Pyruvate Kinase Deficiency (PKLR gene, Basenji)

Pyruvate kinase deficiency is a disorder characterized by the absence of pyruvate kinase in erythrocytes, which leads to a significant reduction in the lifespan of red blood cells and results in a severe form of regenerative hemolytic anemia.

Symptoms

Pyruvate kinase deficiency manifests with symptoms usually appearing between 4 months and 1 year of age in affected dogs. These dogs experience severe anemia reflected by slow growth, weakness and low exercise tolerance. In addition, bone changes characterized by replacement of bone marrow with fibrous tissue (myelofibrosis) and abnormal bone density (osteosclerosis) are observed. As the disease progresses, liver and bone marrow failure usually occurs around 5 years of age, leading to a poor prognosis and death at that stage of life.

Disease Management

Currently, no cure for pyruvate kinase deficiency has been found. While bone marrow transplantation has been used as an option to reduce clinical signs in affected dogs, it is important to note that more research needs to be conducted in this field to evaluate its efficacy and feasibility as a treatment.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

Pyruvate kinase deficiency is characterized by the absence of the pyruvate kinase enzyme in red blood cells, which is encoded by the PKLR gene. This enzyme plays a key role in anaerobic glycolysis, the metabolic pathway by which erythrocytes obtain energy. Consequently, a lack of this enzyme leads to inadequate energy production (in the form of ATP), lysis of erythrocytes or their early destruction in the spleen. In a study by Whitney et al. (1994), a mutation responsible for this condition was identified in the Basenji breed. The mutation consists of a base pair deletion (c.433del) in exon 5 of the PKLR gene. As a result, a truncated protein is produced that lacks the residues that make up the catalytic site of the enzyme. Importantly, different variants have been described in different breeds as likely causes of pyruvate kinase deficiency. Most of the variants described to date are included in our test.

Most affected breeds

Basenji

Bibliography

Whitney KM, Goodman SA, Bailey EM,et al. The molecular basis of canine pyruvate kinase deficiency. Exp Hematol. 1994 Aug;22(9):866-74. PMID: 7520391.