Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

Cornett, Kayla; Menezes, Manoj P.; Bray, Paula; Halaki, Mark; Shy, Rosemary; 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 E.; Eichinger, Katy; Herrmann, David N.; Shy, Michael E.; Burns, Joshua; Scherer, Steven S.; Züchner, Stephan; Saporta, Mario; Lloyd, Thomas E.; Li, Jun; Weiss, Michael D.; Fischbeck, Kenneth H.; Day, John W.; Baloh, Robert H.; Lewis, Richard A.; Fridman, Vera; Ramchandren, Sindhu; Walk, David; Johnson, Nicholas E.; Acsádi, Gyula; Baets, Jonathan; Krischer, J.

doi:10.1001/jamaneurol.2016.0171

Cited by 75 publications

(87 citation statements)

References 17 publications

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“…Studies characterizing the functional decline and rate of progression of neuromuscular disorders such as amyotrophic lateral sclerosis, 27 Duchenne muscular dystrophy, 28 and Charcot-Marie-Tooth disease 29 depend on hand-held dynamometry to capture and track relevant changes in muscle strength. Access to reliable and expansive normative reference values and associated ageand sex-matched z scores are necessary to accurately and precisely quantify response to new interventions and to establish minimum clinically important differences.…”

Section: Resultsmentioning

confidence: 99%

Normative reference values for strength and flexibility of 1,000 children and adults

et al. 2017

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Objective: To establish reference values for isometric strength of 12 muscle groups and flexibility of 13 joint movements in 1,000 children and adults and investigate the influence of demographic and anthropometric factors.Methods: A standardized reliable protocol of hand-held and fixed dynamometry for isometric strength of ankle, knee, hip, elbow, and shoulder musculature as well as goniometry for flexibility of the ankle, knee, hip, elbow, shoulder, and cervical spine was performed in an observational study investigating 1,000 healthy male and female participants aged 3-101 years. Correlation and multiple regression analyses were performed to identify factors independently associated with strength and flexibility of children, adolescents, adults, and older adults. Results:Normative reference values of 25 strength and flexibility measures were generated.Strong linear correlations between age and strength were identified in the first 2 decades of life. Muscle strength significantly decreased with age in older adults. Regression modeling identified increasing height as the most significant predictor of strength in children, higher body mass in adolescents, and male sex in adults and older adults. Joint flexibility gradually decreased with age, with little sex difference. Waist circumference was a significant predictor of variability in joint flexibility in adolescents, adults, and older adults. Conclusions:Reference values and associated age-and sex-stratified z scores generated from this study can be used to determine the presence and extent of impairments associated with neuromuscular and other neurologic disorders, monitor disease progression over time in natural history studies, and evaluate the effect of new treatments in clinical trials. Neurology ® 2017;88:36-43Meaningful, reliable, and sensitive outcome measures are required to monitor treatment and progression of neuromuscular and other neurologic disorders. While there have been substantial advances in the understanding of the pathogenesis and natural history of many neuromuscular disorders, the identification and development of new outcome measures that best reflect the efficacy of specific treatments have not advanced at the same rate. 1 Establishing valid and responsive outcome measures is a priority for the field. 2 To assist in the development of new outcome measures, normative reference values generated from large populations across the lifespan using standardized methods are required. Normative reference values can be utilized to generate z scores, which can be used in multicenter studies to improve outcome measure precision and responsiveness.Muscle weakness and joint contractures predispose to numerous pathologies requiring intervention. Reference data play an important role in identifying and quantifying these impairments and evaluating the effectiveness of interventions. Currently, few comprehensive datasets detail the normal variation of active range of motion in healthy individuals and are limited by the number of joints assessed, 3...

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Section: Resultsmentioning

confidence: 99%

Normative reference values for strength and flexibility of 1,000 children and adults

et al. 2017

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“…In a baseline study of 520 children and adolescents with CMT, disease severity tended to worsen in childhood (3-10 years) in CMT1X and CMT4C, whereas for CMT2A and CMT1B it worsened during adolescence (11-20 years). CMT1A, however, progressed consistently throughout childhood and adolescence [42*]. This is an important observation that has implications for the timing of future trials especially if the findings are confirmed in the ongoing longitudinal natural history study.…”

Section: Therapeutic Advances In Cmt2mentioning

confidence: 99%

“…The CMT neuropathy score and CMTpaeds are disease severity scales based on symptoms, clinical examination and tasks, and for the CMTNS, neurophysiology [42,44]. In the recent vitamin C trials for CMT1A, the original version of the CMTNS was unable to detect disease progression over two years highlighting the need for new outcome measures [45].…”

Section: Therapeutic Advances In Cmt2mentioning

confidence: 99%

Recent advances in the genetic neuropathies

Rossor

Tomaselli

Reilly

2016

Current Opinion in Neurology

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Purpose of review Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neuromuscular diseases with a population prevalence of 1 in 2500. This review will cover recent advances in the genetics and pathomechanisms of CMT and how these are leading to the development of rational therapies. Recent findings Pathomechanistic and therapeutic target advances in CMT include the identification of the ErbB receptor signalling pathway as a therapeutic target in CMT1A and pharmacological modification of the unfolded protein response in CMT1B. In CMT2D, due to mutations in GARS, VEGF-mediated stimulation of the Nrp1 receptor has been identified as a therapeutic target. Preclinical advances have been accompanied by the publication of large natural history cohorts and the identification of a sensitive biomarker of disease (muscle MRI) that is able to detect disease progression in CMT1A over one year. Summary Advances in next generation sequencing technology, cell biology and animal models of CMT are paving the way for rational treatments. The combination of robust natural history data and the identification of sensitive biomarkers mean that we are now entering an exciting therapeutic era in the field of the genetic neuropathies.

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“…While several genes have been implicated, subtypes have been identified based on the nerve pathology, inheritance pattern, age of onset, and severity. These groupings permit clinical description of cohorts of patients with similar phenotypic presentations and trajectories . Identification of the causative genetic mutations and advances in therapeutic approaches make the development of potential treatment strategies for CMT possible.…”

Section: Acknowledgmentmentioning

confidence: 99%