Pilot study of a virtual weight management program for Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Young people with Duchenne muscular dystrophy (DMD) are at increased risk of obesity. Weight management is important to families; however, several barriers exist. This pilot study aimed to investigate the feasibility and acceptability of a co-designed weight management program for DMD. METHODS: The Supporting Nutrition and Optimizing Wellbeing Program (SNOW-P) was a single-arm diet and behavior weight management intervention delivered via weekly telehealth/phone visits over 6 weeks to young people with DMD and obesity (body mass index (BMI) ≥95th percentile) and their caregivers. Using an online survey, caregivers of boys with DMD were consulted on the structure and topics delivered in SNOW-P. Primary outcomes were feasibility and acceptability; secondary outcomes were weight, physical function, and quality of life at 6- and 12-weeks follow-up. RESULTS: Of nineteen eligible participants, eight were enrolled (median age 11.4 years, range 4.9-15.8), and seven completed the program. Visit attendance was high (88%-100%); most participants reported high satisfaction and that participation was easy. Suggested changes included online and visual DMD-specific resources. At 6-weeks, median change in weight z-scores was -0.01 (IQR: -0.23, 0.17) indicating that on average, weight gain tracked as expected for age. Waist circumference measured by caregivers lacked accuracy and the completion rate of caregiver-reported secondary outcome measures (e.g., food diaries) was low. DISCUSSION: A co-designed, telehealth/phone weight management program appeared to be feasible and acceptable in a small group of boys with DMD. An adapted, hybrid telehealth and face-to-face program is recommended for efficacy testing.

Exploring caregivers' attitudes and beliefs about nutrition and weight management for young people with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Obesity disproportionately affects children and adolescents with Duchenne muscular dystrophy (DMD) and with adverse consequences for disease progression. This study aims to: explore barriers, enablers, attitudes, and beliefs about nutrition and weight management; and to obtain caregiver preferences for the design of a weight management program for DMD. METHODS: We surveyed caregivers of young people with DMD from four Australian pediatric neuromuscular clinics. Survey questions were informed by the Theoretical Domains Framework and purposefully designed to explore barriers and enablers to food and weight management. Caregivers were asked to identify their preferred features in a weight management program for families living with DMD. RESULTS: Fifty-three caregivers completed the survey. Almost half (48%) perceived their son as above healthy weight. Consequences for those children were perceived to be self-consciousness (71%), a negative impact on self-esteem (64%) and movement (57%). Preventing weight gain was a common reason for providing healthy food and healthy eating was a high priority for families. Barriers to that intention included: time constraints, selective food preferences, and insufficient nutrition information. Caregivers preferred an intensive six-week weight management program addressing appetite management and screen time. DISCUSSION: Managing weight is an important issue for caregivers of sons with DMD; yet several barriers exist. Individualized 6 week programs are preferred by caregivers to improve weight management for DMD.

Conservative management of hand impairment in children and adolescents with heritable disorders of connective tissue: A scoping review.

AIMS: To synthesize and critically appraise available interventions in the conservative management of hand impairment for children and adolescents with heritable disorders of connective tissue (HDCT). METHODS: A search of peer-reviewed literature and online platforms were included with data regarding hand impairment and function, conservative management and outcome measures extracted and appraised. Levels of evidence were applied to published literature. RESULTS: Ten peer-reviewed papers, eleven webpages and YouTube videos met the inclusion criteria. Reported interventions included: strengthening, orthoses, assistive equipment, education and pacing. Evidence of intervention effectiveness and evidence-based guidance on dosage were absent, with no consistency of outcome measures monitoring intervention effectiveness. Online platforms posted by health professionals predominantly provided advice for families without clinical detail of interventions. CONCLUSIONS: There is a consistent suite of interventions identified in both peer-reviewed literature and online platforms used by clinicians and families to manage hand impairment for children and adolescents with HDCT. Clear dosage parameters and outcome measures are needed in future intervention studies to determine the effectiveness of interventions and guide clinicians in how best to treat hand impairment. Increasing accountability and quality of online resources posted by health professionals for families is warranted to ensure dosage details and precautions are provided.

