Glycogen storage diseases: An update

Table 1 Overview of glycogen storage diseases

GSD type (eponym)	OMIM#	Defective enzyme or transporter	Gene/inheritance	Gene location	Primary tissue involvement	Distinctive features
GSD-0	GSD-0a: 240600	Liver glycogen synthase	GYS2/AR	12p12.1	Liver	No hepatomegaly. Postprandial hyperglycemia, glycosuria, and hyperlactatemia. Extremely low amount of glycogen in liver tissue
	GSD-0b: 611556	Muscle glycogen synthase	GYS1/AR	19q13.33	Muscle	Cardiac involvement, risk of sudden cardiac arrest
GSD-I (von Gierke)	GSD-Ia: 232200	Glucose-6-phosphatase	G6PC/AR	17q.21	Liver	Coagulopathy, anemia, osteopenia, osteoporosis, renal dysfunction, HA, HCC
	GSD-Ib: 232220	Glucose-6-phosphatase transporter	SLC37A4/AR	11q23.3	Liver	Neutropenia, neutrophil dysfunction, recurrent infections, oral and intestinal mucosal ulcers, IBD, autoimmunity
GSD-II (Pompe)	232300	Acid α-glucosidase	GAA/AR	17q25.3	Muscle	Cardiomyopathy, infantile-onset form. Muscle weakness, late-onset form
Danon disease (formerly GSD-IIb)	300257	Lysosome-associated membrane protein-2	LAMP2/XLD	Xq24	Muscle	Skeletal and cardiac myopathy, arrhythmia, intellectual disability
GSD of heart	600858	AMP-activated protein kinase, γ-2 regulatory subunit	PRKAG2/AD	7q36.1	Muscle	Severe ventricular hypertrophy. Electrocardiographic preexcitation and conduction system disease. Premature sudden cardiac death (< 40 yr)
GSD of heart, lethal congenital	261740	AMP-activated protein kinase, γ-2 noncatalytic subunit	PRKAG2/AD	7q36.1	Muscle	Some mutations (R531Q, R384T) cause more severe phenotype. Fetal onset, extreme cardiomegaly, death in infancy
GSD-III (Cori/Forbes)	IIIa/IIIb: 232400	Glycogen debrancher enzyme	AGL/AR	1p21.2	IIIa: Liver + muscle; IIIb: Liver	Liver fibrosis, cirrhosis, HA, HCC (as a complication of cirrhosis). IIIa: Elevated CK, motor developmental delay, myopathy, cardiomyopathy
GSD-IV (Andersen)	232500	Glycogen branching enzyme	GBE1/AR	3p12.2	Liver	Classical hepatic form (rapidly progressive liver disease, HSM, cirrhosis, HCC). Non-progressive hepatic form. Neuromuscular presentation (perinatal, congenital, childhood and adult forms). Myopathy, cardiomyopathy, neuropathy, CNS involvement, APBD. Amylopectin aggregations in liver
GSD-V (McArdle)	232600	Muscle glycogen phosphorylase	PYGM/AR	11q13.1	Muscle	Exercise intolerance, muscle cramps, rhabdomyolysis, myoglobinuria, “second wind” phenomenon
GSD-VI (Hers)	232700	Liver glycogen phosphorylase	PYGL/AR	14q22.1	Liver	Phenotypic variability (overlap with GSD-IX). Severe hepatic involvement reported. Mild hypotonia and cardiopathy reported. Excessive glycogen accumulation with structurally normal glycogen in liver tissue. Enzyme deficiency in erythrocytes, leukocytes
GSD-VII (Tarui)	232800	Muscle phosphofructokinase	PFKM/AR	12q13.11	Muscle	Exertional myopathy, exercise intolerance, muscle cramps, hemolytic anemia. Rapidly progressive infantile form (multisystem involvement, seizures, cardiomyopathy)
GSD-IX	GSD-IXa1 (XLG-1): 306000	Phosphorylase kinase, α-subunit, liver	PHKA2/XLR	Xp22.13	Liver	The most common subtype. Symptomatic female carriers due to X chromosome inactivation. Clinical symptoms and laboratory abnormalities gradually disappear with age. Severe phenotypes reported
	GSD-IXb: 261750	Phosphorylase kinase, β-subunit	PHKB/AR	16q12.1	Liver	Marked accumulation of glycogen in both liver and muscle. Muscle symptoms are generally mild or absent
	GSD-IXc: 613027	Phosphorylase kinase, γ-subunit	PHKG2/AR	16p11.2	Liver	More severe phenotype with increased risk for liver fibrosis and cirrhosis
	GSD-IXd: 300559	Phosphorylase kinase, α-subunit, muscle	PHKA1/XLR	Xq13.1	Muscle	Muscle weakness and muscle cramps during exercise. Mostly in adults
GSD-X	261670	Muscle phosphoglycerate mutase	PGAM2/AR	7p13	Muscle	Exercise intolerance, muscle cramps and pain, rhabdomyolysis, myoglobinuria
Fanconi-Bickel syndrome (formerly GSD-XI)	227810	Glucose transporter 2	SLC2A2/AR	3q26.2	Liver	Hepatorenal involvement. Proximal renal tubular dysfunction. Osteoporosis/rickets. Different patterns of dysglycemia. Postprandial hyperglycemia and hypergalactosemia
GSD-XI	612933	Lactate dehydrogenase A	LDHA/AR	11p15.1	Muscle	Exertional myoglobinuria, easy fatigability, exercise induced myalgia, erythematosquamous skin lesions on the extensor surfaces of the extremities
GSD-XII	611881	Fructose-1,6-bisphosphate aldolase A	ALDOA/AR	16p11.2	Muscle	Rhabdomyolysis induced by fever and/or exercise, hemolytic anemia with or without myopathy or cognitive dysfunction
GSD-XIII	612932	Enolase 3 (β-enolase)	ENO3/AR	17p13.2	Muscle	Exercise intolerance, exercise induced myalgia, muscle weakness
GSD-XV	613507	Glycogenin-1	GYG1/AR	3q24	Muscle	Ventricular arrhythmogenic cardiomyopathy, progressive muscle weakness

GSD: Glycogen storage disease; HA: Hepatic adenoma; HCC: Hepatocellular carcinoma; AR: Autosomal recessive; XLR: X-linked recessive; XLD: X-linked dominant; CK: Creatinine kinase; CNS: Central nervous system; APBD: Adult polyglucosan body disease: IBD: Inflammatory bowel disease.