Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

Functional outcome measures for infantile Charcot-Marie-Tooth disease: a systematic review.

A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.

Repeatability, consistency, and accuracy of hand-held dynamometry with and without fixation for measuring ankle plantarflexion strength in healthy adolescents and adults.

INTRODUCTION: Hand-held dynamometry (HHD) is commonly used to measure ankle plantarflexion strength but has variable reliability measuring higher forces. Fixed HHD is suggested to improve reliability. We, therefore, compared the reliability, consistency, and accuracy of measuring plantarflexion strength. METHODS: Plantarflexion strength was measured in 25 healthy individuals with fixed HHD and HHD alone. Intraclass correlation coefficients (ICC2,2 ), SEM, minimal detectable change, and Spearman correlation coefficients were calculated to assess inter-trial repeatability, consistency, agreement, and accuracy. RESULTS: Both methods were repeatable (ICC2,2 0.96 to 0.98) and highly correlated (Spearman rho = 0.815; P < 0.01). Fixed HHD produced significantly higher force outputs. HHD alone provided more consistent force values. CONCLUSIONS: Both methods of measuring ankle plantarflexion force were reliable. Force measured with fixed HHD will likely be more accurate for adults and individuals with greater strength, while HHD alone will be more consistent for individuals with lower strength. Muscle Nerve 56: 896-900, 2017.

Muscle weakness in children with neurofibromatosis type 1.

AIM: To investigate if children with neurofibromatosis type 1 (NF1) have reduced muscle strength compared with children with typical development. METHOD: Maximal isometric strength of 15 upper and lower limb muscle groups was evaluated in 30 children with NF1 (16 males, 14 females; aged 4-16y) and 30 age-, sex-, height-, and weight-matched controls using hand-held dynamometry by a single evaluator. Both the left and right sides were assessed. RESULTS: Children with NF1 were significantly weaker than children with typical development across all 15 muscle groups assessed (p<0.05). Apart from elbow flexion, there were no differences between the left and right sides (p>0.05). Magnitude of differences between the children with NF1 compared with the controls ranged from 3% to 43%. Males and females were equally affected. INTERPRETATION: This study shows that children with NF1 have reduced muscle strength compared with children with typical development. This muscle weakness is present from the earliest stages of the disease assessed and persists throughout childhood with no sex difference. These results support recent evidence from mouse studies that NF1 is associated with a primary myopathy.

Relationship between cognitive dysfunction, gait, and motor impairment in children and adolescents with neurofibromatosis type 1.

AIM: Motor skill impairment and cognitive dysfunction are commonly reported features of neurofibromatosis type 1 (NF1). We characterized and determined the relationship between motor impairment, gait variables, and cognitive function in children and adolescents with NF1. METHOD: Motor function, gait, and neurocognitive abilities were assessed in 46 children and adolescents with NF1 (26 males, 20 females; age range 7-17 y; mean age 11 y 1 mo, SD 3 y 2 mo). Tests to establish correlations between neurocognitive, motor, and gait variables were performed. RESULTS: Compared with normative data, 28/39 of our NF1 cohort demonstrated impaired performance for balance and upper limb coordination and 16/38 for running speed and agility. Gait data revealed a strategy to preserve balance at the expense of velocity, with the unexpected exception of a tendency for reduced base of support. Neurocognitive testing confirmed mean IQ in the low average range (86.0) and deficits in spatial working memory and strategy generation. Significant correlations between a number of neurocognitive measures and motor abilities and gait were identified. The largest associations were between gait width and spatial working memory (r=0.594) and running speed and agility with strategy generation (r=0.549). INTERPRETATION: We have identified a relationship between balance, running speed and agility, gait, and cognition in children with NF1. Findings suggest a shared abnormal neurodevelopmental process underlying some cognitive and motor abilities in NF1. Results are discussed within the context of evidence highlighting abnormal dopamine-mediated corticostriatal circuitry in NF1.

Randomized trial of botulinum toxin to prevent pes cavus progression in pediatric Charcot-Marie-Tooth disease type 1A.