Proxy-reported sensory measures for children and adolescents with neurodevelopmental disorders: A systematic review.

AIM: To determine the quality and utility of proxy-reported sensory measures for children and adolescents with neurodevelopmental disorders (such as autism spectrum disorder, attention-deficit/hyperactivity disorder, movement disorders, and intellectual disability). METHOD: We systematically searched 11 databases. We applied the updated Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias checklist and criteria for good measurement properties to evaluate instrument development and psychometric properties. Findings were summarized using a COSMIN adaptation of Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: From 11 databases, 6748 articles were screened. Ninety-one full-length articles were reviewed after removing excluded studies and manual searches conducted by two reviewers. Data were extracted for 12 measures from 20 articles. Of the 12 measures, only three provided sufficient data to evaluate content validity and psychometric measurement properties. The Participation and Sensory Environment Questionnaire-Home (PSEQ-H) was the only measure that satisfied moderate content validity and moderate-to-high quality for measurement properties. These properties included: structural validity, hypothesis testing for construct validity, internal consistency, reliability, and measurement error. INTERPRETATION: One measure, the PSEQ-H, met eight criteria for good measurement properties. To facilitate evidence-informed clinical decision-making, all psychometric properties of all 12 sensory-based, proxy-reported measures were presented. The importance of consumer engagement in measure development and the need for ongoing evaluation of measures against contemporaneous standards is recommended. WHAT THIS PAPER ADDS: Three measures provided studies on content validity and psychometric measurement properties. The Participation and Sensory Environment Questionnaire-Home had moderate quality for content validity studies and high-to-moderate quality evidence for psychometric properties. The Participation and Sensory Environment Questionnaire was the only measure that included consumer involvement through qualitative interviews and pilot testing. Consumer involvement in measure development is important for content validity. Ongoing evaluation of measures against contemporaneous standards is recommended.

Clinical applications of machine learning in predicting 3D shapes of the human body: a systematic review.

BACKGROUND: Predicting morphological changes to anatomical structures from 3D shapes such as blood vessels or appearance of the face is a growing interest to clinicians. Machine learning (ML) has had great success driving predictions in 2D, however, methods suitable for 3D shapes are unclear and the use cases unknown. OBJECTIVE AND METHODS: This systematic review aims to identify the clinical implementation of 3D shape prediction and ML workflows. Ovid-MEDLINE, Embase, Scopus and Web of Science were searched until 28th March 2022. RESULTS: 13,754 articles were identified, with 12 studies meeting final inclusion criteria. These studies involved prediction of the face, head, aorta, forearm, and breast, with most aiming to visualize shape changes after surgical interventions. ML algorithms identified were regressions (67%), artificial neural networks (25%), and principal component analysis (8%). Meta-analysis was not feasible due to the heterogeneity of the outcomes. CONCLUSION: 3D shape prediction is a nascent but growing area of research in medicine. This review revealed the feasibility of predicting 3D shapes using ML clinically, which could play an important role for clinician-patient visualization and communication. However, all studies were early phase and there were inconsistent language and reporting. Future work could develop guidelines for publication and promote open sharing of source code.

Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease.

BACKGROUND AND OBJECTIVES: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy and often presents during childhood. Guidelines for the optimal management of common problems experienced by individuals with CMT do not exist, for either children or adults. We formed the Paediatric CMT Best Practice Guidelines Consortium to develop evidence and consensus-based recommendations for the clinical management of children and adolescents with CMT, with the primary objective of promoting optimal, standardised care globally. METHODS: Development of this clinical practice guideline involved a series of systematic reviews covering 10 clinical questions, modified Delphi methodology involving an international panel of clinicians to generate consensus where evidence did not exist, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the body of literature and formulate recommendations. RESULTS: The final guideline includes three evidence-based and 31 consensus-based recommendations. They encompass the management of muscle weakness, balance and mobility impairment, sensory symptoms, muscle cramps, impaired upper limb function, respiratory impairment, maintenance of joint range of motion and non-surgical management of joint deformity. Consensus was not achieved in some management areas, reflecting differences in practice between clinicians and healthcare settings, and highlighting the need for further research. CONCLUSIONS: This clinical practice guideline provides practical and implementable guidance on the management of common clinical problems experienced by children with CMT and advocates for improved access to multidisciplinary care. Successful dissemination and implementation of these recommendations will be critical in ensuring their application across multiple healthcare settings.

