OMIA 001577-9615 : Glycogen storage disease IIIa in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 232400

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2007

Species-specific symbol: GSD IIIa

Species-specific description: Glycogen storage disease IIIa (GSD IIIa) is a disorder of glycogen metabolism characterized by glycogen accumulation in tissue and altered glucose homeostasis. Lethargy, exercise intolerance, and collapse after exercise may become apparent by 14 months of age. Dogs with GSD IIIa are deficient in glycogen debranching enzyme, so instead of breaking down glycogen into glucose, they accumulate abnormal glycogen particles. This mostly happens in liver and muscle, which are the tissues that have the highest levels of glycogen metabolism.

The mode of inheritance is autosomal recessive. The causative mutation is an adenosine deletion causing premature termination of AGL translation. A test is available to detect the mutation. Parents and siblings of affected dogs should be tested. Breeding of affected animals is not recommended. If a carrier must be bred, it is advised to breed that dog only to a dog that has tested as homozygous normal.

Edited by John C. Fyfe, D.V.M., Ph.D.

Mapping: CFA6

Molecular basis: The causative mutation is an adenosine deletion causing premature termination of AGL translation (Gregory et al., 2007). There is an analogous human condition (OMIM# 232400).

Clinical features: Affected dogs show increases in ALT, ALP, and CK within the first year of life. By 14 months of age, lethargy, exercise intolerance, and collapse after exercise may become apparent (Gregory et al., 2007). The disease in curly-coated retrieves is mild compared to what was reported in German shepherds (Ceh et al., 1976; Rafiquzzaman et al., 1976) as a severe metabolic derangement that led to death or euthanasia by 15 months of age. This is likely due to a different mutation or genetic background.

Yi et al. (2012) provided a detailed clinical account of the disorder in Curly Coat Retrievers, having established a colony that segregates for the causal mutation described above. They summarise their findings as: " Abnormally high glycogen deposition was found in liver and muscle, and, consistent with liver and muscle damage, high and gradually increasing activity of enzymes including AST, ALT, ALP and CPK were found in serum. In muscle, increased glycogen deposition was accompanied by disruption of the contractile apparatus and fraying of myofibrils. Progressive, age-related liver fibrosis and muscle damage caused by glycogen accumulation were the major features of GSD IIIa in affected dogs."

Pathology: In a normal dog, the release of glucagon stimulates the breakdown of glycogen. This breakdown happens through the work of phosphorylase and glycogen debranching enzyme. Dogs with GSD IIIa are deficient in glycogen debranching enzyme, so instead of breaking down glycogen into glucose, they accumulate abnormal glycogen particles. This mostly happens in liver and muscle, which are the tissues that have the highest levels of glycogen metabolism (Gregory et al., 2007). Livers of affected animals are dark red, enlarged, and friable, with smooth edges and a grainy surface appearance. On histologic examination, hepatocytes show global cellular swelling with diaphanous eosinophilic (foamy) cytoplasm, but no evidence of inflammation, fibrosis, or cytoplasmic fat. Glycogen accumulation is evident with PAS staining (Gregory et al., 2007). Glucose homeostasis may be sufficiently affected in times of stress to cause hypoglycemia.

Control: Parents of affected dogs are obligate carriers, and siblings should be tested. Breeding of affected animals is not recommended. If a carrier must be bred, it is advised to breed that dog only to a dog that has tested as homozygous normal.

Genetic testing: A test is available to detect the mutation.

Breed: Curly-coated retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
AGL amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase Canis lupus familiaris 6 NC_006588.3 (50112543..50039661) AGL Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Curly-coated retriever Glycogen storage disease IIIa AGL deletion, small (<=20) c.4223delA 2007 17338148

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Brooks, E.D., Yi, H., Austin, S.L., Thurberg, B.L., Young, S.P., Fyfe, J.C., Kishnani, P.S., Sun, B. :
Natural Progression of Canine Glycogen Storage Disease Type IIIa. Comp Med 66:41-51, 2016. Pubmed reference: 26884409.
2014 Yi, H., Brooks, E.D., Thurberg, B.L., Fyfe, J.C., Kishnani, P.S., Sun, B. :
Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl) :, 2014. Pubmed reference: 24509886. DOI: 10.1007/s00109-014-1127-4.
2012 Yi, H., Thurberg, B.L., Curtis, S., Austin, S., Fyfe, J., Koeberl, D.D., Kishnani, P.S., Sun, B. :
Characterization of a canine model of glycogen storage disease type IIIa. Dis Model Mech 5:804-11, 2012. Pubmed reference: 22736456. DOI: 10.1242/dmm.009712.
2007 Gregory, BL., Shelton, GD., Bali, DS., Chen, YT., Fyfe, JC. :
Glycogen storage disease type IIIa in curly-coated retrievers. J Vet Intern Med 21:40-6, 2007. Pubmed reference: 17338148.
1983 Walvoort, HC. :
Glycogen storage diseases in animals and their potential value as models of human disease. J Inherit Metab Dis 6:3-16, 1983. Pubmed reference: 6408305.
1977 Otani, T., Mochizuki, H. :
[Glycogen storage disease (III ?) of dogs]. Jikken Dobutsu 26:172-3, 1977. Pubmed reference: 267585.
1976 Ceh, L., Hauge, J.G., Svenkerud, R., Strande, A. :
Glycogenosis type III in the dog. Acta Vet Scand 17:210-22, 1976. Pubmed reference: 181976.
Rafiquzzaman, M., Svenkerud, R., Strande, A., Hauge, J.G. :
Glycogenosis in the dog. Acta Vet Scand 17:196-209, 1976. Pubmed reference: 1066041.

Edit History


  • Created by Frank Nicholas on 14 Jul 2011
  • Changed by Martha MaloneyHuss on 17 Aug 2011
  • Changed by Martha MaloneyHuss on 23 Aug 2011
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 25 Apr 2013