Von Gierke disease (G6PC gene, Maltese)

Glycogen storage disease (GSD) is a group of inherited metabolic disorders in which there is an abnormal accumulation of glycogen in body tissues. These diseases are caused by defects in enzymes necessary for the synthesis or breakdown of glycogen.

Symptoms

The first clinical signs of this disorder usually manifest from the first months of age, evidenced by fasting hypoglycemia and accumulation of glycogen and fat, especially in the liver and kidney. This condition also causes biochemical changes such as lactic acidosis, hyperlipidemia and hyperuricemia. In addition, affected dogs suffer from enlargement of the liver beyond its normal size (hepatomegaly), weakness, growth retardation, lethargy and may even reach coma.

Disease Management

The treatment and prognosis of glycogen storage disease (GSD) in dogs varies depending on the type and severity of the condition. Genetic testing can be helpful in confirming the disease and determining the specific type of GSD. Typically, affected dogs must follow a strict diet, which is usually high in carbohydrates. However, in most cases, nutritional management is insufficient and other measures are resorted to. Some studies have successfully explored gene replacement therapy using viral vectors expressing the enzyme glucose-6-phosphatase, showing promise in preventing hypoglycemia and extending the life of affected dogs.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Glucose is the main source of cellular energy, obtained from the diet (exogenous pathway) or synthesized in organs such as the liver or kidney (endogenous pathway). The key enzyme for releasing glucose into the bloodstream in endogenous production is glucose-6-phosphatase. Any defect in this enzyme affects endogenous glucose generation, resulting in hypoglycemia during fasting. In the research work of Kishnani et al. (1997), they identified a mutation in the Bichon Maltese breed that consisted of the substitution of a guanine for a cytosine (c.363G>C) in the G6PC gene encoding glucose-6-phosphatase. This substitution causes the amino acid change from methionine (conserved in different species) to isoleucine, resulting in a glucose-6-phosphatase with 15 times less enzymatic activity. It is postulated that this reduction is due to the proximity of methionine to a highly conserved histidine, essential for glucose-6-phosphatase-mediated catalysis.

Most affected breeds

Bichón Maltés

Bibliography

Brooks ED, Landau DJ, Everitt JI, et al. Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy. J Inherit Metab Dis. 2018 Nov;41(6):965-976.

Kishnani PS, Bao Y, Wu JY, et al. Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia. Biochem Mol Med. 1997 Aug;61(2):168-77.

Kishnani PS, Faulkner E, VanCamp S, et al. Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia). Vet Pathol. 2001 Jan;38(1):83-91.

Specht A, Fiske L, Erger K, et al. Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease. J Biomed Biotechnol. 2011;2011:646257.