Glycogen Storage Diseases Molecular Basis of the Disease

Glycogen storage diseases (GSD) are a group of heterogeneous genetic disorders characterized by the accumulation of glycogen in tissues. Eight types of GSD that vary significantly in clinical phenotypes, age of onset, and affected organs have been identified, with an overall incidence of 1 in 20,000 to 25,000 live births.20 They are caused by defects in one of eight genes in glycogen metabolism. Glycogen storage diseases type I to type VII are inherited in an autosomal recessive pattern, and GSD IX is X-linked recessive. A summary of the eight GSD types is presented in Table 8-2. GSD I, II, III, and IV, which are the most common and severe types, are discussed.

GSD I (von Gierke disease) is characterized by hepatomegaly, kidney enlargement, growth retardation, hypoglycemia, hyperuricemia, and hyperlipemia. GSD I has two major subgroups, GSD 1a and GSD 1b. The subgroup GSD1a is caused by deficiency of glucose-6-phosphatase

Table 8-2. Glycogen Storage Diseases


Defective Enzymes

Gene Location

Inheritance Pattern

GSD I (von Gierke disease)

GSDla: Glucose-6-phosphatase



GSDlb: Glucose-6-phosphate translocase



GSD II (Pompe disease)

Lysosomal acid a-1,4-glucosidase



GSD III (Cori disease)




GSD IV (Andersen disease)

Branching enzyme (a-1,4 to a-1,6)



GSD V (McArdle disease)

Phosphorylase (muscle)



GSD VI (Hers disease)

Phosphorylase (liver)








Phosphorylase kinase



(G6Pase), which converts glucose-6-phosphate to glucose and phosphate, the last step in glycogenolysis. The G6PC gene encoding G6Pase is located on 17q21. The subgroup GSD1b results from deficiency in glucose-6-phosphate translocase, encoded by G6PTL gene located on 11q23. Common mutations vary in different ethnic groups.20 The prevalent mutations for GSD1a in different ethnic groups are: R83C and Q347X in caucasians; R83C in Ashkenazi Jews; 459insTA and R83C in Hispanics; V166G in Muslim Arabs; R83H and G727T in Chinese; and G727T in Japanese. For GSD1b, two common mutations, G339C and 1211delCT, are present in whites, while W118R is prevalent in Japanese.

GSD II, also known as Pompe disease, is a lysosomal storage disease caused by the inability to degrade glycogen due to defects in acid a-1,4-glucosidase. The phenotypes range from the most severe infantile disorder to juvenile-and late-onset adult myopathy. Patients with the infantile form usually die from cardiomyopathy before they reach 2 years of age. Acid a-1,4-glucosidase is encoded by a gene (GAA) located at 17q25, and different forms of the protein are obtained by different proteolytic processing. Common mutations have been identified in different ethnic groups.

Patients affected with GSD III, also known as Cori disease, have symptoms similar to but milder than those associated with GSD I. The gene encoding amylo-1-6-glucosidase has 35 exons with 4596bp of coding region and a long 3' UTR of 2371bp. Molecular testing of GSD III is difficult and impractical due to the large size of the gene and the lack of predominant mutations.

GSD IV, also known as Andersen disease, is caused by glycogen branching enzyme deficiency that results in glycogen that is abnormal and insoluble. Intracellular accumulations occur in the liver, brain, heart, skeletal muscles, and skin fibroblasts. Neonates with GSD IV appear normal at birth but develop hepatomegaly and failure to thrive in the first year of life. Patients develop progressive cirrhosis and usually die of liver failure by 2 to 5 years of age. Mutations in the branching enzyme (a-1,4 to a-1,6) have been identified in a limited number of patients.

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