eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Glycogen-Storage Disease Type VI
Updated: Aug 4, 2008
Introduction
Background
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, GSD VI is caused by defects in the hepatic glycogen phosphorylase-activating system. The classic form of GSD VI results from a primary deficiency of liver phosphorylase. Other defects of the phosphorylase cascade system now included in this form of GSD 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]).
Pathophysiology
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.
Frequency
International
The overall frequency of GSD is 1 case per 20,000-25,000 persons, with approximately 30% of cases representing GSD VI, thus making GSD VI one of the most common forms of GSD. Approximately 75% of all cases of GSD VI result from the X-linked recessive forms of phosphorylase kinase deficiency.
Mortality/Morbidity
GSD 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 GSD 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.
Race
GSD VI is most common among members of the Mennonite religious group.1 A specific splice-site mutation in the liver phosphorylase gene (PYGL) occurs in the chromosomes of 3% of this religious group. GSD VI has an estimated frequency of 0.1% in the Mennonite population.
Sex
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 GSD VI are autosomal-recessive and equally affect both sexes.
Age
GSD VI usually manifests during early childhood.
Clinical
History
The most common presentation is in children aged 1-5 years, with a history of protuberant abdomen, growth retardation, and slight delay in motor milestones. These children may also have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.
Physical
Although children may have growth delay and short stature, adolescents and adults often have normal stature. The abdomen of a child with glycogen-storage disease type VI (GSD VI) usually protrudes, and abdominal examination reveals hepatomegaly and increased liver span. In some cases, hepatomegaly may be massive. However, splenomegaly is always absent. Adult patients may have mild or no hepatomegaly. Delay in motor milestones may be noted in a young child, and mild hypotonia and muscle weakness may be present. In an adolescent or adult, muscle strength and tone are usually normal. Some patients may have signs of peripheral neuropathy upon examination.
Causes
GSD VI results from a deficiency in the activity of one of several enzymes in the phosphorylase-activating cascade. Most cases result from defects of phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation. Phosphorylase b kinase is a multimeric unit consisting of 4 different subunits, each coded by a unique gene located on different chromosomes. Mutations in 3 genes (PHKA2, PHKB, and PHKG2) have been demonstrated in patients with phosphorylase b kinase deficiency.2
In addition, several subtypes of phosphorylase kinase deficiency have been identified, based on the tissues affected and the mode of inheritance (autosomal recessive or X-linked recessive).3 The most common subgroup is the X-linked recessive form.
Classic GSD VI results from a primary deficiency of liver phosphorylase (PYGL). Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported.
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 Overview: Glycogen-Storage Disease Type VI |
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| Treatment & Medication: Glycogen-Storage Disease Type VI |
| Follow-up: Glycogen-Storage Disease Type VI |
| References |
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References
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Newgard CB, Fletterick RJ, Anderson LA. The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. Am J Hum Genet. Apr 1987;40(4):351-64. [Medline].
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Further Reading
Keywords
glycogen storage disease type VI, Hers disease, Hers' disease, GSD, GSD VI, glycogenosis, liver phosphorylase deficiency, glycogen phosphorylase, liver phosphorylase, hepatic phosphorylase kinase, X-linked liver glycogenosis, type 6 glycogenosis, hepatophosphorylase deficiency glycogenosis, hypoglycemia, hyperketosis, growth retardation, hepatomegaly, hyperlacticacidemia, hyperuricemia, hyperlipidemia, renal tubule acidosis, phosphorylase kinase deficiency, severe cardiomyopathy, short stature
