Assessment of Energy Metabolism in Metabolic Myopathies

Metabolic myopathies are a group of genetic conditions which affect the production of energy in the muscle and are caused by muscle adenosine triphosphate (ATP) depletion. This group includes disorders of mitochondrial oxidative phosphorylation (mitochondrial myopathies, MM), fatty acid oxidation (FAOD), Pompe disease and generation of glycolytic substrates (muscle glycogenosis, GSDs) from muscle glycogen. At large, these disorders are amenable to treatment including exercise and dietary treatment and/or vitamins cofactors supplementation.

There is a lack of non-invasive biomarkers which could be used to monitor treatment effectiveness. Traditionally, maximal oxygen consumption (VO2 max), quality of life questionnaire, dual-energy x-ray absorptiometry (DXA/DEXA), muscle biopsies, blood lactate and creatine kinase are used as a surrogate biomarker but have a limited validity to assess response to therapeutic interventions in patients with myopathies. The ultimate goal is to established a platform for clinical trials using minimally invasive tests to evaluate energy metabolism in patients with metabolic myopathies in response to therapeutic interventions, such as physiotherapy exercise program. These minimally invasive tests could be used to develop a platform for clinical trials for patients with muscle disease.

The main aim (objective) of this study is to assess the benefit of an intervention: a 12 weeks at-home physiotherapy exercises program for metabolic myopathies by measuring different outcomes pre and post therapeutic intervention using minimally-invasive tests. The investigators will administer a 12-week at-home physiotherapy exercises program to 3 metabolic myopathies pediatric patients between age 10 and 18 years.

The following outcomes will be measured pre and post intervention:

• Glucose breath test: glucose oxidation (in mg/kg/min) measured by 13C glucose oxidation.
• Doubly labelled water & urine test: assess free-living total energy expenditure (in kcal).
• Exercise test: VO2 max (in ml/kg/min).
• Muscle content test: Muscle mass (in grams) measured by DXA.
• Quality of life questionnaire test: Quality of life measure by PedsQL.

The secondary aim (objective) of this study is to show that a glucose breath test measuring glucose oxidation (in mg/kg/min) and a doubly labelled water & urine test measuring total energy expenditure (in kcal) are outcomes that can be used in clinical trials to evaluate therapeutic interventions, along VO2 max, DXA and quality of life questionnaires. In that regard, this is a proof-of-concept study with the aim to describe the two biomarkers results in response to a therapeutic intervention in comparison to VO2-max and DXA scan and quality of life and clinical questionnaire in 3 participants.

The study design is n of 1 and will compare results of the tests pre and post therapeutic interventions in the same patients.

The glucose breath test: for the glucose oxidation (in mg/kg/min) measured by 13C glucose oxidation, results will be plotted as repeated measurements (3 times pre and post-intervention) for each individual participant. Repeat measurements will reduce the intra-individual variability. A 12 weeks at-home physiotherapy exercise protocol has been developed by the investigator team physician and kinesiologists experienced with exercise, children and metabolic myopathies. The therapeutic intervention, a 12 weeks at-home physiotherapy exercises program performed at least 5 times per week, under virtual supervision 3 times per week by a kinesiologist, contains the same type of exercises that are normally prescribed to this population on a clinical basis. All patients will perform the same program to reduce inter-variability.

In parallel, clinical methods such as VO2max, PedsQL and DXA will be measured pre- (baseline) and post-intervention evaluation. The investigators consulted a BCCHRI statistician with regard to the data analysis. Statistical analysis will include the intra-individual data analysis (n=1 study design) and will compare - using a Paired T test -the pre- and post- intervention data obtained from the two stable isotope tracer methods, VO2 max, DXA and quality of life questionnaires. The results of these tests will also be descriptively analyzed and the pre and post-intervention results will be plotted graphically.

The results of this proof of concept study will inform a larger scale project that was initially planned.

Inclusion criteria

• Confirmed diagnosis of the following: Mitochondrial Metabolic Myopathy (mMM), Fatty Acid Oxidation Disorder (FAOD), Pompe disease, or muscle Glycogen Storage Disease (GSD) (McArdle) via demonstration of deficient enzyme activity and / or demonstration of molecular testing confirming respective pathogenic variants and or compatible with disease phenotype.
• Age ≥10 years up to 18 years.
• Any gender.
• No past history of rhabdomyolysis requiring hospitalization.
• No signs or symptoms of infectious disease at least 14 days prior to the commencement of study visit (to mitigate the risk of rhabdomyolysis and coronavirus transmission).
• Participant must speak/understand English.
• Participant must have a smart phone or a tablet with a provider plan or that can be linked to Wi-Fi.
• Participant must have the time to commit to 11 visits at BC Children's Hospital over 21 weeks.

Exclusion criteria

• Any concurrent disorders / conditions that would interfere with /impact the study procedure (breath test and/or low intensity exercise).
• Diabetes Mellitus type I or II.
• Abnormal Cardiac assessment: cardiomyopathy or arrhythmia not allowing physical exercise.