OMIA 000421-9615 : Glycogen storage disease VII in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 232800

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1996

Cross-species summary: Also known as Phosphofructokinase Deficiency

Species-specific description: Phosphofructokinase (PFK) deficiency is an inherited enzyme deficiency causing hemolytic crises and exertional myopathy. A genetic test is available to detect the causative mutation, which is identical in the English springer spaniel, American cocker spaniel and Whippet.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Mapping: CFA27

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Smith et al. (1996) identified the causal mutation as "a nonsense mutation in the penultimate exon of the [muscle type phosphofructokinase] M-PFK gene [now called PFKM], leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein". The single base pair mutation (G2228A) is identical in the English springer spaniel, American cocker spaniel and Whippet (Gerber et al., 2009).

Inal Gultekin et al. (2012) reported a different mutation (a point mutation (c.550C>T; p.Arg184Trp) in the same gene as being causative in Wachtelhund dogs.

Clinical features: Presenting signs include muscle cramps, exercise intolerance, and a mild increase in creatine kinase. Affected dogs can also present in hemolytic crisis with hemoglobinuria and bilirubinuria after excessive excitement, exercise, or hyperthermia. During a crisis, the dog can develop severe anemia, icterus, fever, lethargy, and anorexia. This anemia is regenerative, usually resolving within several days. Affected animals have a normal life span, usually maintaining a normal PCV but persistent bilirubinuria and reticulocytosis. Variable muscle wasting, hepatosplenomegaly, and increased total body iron stores have also been reported (Gerber et al., 2009).

Pathology: PFK, a cytosolic enzyme in the anaerobic pathway, is composed of three subunits: muscle (M-PFK), liver (L-PFK), and platelet (P-PFK) types. These subunits are present in different proportions in different tissues. Affected dogs lack PFK in skeletal muscle, and have only 20% of normal PFK activity in erythrocytes, which is from L-PFK and P-PFK expression (Gerber et al., 2009). Their PFK-deficient erythrocytes have hemoglobin with high oxygen affinity that helps to compensate for transient but severe anemic episodes (Skibild et al., 2001). Hemolytic crises in affected dogs are precipitated by hyperventilation, hyperthermia, and associated alkalemia, which induce intravascular hemolysis (Skibild et al., 2001).

Prevalence: Canine PFK deficiency has been reported in the USA, the UK, and Europe. Of 600 English Springer Spaniels screened in the USA, 14% were carriers and 6% were affected (Skibild, 2001).

Control: Dogs should be tested prior to pursuing athletic work such as field trials. Breeding of affected or carrier animals should be avoided.

Genetic testing: There is a PCR-based test available to detect the mutation in the English springer spaniel, American cocker spaniel and Whippet.

Breeds: American cocker spaniel, English Cocker Spaniel, Wachtelhund, Whippet.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PFKM phosphofructokinase, muscle Canis lupus familiaris 27 NC_006609.3 (6640649..6620300) PFKM Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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
American cocker spaniel English Springer Spaniel Whippet Glycogen storage disease VII PFKM nonsense (stop-gain) c.2228G>A p.W???* 1996 8702726
Wachtelhund Glycogen storage disease VII PFKM missense c.550C>T p.R184W 2012 22446493

