DiagnosisClinical Diagnosis Glycogen storage disease type VI (Hers disease), a disorder of glycogenolysis caused by deficiency of hepatic glycogen phosphorylase, is suspected in an untreated child with the following: HepatomegalyGrowth retardation Ketotic hypoglycemia after an overnight fast OR hypoglycemia after prolonged fasting (e.g., during an illness) Testing Serum concentration ofTriglycerides, cholesterol, and liver transaminases may be mildly elevated. Creatine kinase is normal. Uric acid and lactic acid are normal [Chen 2001, Wolfsdorf & Weinstein 2003].Glucose does not increase following glucagon administration. Liver biopsy shows elevated glycogen content and decreased hepatic phosphorylase enzyme activity. Assay of hepatic glycogen phosphorylase enzyme activity can be performed on erythrocytes, leukocytes, and liver cells. However, the blood enzyme assay should be interpreted with caution as blood enzyme activity may be normal in liver-specific disease.Notes: (1) Even in liver tissue, enzyme assay is challenging. Individuals affected with GSD VI can have residual hepatic glycogen phosphorylase activity. (2) Phosphorylase kinase (PHK) binding is necessary for liver glycogen phosphorylase activation. PHK deficiency (GSD IX) may also cause hepatic glycogen phosphorylase activity to be low (see Differential Diagnosis). (3) Liver glycogen phosphorylase activity can be affected by many allosteric factors and neural and humoral signals that can alter enzyme activity levels.Carrier detection. Assay of enzyme activity is not reliable for carrier detection.Molecular Genetic Testing Gene. PYGL is the only gene in which mutations are known to cause GSD VI.Clinical testingSequence analysis. The mutation detection frequency of sequence analysis is not known, but it is expected to be close to 100%.
Note: The founder mutation, c.1620+1G>A (also known as IVS13+1G>A), causes a splice-site abnormality of the intron 13 splice donor in the Mennonite population [Chang et al 1998].Deletion/duplication analysis. The usefulness of deletion/duplication analysis has not been demonstrated, as no deletions or duplications involving PYGL have been reported to cause GSD VI.Table 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type VIView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPYGLSequence analysisSequence variants 2, 3UnknownClinicalDeletion / duplication analysis 4Deletion / duplication of one or more exons or the whole geneUnknown; none reported 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Including the c.1620+1G>A founder mutation in the Mennonite population. Note: In the Mennonite population only targeted mutation analysis is necessary. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications involving PYGL as causative of glycogen storage disease type VI have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. GSD VI should be considered in any child with hepatomegaly and ketotic hypoglycemia. Children with unexplained hepatomegaly with mild-moderate elevation of transaminase concentrations should have a fasting glucose and ketones check.
Note: (1) The fast must be closely observed if GSD I is still in the differential diagnosis as dangerous hypoglycemia and lactic acidosis can occur in patients with GSD I. (2) Because gluconeogenesis is preserved in GSD VI, an overnight fast is usually well tolerated although ketones can be detected using a blood ketone meter.Because of the limitations associated with enzyme activity assay, molecular genetic testing by sequence analysis of PYGL is now the preferred method for diagnosing GSD VI.
Note: GSD VI and GSD IX are clinically indistinguishable. Because the most common form of GSD IX is inherited in an X-linked manner, PYGL sequence analysis for GSD VI is often performed in females before sequence analysis of PHKA2 for GSD IX. Liver biopsy is reserved for those in whom the diagnosis cannot be confirmed by molecular genetic techniques.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in PYGL.}

Natural History Glycogen storage disease type VI (GSD VI) is usually a relatively mild disorder presenting in infancy and childhood with abdominal distension, hepatomegaly, and growth retardation. 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.Rare variants with severe and recurrent hypoglycemia, severe hepatomegaly, and post-prandial lactic acidosis have been described [Beauchamp et al 2007]. Muscle hypotonia and fatigue with exercise have been reported [Beauchamp et al 2007]. Developmental delay, particularly for the motor milestones, may occur in untreated children. Intellectual development is normal in most children.In untreated individuals growth retardation and osteoporosis are common. In theory, the risk of hepatic adenoma formation in late childhood and adulthood is increased. Clinical and biochemical abnormalities may resolve with age and most adults are asymptomatic. Hypoglycemia can occur during pregnancy.

Genotype-Phenotype Correlations The clinical phenotype varies from mild undetected hypoglycemia to severe recurrent hypoglycemia with hepatomegaly. No clear genotype-phenotype correlation exists. The Mennonite mutation, c.1620+1G>A (see Molecular Genetics), 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].

