Genetics of Glycogen-Storage Disease Type VI
- Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD more...
Glycogen-storage disease type VI (GSD VI) represents a heterogeneous group of hepatic glycogenoses with mild clinical manifestations and benign course. Patients typically exhibit prominent hepatomegaly, growth retardation, and variable but mild episodes of fasting hypoglycemia and hyperketosis during childhood. Hyperlacticacidemia and hyperuricemia are characteristically absent. In addition, patients may demonstrate elevated serum transaminases, hyperlipidemia, hypotonia, and muscle weakness. These clinical features and biochemical abnormalities generally resolve by puberty. Rare variants may have associated proximal renal tubule acidosis, myopathy, peripheral neuropathy, or fatal cardiomyopathy.
In general, glycogen-storage disease type VI is caused by defects in the hepatic glycogen phosphorylase-activating system. The classic form of glycogen-storage disease type VI results from a primary deficiency of liver phosphorylase. Other defects of the phosphorylase cascade system now included in this form of glycogen-storage disease include phosphorylase b kinase deficiency (formerly glycogen-storage disease type IX [GSD IX] and glycogen-storage disease type VIII [GSD VIII]) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase deficiency (formerly glycogen-storage disease type X [GSD X]).
Phosphorylase, the rate-limiting enzyme of glycogenolysis or glycogen breakdown, is activated by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase. Enzyme deficiency anywhere along this pathway results in impaired cleavage of glucose units from the straight chains of the glycogen molecule. In most patients, the enzyme deficiency is incomplete, and gluconeogenesis remains intact. As a result, the ability of the liver to maintain normoglycemia during fasting may be partially impaired, resulting in an increased risk of mild fasting hypoglycemia and associated hyperketosis. Increased levels of urinary ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) are proportional to the degree of fasting. Other biochemical derangements include mild-to-moderate hyperlipidemia, with elevation of serum cholesterol more than elevation of triglycerides and variably elevated serum transaminases with no other evidence of liver dysfunction.
The overall frequency of glycogen-storage disease is 1 case per 20,000-25,000 persons, with approximately 30% of cases representing glycogen-storage disease type VI, thus making glycogen-storage disease type VI one of the most common forms of glycogen-storage disease. Approximately 75% of all cases of glycogen-storage disease type VI result from the X-linked recessive forms of phosphorylase kinase deficiency. Case reports suggest that the X-linked form of glycogen-storage disease type VI may be undiagnosed or underestimated.
Glycogen-storage disease type VI has a rather benign course, with risk of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adult patients exhibit normal stature, motor function, and biochemical parameters. A subset of patients with the autosomal recessive form of glycogen-storage disease type VI due to deficiency of phosphorylase kinase activity may be at increased risk for liver cirrhosis. Rare variants may cause muscle dysfunction, peripheral neuropathy, proximal renal tubule acidosis, or severe cardiomyopathy. The occurrence of hepatocellular carcinoma in one patient with glycogen-storage disease type VI has been reported.
Glycogen-storage disease type VI is most common among members of the Mennonite religious group. A specific splice-site mutation in the liver phosphorylase gene (PYGL) occurs in the chromosomes of 3% of this religious group. Glycogen-storage disease type VI has an estimated frequency of 0.1% in the Mennonite population.
The X-linked recessive form of liver phosphorylase kinase deficiency is primarily expressed in affected males, although asymptomatic males and heterozygous (carrier) females with mild symptoms have been reported. All other forms of glycogen-storage disease type VI are autosomal-recessive and equally affect both sexes.
Glycogen-storage disease type VI usually manifests during early childhood.
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