Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)

INTRODUCTION — There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). Liver phosphorylase deficiency (GSD VI; MIM #232700), also known as Hers disease, is usually a mild form of glycogenosis; however, severe hepatomegaly and recurrent severe hypoglycemia have been described [1]. It is due to deficiency of the liver isoform of phosphorylase.

Liver phosphorylase deficiency is reviewed here. Other GSDs are reviewed separately.

OVERVIEW — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).

Glycogen is most abundant in liver and muscle, which are most affected by disorders of glycogen metabolism. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease. The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

A more extensive overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

EPIDEMIOLOGY — The prevalence of GSD VI is unknown. It is rare in the general population, although it is probably underdiagnosed because of its typically more indolent course compared with other GSDs. GSD VI and IX (deficiencies of liver phosphorylase and the enzyme that regulates its activity, respectively) together account for 25 to 30 percent of all the GSDs, with an estimated prevalence of 1 in 100,000. Most of these are GSD type IX. The disease frequency is 1 in 1000 in a Pennsylvanian Mennonite population with a founder mutation [2]. (See 'Genetics' below.)

PATHOGENESIS — GSD VI is due to a deficiency of liver phosphorylase. Liver glycogen phosphorylase catalyzes the cleavage of 1,4 glucosidic bonds to release glucose 1-phosphate from glycogen (figure 1). Enzyme activity is regulated by phosphorylation by phosphorylase kinase, the deficiency of which causes GSD IX. (See "Phosphorylase b kinase deficiency".)

GENETICS — GSD VI is an autosomal-recessive disorder. It is caused by pathogenic variants in the gene for the liver isoform of glycogen phosphorylase (PYGL), located at 14q21. Missense, nonsense, and splice-site mutations have been described [3,4], although the frequency of null mutations appears less than other GSDs [5]. A founder mutation involving a splice-site alteration was identified in a Pennsylvanian Mennonite population [2]. Similarly, a common truncating variant was described in South China [6].

CLINICAL MANIFESTATIONS — Patients typically present in early childhood with the characteristic features of growth retardation and prominent hepatomegaly [7]. A case series of 61 patients revealed a median age at diagnosis of 1.8 years, ranging from 5 weeks to 38 years [8]. Thirty-five to 53 percent of patients are reported to have short stature [8,9]. Most have mild hypoglycemia, hyperlipidemia, and ketosis, although occasional patients have more significant hypoglycemia [5]. Hypoglycemia and ketosis typically occur after an overnight fast or after prolonged daytime fasting, such as during an illness, although ketosis can be present in the absence of hypoglycemia, potentially leading to diagnostic errors [10]. Skeletal and cardiac muscle are typically not affected. Intellectual development is normal in most cases. The patient may develop osteoporosis if the disease is untreated. Manifestations improve with puberty, with a decrease in hepatomegaly and improvement in growth with attainment of normal adult height [1]. Early-onset cirrhosis was observed in four children (ages 1.4 to 6.1 years) [8].

LABORATORY FINDINGS — Patients often have elevated concentrations of serum transaminases and hyperlipidemia. Plasma concentrations of uric acid are elevated in half of patients at the time of diagnosis but usually normalize with treatment. However, increased uric acid level may recur in adolescence and adulthood [6]. Postprandial lactic acidemia is observed. Biotinidase activity is increased and may be a sensitive biomarker [11]. The activity of serum creatine kinase is normal. Unlike GSD type IX, an attenuated rise in glucose is observed following administration of glucagon.

DIAGNOSIS — The diagnosis of liver phosphorylase deficiency should be considered in a child with unexplained hepatomegaly and ketosis with elevated transaminases. A fasting glucose and test for ketones should be performed, with the caveat that the child needs to be monitored closely if GSD I is being considered because of the risk of significant hypoglycemia. GSD IX is more common and presents similarly to GSD VI but is primarily X linked. Thus, molecular testing of the gene responsible for GSD VI (PYGL) is done first if the patient is female. Testing of the gene responsible for GSD IX (phosphorylase kinase, liver, alpha-2 subunit [PHKA2]) is done first if the patient is male. The increasing use of multigene panels may make this distinction moot.

