Presented by

Dr. Farouq Thabet

Muscle glycogenosis constitute a growing number of inborn errors of glycogen metabolism. Deficiencies of virtually all enzymes which intervene in the synthesis or degradation of glycogen, may cause glycogen storage disease (GSD) because of aberrant storage or utilization of glycogen. The different GSDs are each denoted by a roman numeral that reflects the historical sequence of their discovery and often also by the name of the author of the first description. Muscle glycogenosis may be subclassified into the following categories: disorders of glycogen synthesis; disorders of glycogen breakdown; disorders of glycolysis; and lysosomal glycogenosis. Clinical features are closely related to the enzyme deficiency, with either exercise intolerance associated with rhabdomyolysis episodes, or permanent muscle weakness. Other organs may also be involved such as heart or liver, depending on the involved enzyme and severity of enzyme deficiency. In-vivo metabolic studies with exercise tests and muscle biopsy are important tools allowing precise diagnosis, but the place of dedicated gene panels is rapidly increasing.

The most frequent muscle glycogenosis are McArdle disease (GSDV), Pompe disease (GSDII) and debranching enzyme deficiency (GSDIII), but the field of glycogenosis has been greatly expanded over the past few years with the discovery of new metabolic diseases that have allowed new metabolic pathways to be deciphered. We will emphasize on the clinical and pathological features of recently described muscle glycogenosis caused by GYG1, RBCK1 and PGM1 gene mutations. The initial steps of glycogen synthesis are involved in deficiencies of glycogenin-1 (GYG1). Phosphoglucomutase deficiency disrupts two metabolic pathways: the connection between galactose and glycogen on the one hand, and glucose metabolism on the other. On the other hand, the metabolic consequences of mutations in the ubiquitin ligase gene RBCK1 are still poorly understood.

Disorders of lipid metabolism or fatty acid oxidation (FAO) are rare inborn errors of metabolism, which occur in adults either as progressive muscle weakness of the limbs or as exercise intolerance with exercise-induced muscle stiffness and pain, often accompanied by recurrent episodes of rhabdomyolysis. Although rare, these diseases are increasingly recognised due to the increased use of tandem mass spectrometry (MS/MS) screening method, allowing the detection of accumulated acylcarnitines in blood samples. Currently, the most prevalent FAO disorders are carnitine palmitoyl transferase (CPT II), very-long-chain acyl-CoA dehydrogenase (VLCAD) and multiple acyl-CoA dehydrogenase (MAD) deficiencies. More rare diseases, such as primary carnitine transporter deficiency (PCD) or mutations in PNPLA2 gene, cause muscle lipidosis. However, some patients with recurrent rhabdomyolysis attacks or muscle lipidosis, remain undiagnosed even after thorough biochemical investigations.

Current treatments for most FAO deficiencies are based on frequent carbohydrate-rich meals and a diet low in long-chain fat, and in some cases supplements of medium-chain triglycerides (MCT). These approaches, along with avoidance of fasting, seem more efficient in children and adolescent, than in adults. Carnitine supplementation and riboflavine treatment frequently improve the clinical condition of patients with primary carnitine or MCAD deficiencies. New therapeutic approaches have also recently been developed for CPT II and VLCAD deficiencies, in particular dietary supplementation with triheptanoin, a seven-carbon medium-chain fatty acid, stimulating the anaplerotic pathway.