Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Abyssinian

Pyruvate Kinase Deficiency

Related terms: Erythrocyte pyruvate kinase deficiency; PK deficiency; haemolytic anaemia 

VeNom term: Pyruvate kinase (PK) deficiency (VeNom code: 7024).

Related conditions: anaemia

Outline

Pyruvate kinase deficiency is an inherited condition whereby there is a defect in a gene that codes for an enzyme, pyruvate kinase, which is an important part of the metabolic processes by which cells, including red blood cells, release the energy they need for normal function. Red blood cells cannot release energy by other means so, in cats with this defect, normal cell processes are impaired and the red blood cells die prematurely. This premature death causes a reduction in the number of circulating red blood cells, which in turn results in anaemia (haemolytic anaemia) and a reduced ability to carry oxygen to tissues and organs of the body. Affected cats commonly show external signs of anaemia before 3 years of age, but the severity and precise age of onset of clinical signs vary. The clinical signs of pyruvate kinase deficiency include lethargy, weakness, diarrhoea, pale mucous membranes, lack of appetite, poor coat quality, weight loss and jaundice. Severe anaemia can be life threatening.

Pyruvate kinase deficiency affects both males and females and occurs more frequently in the Abyssinian breed than other cat breeds. It is inherited as an autosomal recessive trait and it is recommended that all Abyssinian cats used for breeding are tested for the defective gene. Clinically affected cats should not be used for breeding, and cats that are carriers for the condition should only be mated with normal cats.


Summary of Information

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1. Brief description

To release the energy they need for normal function, red blood cells are dependent on a process called anaerobic glycolysis. R-type pyruvate kinase is the enzyme involved in the last step of the metabolic pathway of anaerobic glycolysis (in which phosphoenolpyruvate is converted to pyruvate). In cats with pyruvate kinase deficiency, there is a defect in a gene that codes for R-type pyruvate kinase and this impairs the ability of red blood cells to release energy. This interferes with normal cell processes leading to premature cell death. As circulating red blood cells are broken down more quickly in clinically affected cats than the bone marrow can make replacements, their number is reduced leading to anaemia. Clinically affected animals have a reduced ability to carry oxygen to tissues and organs of the body. The haemolytic anaemia may be mild or severe, and may be chronic (persistent) or occur intermittently. Haemolytic crises may occur, in which there is rapid destruction of large numbers of red blood cells,  more rapidly than the body can produce new red blood cells, and this can be life threatening.

The most common clinical sign of pyruvate kinase deficiency in affected cats is lethargy, but other signs include diarrhoea, pale mucous membranes, lack of appetite, poor coat quality, weight loss and jaundice. Occasionally there may also be abnormal enlargement of the spleen (splenomegaly), and affected cats may show pica, where they eat non-nutritive foreign material such as cat litter or fur.

2. Intensity of welfare impact

Although some cats that have inherited the disease may not show visible clinical signs, most cats show mild to severe anaemia, which may be progressive or intermittent. Anaemia causes weakness, nausea and lethargy because there are not enough red blood cells available to carry iron and oxygen to tissues around the body and the condition can be debilitating and life threatening when severe. Affected animals may suffer distress because of the disruption to blood flow and oxygen supply that results from the anaemia and may suffer pain if they develop blood clots. Respiration may also be compromised causing further distress. Jaundice, diarrhoea and weight loss may also occur.  These all contribute to a feeling of malaise. Haemolytic crisis, can be accompanied by fever, back or abdominal pain and shock, and is life threatening.  

There is no curative treatment for the condition. Blood transfusions may be required as an emergency lifesaving procedure during haemolytic crisis but this, along with the hospitalization of the affected animal, may have adverse welfare effects. Surgery to remove the spleen is sometimes recommended and this is a major procedure with a risk of death and has other repercussions for the welfare of the animal, associated with their hospitalization and pain from the procedure.

3. Duration of welfare impact

The age of onset for cats can vary from as young as one month to 5 years, but it most commonly occurs at 3 years of age or less. Mildly affected cats can live a normal lifespan, but more severely affected cats may suffer a shortened lifespan.

4. Number of animals affected

Pyruvate kinase deficiency affects both males and females. Although it is not particularly common in the general cat population; there is a significantly higher frequency of clinically affected and carrier cats in the Abyssinian breed.

