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.[1] 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.[2]
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.

References

  1. โ†‘ Chen YT. Glycogen storage diseases. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), 8th ed, McGraw-Hill, New York, 2001, p.1530.
  2. โ†‘ Modified from uptodate

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