Pyruvate kinase deficiency

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Characteristic 'fragile' erythrocytes seen under light microscopy associated with PK-deficiency[1]

Pyruvate kinase (PK) deficiency is an autosomal recessive genetic disease of dogs, where it causes severe life-threatening immune-mediated hemolytic anemia[2].

Originally documented in Basenjis[3][4], it has since been reported in other breeds, including Labrador Retrievers, Pugs, Beagles and Cairn Terrier[5].

Affected dogs suffer from chronic, degenerative, hemolytic anemia with low hematocrits[6].

Normal red blood cell survival in dogs is about 1 month, but in PK-deficiency, RBCs lifespan is just a few days[7]. PK-deficient dogs have erythrocyte PK activity mediated by the M2-type PK isoenzyme, which is normally present in all tissues during fetal life and remains the major isoenzyme in erythroid precursors[8]. These dogs lack the normal R-type, which begins to appear in normal erythrocytes as erythroid maturation proceeds[9]. The expression of the M2-type isoenzyme is thought to compensate for R-type PK deficiency but it does not prevent hemolysis in vivo.

Clinically affected dogs usually present from 4 months of age with symptoms at a young age, characterized by pale mucous membranes, tachycardia, exercise intolerance and weight loss. Acute hemolytic anemia may be suspected and hepatomegaly and splenomegaly are often noted during abdominal palpation. Heterozygous dogs are usually asymptomatic and inactive homozygous dogs may not show clinical symptoms until later.

Hematological analysis usually reveals a severe, highly regenerative anemia and high serum ferritin concentrations. Some dogs subsequently develop severe hepatic secondary hemochromatosis and progressive myelofibrosis and osteosclerosis of bone marrow[10].

Definitive diagnosis requires DNA testing, and siblings and progeny are advised to be tested as well.

Affected (homozygous) dogs usually die at a young age (1 - 4 years) because of progressive anemia or hepatic failure[11] and palliative care is the mainstay of welfare for these patients prior to euthanasia. Splenectomy and glucorticosteroid therapy are not helpful. Iron chelation may be considered when large iron deposition occurs in tissues.

Experimentally, bone marrow transplantation has been shown to cure the disease and gene therapy, using a foamy-cell vector, has also shown strong efficacy for eliminating clinical signs associated with this disease in dogs, although long term studies are still required[12].

References

  1. [ Cure Byte]
  2. Whitney KM & Lothrop CD (1995) Genetic test for pyruvate kinase deficiency of Basenjis. J Am Vet Med Assoc 207(7):918-921
  3. Whitney KM et al (1994) The molecular basis of canine pyruvate kinase deficiency. Exp Hematol 22(9):866-874
  4. Inal Gultekin G et al (2012) Erythrocytic Pyruvate Kinase Mutations Causing Hemolytic Anemia, Osteosclerosis, and Secondary Hemochromatosis in Dogs. J Vet Intern Med Jul 13
  5. Skelly BJ et al (1999) Identification of a 6 base pair insertion in West Highland White Terriers with erythrocyte pyruvate kinase deficiency. Am J Vet Res 60(9):1169-1172
  6. Whitney KM et al (1994) The molecular basis of canine pyruvate kinase deficiency. Exp Hematol 22:866–874
  7. Weiden PL et al (1976) Severe hereditary haemolytic anaemia in dogs treated by marrow transplantation. Br J Haematol 33:357–362
  8. Black JA et al (1978) Hereditary persistence of fetal erythrocyte pyruvate kinase in the Basenji dog. In: Brewer GJ, editors. The Red Cell. New York, NY: Alan R. Liss. pp:275–290
  9. Takegawa S et al (1983) Change of pyruvate kinase isozymes from M2- to L-type during development of the red cell. Br J Haematol 54:467–474
  10. Harvey JW (2006) Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet Clin Pathol 35(2):144-156
  11. Giger, U (2010) Westie Club America
  12. Trobridge GD et al (2012) Stem cell selection in vivo using foamy vectors cures canine pyruvate kinase deficiency. PLoS One 7(9):e45173