COVID-19 in New South Wales children during 2021: severity and clinical spectrum.

OBJECTIVES: To describe the severity and clinical spectrum of coronavirus disease 2019 (COVID-19) in children during the 2021 New South Wales outbreak of the Delta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DESIGN, SETTING: Prospective cohort study in three metropolitan Sydney local health districts, 1 June - 31 October 2021. PARTICIPANTS: Children under 16 years of age with positive SARS-CoV-2 nucleic acid test results admitted to hospital or managed by the Sydney Children's Hospital Network (SCHN) virtual care team. MAIN OUTCOME MEASURES: Age-specific SARS-CoV-2 infection frequency, overall and separately for SCHN virtual and hospital patients; rates of medical and social reason admissions, intensive care admissions, and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 per 100 SARS-CoV-2 infections; demographic and clinical factors that influenced likelihood of hospital admission. RESULTS: A total of 17 474 SARS-CoV-2 infections in children under 16 were recorded in NSW, of whom 11 985 (68.6%) received SCHN-coordinated care, including 459 admitted to SCHN hospitals: 165 for medical reasons (1.38 [95% CI, 1.17-1.59] per 100 infections), including 15 admitted to intensive care, and 294 (under 18 years of age) for social reasons (2.45 [95% CI, 2.18-2.73] per 100 infections). In an analysis that included all children admitted to hospital and a random sample of those managed by the virtual team, having another medical condition (adjusted odds ratio [aOR], 7.42; 95% CI, 3.08-19.3) was associated with increased likelihood of medical admission; in univariate analyses, non-asthmatic chronic respiratory disease was associated with greater (OR, 9.21; 95% CI, 1.61-174) and asthma/viral induced wheeze with lower likelihood of admission (OR, 0.38; 95% CI, 0.18-0.78). The likelihood of admission for medical reasons declined from infancy to 5-11 years, but rose again for those aged 12-15 years. Sex and Indigenous status did not influence the likelihood of admission. CONCLUSION: Most SARS-CoV-2 infections (Delta variant) in children were asymptomatic or associated with mild disease. Hospitalisation was relatively infrequent, and most common for infants, adolescents, and children with other medical conditions. More children were hospitalised for social than for medical reasons.

Hand Impairment and Function in Children and Adolescents With Heritable Disorders of Connective Tissue.

IMPORTANCE: Heritable disorders of connective tissue (HDCTs) affect hand function and participation in daily activities for children and adolescents. OBJECTIVE: To describe hand impairment and function and determine the extent to which hand impairment and function explain the variation in self-reported functional performance. DESIGN: Cross-sectional observational study. SETTING: Specialist tertiary hospital. PARTICIPANTS: Children and adolescents ages 8-18 yr with HDCTs (N = 73). INTERVENTION: None. OUTCOMES AND MEASURES: Hand function outcomes included grip strength (digital dynamometer), manipulation and dexterity (Functional Dexterity Test, Nine-Hole Peg Test), and fine motor skills (Bruininks-Oseretsky Test of Motor Proficiency). Upper limb hypermobility was assessed using the Upper Limb Hypermobility Assessment Tool. Hand pain and fatigue were recorded for a timed button test and 3- and 9-min handwriting tasks. Functional performance was measured using the Childhood Health Assessment Questionnaire. RESULTS: Scores on all hand function measures were below expected norms. Pain and fatigue were significantly worse after the writing tasks (p < .001) but not the button test (p > .40). Secondary students had significantly lower handwriting scores than primary students (p = .03) but similar grip strength z scores (p = .95). Variation in self-reported functional performance was explained by grip strength (6%) and upper limb hypermobility and dexterity (16%). CONCLUSIONS AND RELEVANCE: Young people with HDCTs have poor hand function attributable to poor grip strength and hand pain and fatigue. Comprehensive upper limb evaluation and ongoing monitoring throughout the school years are warranted to inform timely intervention. What This Article Adds: Children and adolescents with heritable disorders of connective tissue have difficulty with hand function that affect their participation in daily activities. The results of this study can help clinicians identify, assess, and monitor daily activities, performance skills, and symptoms of children and adolescents with HDCTs to promote their participation in all aspects of daily life.