Differential DiagnosisGlycogen storage disease type I (GSD I) is usually associated with more severe hypoglycemia than GSD VI. The easiest method for distinguishing between GSD I and GSD VI is to measure serum lactate concentrations with fasting. The serum lactate concentration rapidly rises with fasting in GSD I, but is normal in GSD VI. Hyperlipidemia and hyperuricemia also are characteristic of GSD I and not GSD VI.Glycogen storage disease type III (GSD III), caused by deficiency of the debrancher enzyme, presents in childhood with hepatomegaly and hypoglycemia that improve with age. In addition, GSD IIIa is characterized by skeletal muscle weakness, elevated serum CK concentrations, and cardiomyopathy. Although not universally seen in young children, elevated serum CK concentrations in the setting of a hepatic GSD are suggestive of GSD III. Hepatic transaminases are often the highest in GSD III of all GSDs; AST/ALT concentrations higher than 1000 U/L are suggestive of GSD III. Glycogen storage disease type IX (GSD IX) is caused by a deficiency of the enzyme phosphorylase kinase, which comprises X-linked phosphorylase a kinase and autosomal recessive phosphorylase b kinase. Phosphorylase kinase is responsible for activating hepatic glycogen phosphorylase. The phenotypes of GSD IX and GSD VI are clinically indistinguishable. As phosphorylase kinase deficiency can itself lead to decreased activity of the enzyme hepatic glycogen phosphorylase, molecular genetic testing is the best way to distinguish between GSD VI and GSD IX. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with GSD VI, a genetics consultation is recommended:Treatment of ManifestationsSome individuals with glycogen storage disease type VI (GSD VI) may not require any treatment, but most have better growth and stamina with therapy. For hypoglycemia, frequent small meals and uncooked cornstarch (1.5-2 g/kg) given one to three times a day may normalize blood glucose concentration and avoid ketosis. For children and adults with no hypoglycemic episodes, a bedtime dose of cornstarch (1.5-2 g/kg) can improve energy and well-being [Nakai et al 1994]. When on cornstarch therapy, children have improved growth and bone density and decreased liver size — findings that may be significant when considering lifestyle-related issues [Author, personal observation].Prevention of Primary ManifestationsHepatomegaly and hypoglycemia may be prevented by administration of uncooked cornstarch (1.5-2 g/kg) one to three times a day.Prevention of Secondary ComplicationsOsteoporosis related to chronic ketosis is common in GSD VI that has not been aggressively treated; treatment with complex carbohydrates or cornstarch may improve bone density. Short stature and delayed puberty, which also occur in the setting of chronic ketosis, improve with better metabolic control. SurveillanceRoutine monitoring of blood glucose concentration and blood ketones to assess control is recommended as well as monitoring of both around periods of increased activity and illness. Note: Since ketosis is usually more severe than hypoglycemia, blood ketone level is more indicative of control than blood glucose concentration. Monitoring of blood ketones upon awakening at least several times per month using a portable blood ketone meter is recommended. The goal is to maintain blood beta-OH-butyrate concentrations lower than 0.3 mmol/L. Hypoglycemia is uncommon on waking since counter-regulation can raise blood glucose concentrations; however, monitoring of blood glucose concentrations at 2 AM to 4 AM can reveal periods of suboptimal control. Height and weight should be measured annually to monitor growth. Although formal studies are lacking, the theoretic small risk of hepatic adenoma increases with age; thus, annual liver ultrasound examinations are recommended beginning at age five years. Bone density determinations are recommended after growth is complete.During pregnancy, women with GSD VI should monitor blood glucose concentrations, given that exacerbations of hypoglycemia may occur.Agents/Circumstances to AvoidAvoid 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 often is not efficacious When hepatomegaly is present, contact sports (or use appropriate cautions) Evaluation of Relatives at RiskIf the family-specific mutations are known it is appropriate to offer molecular genetic testing to at-risk sibs so that early diagnosis can lead to early treatment and avoidance of factors that exacerbate disease. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAlthough clinical and biochemical abnormalities usually resolve with age and most adults are asymptomatic, hypoglycemia can occur during pregnancy. Therapies Under InvestigationAn extended-release cornstarch preparation is presently being tested in other types of GSD. This experimental product may improve maintenance of normoglycemia with fasting for a longer duration and may reduce the number of doses of cornstarch required.