Genetics of Glycogen-Storage Disease Type VI Clinical Presentation

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Jun 28, 2010
 

History

The most common presentation is in children aged 1-5 years, with a history of protuberant abdomen, growth retardation, and slight delay in motor milestones. These children may also have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.

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Physical

Although children may have growth delay and short stature, adolescents and adults often have normal stature. The abdomen of a child with glycogen-storage disease type VI (GSD VI) usually protrudes, and abdominal examination reveals hepatomegaly and increased liver span. In some cases, hepatomegaly may be massive. However, splenomegaly is always absent. Adult patients may have mild or no hepatomegaly. Delay in motor milestones may be noted in a young child, and mild hypotonia and muscle weakness may be present. In an adolescent or adult, muscle strength and tone are usually normal. Some patients may have signs of peripheral neuropathy upon examination.

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Causes

Glycogen-storage disease type VI results from a deficiency in the activity of one of several enzymes in the phosphorylase-activating cascade. Most cases result from defects of phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation. Phosphorylase b kinase is a multimeric unit consisting of 4 different subunits, each coded by a unique gene located on different chromosomes. Mutations in 3 genes (PHKA2, PHKB, and PHKG2) have been demonstrated in patients with phosphorylase b kinase deficiency.[3]

In addition, several subtypes of phosphorylase kinase deficiency have been identified, based on the tissues affected and the mode of inheritance (autosomal recessive or X-linked recessive).[4] The most common subgroup is the X-linked recessive form.

Classic glycogen-storage disease type VI results from a primary deficiency of liver phosphorylase (PYGL). Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported.

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Contributor Information and Disclosures
Author

Lynne Ierardi-Curto, MD, PhD  Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services

Disclosure: Nothing to disclose.

Specialty Editor Board

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, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders

Disclosure: Genzyme Corporation Salary Management position

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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

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

  3. 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].

  4. 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. Apr 1998;102(4):423-9. [Medline].

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

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

  7. 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].

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

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

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

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

  12. 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. Nov 1998;157(11):919-23. [Medline].

  13. 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. Jun 1999;64(6):1541-9. [Medline].

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

  15. 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. Apr 1987;40(4):351-64. [Medline].

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

  17. 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. Jun 2003;79(2):142-5. [Medline].

  18. 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. Jan 1990;149(4):268-71. [Medline].

 
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