Glycogen Storage Diseases: Difference between revisions
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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. | |||
== 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 [[Skeletal Muscle|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|skeletal muscle]].<ref>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.</ref> The common liver ones all have onset in infancy or early childhood. GSD II and GSD V (2%) can have onset in adulthood. | |||
{| class="wikitable" | {| class="wikitable" | ||
|+Table 1. Glycogen metabolism disorders.<ref>Modified from uptodate</ref> | |||
|- | |- | ||
!GSD type | !GSD type | ||
!Deficiency | !Deficiency | ||
!Organ | |||
!Key clinical findings | !Key clinical findings | ||
!Diagnosis | !Diagnosis | ||
Line 9: | Line 41: | ||
|GSD 0a | |GSD 0a | ||
|Glycogen synthase 2 | |Glycogen synthase 2 | ||
|Liver | |||
|Ketotic hypoglycemia, no hepatomegaly | |Ketotic hypoglycemia, no hepatomegaly | ||
|Liver biopsy and enzyme testing, DNA testing | |Liver biopsy and enzyme testing, DNA testing | ||
Line 15: | Line 48: | ||
|GSD 0b | |GSD 0b | ||
|Muscle glycogen synthase | |Muscle glycogen synthase | ||
|Muscle | |||
|Cardiomyopathy, exercise intolerance, weakness | |Cardiomyopathy, exercise intolerance, weakness | ||
|Muscle biopsy (glycogen depletion), enzyme assay, DNA testing | |Muscle biopsy (glycogen depletion), enzyme assay, DNA testing | ||
Line 21: | Line 55: | ||
|GSD I (von Gierke disease) | |GSD I (von Gierke disease) | ||
|glucose-6-phosphatase | |glucose-6-phosphatase | ||
|Liver | |||
|Ketotic hypoglycemia, hepatomegaly | |Ketotic hypoglycemia, hepatomegaly | ||
|DNA testing, liver biopsy, enzyme assay | |DNA testing, liver biopsy, enzyme assay | ||
Line 27: | Line 62: | ||
|GSD II* (Pompe disease) | |GSD II* (Pompe disease) | ||
|Lysosomal acid maltase | |Lysosomal acid maltase | ||
|Muscle | |||
|Hypotonia, muscle weakness, hypertrophic cardiomyopathy, rhabdomyolysis | |Hypotonia, muscle weakness, hypertrophic cardiomyopathy, rhabdomyolysis | ||
|Fibroblast, leukocyte, muscle, or liver enzyme assay, DNA testing | |Fibroblast, leukocyte, muscle, or liver enzyme assay, DNA testing | ||
Line 33: | Line 69: | ||
|GSD IIb* (Danon disease) | |GSD IIb* (Danon disease) | ||
|Lysosome-associated membrane protein 2 | |Lysosome-associated membrane protein 2 | ||
|Muscle | |||
|Hypotonia, hypertrophic cardiomyopathy, rhabdomyolysis | |Hypotonia, hypertrophic cardiomyopathy, rhabdomyolysis | ||
|Muscle biopsy, DNA testing | |Muscle biopsy, DNA testing | ||
Line 39: | Line 76: | ||
|GSD III | |GSD III | ||
|glycogen debrancher | |glycogen debrancher | ||
|Liver | |||
|Ketotic hypoglycemia, hepatomegaly | |Ketotic hypoglycemia, hepatomegaly | ||
|Fibroblast or liver enzyme assay, DNA testing | |Fibroblast or liver enzyme assay, DNA testing | ||
Line 45: | Line 83: | ||
|GSD IV | |GSD IV | ||
|glycogen branching enzyme | |glycogen branching enzyme | ||
|Liver | |||
|Hepatomegaly, cirrhosis, rare neuromuscular presentations | |Hepatomegaly, cirrhosis, rare neuromuscular presentations | ||
|Fibroblast, muscle, or liver biopsy, DNA testing | |Fibroblast, muscle, or liver biopsy, DNA testing | ||
Line 51: | Line 90: | ||
|[[McArdle Disease|GSD V (McArdle disease)]] | |[[McArdle Disease|GSD V (McArdle disease)]] | ||
|muscle phosphorylase | |muscle phosphorylase | ||
|Muscle | |||
|Fatigability, myoglobinuria, rhabdomyolysis | |Fatigability, myoglobinuria, rhabdomyolysis | ||