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.
2012 Inal Gultekin, G., Raj, K., Lehman, S., Hillström, A., Giger, U. :
Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog. Mol Cell Probes 26:243-7, 2012. Pubmed reference: 22446493. DOI: 10.1016/j.mcp.2012.02.004.
2011 Hillström, A., Tvedten, H., Rowe, A., Giger, U. :
Hereditary phosphofructokinase deficiency in wachtelhunds. J Am Anim Hosp Assoc 47:145-50, 2011. Pubmed reference: 21311071. DOI: 10.5326/JAAHA-MS-5619.
2009 Gerber, K., Harvey, JW., D'Agorne, S., Wood, J., Giger, U. :
Hemolysis, myopathy, and cardiac disease associated with hereditary phosphofructokinase deficiency in two Whippets. Vet Clin Pathol 38:46-51, 2009. Pubmed reference: 19228357. DOI: 10.1111/j.1939-165X.2008.00089.x.
2006 Harvey, J.W. :
Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet Clin Pathol 35:144-56, 2006. Pubmed reference: 16783707.
2001 Skibild, E., Dahlgaard, K., Rajpurohit, Y., Smith, B.F., Giger, U. :
Haemolytic anaemia and exercise intolerance due to phosphofructokinase deficiency in related springer spaniels Journal of Small Animal Practice 42:298-300, 2001. Pubmed reference: 11440399.
1999 McCully, K., Chance, B., Giger, U. :
In vivo determination of altered hemoglobin saturation in dogs with M-type phosphofructokinase deficiency Muscle & Nerve 22:621-627, 1999. Pubmed reference: 10331362.
1996 Smith, B.F., Henthorn, P.S., Rajpurohit, Y., Stedman, H., Wolfe, J.H., Patterson, D.F., Giger, U. :
A cDNA encoding canine muscle-type phosphofructokinase. Gene 168:275-6, 1996. Pubmed reference: 8654960.
Smith, B.F., Stedman, H., Rajpurohit, Y., Henthorn, P.S., Wolfe, J.H., Patterson, D.F., Giger, U. :
Molecular basis of canine muscle type phosphofructokinase deficiency Journal of Biological Chemistry 271:20070-20074, 1996. Pubmed reference: 8702726.
1994 Brechue, W.F., Gropp, K.E., Ameredes, B.T., Odrobinak, D.M., Stainsby, W.N., Harvey, J.W. :
Metabolic and work capacity of skeletal muscle of PFK- deficient dogs studied in situ Journal of Applied Physiology 77:2456-2467, 1994. Pubmed reference: 7868469.
Harvey, J.W., Smith, J.E. :
Haematology and Clinical Chemistry of English Springer Spaniel Dogs with Phosphofructokinase Deficiency Comparative Haematology International 4:70-75, 1994.
1992 Giger, U., Smith, B.F., Woods, C.B., Patterson, D.F., Stedman, H. :
Inherited Phosphofructokinase Deficiency in an American Cocker Spaniel Journal of the American Veterinary Medical Association 201:1569-1571, 1992. Pubmed reference: 1289336.
Mhaskar, Y., Harvey, J.W., Dunaway, G.A. :
Developmental Changes of 6-Phosphofructo-1-Kinase Subunit Levels in Erythrocytes from Normal Dogs and Dogs Affected by Glycogen Storage Disease Type-VII Comparative Biochemistry and Physiology B - Comparative Biochemistry 101:303-307, 1992.
1991 Mhaskar, Y., Giger, U., Dunaway, G.A. :
Presence of a Truncated M-Type Subunit and Altered Kinetic Properties of 6-Phosphofructo-1-Kinase Isozymes in the Brain of a Dog Affected by Glycogen Storage Disease Type-VII Enzyme 45:137-144, 1991. Pubmed reference: 1840037.
1990 Harvey, J.W., Mays, M.B.C., Gropp, K.E., Denaro, F.J. :
Polysaccharide Storage Myopathy in Canine Phosphofructokinase Deficiency (Type-VII Glycogen Storage Disease) Veterinary Pathology 27:1-8, 1990. Pubmed reference: 2137952.
1988 Giger, U., Argov, Z., Schnall, M., Bank, W.J., Chance, B. :
Metabolic myopathy in canine muscle-type phosphofructokinase deficiency. Muscle Nerve 11:1260-5, 1988. Pubmed reference: 2976895. DOI: 10.1002/mus.880111210.
1987 Giger, U., Harvey, J.W. :
Hemolysis caused by phosphofructokinase deficiency in English Springer Spaniels: seven cases Journal of the American Veterinary Medical Association 191:453-459, 1987. Pubmed reference: 2958437.
Roudebush, P., Easley, J.R., Harvey, J.W. :
Nonspherocytic haemolytic anaemia due to phosphofructokinase deficiency in an English Springer Spaniel Journal of Small Animal Practice 28:513-516, 1987.
1986 Giger, U., Reilly, MP., Asakura, T., Baldwin, CJ., Harvey, JW. :
Autosomal recessive inherited phosphofructokinase deficiency in English springer spaniel dogs. Anim Genet 17:15-23, 1986. Pubmed reference: 2940948.
1985 Giger, U., Harvey, JW., Yamaguchi, RA., McNulty, PK., Chiapella, A., Beutler, E. :
Inherited phosphofructokinase deficiency in dogs with hyperventilation-induced hemolysis: increased in vitro and in vivo alkaline fragility of erythrocytes. Blood 65:345-51, 1985. Pubmed reference: 3155631.
Vora, S., Giger, U., Turchen, S., Harvey, JW. :
Characterization of the enzymatic lesion in inherited phosphofructokinase deficiency in the dog: an animal analogue of human glycogen storage disease type VII. Proc Natl Acad Sci U S A 82:8109-13, 1985. Pubmed reference: 2933748.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Martha MaloneyHuss on 08 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 22 Jun 2012
  • Changed by Frank Nicholas on 03 Sep 2012
  • Changed by Frank Nicholas on 28 Aug 2016