Inborn errors of energy metabolism associated with myopathies

Abstract

Inherited neuromuscular disorders affect approximately one in 3,500 children. Structural muscular defects are most common; however functional impairment of skeletal and cardiac muscle in both children and adults may be caused by inborn errors of energy metabolism as well. Patients suffering from metabolic myopathies due to compromised energy metabolism may present with exercise intolerance, muscle pain, reversible or progressive muscle weakness, and myoglobinuria. In this review, the physiology of energy metabolism in muscle is described, followed by the presentation of distinct disorders affecting skeletal and cardiac muscle: glycogen storage diseases types III, V, VII, fatty acid oxidation defects, and respiratory chain defects (i.e., mitochondriopathies). The diagnostic work-up and therapeutic options in these disorders are discussed.

Figure 1

Mitochondrial biochemical pathways involved in energy production: including fatty acid oxidation, the respiratory chain, and TCA-cycle (Krebs-cycle) CPT1: Carnitine-Palmitoyltransferase 1; CPT2: Carnitine-Palmitoyltransferase 2; CAT: Carnitine-/Acylcarnitine-Transferase; LC: Long-chain; TCA: Tricarboxylic acid cycle.

Figure 2

llustration of biochemical interactions: the carnitine shuttle, fatty acid oxidation, and glycolysis. The mitochondrial membrane is not permeable to long-chain fatty acids. The carnitine shuttle has to be used to transfer long-chain fatty acids to the mitochondrial matrix space. Once in the mitochondrial matrix space, long-chain acylcarnitines are converted back to long-chain acyl-coenzyme A derivatives and free carnitine via CPT2. Free carnitine is released and the acyl-coenzyme A derivatives will enter the beta-oxidation pathway. CPT1: Carnitine-Palmitoyltransferase 1; CPT2: Carnitine-Palmitoyltransferase 2; CAT: Carnitine-/Acylcarnitine-Transferase; LC: Long-chain; TCA: Tricarboxylic acid cycle; PC: Pyruvate Carcoxylase; PDH: Pyruvate Dehydrogenase.