Inheritance for glycogen storage diseases (GSDs) is autosomal recessive except for GSD type VIII/IX, which is X-linked. Incidence is estimated at about 1/25,000 births, which may be an underestimate because milder subclinical forms may be undiagnosed. For a more complete listing of glycogen storage diseases, see table Glycogen Storage Diseases and Disorders of Gluconeogenesis.
Age of onset, clinical manifestations, and severity vary by type, but symptoms and signs are most commonly those of hypoglycemia and myopathy.
Diagnosis of glycogen storage diseases is suspected by history, examination, and detection of glycogen and intermediate metabolites in tissues by MRI or biopsy. Diagnosis is confirmed by DNA analysis or less commonly by detecting a significant decrease of enzyme activity in liver (types I, III, VI, and VIII/IX), muscle (types IIb, III, VII, and VIII/IX), skin fibroblasts (types IIa and IV), or red blood cells (type VII) or by lack of an increase in venous lactate with forearm activity/ischemia (types V and VII). (See also testing for suspected inherited disorders of metabolism.)
Prognosis and treatment of glycogen storage diseases vary by type, but treatment typically includes dietary supplementation with cornstarch to provide a sustained source of glucose for the hepatic forms of GSD and exercise avoidance for the muscle forms.
Defects in glycolysis (rare) may cause syndromes similar to GSDs. Deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase mimic the myopathies of GSD types V and VII; deficiencies of glucose transport protein 2 (Fanconi-Bickel syndrome) mimic the hepatopathy of other GSD types (eg, I, III, IV, VI).
Glycogen Storage Diseases and Disorders of Gluconeogenesis
Disease (OMIM Number) |
Defective Proteins or Enzymes |
Comments |
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GSD I (von Gierke disease) |
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Most common type of GSD I: Ia (> 80%) Onset: Before 1 year Clinical features: Before 1 year, severe hypoglycemia, lactic acidosis, and hepatomegaly; later, hepatic adenomas, renomegaly with progressive renal insufficiency and hypertension, short stature, hypertriglyceridemia, hyperuricemia, platelet dysfunction with epistaxis, and anemia In type Ib, less severe but includes neutropenia, neutrophil dysfunction with recurrent infections, and inflammatory bowel disease Treatment: Uncooked cornstarch 1.5–2.5 g/kg orally every 4–6 hours or lactose-free formula with maltodextrin to maintain normoglycemia; nocturnal feedings (important); fructose and galactose restriction; for lactic acidosis, bicarbonate 0.25 to 0.5 mmol/kg 4 times a day; allopurinol to keep uric acid to < 6.4 mg/dL; liver and kidney transplantation (may be successful) For type Ib patients with neutropenia, G-CSF |
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Type Ia (232200*) |
Glucose-6-phosphatase |
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Type Ib (232220*) |
Glucose-6-phosphate translocase T1 |
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Type Ic (232240*) |
Glucose-6-phosphate translocase T2 |
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Type Id (232240*) |
Glucose-6-phosphate translocase T3 |
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GSD II (Pompe disease; 232300*) |
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Onset: Infancy, childhood, or adulthood; residual enzyme activity in child and adult forms Clinical features: In infantile form, cardiomyopathy with heart failure, severe hypotonia, macroglossia In juvenile and adult forms, skeletal myopathy with delayed motor development, progressive peripheral and respiratory muscle weakness In type IIb, intellectual disability Treatment: For symptomatic patients, enzyme replacement (alglucosidase alfa) For cardiomyopathy, heart transplantation |
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Type IIa |
Lysosomal acid alpha-glucosidase |
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Type IIb (Danon) |
Lysosomal membrane protein-2 |
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GSD III (Forbes disease, Cori disease, limit dextrinosis; 232400*) |
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Frequency: IIIa, 85%; IIIb, 15%; IIIc and IIId, rare Onset: Infancy or childhood Clinical features: In type IIIa, liver and muscle involvement with features of types Ia and II In type IIIb, only liver involvement plus features of type Ia In types IIIc and IIId, various features depending on tissue affected Treatment: Uncooked cornstarch and continuous feeding to maintain normoglycemia, high-protein diet to stimulate gluconeogenesis |
