Glycogen storage disease

Glycogen Storage Disease (GSD)

The molecular structure of glycogen, central to understanding Glycogen Storage Diseases.

Glycogen Storage Disease (GSD), also known as glycogenosis and dextrinosis, refers to a group of metabolic disorders characterized by enzyme deficiencies affecting glycogen synthesis, glycogen breakdown, or glycolysis (the breakdown of glucose).

typically in muscles and/or liver cells.

GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn error of metabolism (genetically defective enzymes) involved in these processes. In livestock, acquired GSD is caused by intoxication with the alkaloid castanospermine.

Types

Type (Eponym)	Enzyme deficiency (Gene)	Incidence (births)	Hypo- glycemia?	Hepato- megaly?	Hyperlip- idemia?	Muscle symptoms	Development/ prognosis	Other symptoms
GSD 0	Glycogen synthase (GYS2)	?	Yes	No	No	Occasional muscle cramping	Growth failure in some cases
GSD I / GSD 1 (von Gierke's disease)	Glucose-6-phosphatase (G6PC / SLC37A4)	1 in 50,000 – 100,000	Yes	Yes	Yes	None	Growth failure	Lactic acidosis, hyperuricemia
GSD II / GSD 2 (Pompe disease )	Acid alpha-glucosidase (GAA)	1 in 13,000.	No	Yes	No	Muscle weakness	Progressive proximal skeletal muscle weakness with varied timeline to threshold of functional limitation (early childhood to adulthood). Approximately 15% of the Pompe population is classified as infantile Pompe which is typically deadly within the first year if untreated.	Heart failure (infantile), respiratory difficulty (due to muscle weakness)
GSD III / GSD 3 (Cori's disease or Forbes' disease)	Glycogen debranching enzyme (AGL)	1 in 100,000	Yes	Yes	Yes	Myopathy
GSD IV / GSD 4 (Andersen disease)	Glycogen branching enzyme (GBE1)	1 in 500,000	No	Yes, also cirrhosis	No	Myopathy and dilated cardiomyopathy	Failure to thrive, death at age ~5 years
GSD V / GSD 5 (McArdle disease)	Muscle glycogen phosphorylase (PYGM)	1 in 100,000 – 500,000	No	No	No	Exercise-induced cramps, Rhabdomyolysis		Renal failure by myoglobinuria, second wind phenomenon
GSD VI / GSD 6 (Hers' disease)	Liver glycogen phosphorylase (PYGL) Muscle phosphoglycerate mutase (PGAM2)	1 in 65,000 – 85,000	Yes	Yes	Yes	None	initially benign, developmental delay follows.
GSD VII / GSD 7 (Tarui's disease)	Muscle phosphofructokinase (PKFM)	1 in 1,000,000	No	No	No	Exercise-induced muscle cramps and weakness	developmental delay	In some haemolytic anaemia
GSD IX / GSD 9	Phosphorylase kinase (PHKA2 / PHKB / PHKG2 / PHKA1)	?	Yes	Yes	Yes	None	Delayed motor development, Developmental delay
GSD X / GSD 10	Phosphoglycerate mutase (PGAM2)	?	?	?	?	Exercise-induced muscle cramps and weakness		Myoglobinuria
GSD XI / GSD 11	Muscle lactate dehydrogenase (LDHA)	?	?	?	?
Fanconi-Bickel syndrome formerly GSD XI / GSD 11, no longer considered a GSD	Glucose transporter (GLUT2)	?	Yes	Yes	No	None
GSD XII / GSD 12 (Aldolase A deficiency)	Aldolase A (ALDOA)	?	No	In some	No	Exercise intolerance, cramps. In some Rhabdomyolysis.		Hemolytic anemia and other symptoms
GSD XIII / GSD 13	β-enolase (ENO3)	?	No	?	No	Exercise intolerance, cramps	Increasing intensity of myalgias over decades	Serum CK: Episodic elevations; Reduced with rest
GSD XV / GSD 15	Glycogenin-1 (GYG1)	Rare	No	No	No	Muscle atropy	Slowly progressive weakness over decades	None

Remarks:

• Some GSDs have different forms, e.g. infantile, juvenile, adult (late-onset).
• Some GSDs have different subtypes, e.g. GSD1a / GSD1b, GSD9A1 / GSD9A2 / GSD9B / GSD9C / GSD9D.
• GSD type 0: Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.
• GSD type VIII (GSD 8): In the past it was considered a distinct condition, however it is now classified with GSD type VI or GSD IXa1; it has been described as X-linked recessive inherited.
• GSD type XI (GSD 11): Fanconi-Bickel syndrome, hepatorenal glycogenosis with renal Fanconi syndrome, no longer considered a glycogen storage disease.
• GSD type XIV (GSD 14): Now classed as Congenital disorder of glycosylation type 1 (CDG1T), affects the phosphoglucomutase enzyme (gene PGM1).
• Lafora disease is considered a complex neurodegenerative disease and also a glycogen metabolism disorder.

Diagnosis

Micrograph of glycogen storage disease with histologic features consistent with Cori disease. Liver biopsy. H&E stain.

Treatment

Treatment is dependent on the type of glycogen storage disease. GSD I is typically treated with frequent small meals of carbohydrates and cornstarch, called modified cornstarch therapy, to prevent low blood sugar, while other treatments may include allopurinol and human granulocyte colony stimulating factor.

Epidemiology

Overall, according to a study in British Columbia, approximately 2.3 children per 100,000 births (1 in 43,000) have some form of glycogen storage disease. In the United States, they are estimated to occur in 1 per 20,000–25,000 births. Dutch incidence rate is estimated to be 1 per 40,000 births. While a Mexican incidence showed 6.78:1000 male newborns.

Types of GSD

GSD is categorized into different types based on the enzyme deficiency and affected tissues:

• Type I (Von Gierke Disease): Affects glucose release from the liver.
• Type II (Pompe Disease): Involves muscle and liver glycogen breakdown.
• Type III (Cori or Forbes Disease): Affects liver and muscle glycogen breakdown.
• Others: There are several other types, each with specific enzyme deficiencies.

Causes

GSDs are caused by genetic mutations that result in the deficiency of enzymes responsible for glycogen metabolism. These are typically inherited in an autosomal recessive pattern.

Symptoms

Symptoms vary depending on the type of GSD but may include:

• Hypoglycemia (low blood sugar)
• Muscle weakness or cramps
• Enlarged liver
• Growth retardation

Diagnosis

Genetic testing, a tool used in the diagnosis of GSD.

Diagnosis of GSD involves:

• Blood tests to measure enzyme levels
• Liver or muscle biopsy
• Genetic testing

Treatment

Treatment depends on the specific type of GSD:

• Dietary management (e.g., frequent high-carbohydrate meals to prevent hypoglycemia in Type I GSD)
• Enzyme replacement therapy for certain types like Type II GSD
• Supportive treatments for symptoms like muscle cramps

External Links

• Genetic and Rare Diseases Information Center - Glycogen Storage Disease Type I
• Mayo Clinic - Glycogen Storage Disease

Classification	ICD-10: E74.0 ICD-9-CM: 271.0 MeSH: D006008