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPYGL14q22​.1Glycogen phosphorylase, liver formPYGL homepage - Mendelian genesPYGLData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Glycogen Storage Disease Type VI (View All in OMIM) View in own window 232700GLYCOGEN STORAGE DISEASE VINormal allelic variants. PYGL is 39,298 bases in size and has 20 coding exons. More than 40 different normal variants have been described, but their clinical significance is unclear.Pathologic allelic variants. Nineteen different mutations have been identified. Nonsense, splice-site, and frameshift mutations and two mutations resulting in null alleles have been reported [Burwinkel et al 1998, Chang et al 1998, Tang et al 2003, Beauchamp et al 2007]. No common mutation has been described in the general population. Most mutations are missense mutations affecting activation or binding of substrate or pyrophosphate. The c.1620+1G>A founder mutation in the Mennonite population causes a splice-site abnormality of the intron 13 splice donor leading to either skipping of exon 13 or use of a cryptic splice site [Chang et al 1998]. Table 2. Selected PYGL Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change Reference Sequencesc.38A>C ^{2p.Gln13ProNM_002863​.3
NP_002854​.3c.280C>T 3p.Arg94*c.529-1G>C 4Skipping of exon 5c.698G>A 5p.Gly233Aspc.1016A>G 4p.Asn339Serc.1131C>G 4p.Asn377Lysc.1195C>T 2p.Arg399*c.1366G>A 2p.Val456Metc.1471C>T 2p.Arg491Cysc.1620+1G>A 6(IVS13+1G>A)c.1768+1G>A 4,7c.1895A>T 2p.Asn632Ilec.1900G>C 2p.Asp634Hisc.[1964_1979inv6;1969+1_+4delGTAC] 2, 8c.2017G>A 2p.Glu673Lysc.2023T>A 2p.Ser675Thrc.2024C>T 2p.Ser675Leuc.2042A>C 2p.Lys681Thrc.2461T>C 3p.Tyr821HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Beauchamp et al [2007]3. Unreported mutations confirmed by the authors4. Burwinkel et al [1998]5. Tang et al [2003]6. Chang et al [1998]; Mennonite founder mutation7. Retention of intron 14/use of cryptic splice site8. Nomenclature denotes two changes in one allele; transcription of this allele results in use of cryptic splice site.Normal gene product. The enzyme liver glycogen phosphorylase cleaves the α(1→4) glycosidic bonds between the glycosyl residues at the periphery of the glycogen molecule to release glucose-1-phosphate. The process 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 for by different genes. The isoforms show some sequence homology and require pyridoxal phosphate as a cofactor. Glycogen phosphorylase is highly regulated by allosteric effectors and by phosphorylation of the Ser14 residue by phosphorylase kinase [Rath et al 2000]. This phosphorylation occurs in response to glucagon or epinephrine and activates the enzyme [Chen 2001]. The enzyme is inhibited when dephosphorylated by protein phosphatase 1. In contrast to the muscle isoenzyme, the liver isoenzyme shows a minimal increase in activity in the presence of AMP.The human liver glycogen phosphorylase is a homodimer that has a regulatory aspect and a catalytic aspect. The regulatory aspect contains the phosphorylation peptide and the AMP binding site. This regulatory domain interacts with the phosphorylase kinase, allosteric effectors, and phosphatase. The catalytic aspect binds to glycogen. Each monomer comprises an N-terminal domain and a C-terminal domain. Pyridoxal phosphate is bound covalently to the lysine in position 680 in the C-terminal domain. The catalytic region is present at the interphase of the N- and C-terminal domains. Forty residues in this region undergo structural rearrangement during the process of activation to facilitate glycogen binding and breakdown [Rath et al 2000].Abnormal gene product. The mutations c.1366G>A (p.Val456Met), c.2023T>A (p.Ser675Thr), c.2024C>T (p.Ser675Leu), and c.2017G>A (p.Glu673Lys) affect substrate binding to the enzyme; c.1471C>T (p.Arg491Cys) and c.2042A>C (p.Lys681Thr) affect binding of the co-factor pyridoxal phosphate; and c.38A>C (p.Gln13Pro) affects activation of the enzyme by phosphorylase kinase. The mutation c.698G>A (p.Gly233Asp) causes the smaller glycine molecule to be replaced by the larger aspartic acid molecule, thus disrupting a tight hairpin bend in the secondary structure of the protein [Tang et al 2003], leading to a mild phenotype. The founder mutation in the Mennonite population, c.1620+1G>A, causes abnormal splicing with skipping of exon 13 or use of cryptic splice site, which generates a protein deficient in either 34 or three amino acids, respectively, with the reading frame maintained. This protein is expected to have some residual enzyme activity [Chang et al 1998].}