5. Diagnosis

Pyruvate kinase deficiency can be diagnosed by a veterinarian using blood sample analysis which can identify reduced red blood cell concentration as well as some other biochemical indicators. A genetic test can also be conducted using blood samples, to detect cats carrying the defective gene and to identify and differentiate between genetically homozygous affected cats, unaffected heterozygous carriers and normal cats without the defective gene.

6. Genetics

Pyruvate kinase deficiency is inherited as an autosomal recessive trait, caused by a mutation in the gene that codes for the enzyme pyruvate kinase. Cats with two copies of the defective gene, one from each parent, will have the condition, although not all of these cats will show external signs of anaemia. Cats which inherit one copy of the defective gene, from one parent only, will not be clinically affected but will carry the gene and may pass it onto their offspring.

7. How do you know if an animal is a carrier or likely to become affected?

A genetic test can reliably distinguish between affected, carrier and normal cats. However, not all cats with inherited pyruvate kinase deficiency will go on to develop clinical signs of the condition.

8. Methods and prospects for elimination of the problem

Abyssinian cats used for breeding should be tested for the defective gene. Affected cats should not be used for breeding, and cats who are carriers for the condition should only be mated with genetically normal cats. However, pyruvate kinase deficiency status should not be the sole selection criterion in a breeding program since the Abyssinian breed has predispositions to other diseases.


For further details about this condition, please click on the following:
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1.  Clinical and pathological effects

All cells require energy to function and they gain this energy via aerobic (using oxygen) or anaerobic (without oxygen) respiration. Red blood cells do not contain mitochondria, cell organelles that are needed to generate energy using aerobic respiration, and are therefore dependent on anaerobic glycolysis, the metabolic process by which glucose is converted into pyruvate, for energy. Pyruvate kinase is the enzyme involved in the last step of anaerobic glycolysis (in which phosphoenolpyruvate is converted to pyruvate). Four types of pyruvate kinase enzyme are coded by two different genes - PKLR and PKM - and the type expressed depends on developmental state and cell type. Red blood cells specifically contain R type pyruvate kinase (Ford et al 1992). When there is a deficiency in R-type pyruvate kinase, the red blood cells are unable to produce the energy needed to function properly. This interferes with normal cell processes and leads to premature cell death, through dehydration. First, the cell membrane becomes more permeable to potassium and potassium leaks out of the cell, which also draws out water. Red blood cells shrink and stop functioning and are destroyed in the liver and the spleen (Giger et al 1997). Pyruvate kinase activity in red blood cells is severely reduced in cats with inherited pyruvate kinase deficiency, while in cats that carry one copy of the mutated gene the activity of the enzyme is approximately reduced by half (Ford et al 1992). Carriers are not clinically affected since healthy functioning bone marrow is capable of replacing red blood cells as they are damaged or destroyed.   

The premature death of the red blood cells in cats with this condition (normal red blood cells have a life span of around three months) causes a reduction in the number circulating in the blood, leading to haemolytic anaemia, as the red blood cells are broken down more quickly than the bone marrow can make replacements. This results in clinically affected animals having a reduced ability to carry oxygen to tissues and organs of the body. Anaemia may be mild or severe, and may be chronic (persistent) or occur intermittently. It can be triggered by stress, such as that caused by infectious diseases or parturition (Kohn & Fumi 2008).

The most common clinical sign of pyruvate kinase deficiency in affected cats is lethargy, but other signs include diarrhoea, pale mucous membranes, lack of appetite, poor coat quality, weight loss and jaundice (Kohn & Fumi 2008). Occasionally there may also be abnormal enlargement of the spleen (splenomegaly), and affected cats may show pica, where they eat non-nutritive foreign material such as cat litter or fur.

Haemolytic anaemia is characterised by a reduced concentration of red blood cells and haematocrit (packed cell volume, measuring the ‘thickness’ of blood) and haemoglobin concentration (Barrs et al 2009). An abnormally elevated level of proteins in the blood serum (hyperglobulinaemia) is commonly found in clinically affected cats, as well as increased levels of certain liver enzymes as a result of the breakdown and excretion of red blood cells. The anaemia may be severe enough to result in inadequate oxygen transport and supply to the tissues for their needs. This causes lethargy and malaise, and reduced activity and appetite are common. Heart rate may be elevated to compensate, to some extent, for the poor oxygen-carrying capacity of the blood. As the anaemia becomes worse, organ damage can occur, due to insufficient oxygen supply, and the damage may be very severe.