L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Impact of heritable disorders of connective tissue on daily life of children: Parent perspectives.

AIM: The aim of this study was to investigate parent perspectives on how heritable disorders of connective tissue (HDCT) affect a child's everyday life. In addition, this study aimed to determine if parents seeking health professional services perceive their children with HDCT to have difficulties with activities reliant on hand function. METHODS: This cross-sectional study used a questionnaire for parents to explore the impact of an HDCT on a child's ability to carry out everyday activities. Parents of children (8-18 years) attending a tertiary connective tissue dysplasia clinic, over a 12-month period, were invited to participate. RESULTS: We analysed 100 surveys completed by parents. Children with Ehlers-Danlos syndrome-hypermobile type, joint hypermobility syndrome (48%) and osteogenesis imperfecta (42%) were the largest diagnostic groups represented. Pain (73%) and fatigue (68%) were the most common symptoms parents perceived to affect day-to-day activities. More parents were satisfied with their child's self-care (61%) than school participation (33%). Keeping up with handwriting (71%) and gross motor activities (70%) were the most frequently reported difficulties at school. Most parents (65%) reported leisure activity difficulties, with pain (64%) and fatigue (60%) as the main contributing factors. CONCLUSIONS: This study has provided new knowledge about the concerns of parents with their child's engagement in everyday life including the impact of HDCT on hand function. Further research is needed on effective management strategies to reduce symptoms and improve hand function for these children.

Reliability of the Charcot-Marie-Tooth functional outcome measure.

The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC1,1 0.825-0.989) and z-scores (ICC1,1 0.762-0.969). Reliability of the CMT-FOM total score was excellent (ICC1,1 0.983, 95% CI 0.958-0.995). The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.

Sensory dysregulation in tic disorders is associated with executive dysfunction and comorbidities.

BACKGROUND: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited. OBJECTIVE: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations. METHODS: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale. RESULTS: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001). CONCLUSION: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.

Magnetic resonance imaging of the anterior compartment of the lower leg is a biomarker for weakness, disability, and impaired gait in childhood Charcot-Marie-Tooth disease.

INTRODUCTION: Biomarkers of disease severity in Charcot-Marie-Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. METHODS: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. RESULTS: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. DISCUSSION: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59:213-217, 2019.

Balance impairment in pediatric charcot-marie-tooth disease.

INTRODUCTION: Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS: The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS: Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION: Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.

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.

An exploratory study into an adapted use of the Alert Program for tic disorder in children.

OBJECTIVES: This preliminary study explored whether an adapted approach to the Alert Program, that uses sensorimotor strategies, might assist with management of tic disorders in children. The Alert Program, a program that uses sensorimotor strategies for self-regulation in children with neurodevelopmental disorders, had not been trialled with children with tic disorders. METHODS: Ten children with tic disorder were assessed using the Dunn Sensory Profile 2 (SP2), the Yale Global Tic Severity Scale (YGTSS) and the Parent Tic Questionnaire (PTQ). Participants attended three 60-90-minute appointments with an occupational therapist and clinical psychologist for implementation of the adapted Alert Program. RESULTS: The YGTSS showed tic reduction in all participants. The total YGTSS pre-intervention mean score of 46.5 improved to 17.7 post-therapy. Five participants reported no impairment post-therapy. PTQ scores reduced in nine participants. On the SP2, 30% of participants scored as having sensory sensitivities that impaired daily function. CONCLUSIONS: This exploratory study found trialling an adapted approach to the Alert Program that uses sensorimotor-based approach decreased tic severity in children with tic disorders. A randomised controlled trial is needed to establish the effectiveness and feasibility of this approach.