Pes cavus in Charcot-Marie-Tooth disease type 1A (CMT1A) is thought to be due to muscle imbalance of the lower leg. Botulinum toxin type A (BoNT-A) can modify foot deformity in other conditions of muscle imbalance. We tested the safety and effectiveness of BoNT-A on pes cavus progression in pediatric CMT1A. A 24-month, randomized, single-blind trial of BoNT-A was undertaken in 10 affected children (20 legs), aged 3-14 years. The treated leg received intramuscular BoNT-A injections at 6-month intervals in the tibialis posterior and peroneus longus. The control leg received no injections. Primary outcome was radiographic alignment at 24 months. Secondary outcomes were foot posture, ankle flexibility, and strength, assessed every 6 months. Radiographically, BoNT-A produced a small non-significant reduction in cavus progression. There was no effect of BoNT-A on secondary outcomes. There were no serious adverse events. At 24 months, the intramuscular BoNT-A injections proved safe and well-tolerated but did not affect the progression of pes cavus in CMT1A.

Interventions for increasing ankle range of motion in patients with neuromuscular disease.

BACKGROUND: Reduced ankle dorsiflexion range of motion, or ankle equinus, is a common and disabling problem for patients with neuromuscular disease. Clinicians devote considerable time and resources implementing interventions to correct this problem although few of these interventions have been subject to rigorous empirical investigation. OBJECTIVES: To assess the effect of interventions to reduce or resolve ankle equinus in people with neuromuscular disease. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (August 2009), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009), MEDLINE (1966 to August 2009), EMBASE (1980 to August 2009), CINAHL 1982 to August 2009), AMED (1985 to August 2009) and The Physiotherapy Evidence Database (PEDro) (1929 to August 2009). We searched the reference lists of identified articles and also contacted known experts in the field to identify additional or unpublished data. SELECTION CRITERIA: Randomised controlled trials evaluating interventions for increasing ankle dorsiflexion range of motion in neuromuscular disease. Outcomes included ankle dorsiflexion range of motion, functional improvement, foot alignment, foot and ankle muscle strength, health-related quality of life, satisfaction with the intervention and adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Four studies involving 149 participants met inclusion criteria for this review. Two studies assessed the effect of night splinting in a total of 26 children and adults with Charcot-Marie-Tooth disease type 1A. There were no statistically or clinically significant differences between wearing a night splint and not wearing a night splint. One study assessed the efficacy of prednisone treatment in 103 boys with Duchenne muscular dystrophy. While a daily dose of prednisone at 0.75 mg/kg/day resulted in significant improvements in some strength and function parameters compared with placebo, there was no significant difference in ankle range of motion between groups. Increasing the prednisone dose to 1.5 mg/kg/day had no significant effect on ankle range of motion. One study evaluated early surgery in 20 young boys with Duchenne muscular dystrophy. Surgery resulted in increased ankle dorsiflexion range at 12 months but functional outcomes favoured the control group. By 24 months, many boys in the surgical group experienced a relapse of achilles tendon contractures. AUTHORS' CONCLUSIONS: There is no evidence of significant benefit from any intervention for increasing ankle range of motion in Charcot-Marie-Tooth disease type 1A or Duchenne muscular dystrophy. Further research is required.

Relationship between foot strength and motor function in preschool-age children.

Foot weakness occurs in many paediatric neuromuscular disorders, which overtime can cause considerable functional motor difficulties. Measuring foot strength with hand-held dynamometry is reliable in preschool-age children, but its validity in this age group is unknown. If foot strength measures are collected as endpoints in clinical trials, they should represent functionally meaningful outcomes. We evaluated the foot strength-motor function relationship in 60 healthy children aged 2-4 years. Foot strength measures included inversion, eversion, dorsiflexion and plantarflexion using hand-held dynamometry. Motor function parameters included time to run 10-m, standing long jump distance and vertical jump height. Measures of foot strength showed significant correlations with all measures of motor function (r=0.40-0.57, p<0.001). Hand-held dynamometry may be used as a valid and functionally meaningful measure of foot strength in very young children.

Safety and efficacy of progressive resistance exercise for Charcot-Marie-Tooth disease in children: a randomised, double-blind, sham-controlled trial.