When red blood cells break down, a substance called bilirubin is formed and abnormally high levels of bilirubin (hyperbilirubinaemia) are found in cats with pyruvate kinase deficiency (Kohn et al 2006), and this can build up in the blood and other tissues faster than the liver can remove it, causing yellowish pigmentation of the skin (jaundice), the production of darker urine and contributes to a feeling of illness (eg nausea, weakness). It can also lead to kidney failure.

New red blood cells are created in bone marrow, and amongst other signs in clinically affected cats, there is an abnormally high level of immature red blood cells, called reticulocytes (Barrs et al 2009). This can lead to increased and more efficient turnover of red blood cells, which may somewhat combat the anaemia seen in clinically affected animals. However, haemolytic crises may occur, where there is rapid destruction of large numbers of red blood cells faster than the body can produce new ones, and this can be life threatening. Haemolytic crisis may be accompanied by fever, back or abdominal pain and shock.

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2. Intensity of welfare impact

The severity of signs associated with pyruvate kinase deficiency are variable and some cats that have inherited the disease may not show clinical signs. Alternatively, mild to severe anaemia may occur and this may be progressive or it may be intermittent. Anaemia causes weakness, nausea and lethargy and this can be debilitating and life threatening if severe. This is because there are not enough red blood cells available to carry vital iron and oxygen to tissues around the body. They may suffer distress because of the disruption to blood flow and oxygen supply that results from the anaemia and may suffer pain if they develop blood clots. Respiration may also be compromised causing further distress. Jaundice, diarrhoea and weight loss may also occur. These all contribute to a feeling of malaise.

There is no curative treatment for the condition since the presence of R-type pyruvate kinase isoenzymes is genetically determined. Glucocorticoids may prevent or delay red blood cell destruction to some extent and a splenectomy, the removal of spleen tissue, can be performed to remove a major site of red blood cell destruction and to stabilise the volume of red blood cells in blood (Kohn & Fumi 2008). This is a major procedure with a risk of death and has other repercussions for the welfare of the animal, associated with their hospitalization and pain from the procedure.

During a haemolytic crisis, where there is a rapid destruction of red blood cells and at a rate that is much faster than they can be replaced, cats may suffer fever, back or abdominal pain and shock.  Blood transfusions are required as an emergency lifesaving procedure, but this along with the hospitalization of the affected animal may have adverse welfare effects.

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3. Duration of welfare impact

Some cats with pyruvate kinase deficiency may not show any noticeable outward signs of illness, and the age of onset for those that do show outward clinical signs is variable, from as young as one month of age up to 5 years. It is common for the clinical signs to develop at 3 years or less, with an average (median) age of onset of 1.7 years (Kohn & Fumi 2008). Mildly affected cats can live out a normal lifespan, but more severely affected cats may suffer a shortened lifespan. In a follow-up study of 14 cats with pyruvate kinase deficiency, 6 cats died or were euthanased from the condition and the ages ranged from 1 month to 7.5 years after diagnosis (Kohn & Fumi 2008).

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4. Number of animals affected

Pyruvate kinase deficiency affects both males and females. It is not particularly common in the general cat population; the first case of feline pyruvate kinase deficiency was reported in 1992 in the USA and around 6% of 14,179 cats in the USA and UK sampled had the gene mutation associated with pyruvate kinase deficiency (Grahn et al 2012). The Abyssinian breed has a higher frequency of carrying the mutant allele and is therefore more at risk of developing the disease; the frequency of the mutant allele associated with pyruvate kinase deficiency is between 10% and 28% of Abyssinian cats sampled in Japan (Kushida et al 2015), USA, UK (Grahn et al 2012), Germany (Kohn et al 2005) and Australia (Barrs et al 2009). In Germany and other European countries, 8% of Abyssinian cats tested (19 of 239) were homozygous (genetically affected) whilst 57% (57 of 239) were heterozygous carriers for the condition (Kohn & Fumi 2008).

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5. Diagnosis

Analysis of biochemistry of blood samples can diagnose pyruvate kinase deficiency. Affected cats have reduced concentration of red blood cells, haematocrit (packed cell volume, measuring the thickness of blood) and haemoglobin concentration (Barrs et al 2009).