Natural history of Charcot-Marie-Tooth disease during childhood.

OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p < 0.001). There was no difference between males and females (mean difference, 0.5; 95% confidence interval [CI], -0.9 to 1.9; p = 0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change, -0.3; 95% CI, -0.6 to -0.05; p = 0.02), balance (z-score change, -1.0; 95% CI, -1.9 to -0.09; p = 0.03), and long jump (z-score change, -0.4; 95% CI, -0.7 to -0.02; p = 0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 ± 4.2 (12% change from baseline; p < 0.001), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 participants with CMT4C/SH3TC2 mutations progressed by 3.0 ± 4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years; mean difference, 1.1; 95% CI, -0.6 to 2.7; p = 0.19), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.

Established and novel measures of upper limb impairment in children with Charcot-Marie-tooth disease type 1A and riboflavin transporter deficiency type 2.

Hand function is a problem in patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and Riboflavin Transporter Deficiency type 2 (RTD2). However, a detailed understanding of upper limb involvement in these conditions is lacking. The aim of this pilot study was to compare hand and upper limb function between children with CMT1A, RTD2 and healthy controls using established and novel outcome measures. Three age-and sex-matched groups of four children (5-15 years, 1 male/group) with CMT1A, RTD2, and healthy controls were assessed for function, strength, and sensation. Fatigue and muscle activity of the FDI was also assessed using a submaximal contraction at 40% of the participants' maximal voluntary contraction. Functional measures were most affected in children with RTD2 followed by children with CMT1A, compared to healthy controls. Strength was similarly impaired in CMT1A and RTD2 compared to controls (p < 0.05). Sensation was significantly impaired in RTD2 compared to CMT1A and controls (p = 0.008). While time to fatigue did not differ between groups, a decline in muscle activity while force remained constant showed that controls compensated with other muscles during the fatigue task while children with CMT1A and RTD2 did not have this compensatory ability. Children with CMT1A and RTD2 exhibited marked hand/upper limb impairment. These results suggest the upper limb should be a focus of rehabilitative therapy in affected children using sensitive outcome measures of strength and sensation, as well as functional activities of daily living, which are most relevant to the patient.

Handwriting difficulties of children with Charcot-Marie-Tooth disease type 1A.

Hand weakness and impaired manual dexterity have been reported in children with Charcot-Marie-Tooth disease type 1A (CMT1A). This early onset of upper limb involvement might explain frequent clinical referrals for assessment and treatment of impaired handwriting performance. The aim of this study was to examine the impact of CMT1A on handwriting speed and legibility, and identify demographic, anthropometric, and physical measures that might relate to handwriting performance. Handwriting speed (Handwriting Speed Test), handwriting legibility (Evaluation Tool of Children's Handwriting-Cursive), and hand strength (hand-held dynamometry of tip pinch, lateral pinch and grip) were assessed in 30 children with CMT1A (aged 8-17 years) and 30 age- and sex-matched controls. Children with CMT1A exhibited 34% slower handwriting speed (p < 0.0001) with 4% reduced legibility (p = 0.001) and 37-48% lower hand strength (p < 0.0001). All measures of strength, age, height, and weight were positively associated with handwriting speed (r = 0.39-0.79, p < 0.01). None of these factors related to handwriting legibility (p > 0.05). Regression modelling identified a diagnosis of CMT1A, lateral pinch weakness and younger age as significant independent predictors of slower handwriting speed, explaining 78% of the variance. Children with CMT1A have considerable handwriting difficulties, primarily with speed, and substantial associated hand and finger weakness. Understanding the cause-effect relationship between strength and function might provide modifiable targets for upper limb intervention.