|Muscle biopsy, muscle enzyme assay, DNA testing | |Muscle biopsy, muscle enzyme assay, DNA testing | ||
Line 57: | Line 97: | ||
|GSD VI (Hers disease) | |GSD VI (Hers disease) | ||
|liver phosphorylase | |liver phosphorylase | ||
|Liver | |||
|Hepatomegaly, mild hypoglycemia | |Hepatomegaly, mild hypoglycemia | ||
|Liver biopsy and enzyme assay, DNA testing | |Liver biopsy and enzyme assay, DNA testing | ||
Line 63: | Line 104: | ||
|GSD VII (Tarui disease) | |GSD VII (Tarui disease) | ||
|phosphofructokinase deficiency | |phosphofructokinase deficiency | ||
|Muscle | |||
|Fatigability, myoglobinuria, rhabdomyolysis | |Fatigability, myoglobinuria, rhabdomyolysis | ||
|Muscle enzyme assay, DNA testing | |Muscle enzyme assay, DNA testing | ||
Line 69: | Line 111: | ||
|Phosphoglycerate kinase deficiency | |Phosphoglycerate kinase deficiency | ||
|Phosphoglycerate kinase | |Phosphoglycerate kinase | ||
|Muscle | |||
|Hemolysis, fatigability, myoglobinuria, CNS dysfunction, rhabdomyolysis | |Hemolysis, fatigability, myoglobinuria, CNS dysfunction, rhabdomyolysis | ||
|Muscle/RBC enzyme assay, DNA testing | |Muscle/RBC enzyme assay, DNA testing | ||
Line 75: | Line 118: | ||
|GSD IX | |GSD IX | ||
|phosphorylase kinase | |phosphorylase kinase | ||
|Muscle | |||
|Hepatomegaly, mild hypoglycemia, fatigability, exercise intolerance | |Hepatomegaly, mild hypoglycemia, fatigability, exercise intolerance | ||
|Liver/muscle biopsy, enzyme assay, DNA testing | |Liver/muscle biopsy, enzyme assay, DNA testing | ||
Line 81: | Line 125: | ||
|GSD X | |GSD X | ||
|phosphoglycerate mutase | |phosphoglycerate mutase | ||
|Muscle | |||
|Fatigability, myoglobinuria, exercise intolerance, rhabdomyolysis | |Fatigability, myoglobinuria, exercise intolerance, rhabdomyolysis | ||
|Muscle biopsy and enzyme assay, DNA testing | |Muscle biopsy and enzyme assay, DNA testing | ||
Line 87: | Line 132: | ||
|GSD XI | |GSD XI | ||
|lactate dehydrogenase A and B | |lactate dehydrogenase A and B | ||
|Muscle | |||
|Fatigability, myoglobinuria, rhabdomyolysis | |Fatigability, myoglobinuria, rhabdomyolysis | ||
|Muscle or RBC enzyme assay, DNA testing | |Muscle or RBC enzyme assay, DNA testing | ||
Line 93: | Line 139: | ||
|GLUT2 deficiency (Fanconi-Bickel syndrome) | |GLUT2 deficiency (Fanconi-Bickel syndrome) | ||
|GLUT2 | |GLUT2 | ||
|Liver | |||
|Growth retardation, renal Fanconi syndrome, galactosemia | |Growth retardation, renal Fanconi syndrome, galactosemia | ||
|Clinical features, DNA testing | |Clinical features, DNA testing | ||
Line 99: | Line 146: | ||
|GSD XII | |GSD XII | ||
|aldolase A | |aldolase A | ||
|Muscle | |||
|Hemolysis, jaundice, myoglobinuria, muscle weakness, fatigability, rhabdomyolysis | |Hemolysis, jaundice, myoglobinuria, muscle weakness, fatigability, rhabdomyolysis | ||
|Muscle or RBC enzyme assay, DNA testing | |Muscle or RBC enzyme assay, DNA testing | ||
Line 105: | Line 153: | ||
|GSD XIII | |GSD XIII | ||
|beta-enolase | |beta-enolase | ||
|Muscle | |||
|Exercise intolerance, increased CPK, rhabdomyolysis | |Exercise intolerance, increased CPK, rhabdomyolysis | ||
|Muscle biopsy, enzyme assay, DNA testing | |Muscle biopsy, enzyme assay, DNA testing | ||
Line 111: | Line 160: | ||
|GSD XIV | |GSD XIV | ||
|phosphoglucomutase 1 | |phosphoglucomutase 1 | ||
|Muscle | |||
|Exercise intolerance, myoglobinuria, increased CPK, rhabdomyolysis, myoglobinuria | |Exercise intolerance, myoglobinuria, increased CPK, rhabdomyolysis, myoglobinuria | ||