BACKGROUND: Exercise is potentially therapeutic for neuromuscular disorders, but a risk of harm exists due to overwork weakness. We aimed to assess the safety and efficacy of progressive resistance exercise for foot dorsiflexion weakness in children with Charcot-Marie-Tooth disease. METHODS: We did this randomised, double-blind, sham-controlled trial across the Sydney Children's Hospitals Network (NSW, Australia). Children aged 6-17 years with Charcot-Marie-Tooth disease were eligible if they had foot dorsiflexion weakness (negative Z score based on age-matched and sex-matched normative reference values). We randomly allocated (1:1) children, with random block sizes of 4, 6, and 8 and stratification by age, to receive 6 months (three times per week on non-consecutive days; 72 sessions in total) of progressive resistance training (from 50% to 70% of the most recent one repetition maximum) or sham training (negligible non-progressed intensity), using an adjustable exercise cuff to exercise the dorsiflexors of each foot. The primary efficacy outcome was the between-group difference in dorsiflexion strength assessed by hand-held dynamometry (expressed as a Z score) from baseline to months 6, 12, and 24. The primary safety outcome was the between-group difference in muscle and intramuscular fat volume of the anterior compartment of the lower leg assessed by MRI (expressed as a scaled volume) from baseline to 6 months and 24 months. Participants, parents, outcome evaluators, and investigators other than the treatment team were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000552785. FINDINGS: From Sept 2, 2013, to Dec 11, 2014, we randomly assigned 60 children to receive progressive resistance exercise (n=30) or sham training (n=30), and 55 (92%) children completed the trial. ANCOVA-adjusted Z score differences in dorsiflexion strength between groups were 0 (95% CI -0·37 to 0·42; p=0·91) at 6 months, 0·3 (-0·23 to 0·81; p=0·27) at 12 months, and 0·6 (95% CI 0·03 to 1·12; p=0·041) at 24 months. Scaled muscle and fat volume was comparable between groups at 6 months (ANCOVA-adjusted muscle volume difference 0, 95% CI -0·03 to 0·10, p=0·24; and fat volume difference 0, 95% CI -0·01 to 0·05, p=0·25) and 24 months (0, -0·08 to 0·12, p=0·67; and 0, -0·05 to 0·03, p=0·58). No serious adverse events were reported. INTERPRETATION: 6 months of targeted progressive resistance exercise attenuated long-term progression of dorsiflexion weakness without detrimental effect on muscle morphology or other signs of overwork weakness in paediatric patients with Charcot-Marie-Tooth disease. FUNDING: Muscular Dystrophy Association and Australian National Health and Medical Research Council.

Correlates of functional ankle instability in children and adolescents with Charcot-Marie-Tooth disease.

BACKGROUND: Functional ankle instability (FAI) is commonly reported by children and adolescents with Charcot-Marie-Tooth disease (CMT), however,, the specific variables associated with FAI remain unknown. An improved understanding of these variables may suggest interventions to improve ankle stability and possibly prevent the long-term complications associated with ankle instability in this population. The aim of this study was to therefore investigate the relationship between FAI and other functional, structural, anthropometric and demographic characteristics in a cross sectional sample of children and adolescents with CMT. METHODS: Thirty children and adolescents with CMT aged 7-18 years were recruited from the Peripheral Neuropathy Clinics of a large tertiary paediatric hospital. Measures of FAI were obtained using the Cumberland Ankle Instability Tool (CAIT). Demographic and anthropometric data was also collected. Other variables collected included foot structure (Foot Posture Index), ankle range of motion (weight bearing lunge) and functional parameters (balance, timed motor function and falls). Descriptive statistics were calculated to characterise the participants. Pearson's correlation coefficients were calculated to investigate the correlates of right and left FAI and demographic (age), anthropometric (height, weight, BMI), foot/ankle (foot structure and ankle flexibility) and functional parameters (balance task, timed motor function and falls frequency). Point biserial correlation was employed to correlate gender with right and left FAI. RESULTS: All but one study participant (n = 29) reported moderate to severe bilateral FAI with females reporting significantly greater ankle instability than males. FAI was significantly associated with cavus foot structure (r = .69, P < .001), female gender (r = -.47, P < .001) and impaired balance (r = .50, P < .001). CONCLUSIONS: This study confirms FAI is common in children and adolescents with CMT. An examination of the correlates of FAI suggests interventions, which target balance, and normalise foot structure should be explored to evaluate whether they might help to improve ankle stability in this population.

Measuring Ankle Instability in Pediatric Charcot-Marie-Tooth Disease.