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Types IIIa and IIIb |
Debrancher enzyme (amyloglucosidase and oligoglucanotransferase) |
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Type IIIc |
Amyloglucosidase only |
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Type IIId |
Oligoglucanotransferase only |
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GSD IV (Andersen disease; 232500*) |
Branching enzyme |
Onset: Early infancy; rarely, the neonatal period, late childhood, or adulthood (manifesting as a variant nonprogressive or a neuromuscular form) Clinical features: Hepatomegaly with progressive cirrhosis and hypoglycemia, esophageal varices, and ascites; splenomegaly; failure to thrive In neuromuscular forms, hypotonia and muscle atrophy Treatment: None known For cirrhosis, liver transplantation, which treats the primary disease as well |
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GSD V (McArdle disease; 232600*) |
Muscle phosphorylase |
Onset: Adolescence or early adulthood Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis Treatment: Carbohydrate administration before exercise, high-protein diet |
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GSD VI (Hers disease; 232700*) |
Liver phosphorylase |
Frequency: Rare Onset: Early childhood Clinical features: Benign course with symptoms lessening with aging; growth retardation, hepatomegaly, hypoglycemia, hyperlipidemia, ketosis Treatment: Uncooked cornstarch to maintain normoglycemia |
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GSD VII (Tarui disease; 232800*) |
Phosphofructokinase |
Onset: Middle childhood Clinical features: Exercise intolerance due to muscle cramps, rhabdomyolysis, hemolysis Treatment: Nonspecific, avoidance of excessive exercise |
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GSD VIII/IX† |
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Onset: Heterogeneous Clinical features: Heterogeneous; hepatomegaly, growth retardation, muscle hypotonia, hypercholesterolemia Treatment: Nonspecific |
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Type IXa1 and IXa2 (306000*) |
X-linked phosphorylase kinase |
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Type IXb (261750*) |
Liver and muscle phosphorylase kinase |
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Type IXc (613027*) |
Liver phosphorylase kinase |
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Type IXd (300559*) |
Muscle phosphorylase kinase |
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GSD 0 (240600*) |
Glycogen synthase |
Onset: Variable but often after cessation of nighttime feedings or intercurrent illness Clinical features: Fasting hypoglycemia and ketosis, postprandial lactic acidosis Treatment: Frequent protein-rich meals, uncooked cornstarch at bedtime |
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Fanconi-Bickel syndrome (227810*) |
Glucose transporter-2 |
Onset: Infancy Clinical features: Failure to thrive, abdominal distention, hepatomegaly, renomegaly, mild fasting hypoglycemia and hyperlipidemia, glucose intolerance, renal Fanconi syndrome Treatment: Diet similar to that for diabetes, high fructose intake to maintain normoglycemia, replacement of renally lost electrolytes, vitamin D |
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Fructose 1,6-biphosphatase deficiency (229700*) |
Fructose 1,6-biphosphatase |
Onset: Infancy or early childhood Clinical features: Episodic hyperventilation, apnea, hypoglycemia, ketosis, or lactic acidosis; episodes provoked by fasting, febrile infection, or ingestion of fructose, sorbitol, or glycerol Treatment: Avoidance of fasting and fructose, sorbitol, and glycerol; uncooked cornstarch |
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Phosphoenolpyruvate carboxykinase deficiency (261680*) |
Phosphoenolpyruvate carboxykinase |
Onset: Childhood Clinical features: Failure to thrive, hypotonia, hepatomegaly, lactic acidosis, hypoglycemia Treatment: Avoidance of fasting, uncooked cornstarch |
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* For complete gene, molecular, and chromosomal location information, see the Online Mendelian Inheritance in Man® (OMIM®) database. † Former type VIII is now included in type IXa. G-CSF = granulocyte colony-stimulating factor; GSD = glycogen storage disease. |
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