Glycogen Storage Diseases

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Several pathogenic variants affecting the proteins involved in glycogen synthesis, degradation, or regulation can cause errors in glucose and glycogen metabolism. These mutations can result in glycogen storage diseases (GSDs), which lead to abnormal glycogen storage. The diseases are categorized according to the order in which the responsible enzyme defect was identified. GSDs can manifest at any age, ranging from in utero to adulthood.

Physiology

Glycogen is the stored form of glucose that acts as a buffer for glucose requirements. It is synthesized during periods of dietary carbohydrate intake and broken down when glucose demand is high or when the diet lacks sufficient carbohydrates.

Its structure comprises of long chains of glucose molecules linked together through 1-4 bonds, with a branch point every 4 to 10 residues linked through a 1-6 bond. Glycogen is synthesized when there is an excess of dietary carbohydrates, and it is broken down when glucose is in high demand or when the diet lacks sufficient carbohydrates.

Glycogen is mainly present in the liver and muscles and serves the following functions:

• In the liver, glycogen maintains glucose levels in the body by storing glucose. It releases glucose to other tissues that cannot produce enough glucose during fasting.
• In muscles, glycogen is an energy source for high-intensity activities. Its breakdown provides substrates for ATP generation, which is required for muscular activities.

There are several genetic disorders, known as glycogen storage diseases, that can result from abnormalities in glycogen metabolism. These diseases can affect the liver and muscles, with the specific symptoms depending on the enzyme affected and the physiological role of that enzyme in the affected tissue.

Clinical Features

Disorders of glucose and glycogen metabolism mainly affect the liver and skeletal muscles, with the clinical presentation dependent on the enzyme affected (as shown in Table 1). Abnormal glycogen metabolism in the liver manifests as hypoglycemia and hepatomegaly, while abnormal metabolism in muscle results in muscle cramps, exercise intolerance, easy fatigability, progressive weakness, and variable cardiac involvement. Some forms of these disorders may have complications of neurologic involvement and haemolysis in addition to both liver and muscle symptoms.

In individuals with liver glycogen metabolism disorders, glycogen stores glucose and releases it to other tissues during fasting. Children with hepatic glycogen metabolism disorders experience fasting hypoglycemia and ketosis, often accompanied by hepatomegaly. These symptoms improve with glucose administration or eating, and affected children may have poor weight gain but are typically developmentally normal.

In muscle, glycogen serves as the primary source of energy for high-intensity activities. Defects in glycogen metabolism usually cause symptoms after short periods of moderate-to-intense exercise, such as muscle pain, cramps, rhabdomyolysis, and myoglobinuria. Muscle weakness involving trunk and extremity muscles is typical of defects in lysosomal glycogenolysis and glycogen synthesis pathways. Certain glycogenolytic and glycolytic enzyme defects may present with weakness instead of cramps, and some defects, such as glycogen synthetase deficiency, cause exercise intolerance.

A few glycogen storage diseases affect both skeletal muscle and myocardium, resulting in muscle and heart symptoms. These disorders include defects in lysosomal acid maltase, lysosome-associated membrane protein 2, glycogenin I deficiency, and muscle glycogen synthase deficiency.

In summary

• A GSD affecting the liver should be considered in patients presenting with fasting hypoglycemia and ketosis, with or without hepatomegaly, whose symptoms improve with glucose administration or eating.
• A GSD affecting the muscle should be considered in patients with muscle pain, cramps, exercise intolerance, easy fatigability, progressive weakness, myoglobinuria, and variable degrees of cardiomyopathy.

Classification

There are 15 types of GSDs. Five of them account for 94% of all cases: GSD I (25%), GSD III (24%), GSD VI and IX (30%) which all involve the liver; and GSD II (15%) which involves skeletal muscle. The common liver ones all have onset in infancy or early childhood. GSD II and GSD V (2%) can have onset in adulthood.

Table 1. Glycogen metabolism disorders.

