Glycogen Storage Disease Type VI
Synonym: GSD VI
Emma Labrador, RN
Connecticut Children’s Medical Center
Hartford, Connecticut
David A Weinstein, MD, MMSc
University of Connecticut;
Connecticut Children’s Medical Center
Hartford, Connecticut
Initial Posting: April 23, 2009; Last Update: November 27, 2019.
Estimated reading time: 16 minutes
Summary
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.
Diagnosis
Glycogen storage disease type VI (formerly known as Hers disease) is a disorder affecting hepatic glycogenolysis due to a deficiency of glycogen phosphorylase. This critical enzyme catalyzes the rate-limiting step in glycogen degradation.
Suggestive Findings
Glycogen storage disease type VI (GSD VI) should be suspected in individuals with the following:
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of GSD VI, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing is recommended when the affected individual is from a high-risk population (see Prevalence) or has an affected relative.
Single-gene testing. Sequence analysis of PYGL detects missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Targeted analysis for the founder pathogenic variant,
c.1620+1G>A (also known as IVS13+1G>A), can be performed first in individuals of Mennonite ancestry.
A
glycogen storage disease multigene panel that includes
PYGL and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by glycogen storage disorder, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Glycogen Storage Disease Type VI
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|
|
PYGL
| Sequence analysis 3 | >95% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown but rare 4 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Data derived from personal experience and the subscription-based professional view of the Human Gene Mutation Database [Stenson et al 2020]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
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
Muscle concerns
Growth
Skeletal concerns
Renal concerns
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].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Glycogen Storage Disease Type VI
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| Disorder | Gene(s) | MOI | Features of Differential Diagnosis Disorder |
|---|
| Overlapping w/GSD VI | Distinguishing from GSD VI |
|---|
| Phosphorylase kinase deficiency (GSD IX) |
PHKA2
PHKB
PHKG2
| XL
AR | Hepatomegaly Fasting ketosis Hypoglycemia ↑ AST/ALT ↑ lipids
|
|
Hepatic glycogen synthase deficiency (GSD 0)
(OMIM 240600) |
GYS2
| AR | Fasting hypoglycemia Ketosis
|
|
| Glucose-6-phosphatase deficiency (GSD Ia) |
G6PC1
| AR | Hepatomegaly Fasting hypoglycemia ↑ AST/ALT Hyperlipidemia
|
|
| Glucose-6-phosphate transporter deficiency (GSD Ib) |
SLC37A4
| AR | Hepatomegaly Fasting hypoglycemia ↑ AST/ALT Hyperlipidemia
| Neutropenia Crohn disease Hyperuricemia
|
| Debranching enzyme deficiency (GSD III) |
AGL
| AR | Hepatomegaly Fasting hypoglycemia ↑ AST/ALT Hyperlipidemia Low prealbumin
|
|
| Branching enzyme deficiency (GSD IV) |
GBE1
| AR | Hepatomegaly ↑ AST/ALT ↓ prealbumin
| Lack of hypoglycemia until end-stage liver disease |
| GLUT2 deficiency (Fanconi-Bickel syndrome; GSD XI) (OMIM 227810) |
SLC2A2
| AR | Hepatomegaly Fasting hypoglycemia Fasting ketosis ↑ AST/ALT Low prealbumin
|
|
| Fructose-1,6-bisphosphatase deficiency 1 |
FBP1
| AR | Hepatomegaly Fasting hypoglycemia ↑ AST/ALT
| Fasting hyperlactatemia |
| Alpha-1 antitrypsin deficiency-related hepatitis 2 |
SERPINA1
| AR |
| Lack of fasting hypoglycemia & ketosis |
| Glycerol kinase deficiency (OMIM 307030) |
GK
| XL | Hypoglycemia | Ketoacidosis & extremely ↑ glycerol |
| PRKAG2 deficiency (See Hypertrophic Cardiomyopathy Overview.) |
PRKAG2
| AD |
|
|
| Niemann-Pick disease type B 3 (See ASM Deficiency.) |
SMPD1
| AR | Hepatomegaly Growth failure Hyperlipidemia
|
|
| Gaucher disease 3 | GBA1 (GBA) |
AD = autosomal dominant; AR = autosomal recessive; ASM = acid sphingomyelinase; GSD = glycogen storage disease; MOI = mode of inheritance; XL = X-linked
- 1.
