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 (or likely 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, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic PYGL variants of uncertain significance (or of one known PYGL pathogenic variant and one PYGL variant of uncertain significance) does not establish or rule out the diagnosis.

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 overstorage 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 overstorage of glycogen and high protein diet, the consensus guidelines recommend screening for kidney 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 1:65,000-85,000 live births; however, 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 (NCT02318966). 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.

Mode of Inheritance

Glycogen storage disease type VI (GSD VI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one PYGL pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• The offspring of an individual with GSD VI are obligate heterozygotes (carriers) for a pathogenic variant in PYGL.
• A higher carrier rate for GSD VI exists in the Mennonite population (see Prevalence), increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a pathogenic variant in PYGL. If the reproductive partner of the proband is heterozygous for a PYGL pathogenic variant, offspring are at 50% risk of being affected and 50% risk of being carriers.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a PYGL pathogenic variant.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the PYGL pathogenic variants in the family.

Biochemical testing is not reliable for carrier testing.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the PYGL pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Biochemical testing is not reliable for prenatal diagnosis.

Molecular Pathogenesis

Glycogen phosphorylase, which requires pyridoxal phosphate as a cofactor, cleaves the α(1→4) glycosidic bonds between the glycosyl residues at the periphery of the glycogen molecule to release glucose-1-phosphate. This enzymatic reaction is the rating-limiting process in glycogenolysis, and it is repeated until the proximal four residues before the branch point of that particular glycogen chain are reached. The three isoforms of glycogen phosphorylase – muscle, liver, and brain – are encoded by different genes.

Liver glycogen phosphorylase, encoded by PYGL, forms a homodimer that has a regulatory domain and a catalytic domain:

• Regulatory domain
  • Contains the phosphorylation peptide and the AMP binding site;
  • Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
• Catalytic domain binds to glycogen.

Mechanism of disease causation. GSD VI results from a loss of function of liver glycogen phosphorylase [Burwinkel et al 1998, Beauchamp et al 2007]. Most pathogenic variants are missense variants affecting activation or binding of substrate or pyrophosphate.

Acknowledgments

The authors also wish to thank Drs Holmes Morton and Kevin Strauss for sharing their experience with the Mennonite population.

Author History

Aditi I Dagli, MD; University of Florida (2009-2019)
Emma Labrador, RN (2019-present)
David A Weinstein, MD, MMSc (2009-present)

Revision History

• 27 November 2019 (ha) Comprehensive update posted live
• 17 May 2011 (me) Comprehensive update posted live
• 23 April 2009 (et) Review posted live
• 4 February 2009 (ad) Original submission

Literature Cited

• Beauchamp NJ, Taybert J, Champion MP, Layet V, Heinz-Erian P, Dalton A, Tanner MS, Pronicka E, Sharrard MJ. High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis. 2007;30:722–34. [PubMed: 17705025]
• Burwinkel B, Bakker HD, Herschkovitz E, Moses SW, Shin YS, Kilimann MW. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. 1998;62:785–91. [PMC free article: PMC1377030] [PubMed: 9529348]
• Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker LG. Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum Mol Genet. 1998;7:865–70. [PubMed: 9536091]
• Chen MA, Weinstein DA. Glycogen storage diseases: diagnosis, treatment, and outcome. Transl Sci Rare Dis. 2016;1:45–72. Available online. Accessed 5-10-23.
• Hers HG. Rev Int Hepatol. 1959;9:35–55. [Enzymatic studies of hepatic fragments; application to the classification of glycogenoses.] [PubMed: 13646331]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Kishnani PS, Goldstein J, Austin SL, Arn P, Bachrach B, Bali DS, Chung WK, El-Gharbawy A, Bown LM, Kahler S, Pendyal S, Ross KM, Tsilianidis L, Weinstein DA, Watson MS, et al. Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21:772–89. [PubMed: 30659246]
• Manzia TM, Angelico R, Toti L, Cillis A, Ciano P, Orlando G, Anselmo A, Angelico M, Tisone G. Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports. Transplant Proc. 2011;43:1181–3. [PubMed: 21620082]
• Okechuku GO, Shoemaker LR, Dambska M, Brown LM, Mathew J, Weinstein DA. Tight metabolic control plus ACE inhibitor therapy improves GSD I nephropathy. J Inherit Metab Dis. 2017;40:703–8. [PubMed: 28612263]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Roscher A, Patel J, Hewson S, Nagy L, Feigenbaum A, Kronick J, Raiman J, Schulze A, Siriwardena K, Mercimek-Mahmutoglu S. The natural history of glycogen storage disease type VI and IX: Long-term outcome from the largest metabolic center in Canada. Mol Genet Metab. 2014;113:171–6. [PubMed: 25266922]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stetten D Jr, Stetten MR. Glycogen metabolism. Physiol Rev. 1960;40:505–37. [PubMed: 13834511]
• Wilson LH, Cho JH, Estrella A, Smyth JA, Wu R, Chengsupanimit T, Brown LM, Weinstein DA, Lee YM. Liver glycogen phosphorylase deficiency leads to profibrogenic phenotype in a murine model of glycogen storage disease type VI. Hepatol Commun. 2019;3:1544–55. [PMC free article: PMC6824077] [PubMed: 31701076]