Children with Charcot-Marie-Tooth disease frequently suffer ankle sprain and experience chronic ankle instability; however, no pediatric self-reported measures of chronic ankle instability exist. The aim was to modify and validate the most reliable measure of chronic ankle instability in adults: the Cumberland Ankle Instability Tool. The Cumberland Ankle Instability Tool-Youth was tested for reliability, construct validity, and sensitivity to discriminate between 104 children aged 8 to 16 years: 31 children with Charcot-Marie-Tooth disease, 31 unaffected children with a history of ankle sprains, and 42 controls. Children with Charcot-Marie-Tooth disease had lower scores compared to unaffected children with a history of sprains (χ2 = 15.10; P < .001) and controls (χ2 = 33.69; P < .001). Scores moderately correlated to visual analog scale scores of ankle steadiness (r s = 0.684; P < .001), and "good" test-retest reliability was identified (ICC2,1 = 0.73). The Cumberland Ankle Instability Tool-Youth demonstrated excellent sensitivity and construct validity, identifying chronic ankle instability as a common problem for children with Charcot-Marie-Tooth disease.

Factors associated with foot and ankle strength in healthy preschool-age children and age-matched cases of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease affects foot and ankle strength from the earliest stages of the disease; however, little is known about factors influencing normal strength development or the pathogenesis of foot weakness and deformity in Charcot-Marie-Tooth disease. The authors investigated factors associated with foot and ankle strength in healthy preschool-age children and compared to age-matched cases of Charcot-Marie-Tooth disease type 1A. In healthy children, ankle dorsiflexion range of motion was one of the strongest independent correlates of foot and ankle strength. Compared with healthy children, those with Charcot-Marie-Tooth disease type 1A had significantly less dorsiflexion strength and range as well as imbalance in inversion-to-eversion and plantarflexion-to-dorsiflexion strength ratios. Given the association between ankle dorsiflexion strength and range in the healthy children, and the abnormality of these parameters in Charcot-Marie-Tooth disease, investigation of the cause-effect relationship is warranted to identify more targeted therapy and further understand the pathogenesis of foot deformity in Charcot-Marie-Tooth disease.

Serial night casting increases ankle dorsiflexion range in children and young adults with Charcot-Marie-Tooth disease: a randomised trial.

QUESTION: Does 4 weeks of serial night casting followed by 4 weeks of stretching of the gastrocnemius and soleus improve ankle dorsiflexion range and other outcomes compared with no intervention in children and young adults with Charcot-Marie-Tooth disease? DESIGN: Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS: 30 children and young adults with Charcot-Marie-Tooth disease and restricted ankle dorsiflexion range. INTERVENTION: The experimental group received 4 weeks of serial night casting followed by 4 weeks of weightbearing stretches. The control group received no intervention. OUTCOME MEASURES: Primary outcome was ankle dorsiflexion range; secondary outcomes included foot deformity, mobility, balance, falls, and self-reported activity limitations. Outcomes were measured at baseline, 4, and 8 weeks. RESULTS: By 4 weeks, serial night casting had increased ankle dorsiflexion range by a mean of 4 deg (95% CI 2 to 6) more in the experimental group than the control group. After a further 4 weeks of weightbearing stretches, the experimental group still had a mean of 3 deg (95% CI 0 to 5) more ankle dorsiflexion range than the control group. Other than reduced time to walk 10 metres at self-selected pace favouring night casting at 4 weeks, outcomes did not differ between groups at any time point. Two minor adverse events were reported in the experimental group. CONCLUSION: 4 weeks of serial night casting increased ankle dorsiflexion range compared with no intervention, but at 8 weeks there was no significant difference between groups.

Effect of oral curcumin on Déjérine-Sottas disease.

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50 mg/kg/day oral curcumin for the first 4 months and 75 mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.

Reliability of quantifying foot and ankle muscle strength in very young children.

Preschool-age children with neuromuscular disorders are often excluded from clinical trials due to the lack of reliable and objective strength measures. We evaluated the reliability of measuring foot and ankle muscle strength in 60 healthy children age 2-4 years. The strength of foot inversion and eversion, ankle plantarflexion, and dorsiflexion was measured using a hand-held dynamometer. Intrarater and interrater reliability of two assessors was determined for each muscle group using intraclass correlation coefficients (ICCs), 95% confidence intervals (CIs), and standard error of measurement (SEM). For all muscle groups intrarater (ICC(2,2) = 0.85-0.94, 95% CI = 0.75-0.96, SEM = 1.5-4.7 N) and interrater (ICC(2,1) = 0.88-0.96, 95% CI = 0.81-0.98, SEM = 1.2-4.6 N) reliability was high for all children. As expected, reliability was generally highest in 3- and 4-year-old children and lowest in 2-year-old children. Hand-held dynamometry can reliably measure foot and ankle strength in very young children and may help aid in diagnosis and in characterizing disease progression in disorders affecting the foot and ankle.