela

AU - Pareyson, Davide

AU - Laurá, Matilde

AU - Bhandari, Trupti

AU - Muntoni, Francesco

AU - Reilly, Mary M.

AU - Finkel, Richard S.

AU - Sowden, Janet

AU - Eichinger, Katy J.

AU - Herrmann, David N.

AU - Shy, Michael E.

AU - Burns, Joshua

AU - Scherer, Steven

AU - Züchner, Stephan

AU - Saporta, Mario

AU - Lloyd, Thomas

AU - Li, Jun

AU - Weiss, Michael D.

AU - Fischbeck, Kenneth

AU - Day, John

AU - Baloh, Robert

AU - Lewis, Richard A.

AU - Fridman, Vera

AU - Ramchandren, Sindhu

AU - Walk, David

AU - Johnson, Nicholas

AU - Acsadi, Gyula

AU - Baets, Jonathan

AU - Krischer, Jeffery

PY - 2016/6

Y1 - 2016/6

N2 - IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional studywas 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. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.

AB - IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional studywas 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. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE 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.

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