Molecular update and therapeutic trials in muscle disorders of glycogen and lipid metabolism

Several disorders of glycogen metabolism affect skeletal muscle and up to now 13 different enzymatic defects have been recognized. Glycolytic disorders and phosphorylase deficiency present as predominant signs exercise intolerance, cramps and myoglobinuria. Infantile acid maltase deficiency is characterized by cardiomegaly, juvenile and adult acid maltase deficiencies have as major clinical signs limb weakness and respiratory insufficiency. Glycogenosis type II is undergoing a therapeutic trial with recombinant alpha-glucosidase replacement that has demonstrated a good response in the infantile form. Current therapy of adult AMD is nutritional (high protein diet) but a future trial of enzyme replacement is under preparation. Patients with lipid storage myopathies (LSM) are typified by inhibited beta-oxidation and increased intramyocellular lipid content. Most enzyme defects pertain to fatty acid transport in mitochondria of beta-oxidation such as carnitine palmityl transferase, very long chain acylCoA transferase, trifunctional enzyme, medium and short chain acylCoA transferase. LSM are characterized by muscle weakness, myoglobinuria and exercise intolerance. Primary carnitine deficiency is an autosomal recessive disorder characterized by recurrent hypoketotic hypoglycaemia and cardiomyopathy. A gene encoding for the high affinity carnitine transporter OCTN2 is mutated in these patients. Carnitine supplementation is an efficacious treatment and reverses the dilatative cardiomyopathy. Metabolic myopathies are caused by inability of the muscle to utilize fuel: i.e. fatty acids, glycogen or glucose.