Glycogen Storage Disease Type Vi

Clinical characteristics.

Glycogen storage disease type VI (GSD VI) is a disorder of glycogenolysis caused by deficiency of hepatic glycogen phosphorylase. This critical enzyme catalyzes the rate-limiting step in glycogen degradation, and deficiency of the enzyme in the untreated child is characterized by hepatomegaly, poor growth, ketotic hypoglycemia, elevated hepatic transaminases, hyperlipidemia, and low prealbumin level. GSD VI is usually a relatively mild disorder that presents in infancy and childhood; rare cases of more severe disease manifesting with recurrent hypoglycemia and marked hepatomegaly have been described. More common complications in the setting of suboptimal metabolic control include short stature, delayed puberty, osteopenia, and osteoporosis. Hepatic fibrosis commonly develops in GSD VI, but cirrhosis and hypertrophic cardiomyopathy are rare. Clinical and biochemical abnormalities may decrease with age, but ketosis and hypoglycemia can continue to occur.

Diagnosis/testing.

The diagnosis of GSD VI is established in a proband with typical clinical findings and/or biallelic pathogenic variants in PYGL identified by molecular genetic testing.

Management.

Treatment of manifestations: Some individuals with GSD VI may not require any treatment, but treatment with cornstarch and protein improves growth, stamina, and ameliorates biochemical abnormalities including hypoglycemia and ketosis. Even in those with no hypoglycemia, a bedtime dose of cornstarch improves energy and prevents ketosis.

Surveillance: Monitoring of blood glucose and blood ketone levels at least several times per month during times of stress including illness, intense activity, periods of rapid growth, or any time at which intake of food is reduced. Annual liver ultrasound examinations should start at age five years. Bone density exam is recommended when puberty is complete.

Agents/circumstances to avoid: Excessive amounts of simple sugars; glucagon administration as a rescue therapy for hypoglycemia; growth hormone therapy for short stature; contact sports when hepatomegaly is present.

Evaluation of relatives at risk: If the family-specific pathogenic variants are known, it is appropriate to offer molecular genetic testing to at-risk sibs so that early treatment and avoidance of factors that exacerbate disease can be initiated.

Genetic counseling.

GSD VI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Suggestive Findings

Glycogen storage disease type VI (GSD VI) should be suspected in individuals with the following:

• Hepatomegaly
• Poor growth
• Ketotic hypoglycemia
• Elevated hepatic transaminases
• Hyperlipidemia
• Low prealbumin level
• Abdominal ultrasound showing hepatomegaly with diffuse echogenicity

Establishing the Diagnosis

The diagnosis of GSD VI is established in a proband with typical clinical findings and/or biallelic pathogenic variants in PYGL identified by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing).

A liver biopsy is reserved for those in whom the diagnosis cannot be confirmed by molecular genetic techniques [Kishnani et al 2019].

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GSD VI is fairly broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1) whereas those with a phenotype indistinguishable from other inherited disorders with hepatomegaly are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Typical presentation. Glycogen storage disease type VI (GSD VI) is usually a relatively mild disorder presenting in infancy and childhood with abdominal distention, hepatomegaly, and growth restriction.

Hypoglycemia. If present, hypoglycemia is mild and may manifest during an illness after prolonged fasting. Ketotic hypoglycemia after an overnight fast is the salient feature of this disorder.

Liver concerns

• Fibrosis/cirrhosis occurrence. Fibrosis commonly develops in GSD VI, but cirrhosis is rare [Roscher et al 2014, Wilson et al 2019].
• Tumor risk. While rare, hepatic adenomas and hepatocellular carcinoma can develop [Manzia et al 2011, Roscher et al 2014].

Muscle concerns

• Muscle hypotonia and fatigue with exercise have been reported [Beauchamp et al 2007]. Delay in motor milestones may occur in untreated children.
• Muscle cramping is a common complaint in GSD VI if protein deficiency is present. The cramping is usually in the lower extremities and typically occurs with activity and overnight [DA Weinstein, unpublished data].
• Hypertrophic cardiomyopathy. Secondary muscle involvement can occur from over-storage of glycogen. Rare cases of hypertrophic cardiomyopathy have been reported [Roscher et al 2014].

Growth

• In untreated individuals. Poor growth and delayed puberty are common findings.
• With treatment
  • Growth normalizes;
  • Final height is usually appropriate for genetic potential.

Skeletal concerns

• Osteopenia and osteoporosis are common in untreated individuals.
• Bone mineral density can normalize with treatment [Chen & Weinstein 2016].

Renal concerns

• Due to the over-storage of glycogen and high protein diet, the consensus guidelines recommend screening for renal disease.
• Renal abnormalities including proteinuria, however, are rarely seen in GSD VI [Okechuku et al 2017].

Intellectual development is normal in most children.

Atypical form. Rare variants with severe and recurrent hypoglycemia, severe hepatomegaly, and postprandial hyperlactatemia have been described [Beauchamp et al 2007].

Adulthood. Clinical and biochemical abnormalities may improve with age and many adults are asymptomatic.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlation exists.

The Mennonite pathogenic variant, c.1620+1G>A generates a transcript lacking all or part of exon 13 while maintaining the reading frame. Either protein isoform is expected to have some residual enzyme activity, which may explain the milder GSD VI phenotype in the Mennonite population [Chang et al 1998].

Nomenclature

GSD VI (Hers disease) was first reported by Hers [1959] and Stetten & Stetten [1960]. GSD VI was referred to as Hers disease based on Hers’ prediction that the GSDs were a heterogeneous group that would ultimately be categorized into specific types.

GSD VI now refers to liver glycogen phosphorylase deficiency.

Prevalence

Liver glycogen phosphorylase deficiency affects approximately 1:65,000-1:85,000 live births; hoever, many people with this condition are undiagnosed. GSD VI is equally prevalent in males and females. The Mennonite population is at increased risk for GSD VI, with a prevalence of 1:1,000 resulting from the founder variant c.1620+1G>A. It is estimated that 3% of the Mennonite population are heterozygous (i.e., are carriers) for this pathogenic variant [Chang et al 1998]. There also appears to be an increased prevalence of GSD VI in Scotland and Northern Africa, but the frequency is not known [Chen & Weinstein 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type VI (GSD VI), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Note: Some individuals with GSD VI may not require any treatment, but most have better growth and stamina with therapy.

Surveillance

Agents/Circumstances to Avoid

Avoid the following:

• Excessive amounts of simple sugars to prevent excessive hepatic glycogen deposition
• Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase
• Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications
• Contact sports when hepatomegaly is present (or use appropriate cautions)

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic at-risk sibs to identify as early as possible those who would benefit from prompt initiation of treatment and avoidance of factors that exacerbate disease.

Molecular genetic testing is indicated if the pathogenic variants in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

A pregnant woman with GSD VI must be vigilant in monitoring for hypoglycemia and ketosis during pregnancy. Cornstarch and protein supplementation (2-4x/day) are needed during pregnancy to prevent ketosis and premature labor. The goal is to maintain euglycemia throughout pregnancy to prevent morbidity and mortality to the fetus due to activation of counterregulatory hormones resulting in lipolysis and ketosis. Increasing protein intake may be necessary to provide an alternate source of glucose via gluconeogenesis.

Therapies Under Investigation

An extended-release cornstarch preparation is presently being tested as part of the Clinical Trials GLYDE study. This experimental product may improve maintenance of normoglycemia with fasting for a longer duration and may reduce the number of doses of cornstarch required.

There is also an ongoing trial looking for a biomarker for glycogen storage disease (NCT02385162).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.