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.

Feasibility of the Archercise biofeedback device to strengthen foot musculature.

BACKGROUND: Foot muscle weakness can produce foot deformity, pain and disability. Toe flexor and foot arch exercises focused on intrinsic foot muscle strength and functional control may mitigate the progression of foot deformity and disability. Ensuring correct exercise technique is challenging due to the specificity of muscle activation required to complete some foot exercises. Biofeedback has been used to improve adherence, muscle activity and movement patterns. We investigated the feasibility of using a novel medical device, known as "Archercise", to provide real-time biofeedback of correct arch movement via pressure change in an inflatable bladder, and foot location adherence via sensors embedded in a footplate during four-foot exercises. METHODS: Thirty adults (63% female, aged 23-68 years) performed four-foot exercises twice on the Archercise sensor footplate alone and then with biofeedback. One-way repeated measures ANOVA with pairwise comparisons were computed to assess the consistency of the exercise protocol between trial 1 and trial 2 (prior to biofeedback), and the effectiveness of the Archercise biofeedback device between trial 2 and trial 3 (with biofeedback). Outcome measures were: Arch movement exercises of arch elevation and lowering speed, controlled arch elevation, controlled arch lowering, endurance of arch elevation; Foot location adherence was determined by percentage of time the great toe, fifth toe and heel contacted footplate sensors during testing and were analysed with paired sample t-tests. Participant survey comments on the use of Archercise with biofeedback were reported thematically. RESULTS: Seventeen (89%) arch movement and foot location variables were collected consistently with Archercise during the foot exercises. Archercise with biofeedback improved foot location adherence for all exercises (p = 0.003-0.008), coefficient of determination for controlled arch elevation (p < 0.0001) and endurance area ratio (p = 0.001). Twenty-nine (97%) participants reported Archercise with biofeedback, helped correct exercise performance. CONCLUSIONS: Archercise is a feasible biofeedback device to assist healthy participants without foot pathologies perform foot doming exercises. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): 12616001559404. Registered 11 November 2016, http://www.ANZCTR.org.au/ACTRN12616001559404p.aspx.