Glycogen Storage Disease, Glycogenoses

Scientists first described inborn errors of metabolism, also termed inherited disorders of metabolism, early in the 20th century and since then have determined the biochemical and genetic bases of a great number of these disorders both in humans and in an increasing number of companion animals.

Glycogenoses is a group of inborn errors of metabolism in which an enzyme necessary for the synthesis or degradation of glycogen is absent.

Signs of Glycogen Storage Disease

Clinical signs of glycogen storage disease usually develop in the first year of life and typically include progressive muscle weakness (often exercise related), muscle atrophy, poor growth, as compared to normal littermates. Some puppies may regurgitate their food that can lodge in the air passageways and cause aspiration pneumonia. Others may have cardiac abnormalities.

Types of Glycogen Storage Disease

The glycogen storage disease reported in dogs and cats include the following:

1. Glycogenosis Type Ia (deficient enzyme: glucose-6-phosphatase). Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver causing severe hypoglycemia.
2. Glycogenosis Type II (deficient enzymes: acid maltase or alpha-1, 4-glucosidase). This type of disease has been described in Lapland dogs.
3. Glycogenosis Type III (deficient enzyme: amylo-1,6-glucosidase). This type of disease has been described in German Shepherds and Akita dogs. Progressive enlargement of the liver (hepatomegaly) is an additional clinical feature in these dogs.
4. Glycogenosis Type IV (deficient agent: alpha-1,4-D-glucan). This type of disease has been described in Norwegian Forest cats.
5. Glycogenosis Type VII (deficient enzyme: phosphofructokinase [PFK]). This type of disease has been reported in English Springer spaniel dogs. These dogs rare show clinical signs of muscle disorders (myopathy). Instead, they usually present with hemolytic anemia and hemoglobinuria due to defective red blood cells. Screening for PFK deficiency is recommended for English Springer spaniels with suspicious clinical signs and before using any for field trials or breeding in order to prevent the further spread of this hereditary disorder [4].

Treatment of Glycogen Storage Disease

There are no effective treatments for these diseases and most patients are euthanized due to progressive debilitation within the first one to two years of life. The availability of metabolic screening tests has advanced the biochemical and genetic characterization in affected breeds of companion animals of inherited metabolic disorders involving amino acid, carbohydrate, fatty acid, and metal metabolism. Advances in gene therapy have led to the development of new treatments for inherited disorders of metabolism, and animal models have played a critical role in this research. For example, glycogen storage disease type Ia in dogs was highly responsive to adeno-associated viral vector-mediated gene therapy, which prolonged survival and for more than a year prevented hypoglycemia during fasting.

Gene therapy for other glycogen storage diseases and metabolic disorders will also be feasible. The further development of gene therapy for inherited disorders of metabolism could lead to curative therapy for affected humans and animals alike.

Prevention of Glycogen Storage Disease

Inborn errors of metabolism impose a significant genetic burden on purebred dogs and cats. The glycogen storage diseases are a category of such disorders. Specific DNA-based carrier tests are needed for definitive, noninvasive diagnosis and to prevent at-risk matings. It has been recently suggested that glycogen storage disease type IIIa (GSD IIIa) is caused by a mutation of the glycogen debranching enzyme gene (AGL) in Curly-Coated Retrievers [3]. A DNA sequence-based carrier test was developed, and carriers were identified in the United States, New Zealand, Australia, and Finland.

References:
1. A practical guide to canine and feline neurology. Curtis W. Dewey, Anton G. Hoffman, Carol Rudowsky
2. Gene therapy for inhereted metabolic disorders in companion animals. Koeberl DD, Pinto C, Brown T, Chen YT. In: ILAR J. 2009;50(2):122-7.
3. Glycogen storage disease type IIIa in curly-coated retrievers. Gregory BL, Shelton GD, Bali DS, Chen YT, Fyfe JC. In: J Vet Intern Med. 2007 Jan-Feb;21(1):40-6
4. Hemolytic anaemia and exercise intolerance due to phosphofructokinase deficiency in related springer spaniels. Skibild E, Dahlgaard K, Rajpurohit Y, Smith BF, Giger U. In: J Small Anim Pract. 2001 Jun;42(6):298-300.