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Genetics of Glycogen-Storage Disease Type VI

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD  more...
Updated: Apr 02, 2014


Glycogen-storage disease type VI (GSD VI) represents a heterogeneous group of hepatic glycogenoses with mild clinical manifestations and benign course. Patients typically exhibit prominent hepatomegaly, growth retardation, and variable but mild episodes of fasting hypoglycemia and hyperketosis during childhood. Hyperlacticacidemia and hyperuricemia are characteristically absent. In addition, patients may demonstrate elevated serum transaminases, hyperlipidemia, hypotonia, and muscle weakness. These clinical features and biochemical abnormalities generally resolve by puberty. Rare variants may have associated proximal renal tubule acidosis, myopathy, peripheral neuropathy, or fatal cardiomyopathy.

In general, glycogen-storage disease type VI is caused by defects in the hepatic glycogen phosphorylase-activating system. The classic form of glycogen-storage disease type VI results from a primary deficiency of liver phosphorylase. Other defects of the phosphorylase cascade system now included in this form of glycogen-storage disease include phosphorylase b kinase deficiency (formerly glycogen-storage disease type IX [GSD IX] and glycogen-storage disease type VIII [GSD VIII]) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase deficiency (formerly glycogen-storage disease type X [GSD X]).



Phosphorylase, the rate-limiting enzyme of glycogenolysis or glycogen breakdown, is activated by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent protein kinase. Enzyme deficiency anywhere along this pathway results in impaired cleavage of glucose units from the straight chains of the glycogen molecule. In most patients, the enzyme deficiency is incomplete, and gluconeogenesis remains intact. As a result, the ability of the liver to maintain normoglycemia during fasting may be partially impaired, resulting in an increased risk of mild fasting hypoglycemia and associated hyperketosis. Increased levels of urinary ketones and serum ketone bodies (eg, acetoacetate, beta-hydroxybutyrate) are proportional to the degree of fasting. Other biochemical derangements include mild-to-moderate hyperlipidemia, with elevation of serum cholesterol more than elevation of triglycerides and variably elevated serum transaminases with no other evidence of liver dysfunction.





The overall frequency of glycogen-storage disease is 1 case per 20,000-25,000 persons, with approximately 30% of cases representing glycogen-storage disease type VI, thus making glycogen-storage disease type VI one of the most common forms of glycogen-storage disease. Approximately 75% of all cases of glycogen-storage disease type VI result from the X-linked recessive forms of phosphorylase kinase deficiency. Case reports suggest that the X-linked form of glycogen-storage disease type VI may be undiagnosed or underestimated.[1]


Glycogen-storage disease type VI has a rather benign course, with risk of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adult patients exhibit normal stature, motor function, and biochemical parameters. A subset of patients with the autosomal recessive form of glycogen-storage disease type VI due to deficiency of phosphorylase kinase activity may be at increased risk for liver cirrhosis. Rare variants may cause muscle dysfunction, peripheral neuropathy, proximal renal tubule acidosis, or severe cardiomyopathy. The occurrence of hepatocellular carcinoma in one patient with glycogen-storage disease type VI has been reported.[2]


Glycogen-storage disease type VI is most common among members of the Mennonite religious group.[3] A specific splice-site mutation in the liver phosphorylase gene (PYGL) occurs in the chromosomes of 3% of this religious group. Glycogen-storage disease type VI has an estimated frequency of 0.1% in the Mennonite population.


The X-linked recessive form of liver phosphorylase kinase deficiency is primarily expressed in affected males, although asymptomatic males and heterozygous (carrier) females with mild symptoms have been reported. All other forms of glycogen-storage disease type VI are autosomal-recessive and equally affect both sexes.


Glycogen-storage disease type VI usually manifests during early childhood.

Contributor Information and Disclosures

Lynne Ierardi-Curto, MD, PhD Attending Physician, Division of Metabolism, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

  1. Chen ST, Chen HL, Ni YH, et al. X-linked liver glycogenosis in a Taiwanese family: transmission from undiagnosed males. Pediatr Neonatol. 2009 Oct. 50(5):230-3. [Medline].

  2. Manzia TM, Angelico R, Toti L, et al. Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports. Transplant Proc. 2011 May. 43(4):1181-3. [Medline].

  3. Chang S, Rosenberg MJ, Morton H. Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum Mol Genet. 1998 May. 7(5):865-70. [Medline].

  4. Albash B, Imtiaz F, Al-Zaidan H, Al-Manea H, Banemai M, Allam R, et al. Novel PHKG2 mutation causing GSD IX with prominent liver disease: report of three cases and review of literature. Eur J Pediatr. 2013 Dec 11. [Medline].

  5. Burwinkel B, Rootwelt T, Kvittingen EA. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res. 2003. 54(6):834-839. [Medline].

  6. Burwinkel B, Amat L, Gray RG. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum Genet. 1998 Apr. 102(4):423-9. [Medline].

  7. Davit-Spraul A, Piraud M, Dobbelaere D, Valayannopoulos V, Labrune P, Habes D, et al. Liver glycogen storage diseases due to phosphorylase system deficiencies: diagnosis thanks to non invasive blood enzymatic and molecular studies. Mol Genet Metab. 2011 Sep-Oct. 104(1-2):137-43. [Medline].

  8. Bashan N, Iancu TC, Lerner A. Glycogenosis due to liver and muscle phosphorylase kinase deficiency. Pediatr Res. 1981 Apr. 15(4 Pt 1):299-303. [Medline].

  9. Beauchamp NJ, Dalton A, Ramaswami U, et al. Glycogen storage disease type IX: High variability in clinical phenotype. Mol Genet Metab. 2007 Sep-Oct. 92(1-2):88-99. [Medline].

  10. Beauchamp NJ, Taybert J, Champion MP et al. High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis. Oct 2007. 30:722-734. [Medline].

  11. Burwinkel B, Bakker HD, Herschkovitz E. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. 1998 Apr. 62(4):785-91. [Medline].

  12. Burwinkel B, Bakker HD, Herschkovitz E, et al. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. 1998 Apr. 62(4):785-91. [Medline].

  13. Chen Y-T, Burchell A. Glycogen storage diseases. The Metabolic and Molecular Bases of Inherited Disease. 1995. Vol 1: 935-65.

  14. Goldberg T, Slonim AE. Nutrition therapy for hepatic glycogen storage diseases. J Am Diet Assoc. 1993 Dec. 93(12):1423-30. [Medline].

  15. Hendrickx J, Bosshard NU, Willems P. Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. Eur J Pediatr. 1998 Nov. 157(11):919-23. [Medline].

  16. Hendrickx J, Lee P, Keating JP. Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Am J Hum Genet. 1999 Jun. 64(6):1541-9. [Medline].

  17. Kotb MA, Abdallah HK, Kotb A. Liver glycogenoses: are they a possible cause of polyneuropathy? A cross-sectional study. J Trop Pediatr. 2004 Aug. 50(4):196-202. [Medline].

  18. Newgard CB, Fletterick RJ, Anderson LA. The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. Am J Hum Genet. 1987 Apr. 40(4):351-64. [Medline].

  19. Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol. May 2007. 13:2541-2553. [Medline].

  20. Tang NL, Hui J, Young E, et al. A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity. Mol Genet Metab. 2003 Jun. 79(2):142-5. [Medline].

  21. Willems PJ, Gerver WJ, Berger R. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr. 1990 Jan. 149(4):268-71. [Medline].

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