Triheptanoin's Effect on Fatty Acid Oxidation and Exercise Tolerance in Patients With Debrancher Deficiency, Glycogenin-1 Deficiency and Phosphofructoinase Deficiency at Rest and During Exercise. A Randomized, Double-blind, Placebo-controlled, Cross-over Study

BACKGROUND:

Neuromuscular diseases affect more than 5% of the population in Western countries. Some of the more rare neuromuscular disorders are patients with metabolic myopathies, which are hereditary disorders caused by enzymatic defects of intermediary metabolism. The disorders are generally subdivided in two major groups affecting either carbohydrate metabolism (the glycogenosis) or lipid metabolism. Patients suffer from recurrent episodes of exercise intolerance, muscle pain and muscle contractures/stiffness, and in severe cases rhabdomyolysis (breakdown of skeletal muscle fibers) and myoglobinuria. Recognition of the metabolic block in the metabolic myopathies has started the development of new therapeutic options. Enzyme replacement therapy with recombinant lysosomal acid alpha-glucosidase (rGAA) has revolutionized treatment of early onset Pompe's disease, glycogen storage disease (GSD) II.(1-3) Supplements of riboflavin, carnitine and sucrose show promise in patients with respectively riboflavin-responsive multiple acyl-Coenzyme A (CoA) dehydrogenase deficiency (4), primary carnitine deficiency (5-7) and McArdle disease (8). However, for many of the glycogenosis treatment primarily relies on avoiding precipitating factors, and dietary supplements that bypass the metabolic block.(9) Only a few of the used supplements are validated, and further studies are needed to define efficacious treatments.

A promising product for treatment of glycogenosis is Triheptanoin. Triheptanoin provides patients with medium-length, odd-chain fatty acids that are metabolized into ketones, which replace deficient intermediates in the Tricaboxylic acid (TCA) cycle, thus supporting glucose production through gluconeogenesis, resulting in a lower turnover of glycogen.(10) Triheptanoin has primarily been used in lipid metabolism disorders, where it has shown a remarkable improvement of cardiac and muscular symptoms in three children with VLCAD deficiency and in seven patients with Carnitine palmitoyltransferase (CPT) II deficiency after dietary Triheptanoin supplementation.(10,11)

Metabolic studies in patients with the glycogenosis McArdle disease and Debrancher deficiency has showed that these disorders are associated with an energy deficit caused by reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation. Despite increasing availability of free fatty acid (FFA) during exercise, fatty acid oxidation (FAO) is not increased further, even though the energy deficit is maintained.(12,13)

McArdle disease is one of the largest and most investigated groups of the muscle glycogenosis, caused by mutations in the myophosphorylase gene (PYGM) on chromosome 11 that encodes muscle glycogen phosphorylase.(14). It is know that TCA cycle intermediates are low during exercise in patients with McArdle disease, and most likely the impaired FAO relates to a slowing of the TCA-cycle by limited supply from glycolysis.(15) Triheptanoin, most likely can correct the suspected shortage of anaplerotic intermediates to spark the TCA-cycle in patients with glycogenosis as well, and studies are ongoing in patients with McArdle disease at our research unit Copenhagen Neuromuscular Center. Clinical-Trials.gov Identifier: NCT02432768.