Treatment of Muscle Weakness and Fatigue in Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1), previously termed von Recklinghausen’s disease, is a genetic disorder characterised by the development of tumours on the nerves. NF1 can also affect muscle, with hypotonia, muscle weakness and fatigue able to have a profound impact on paediatric quality of life. This thesis investigates an underlying metabolic myopathy, and the potential of dietary intervention to treat the muscular symptomology in NF1. In Chapter 2, we utilised the Nf1Prx1-/- mouse model to test a range of dietary interventions, including 1) a medium-chain fatty acid (MCFA)/L-carnitine combination, 2) MCFA/L-carnitine with reduced dietary compliance (5/7 days/week), 3) MCFA alone, 4) L-carnitine alone, 5) a “mitochondrial cocktail” (L-carnitine, riboflavin, CoQ10 and creatine), and 6) a low fat diet. Oil Red O (ORO) analysis revealed a significant reduction of intramyocellular lipid (IMCL) accumulation following every dietary intervention, excluding the low fat diet. The MCFA/L-carnitine combination resulted in a significant reduction of IMCL within four weeks, but this was not sustained upon reversion to a standard diet. Lipidome analysis revealed consistent and separable changes in muscle lipidome profiles, by genotype and dietary treatment. Nf1-deficient muscle demonstrated significantly elevated acylcarnitine levels (particular C16 and C18:1) compared to WT. Taken together, these data support the theory of an underling metabolic problem that can be treated by dietary intervention. In Chapter 3, we used a qualitative approach to explore the decision-making process of families who chose to self-supplement their child with L-carnitine. Thematic analysis revealed that primary muscular symptoms and psychosocial repercussions, the ineffectiveness of current treatment strategies, and research availability and accessibility were driving factors in their decision. During L-carnitine supplementation, every parent perceived a significant improvement in their child’s physical abilities. Further guidance around the optimum dose for their child, research accessibility and sharing health findings, and the development of a clinical trial were queried. This study hints at the potential of L-carnitine supplementation in the context of NF1. In Chapter 4, we conducted the first Phase 2a clinical trial of L-carnitine supplementation for NF1-associated muscle weakness and fatigue. Six children aged between 8-12 years with a confirmed diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine supplementation were enrolled in the study. There were no adverse events or side effects reported throughout the study with kidney and liver function tests confirming the safety profile, and compliance rate was high. There was evidence of improved foot strength (plantarflexion and dorsiflexion movements), as well as long jump and six minute walk distances. Plasma acylcarnitines were low, but not within a range clinically linked to carnitine deficiency. Upon three-month follow up, four out of six families elected to continue L-carnitine supplementation. These data support a Phase 3 clinical trial of L-carnitine supplementation in NF1.