Background
Glycogen storage disease type VI (GSD VI), also known as Hers disease, is a type of hepatic glycogenosis characterized by mild clinical manifestations and a benign course. Individuals with GSD VI typically exhibit hepatomegaly, growth retardation, and variable but mild episodes of fasting hypoglycemia and hyperketosis during early childhood. [1] Hyperlacticacidemia and hyperuricemia are characteristically absent. [2] In addition, affected individuals may demonstrate elevated levels of serum transaminases, hyperlipidemia, hypotonia, and muscle weakness. These clinical features and biochemical abnormalities generally resolve by puberty. Rare variants of GSD VI may manifest as proximal renal tubule acidosis, myopathy, peripheral neuropathy, or fatal cardiomyopathy. GSD VI is caused by a deficiency in the hepatic glycogen phosphorylase enzyme.
Pathophysiology
Hepatic glycogen phosphorylase, the rate-limiting enzyme of glycogenolysis, or glycogen breakdown, is activated (active in its phosphorylated form) by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase. Enzyme deficiency at any point along this pathway results in impaired cleavage of glucose units from the non-reducing ends of the glycogen molecule. In most patients, the enzyme deficiency is incomplete, and gluconeogenesis remains intact. [3] As a result, the ability of the liver to maintain normal glucose levels during fasting may be partially impaired, resulting in an increased risk of mild fasting hypoglycemia and associated hyperketosis.
Interestingly, recent studies have found that individuals with GSD VI do not always exhibit hyperglycemia with ketonemia. [3] Increased levels of urinary ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) are often 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 levels of serum transaminases with no other evidence of liver dysfunction.
Glycogen storage disease type IX is a related GSD that involves mutation of the glycogen phosphorylase kinase encoding gene that is responsible for phosphorylating (and thus activating) liver glycogen phosphorylase. [4] The presentation of GSD type IX is therefore similar to that of GSD type VI, so next-generation sequencing should be used to confirm the diagnosis. [5]
Epidemiology
Frequency
GSD VI is very rare and is most common among members of the Mennonite religious group. [6] A specific splice-site mutation in the liver glycogen phosphorylase gene (PYGL) occurs in the genomes of 3% of this religious group. GSD VI has an estimated frequency of 0.1% in the Mennonite population.
Approximately 40 different mutations in the PYGL gene have been reported in the literature. [7, 8, 5] A high frequency of missense mutations was found. [9]
Mortality/Morbidity
Glycogen storage disease type VI has a rather benign course, with risks of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adults with GSD VI exhibit normal stature, motor function, and biochemical parameters. A subset of patients who exhibit high levels of transaminases are at an increased risk of liver fibrosis or cirrhosis. [4] Hepatocellular carcinoma has been reported in one patient with GSD VI. [10]
Sex
All forms of GSD VI are autosomal-recessive and affect both sexes equally.
Age
GSD VI usually manifests during early childhood.
Prognosis
Individuals with GSD VI have an excellent prognosis for normal stature and development, even without dietary management during childhood. Most affected individuals exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty. The overall prognosis of rare GSD VI variants with associated muscle or cardiac involvement depends on the severity of organ dysfunction. For the rare patient with suspected malignant transformation of hepatocellular adenomas, the treatment of choice is orthoptic liver transplantation. [10]
Patient Education
Educate patients with GSD VI and their parents about proper diet management and fasting avoidance techniques. Parents and primary physicians of an affected child with episodes of fasting hypoglycemia should know how to administer intravenous glucose solutions during periods of acute illness with decreased oral intake.
