Canis ISSN: 2398-2942

Pyruvate kinase deficiency

Synonym(s): PK deficiency

Contributor(s): Michael Day, Prof. Urs Giger, Kerry Simpson

Introduction

  • Pyruvate kinase (PK) deficiency is an inherited erythrocyte enzyme deficiency.
  • Canine PK deficiency was first documented in the Basenji in 1971, but has since been reported in several breeds.
  • A range of genetic mutations involving the RLPK gene have been documented.
  • The condition has an autosomal recessive mode of inheritance.
  • PK deficiency has also been reported in cats but presents somewhat differently.
    Print off the owner factsheet on Pyruvate kinase deficiency Pyruvate kinase deficiency to give to your client.

Pathogenesis

Predisposing factors

General

  • This is caused by breed-specific mutations in RLPK gene. Excessive stress and exercise can result in more severe clinical signs.

Pathophysiology

  • Erythrocytes generate energy via anaerobic glycolysis producing adenosine triphosphate (ATP). Two key enzymes are required for the production of ATP - phosphofructokinase (PFK) and pyruvate kinase (PK). Without activity of either of these enzymes, there is insufficient ATP and diphosphoglyceride production so erythrocytes are unable to maintain their viability and structural integrity resulting in destruction of red cells and anemia, and increased hemoglobin-oxygen afffinity. Excessive red cell breakdown can lead to hemosiderin storage and organ (eg liver) compromise. As the animal ages, myelofibrosis and osteosclerosis develops. The pathogenesis of these bone marrow changes has not been determined, but they do not occur in other species that develop PK deficiency (humans, cats and mice). Splenomegaly Abdominal organomegaly results from profound extramedullary hematopoiesis and hemosiderosis.
  • There are two PK genes which encode four isoforms of the enzyme by alternative splicing. The PKLR gene encodes those isoforms found in red blood cells (R-PK) and the liver (L-PK). The PKM gene encodes isoforms found in muscle (M1-PK) and other tissues (M2-PK). Bone marrow erythroid precursors express M2-PK and as they mature to circulating red cells, there is a switch to expression of the R-PK isoform. M2-PK is not functional in mature erythrocytes.
  • The genetic mutation in Basenji PK deficiency is a single base pair deletion in exon 5 of the R-PK gene which results in a shortened form of the protein being produced. In the West Highland White Terrier, the mutation involves an insertion of an additional six base pairs at the 3' end of exon 10 of the R-PK gene which results in a protein with two additional amino acids. The Cairn Terrier appears to share the same mutation as the West Highland White. Missense mutations c.848T>C and c.994G>T result in Pug and Beagle PK deficiency respectively and Labrador Retrievers have a c.799C>T mutation that results in a premature termination codon and loss of over 53% of the protein. However, it should be noted that not all Labradors with clinical sgns of PK deficiency have this mutation.

Timecourse

  • Initial presentation at several months to years of age with progressive decline and death by a maximum of 8 years.
  • Their life expectancy is shortened to a few years (particularly in the Basenji and Labrador) ; however, PK-deficient West Highland terriers have lived to 8 years of age.

Epidemiology

  • Not known.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Gultekin G I, Raj K, Foureman P, Lehmans S, Manhart K, Abdulmalik O, Giger U (2012) Erythrocytic pyruvate kinase mutations causing hemolytic anemia, osteosclerosis, and secondary hemochromatosis in dogs. J Vet Intern Med 26(4), 935-944 PubMed.
  • Takatu A, Nash R A, Zaucha Y M, Little M T, Georges G E, Sale G E, Zellmer E, Kuhr C S, Lothrop C D, Storb R (2003) Adoptive immunotherapy to increase the level of donor haematopoietic chimerism after nonmyeloablative marrow transplantation for severe canine hereditary hemolytic anemia. Biolology Blood and Marrow Transplantation9 (11), 674-682 PubMed.
  • Kohn B, Freistedt R, Pekrun A, Wang P, Giger U (1999) Erythrocyte pyruvate kinase deficiency causing chronic hemolytic anemia and osteosclerosis in a longhaired dachshund. Kleintierpraxis 44 (6), 437-45 VetMedResource.
  • Skelly B, Wallace M, Rajpurohit Y, Wang P, Giger U (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 PubMed.
  • Whitney K M, Abraha T, Lothrop C D (1995) Development of retroviral vectors for gene-therapy of canine pyruvate-kinase deficiency. J Cell Biochem March, 415.
  • Whitney K M, Lothrop C D (1995) Genetic test for pyruvate kinase deficiency in Basenjis. JAVMA 207 (7), 918-921 PubMed.
  • Schaer M, Harvey J W, Calderwood-Mays M, Giger U (1992) Pyruvate kinase deficiency causing hemolytic anemia with secondary haemochromatosis in a Cairn Terrier. J Am Anim Hosp Assoc 28 (3), 233-239 VetMedResource.
  • Giger U, Noble N A (1991) Determination of erythrocyte pyruvate kinase deficiency in Basenjis with chronic hemolytic anemia. JAVMA 198 (10), 1755-1761 PubMed.
  • Chapman B L, Giger U (1990) Inherited erythrocyte pyruvate kinase deficiency in the West Highland White Terrier. J Sm Anim Pract 31 (12), 610-616 VetMedResource.
  • Weiden P L, Hackman R C, Deeg H J et al (1981) Long-term survival and reversal of iron overload after marrow transplantation in dogs with congenital hemolytic anemia. Blood 57 (1), 66-70 PubMed.
  • Searcy G P, Tasker J B, Miller D R (1979) Animal model of human disease: pyruvate kinase deficiency in dogs. Am J Pathol 94 (3), 689-692 PubMed.
  • Harvey J W, Kaneko J J, Hudson E B (1977) Erythrocyte pyruvate kinase deficiency in a Beagle dog. Vet Clin Pathol 6 (3), 13-17 PubMed.
  • Searcy G P, Miller D R, Tasker J B (1971) Congenital hemolytic anemia in the Basenji dog due to erythrocyte pyruvate kinase deficiency. Can J Comp Med Vet Sci 35 (1), 67-70 PubMed.

Other sources of information

  • Giger U (2001) Erythrocyte phosphofructokinase and pyruvate kinase deficiency. In: Feldman B F, Zinkl J G, Jain N C eds. Schalms Veterinary Haematology, 5th edition. Philadelphia: Lippincott, Williams & Wilkins, pp 1020-1025.

Organisation(s)


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