Results of an open label feasibility study of sodium valproate in people with McArdle disease

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile

Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group

Supplementary material is available online at https://www.sciencedirect.com/science/article/pii/S0960896621006878#sec0054 .Highlights: • Management of physical activity intolerance in GSD V and GSD VII is nuanced and impacts activities of daily living (ADL). • Guidelines support clinicians in multiple disciplines across the continuum of care and lifespan of patients. • Overview of management, including guidance on physical activity, nutrition, pain, medical emergencies, and rehabilitation. • Considerations for general medical care, including established and emerging concomitant conditions, potential drug-disease interactions, surgery, and obstetrics. • Emerging issues and knowledge gaps are highlighted.Reneo Pharmaceuticals Inc.; International Association for Muscle Glycogen Storage Disease

No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease and healthy controls: A randomized placebo-controlled cross-over study

Patients with glycogen storage disease type V (GSDV), also known as McArdle disease, have blocked glycogen breakdown due to myophosphorylase deficiency, leading to exercise intolerance, muscle pain, and risk of muscle damage. Blood-derived ketone bodies (KBs) constitute an alternative energy source that could fuel the muscle independent of glycogenolysis. However, except for long-time fasting or ketogenic dieting, KBs are present in low quantities. This led us to explore the effects of a drink containing exogenously produced KBs in the form of D-β-hydroxybutyrate esters (KE) on exercise capacity and metabolism in patients with GSDV. Eight GSDV patients and four healthy controls (HC) were included in this placebo-controlled, cross-over study where subjects were randomized to receive a KE drink with 395 mgKE/kg or placebo drink on two separate days 25 min before a submaximal cycle exercise test. The primary outcome was exercise capacity as indicated by heart rate response (HR) to exercise. Secondary outcomes included perceived exertion (PE) and measures of KB, carbohydrate, and fat metabolism during exercise. In GSDV, the KE drink vs. placebo increased plasma KBs and KB oxidation (p ≤ 0.0001) but did not improve exercise capacity as judged from HR (p = 0.120) and PE (p = 0.109). In addition, the KE drink lowered plasma glucose, free fatty acids, and lowered lipolytic rate and glucose rate of appearance compared with placebo. Similar results were found in the HC group. The present study indicates that an increase in KB oxidation by oral KE supplementation does not improve exercise capacity in GSDV possibly because of KB-induced inhibition of lipolysis and liver glucose output. Thus, oral KE supplementation alone cannot be recommended as a treatment option for patients with GSDV

Patient-Reported Experiences with a Low-Carbohydrate Ketogenic Diet: An International Survey in Patients with McArdle Disease.

The low-carbohydrate ketogenic diet (LCKD) has attracted increased attention in recent years as a potential treatment option for individuals with McArdle disease (glycogen storage disease type V), and despite the absence of strong scientific evidence of the LCKD's benefits, increased numbers of individuals with McArdle disease have tried a LCKD. The objective of this study was to collect patient-reported experiences with a LCKD. We aimed to estimate the immediate prevalence of individuals that had tried a LCKD in an international McArdle disease cohort, and we aimed to report on the patient-reported experiences with the diet, both positive and negative. A total of 183 responses were collected from individuals with McArdle disease from 18 countries. We found that one-third of the cohort had tried a LCKD, and almost 90% experienced some degree of positive effect, with the most prominent effects on McArdle disease-related core symptoms (e.g., activity intolerance, muscle pain, and muscle fatigue). Adverse effects were rare and generally rated as mild to moderate. These patient-reported findings underline the need for randomized clinical trials to decisively determine if a LCKD is a suitable nutritional strategy for patients with McArdle disease. The results from this study can prompt and contribute to the design of such a clinical trial

POPDC3 gene variants associate with a new form of autosomal recessive limb grdle muscular dystrophy

Objective: The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cAMP signaling. Besides gastric cancer, no disease association has been described. We here describe a new myopathy associated with this gene. Methods: 1,500 patients with unidentified cause of limb girdle weakness or hyperCKemia were screened for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle MRI, muscle biopsy and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current. Results: We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe and p.Arg261Gln) in five patients from three ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were absent from control populations. Probands’ muscle biopsies were dystrophic and serum creatine kinase levels were elevated (1,050-9,200 U/L). Muscle weakness was proximal with adulthood onset in most patients, affecting lower limbs earlier than upper. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles, while cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using two different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All three mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1. Interpretation: Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy