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Glycogen, also known as animal starch, is a branched polysaccharide that serves as a reserve of carbohydrates in the body; it is stored in the liver and muscle and readily available as an immediate energy source. The formation of glycogen from glucose is known as glycogenesis, and the breakdown of glycogen to form glucose is called glycogen metabolism or glycogenolysis. Increased cyclic adenosine monophosphate (cAMP) catalyzes the breakdown of glycogen (glycogenolysis). The primary hormones that regulate the cycle of glycogenesis and gluconeogenesis are insulin, glucagon, and cortisol. Glycogenolysis is initiated by the action of a specific enzyme called phosphorylase, which yields glucose-1-phosphate (P). Glucose-1-P is an essential compound at the intersection of several metabolic pathways, such as glycolysis, glycogenesis, glycogenolysis, and gluconeogenesis. When glycogenesis occurs, glycogenolysis is inhibited, and vice versa. Impaired glycogen metabolism, characterized by abnormal glycogen accumulation, is associated with inherited metabolic disorders and is collectively known as glycogen storage diseases.

Impaired glycogenolysis can lead to a variety of diseases, including glycogen storage diseases (GSDs), lysosomal storage diseases, and Lafora progressive myoclonus epilepsy. Disruptions in glycogenolysis frequently affect the function of organs, including the liver, skeletal muscle, brain, and kidney. Depending on the affected enzyme in glycogenolysis, a spectrum of syndromes is possible. von Gierke disease is the most common GSD. Type I GSD leads to a deficiency in glucose-6-phosphatase, which is responsible for dephosphorylating glucose-6-P so that glucose can get transported extracellularly to regulate blood glucose levels. The impaired ability to generate glucose results in severe hypoglycemia, hyperuricemia, and increased levels of lactic acid and triglycerides. Due to fat deposition, patients present with a rounded, doll-like face. Without treatment, failure to thrive, hepatomegaly, abnormal swelling, and delayed motor development are present. Long-term complications can develop due to kidney glycogen accumulation, leading to nephropathy, chronic kidney disease, and renal cancer. The main treatment involves maintaining normal glucose levels while avoiding hypoglycemia by instituting frequent meals.[5][10] While glycogen degradation by phosphorylase and debranching enzyme can occur in the cytosol, glycogen is also degraded via a lysosomal pathway, leading to a lysosomal storage disease called Pompe disease (glycogen storage disease Type II). In Pompe disease, a mutation involving lysosomal alpha-glucosidase—also known as acid maltase—develops. As a result, glycogen accumulates in the lysosome and its vesicles, leading to fatal outcomes, including cardiomyopathy and muscular hypotonia. The mechanism of glycogen transportation to lysosomes is not fully understood, but it is believed to occur via macroautophagy. During this process, the cargo is engulfed within double-membrane vesicles known as autophagosomes that fuse with the lysosome.[1]

While glycogen degradation by phosphorylase and debranching enzyme can occur in the cytosol, glycogen is also degraded via a lysosomal pathway, leading to a lysosomal storage disease called Pompe disease (glycogen storage disease Type II). In Pompe disease, a mutation involving lysosomal alpha-glucosidase—also known as acid maltase—develops. As a result, glycogen accumulates in the lysosome and its vesicles, leading to fatal outcomes, including cardiomyopathy and muscular hypotonia. The mechanism of glycogen transportation to lysosomes is not fully understood, but it is believed to occur via macroautophagy. During this process, the cargo is engulfed within double-membrane vesicles known as autophagosomes that fuse with the lysosome.[1] Glycogen storage disease Type III, Cori disease, results from a glycogen debranching enzyme deficiency. As a result, this disease manifests with an accumulation of abnormal glycogen since glycogenolysis halts when glycogen phosphorylase encounters a branching point. The glycogen is then considered abnormal because it reflects very short outer chains. Patients with Cori disease develop ketotic hypoglycemia and hepatomegaly. In rare cases, it can lead to liver cirrhosis and hepatocellular carcinoma.[5] Glycogen storage disease Type V, McArdle disease, develops due to a skeletal muscle glycogen phosphorylase deficiency. Patients display exercise intolerance, muscle weakness, cramping, and pain. Creatine kinase levels are elevated, and myoglobinuria can also develop. A typical symptom of McArdle disease is second wind, where patients can resume exercise when resting briefly. Ingestion of sucrose before exercise can help alleviate symptoms since this becomes the energy source during exercise before resorting to glycogen stores. When glycogen phosphorylase is deficient in the liver, a different disease develops—Type VI GSD. Type VI GSD, or Hers disease, exhibits normal creatine kinase and uric acid levels. Patients present with growth retardation and liver enlargement. Hyperlipidemia and ketotic hypoglycemia also are common.[5]

Glycogen storage disease Type V, McArdle disease, develops due to a skeletal muscle glycogen phosphorylase deficiency. Patients display exercise intolerance, muscle weakness, cramping, and pain. Creatine kinase levels are elevated, and myoglobinuria can also develop. A typical symptom of McArdle disease is second wind, where patients can resume exercise when resting briefly. Ingestion of sucrose before exercise can help alleviate symptoms since this becomes the energy source during exercise before resorting to glycogen stores. When glycogen phosphorylase is deficient in the liver, a different disease develops—Type VI GSD. Type VI GSD, or Hers disease, exhibits normal creatine kinase and uric acid levels. Patients present with growth retardation and liver enlargement. Hyperlipidemia and ketotic hypoglycemia also are common.[5] In Lafora progressive myoclonus epilepsy, increased phosphorylation of glycogen is present in several tissues, leading to toxicity and cell death in neurons. Symptoms include ataxia, seizures, myoclonus, and dementia. Abnormal phosphorylation levels in glycogen lead to longer chains and irregular branch points that render the polymer insoluble and degradation-resistant. As a result, patients with this condition have a conglomerate of inclusion bodies called Lafora bodies.[5]