Glycogen storage disease

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Normal hepatic glycogen staining (top) versus a dog liver with glycogen storage disease (bottom)[1]

Glycogen storage disease (Glycogenosis) is a genetic lysosomal storage disease of dogs characterized by excessive glycogen storage due to inherited deficiency of glucose-6-phosphatase (G6Pase).

Three forms of glycogen storage disease have been recognized in dogs:

Without G6Pase activity, all endogenous glucose production is impaired as this critical enzyme catalyzes the final step of both gluconeogenesis and glycogenolysis. Consequently, circulating blood glucose levels cannot be increased in response to positive glucoregulatory stimuli leading to a condition characterized by fasting hypoglycemia, as well as accumulation of glycogen and fat, particularly within liver and kidney tissues[5]. Shunting of glucose-6-phosphate (G6P) into alternative metabolic pathways results in lactic acidosis, hypertriglyceridemia, and hyperuricemia[6].

Liver and muscle damages are common features in GSD IIIa patients, and serum enzyme activities related to these organs are often elevated in the patients. High levels of glycogen are detected in liver biopsies from four months of age[7].

Biochemical analysis of blood usually shows elevated AST and ALT levels, hypercholesterolemia and lactic acidemia[8].

Affected dogs are often young (under two years of age) and present with failure to thrive, episodic exercise intolerance, collapse, lethargy, hepatomegaly, liver fibrosis and cirrhosis[9].

A differential diagnosis would include other storage diseases such as mucopolysaccharidosis, phosphofructokinase deficiency, chronic hepatitis of Bedlinton Terriers as well as ketoacidosis due to diabetes mellitus and other causes of hepatomegaly such as congestive heart failure.

Diagnosis is based on genetic testing performed on blood or saliva from dogs using PCR and direct sequencing of the exon mutation sequence.

Although nutritional therapy is effective in moderating disease, alternative therapies such as novel longer-acting starches and/or gene therapy strategies are attractive as they may provide significant improvements in quality of life.

Experimental gene therapy with double-stranded adeno-associated virus vectors encoding human glucose-6-phosphatase has shown promise at alleviating clinical symptoms in dogs[10].

Prognosis for this condition is poor and most dogs succumb to these diseases at a young age.

References

  1. Weinstein DA et al (2010) Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Hum Gene Ther 21(7):903-910
  2. Kishnani PS et al (2001) Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol 38(1):83-91
  3. Gregory BL et al (2007) Glycogen storage disease type IIIa in curly-coated retrievers. J Vet Intern Med 21(1):40-46
  4. Jolly RD et al (2002) Polyglucosan body disease in a mixed-breed dog. N Z Vet J 50(1):32-35
  5. Chen YT & Burchell A (1995) Glycogen storage diseases. In: Schriver C, Beaudet A, editors. The Metabolic and Molecular Basis of Inherited Disease. New York, NY, USA: McGraw-Hill. pp:905–934
  6. Chou JY et al (2002) Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Current Molecular Medicine 2(2):121–143
  7. Yi H et al (2012) Characterization of a canine model of glycogen storage disease type IIIa. Dis Model Mech 5(6):804-811
  8. Crane B et al (2012) Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia. Gene Ther 19(4):443-452
  9. Kishnani PS et al (1997) Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. Biochem Mol Med 61(2):168-177
  10. Demaster A et al (2012) Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia. Hum Gene Ther 23(4):407-418