|Muscle biopsy, enzyme assay, DNA testing | |Muscle biopsy, enzyme assay, DNA testing | ||
Line 117: | Line 167: | ||
|GSD XV | |GSD XV | ||
|glycogenin 1 | |glycogenin 1 | ||
|Muscle | |||
|Muscle weakness, arrhythmias | |Muscle weakness, arrhythmias | ||
|<span | |<span class="oo-ui-widget oo-ui-widget-enabled oo-ui-buttonElement oo-ui-buttonElement-frameless oo-ui-iconElement oo-ui-labelElement oo-ui-buttonWidget" aria-disabled="false"></span>Muscle biopsy (glycogen depletion), DNA testing | ||
|No specific treatment | |No specific treatment | ||
|- | |- | ||
| colspan=" | | colspan="6" |* 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. | ||
|} | |} | ||
{{Reliable sources}} | {{Reliable sources}} | ||
[[Category:Neuromuscular Disorders]] | [[Category:Neuromuscular Disorders]] |
Revision as of 21:31, 5 March 2023
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.
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.
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 | 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 | Hypotonia, muscle weakness, hypertrophic cardiomyopathy, rhabdomyolysis | Fibroblast, leukocyte, muscle, or liver enzyme assay, DNA testing | Enzyme replacement therapy, commercial glucose polymers, liver transplantation |
GSD IIb* (Danon disease) | Lysosome-associated membrane protein 2 | Muscle | Hypotonia, hypertrophic cardiomyopathy, rhabdomyolysis | Muscle biopsy, DNA testing | No specific treatment |
GSD III | glycogen debrancher | Liver | 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 | 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 | Muscle | Fatigability, myoglobinuria, rhabdomyolysis | Muscle enzyme assay, DNA testing | No specific treatment |
Phosphoglycerate kinase deficiency | Phosphoglycerate kinase | Muscle | Hemolysis, fatigability, myoglobinuria, CNS dysfunction, rhabdomyolysis | Muscle/RBC enzyme assay, DNA testing | Bone marrow transplantation |
GSD IX | phosphorylase kinase | Muscle | Hepatomegaly, mild hypoglycemia, fatigability, exercise intolerance | Liver/muscle biopsy, enzyme assay, DNA testing | Commercial glucose polymers, liver transplantation |
GSD X | phosphoglycerate mutase | Muscle | Fatigability, myoglobinuria, exercise intolerance, rhabdomyolysis | Muscle biopsy and enzyme assay, DNA testing | No specific treatment |
GSD XI | lactate dehydrogenase A and B | 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 | Muscle | Hemolysis, jaundice, myoglobinuria, muscle weakness, fatigability, rhabdomyolysis | Muscle or RBC enzyme assay, DNA testing | No specific treatment |
GSD XIII | beta-enolase | Muscle | Exercise intolerance, increased CPK, rhabdomyolysis | Muscle biopsy, enzyme assay, DNA testing | No specific treatment |
GSD XIV | phosphoglucomutase 1 | Muscle | Exercise intolerance, myoglobinuria, increased CPK, rhabdomyolysis, myoglobinuria | Muscle biopsy, enzyme assay, DNA testing | No specific treatment |
GSD XV | glycogenin 1 | Muscle | Muscle weakness, arrhythmias | Muscle biopsy (glycogen depletion), DNA testing | No specific treatment |
* 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. |
Literature Review
- Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf
- Articles from all years: PubMed search, Google Scholar search.
- TRIP Database: clinical publications about evidence-based medicine.
- Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,