GSD type	Deficiency	Organ	Key clinical findings	Diagnosis	Therapy
GSD 0a	Glycogen synthase 2	Liver	Ketotic hypoglycemia, no hepatomegaly	Liver biopsy and enzyme testing, DNA testing	Uncooked cornstarch, commercial glucose polymers, liver transplantation
GSD 0b	Muscle glycogen synthase	Muscle (Skeletal and cardiac)	Cardiomyopathy, exercise intolerance, weakness	Muscle biopsy (glycogen depletion), enzyme assay, DNA testing	No specific treatment
GSD I (von Gierke disease)	glucose-6-phosphatase	Liver	Ketotic hypoglycemia, hepatomegaly	DNA testing, liver biopsy, enzyme assay	Uncooked cornstarch, allopurinol, G-CSF, commercial glucose polymers, liver transplantation
GSD II* (Pompe disease)	Lysosomal acid maltase	Muscle (Skeletal and cardiac)	Hypotonia, muscle weakness, hypertrophic cardiomyopathy, rhabdomyolysis	Fibroblast, leukocyte, muscle, or liver enzyme assay, DNA testing	Enzyme replacement therapy, commercial glucose polymers
GSD IIb* (Danon disease)	Lysosome-associated membrane protein 2	Muscle (Skeletal and cardiac)	Hypotonia, hypertrophic cardiomyopathy, rhabdomyolysis	Muscle biopsy, DNA testing	No specific treatment
GSD III (Cori Disease)	glycogen debrancher	Liver +/- Muscle	Ketotic hypoglycemia, hepatomegaly	Fibroblast or liver enzyme assay, DNA testing	Uncooked cornstarch, commercial glucose polymers, liver transplantation
GSD IV	glycogen branching enzyme	Liver	Hepatomegaly, cirrhosis, rare neuromuscular presentations	Fibroblast, muscle, or liver biopsy, DNA testing	Commercial glucose polymers, liver transplantation
GSD V (McArdle disease)	muscle phosphorylase	Skeletal Muscle	Fatigability, myoglobinuria, rhabdomyolysis	Muscle biopsy, muscle enzyme assay, DNA testing	Sucrose prior to exercise
GSD VI (Hers disease)	liver phosphorylase	Liver	Hepatomegaly, mild hypoglycemia	Liver biopsy and enzyme assay, DNA testing	Commercial glucose polymers, liver transplantation
GSD VII (Tarui disease)	phosphofructokinase deficiency	Skeletal Muscle	Fatigability, myoglobinuria, rhabdomyolysis	Muscle enzyme assay, DNA testing	No specific treatment
Phosphoglycerate kinase deficiency	Phosphoglycerate kinase	Skeletal Muscle	Hemolysis, fatigability, myoglobinuria, CNS dysfunction, rhabdomyolysis	Muscle/RBC enzyme assay, DNA testing	Bone marrow transplantation
GSD IX	phosphorylase kinase	Skeletal Muscle	Hepatomegaly, mild hypoglycemia, fatigability, exercise intolerance	Liver/muscle biopsy, enzyme assay, DNA testing	Commercial glucose polymers, liver transplantation
GSD X	phosphoglycerate mutase	Skeletal Muscle	Fatigability, myoglobinuria, exercise intolerance, rhabdomyolysis	Muscle biopsy and enzyme assay, DNA testing	No specific treatment
GSD XI	lactate dehydrogenase A and B	Skeletal Muscle	Fatigability, myoglobinuria, rhabdomyolysis	Muscle or RBC enzyme assay, DNA testing	No specific treatment
GLUT2 deficiency (Fanconi-Bickel syndrome)	GLUT2	Liver	Growth retardation, renal Fanconi syndrome, galactosemia	Clinical features, DNA testing	Frequent, small meals, uncooked cornstarch or nocturnal enteral nutrition, electrolytes, carnitine, and vitamin D as needed, restriction of galactose
GSD XII	aldolase A	Skeletal Muscle	Hemolysis, jaundice, myoglobinuria, muscle weakness, fatigability, rhabdomyolysis	Muscle or RBC enzyme assay, DNA testing	No specific treatment
GSD XIII	beta-enolase	Skeletal Muscle	Exercise intolerance, increased CPK, rhabdomyolysis	Muscle biopsy, enzyme assay, DNA testing	No specific treatment
GSD XIV	phosphoglucomutase 1	Skeletal Muscle	Exercise intolerance, myoglobinuria, increased CPK, rhabdomyolysis, myoglobinuria	Muscle biopsy, enzyme assay, DNA testing	No specific treatment
GSD XV	glycogenin 1	Muscle (Skeletal and cardiac)	Muscle weakness, arrhythmias	Muscle biopsy (glycogen depletion), DNA testing	No specific treatment
Diseases that affect muscle are highlighted in a salmon colour * Initially, these diseases were categorized as GSDs. Later, it was discovered that the buildup of glycogen in lysosomes that is observed in these diseases is caused by impaired lysosomal metabolism, rather than a lack of energy from glycogen/glucose metabolism. As a result, these conditions are now viewed as both GSDs and lysosomal storage diseases.

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