Fructose-1,6-bisphosphatase deficiency is one example of a disorder of gluconeogenesis; other should also be considered.
- 2.
Alpha-1 antitrypsin deficiency-related hepatitis is one example of a primary liver disease; other primary liver diseases should also be considered.
- 3.
Niemann-Pick disease type B and Gaucher disease are examples of metabolic storage disorders; other metabolic storage disorders should also be considered.
Mitochondrial disorders should also be considered in the differential diagnosis of GSD VI (see Mitochondrial Disorders Overview).
Management
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.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with GSD VI
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| System/Concern | Evaluation | Comment |
|---|
Gastrointestinal/
Hepatic
| Assessment of liver size Abdominal ultrasound
| Involvement of specialists in GSD VI (gastroenterologist, endocrinologist, metabolic geneticist) |
|
Other
| Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
Treatment of Manifestations
Note: Some individuals with GSD VI may not require any treatment, but most have better growth and stamina with therapy.
Table 4.
Treatment of Manifestations in individuals with GSD VI
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Manifestations/
Concern | Treatment | Considerations/Other |
|---|
|
Hypoglycemia
| Frequent small meals Uncooked cornstarch (1-1.5 g/kg) 1-4x/day Protein 2-3 g/kg body weight per day Glycosade 1 from waxy maize, proven beneficial in children age >5 yrs & adults to extend overnight fast duration
| Doses adjusted to keep glucose concentrations at 75-100 mg/dL (4.2-5.6 mmol/L) & beta-OH-butyrate concentrations ≤0.2 mmol/L |
|
Hepatomegaly
|
| To ↓ liver size |
Growth
restriction
| Cornstarch & protein supplementation |
|
Decreased
bone density
|
| Primarily due to ketosis |
Muscle
cramping
| Protein 2-3 grams per kg body weight per day | Muscle cramping is usually due to undertreatment & protein deficiency. |
- 1.
Extended-release cornstarch
General Nutrition Recommendations
[Kishnani et al 2019]
Protein
Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
Protein intake should be distributed throughout the day.
Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
Carbohydrates
Carbohydrates should provide 45%-50% of total calories.
Complex carbohydrates should be consumed with each meal to provide a sustained source.
Overtreatment with cornstarch can be detrimental.
Small amounts of dairy and fruits are allowed in the diet.
Simple sugars should be limited to 5 g.
Fats
Fats should provide 25%-30%of total calories.
Diet should include good sources of poly-and mono-unsaturated fatty acids.
Saturated fats should provide <10% of total calories.
Cholesterol should be restricted to <300 mg/day.
Surveillance
Table 5.
Recommended Surveillance for Individuals with GSDVI
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| System/Concern | Evaluation | Frequency |
|---|
|
Ketosis
| Blood ketone level upon wakening using portable blood ketone meter. | At least several times per month 1; goal is to maintain blood beta-OH-butyrate concentrations <0.3 mmol/L. |
|
Hypoglycemia
| Self-glucose monitoring | At least several times per month & as needed 1 |
|
Gastrointestinal
| Liver ultrasound | Annually beginning at age 5 yrs |
|
Skeletal
| Bone density | When puberty is complete & as clinically indicated |
|
Renal
| 24-hr urine to screen for microalbuminuria | Annually |
- 1.
Glucose and ketone levels should also be measured during times of stress including illness, intense activity, periods of rapid growth, or any time at which intake of food is reduced and before and after changes are made to the amount of cornstarch or protein intake. Monitoring recommendations should be tailored to individual needs.
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
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
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.
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.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Association for Glycogen Storage Disease
Association for Glycogen Storage Disease UK (AGSD-UK)
9 Lindop Road
Altrincham Cheshire WA15 9DZ
United Kingdom
Phone: 0161 980 7303
European Reference Network for Hereditary Metabolic Disorders (MetabERN)
Metabolic Support UK
United Kingdom
Phone: 0845 241 2173
University of Florida GSD International Natural History Registry
Phone: 352-273-6655
Email: lfiske@peds.ufl.edu
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Glycogen Storage Disease Type VI: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
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:
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.
Table 6.
Notable PYGL Pathogenic Variants
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| Reference Sequences | DNA Nucleotide Change
(Alias 1) | Predicted Protein Change | Comment [Reference] |
|---|
|
NM_002863.3
| c.1620+1G>A
(IVS13+1G>A) | -- | Mennonite founder variant [Chang et al 1998] |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Chapter Notes
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
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