The diagnosis can also be confirmed by reduced or absent enzyme activity in liver tissue, but enzyme activity can be affected by other factors, leading to erroneous results. Assay of enzyme activity for both phosphorylase and phosphorylase b kinase (PBK) may be performed on erythrocytes and leukocytes. However, false negatives (normal enzyme activity detected) are common because the deficiency is isolated to the liver. Thus, molecular testing for PYGL gene mutations is the preferred confirmatory diagnostic tool [12]. For the Mennonite population, it is only necessary to test for the one mutation found specifically in that group (c.1620+1G>A). For others, sequencing of the gene is necessary.

Liver biopsy with assay of enzyme activity is performed if molecular testing is nondiagnostic.

DIFFERENTIAL DIAGNOSIS — Phosphorylase b kinase (PBK) is necessary for activation of liver glycogen phosphorylase. Thus, PBK deficiency (GSD IX) has a similar clinical presentation to GSD VI. However, the response to glucagon is normal in GSD IX, unlike GSD VI. In addition, the majority of cases of PBK deficiency are X linked. (See "Phosphorylase b kinase deficiency".)

Hypoglycemia is usually more severe in GSD I. In addition, fasting serum lactate is elevated in GSD I and normal in GSD VI. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)

GSD III presents with hypoglycemia and hepatomegaly, but most of these children also have skeletal muscle weakness associated with an elevated serum creatinine kinase (CK). (See "Glycogen debrancher deficiency (glycogen storage disease III, Cori disease)".)

TREATMENT — Patients with hypoglycemia should have frequent, small meals and increased protein intake (2 to 3 g/kg/day) [13]. Alternatively, uncooked cornstarch can be used at a dose of 1 to 2 g/kg per dose, between meals and at bedtime. The bedtime dose is generally higher than the between meal doses. Young infants (under six months of age) may develop gastrointestinal distress (colicky symptoms or diarrhea) with cornstarch administration because pancreatic amylase has not reached a normal adult level. Preprandial glucose monitoring is useful in adjusting therapy. Treatment with cornstarch may improve growth, hepatomegaly, bone density, serum analytes, and stamina due to better metabolic control, even in patients without hypoglycemic episodes [1]. A pregnant individual with GSD VI should have their blood glucose monitored. Bone density testing should be assessed once the individual has stopped growing [1]. Published guidelines for the diagnosis and management of GSD VI are available [13].

PROGNOSIS — The disease typically has a benign course and improves with age, although hypoglycemia can occur during pregnancy [1]. Hepatomegaly resolves in most cases. Patients may be at increased risk for developing hepatic tumors [14,15]. Liver ultrasound to screen for hepatic adenoma should be performed annually beginning around 10 years of age.

SUMMARY

●Genetics – Liver phosphorylase deficiency, also called glycogen storage disease type VI (GSD VI), is caused by pathogenic variants in the gene for the liver isoform of glycogen phosphorylase (PYGL) (figure 1). (See 'Pathogenesis' above and 'Genetics' above.)

●Clinical manifestations – Patients typically present in early childhood with the characteristic features of growth retardation, prominent hepatomegaly, mild hypoglycemia, and ketosis (table 1). (See 'Clinical manifestations' above.)

●Diagnosis – Molecular testing for PYGL gene mutations is the preferred confirmatory diagnostic tool. (See 'Diagnosis' above.)

●Differential diagnosis – Phosphorylase b kinase (PBK) deficiency (GSD IX) has a similar clinical presentation to GSD VI. However, the response to glucagon is normal in GSD IX, unlike GSD VI. (See 'Differential diagnosis' above and 'Laboratory findings' above.)

●Treatment – Patients are treated with uncooked cornstarch between meals and at bedtime to prevent hypoglycemia and ketosis, in addition to a high-protein diet. Treatment may improve growth, hepatomegaly, bone density, serum analytes, and stamina. (See 'Treatment' above.)

●Prognosis – The disease typically has a benign course and improves with age. However, patients may be at increased risk for hepatic tumors. (See 'Prognosis' above.)