Pyruvate Kinase Deficiency (PKLR gene, Pug)

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 Gultekin et al. (2012) a nonsense mutation in the PKLR gene related to pyruvate kinase deficiency was identified in the Doguillo breed. The mutation consists of a single base substitution in exon 7 (c.848T>C). This change involves the substitution of a valine for an alanine in a region highly conserved among mammalian species. This type of nonsense variant located in the middle of the protein appears to affect function, but is unlikely to alter protein stability. Importantly, different variants have been described in different breeds as likely to cause pyruvate kinase deficiency. Most of the variants described to date are included in our test.

Most affected breeds

Bibliography

Gultekin GI, Raj K, Foureman P,et al. Erythrocytic pyruvate kinase mutations causing hemolytic anemia, osteosclerosis, and secondary hemochromatosis in dogs. J Vet Intern Med. 2012 Jul-Aug;26(4):935-44.