Genetics of Glycogen Storage Disease Type VI (Hers Disease)

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.

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]

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.

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]

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.

The most common presentation of glycogen storage disease type VI (GSD VI), also known as Hers disease, is in children aged 1-5 years who have a history of protuberant abdomen, growth retardation, and slight delay in motor milestones. These children may also have a history of mild fasting hypoglycemia. Some individuals with GSD VI remain asymptomatic, and routine physical examination reveals hepatomegaly.

A 2003 case report described a 9-year-old boy diagnosed with GSD VI who had short stature and hepatomegaly.[11] Notably, this patient did not show fasting hypoglycemia, and DNA sequencing indicated a missense mutation in exon 6 of the PYGL gene.

In 2017, a child from India who presented with hepatomegaly, short stature, and elevated levels of transaminases was diagnosed with GSD VI at age 2.5 years.[12] The diagnosis of GSD VI was confirmed via next-generation sequencing (NGS), which uncovered a nonsense mutation in exon 11 of the PYGL gene that had not previously been reported.[12]

A 2015 report described a 3-year-old white girl diagnosed with GSD VI who presented with recurrent ketotic hypoglycemia but no hepatomegaly.[13]

Although children with GSD VI may have growth delay and short stature, adolescents and adults with the condition often have normal stature. The abdomen of a child with 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. Adults with GSD VI may have mild or no hepatomegaly. Delays in motor milestones may be noted in young children with GSD VI. In adolescents and adults with GSD VI, muscle strength and tone are usually normal. Neuropathy can be associated with the disease; two children with GSD VI were reported to have axonopathy.[14]

Classic GSD VI results from a primary deficiency of hepatic glycogen phosphorylase. The gene that encodes liver glycogen phosphorylase, PYGL, resides on chromosome 14q22.1.[15, 12]

The extent and severity of biochemical abnormalities vary in children with glycogen storage disease type VI (GSD VI), also known as Hers disease. Blood glucose levels should be assessed; after a short fast (3-5 hours), mild hypoglycemia may develop in younger patients.

Levels of urine ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) may be elevated during a short fast and are proportional to the degree of fasting. Mild hyperlipidemia may be present, with serum cholesterol elevations higher than serum triglycerides. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may be mildly elevated. Other liver function test findings are usually normal in the absence of cirrhosis.

Patients with proximal renal tubule acidosis may have increased urine pH levels with abnormal levels of calcium, phosphate, and amino acids and decreased blood pH levels with a normal anion gap.

Liver volume quantitation may be performed using abdominal MRI or CT scanning.

Evaluation of a patient with suspected GSD VI requires monitored assessment of fasting adaptation in an inpatient setting. After 3-5 hours of fasting, patients with GSD VI typically exhibit hypoglycemia with a normal serum lactic acid level. This same pattern occurs in patients with glycogen storage disease type 0 (GSD 0), glycogen storage disease type III (GSD III), and hereditary fructose intolerance (HFI). HFI can be identified via development of hypoglycemia and increased lactic acid after oral fructose loading.

A fasted glucagon challenge may further narrow the field of diagnostic possibilities. Patients with GSD VI may have a normal hyperglycemic response without change in lactic acid after glucagon administration, although results may be inconclusive.

Molecular diagnostic testing for a specific mutation in the PYGL gene may be used to identify carriers and affected children in the Mennonite population.

Definitive diagnosis of GSD VI requires a liver biopsy and enzyme assay. Histologic examination and determination of glycogen content may also be performed.

An enzyme assay can be performed in more easily obtainable cells, including RBCs and WBCs. However, owing to the presence of isoenzymes, normal enzyme activity in these cells does not exclude the possibility of isolated hepatic involvement in an affected patient.

Histologic analysis of the liver typically reveals glycogen-distended hepatocytes. The accumulated glycogen (ie, alpha particles, rosette form) appears frayed or burst and is less compact than the glycogen present in glycogen storage disease type I or III. Interlobular fibrous septa and low-grade inflammatory changes may be seen. Liver glycogen content may also be increased as much as 4-fold, although muscle glycogen remains normal in structure and quantity.

Patients with glycogen storage disease type VI (GSD VI), also known as Hers disease, should be referred to a dietitian experienced with glycogen storage diseases (GSDs) and the management of disorders associated with an increased risk of hypoglycemic episodes.

Dietary management is the only form of treatment necessary for this rather mild glycogen storage disease. Avoiding prolonged fasting and eating frequent meals are recommended.[16] A high-protein diet is recommended for patients with GSD VI who exhibit fasting hypoglycemia.[4, 17]

A small 2015 study reported the use of extended-release cornstarch to maintain normal glucose levels during overnight fasting in patients with different types of GSDs, including GSD VI. It was found to be beneficial in some patients.[18]

Activity should not be restricted unless significant hepatomegaly is present; recommend that patients with significant hepatomegaly avoid contact sports and activities.

Instruct patients who exhibit episodes of fasting hypoglycemia to avoid prolonged fasts (in excess of 5-7 hours). During an acute illness with decreased oral intake, maintain normoglycemia with intravenous infusion of glucose-containing solution.

Perform follow-up evaluation to assess physical growth and to prevent hypoglycemic episodes by adjusting diet, as needed.

Drug therapy is not currently a component of the standard of care for glycogen storage disease type VI (GSD VI), also known as Hers disease.