A genetic test can also be conducted using blood samples, to detect cats carrying the defective gene and to determine between homozygous affected cats, heterozygous unaffected carriers and normal cats.

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6. Genetics

Pyruvate kinase deficiency is inherited in Abyssinian cats as an autosomal recessive trait (Giger et al 1997, Kushida et al 2015). Cats with two copies of the defective gene, one from each parent, will be genetically affected by the condition, although the severity of clinical signs shown are variable and some cats may not show any signs of the condition. Cats which inherit one copy of the defective gene, from one parent only, will not be clinically affected but will carry the gene and may pass it onto offspring.

The mutation in the feline PKLR gene causes feline pyruvate kinase deficiency. A single nucleotide polymorphism occurs when a splicing defect causes a deletion in the mRNA, which specify the amino acid sequence of gene expression, and this deletion is substituted for in the DNA sequence (Giger et al 1997, Kushida et al 2015). It seems likely that with varied splicing, the normal and mutant alleles may be expressed in different quantities which could explain the intermittent presenting signs of the condition.

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7. How do you know if an animal is a carrier or likely to become affected?

A polymerase chain reaction test, using blood samples, can reliably distinguish between affected, carrier and normal cats. However, not all cats with inherited pyruvate kinase deficiency will go on to develop clinical signs of the condition.

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8. Methods and prospects for elimination of the problem

The age of onset and severity of clinical signs of pyruvate kinase deficiency are variable and it is therefore likely that cats can reach breeding age before clinical signs develop. A high proportion of Abyssinian cats are heterozygous – that is, they carry one copy of the defective gene and therefore, if bred from, the condition can be unknowingly spread in the population. It is therefore highly recommended that all Abyssinian cats used for breeding are tested for the defective gene. Homozygous cats should not be used for breeding, and carriers should only be mated with normal cats. However, pyruvate kinase status should not be the sole selection criterion in a breeding program since the Abyssinian breed has predispositions to other diseases, including another inherited erythrocyte defect known as erythrocytic osmotic fragility (Barrs et al 2009). Additional environmental factors may be required to induce disease, such as stress and activity level and this should be taken into consideration.

For other cats breeds which have included Abyssinian breed lines in their breed development eg Bengal, Egyptian Mau and Singapura, there may be an increased frequency of the gene mutation associated with pyruvate kinase deficiency (Grahn et al 2012). It is therefore recommended that these breeds are also monitored for the condition.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

 Barrs V, Giger U, Wilson B, Chan C, Lingard A, Tran L, Seng A, Canfield P and Beatty J (2009) Erythrocytic pyruvate kinase deficiency and AB blood types in Australian Abyssinian and Somali cats. Australian Veterinary Journal 87: 39–44

Ford S, Giger U, Duesberg C, Beutler E and Wang P (1992) Inherited erythrocyte pyruvate kinase (PK) deficiency causing hemolytic anemia in an Abyssinian cat. Journal of Veterinary Internal Medicine 6: 123.

Giger U, Rajpurohit Y, Wang P, Ford S, Kohn B, Patterson DF, Beutler E and Henthorn PS (1997) Molecular basis of erythrocyte pyruvate kinase (R-PK) deficiency in cats. Blood 90: 5b

Grahn RA, Grahn JC, Penedo MC, Helps CR and Lyons LA (2012) Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of domestic cats. BMC Veterinary Research 8: 207

Kohn B and Fumi C (2008) Clinical course of pyruvate kinase deficiency in Abyssinian and Somali cats. Journal of Feline Medicine & Surgery 10: 145–153

Kohn B, Fumi C, Seng A and Giger U (2005) Anemia due to erythrocytic pyruvate kinase deficiency and its incidence in Somali and Abyssinian cats in Germany. Kleintierpraxis 50: 305–312

Kohn B, Weingart C, Eckmann V, Ottenjann M and Leibold W (2006) Primary Immune-Mediated Hemolytic Anemia in 19 Cats: Diagnosis, Therapy, and Outcome (1998-2004). Journal of Veterinary Internal Medicine 20: 159–166

Kushida K, Giger U, Tsutsui T, Inaba M, Konno Y, Hayashi K, Noguchi K, Yabuki A, Mizukami K, Kohyama M, Endo Y and Yamato O (2015) Real-time PCR genotyping assay for feline erythrocyte pyruvate kinase deficiency and mutant allele frequency in purebred cats in Japan. The Journal of Veterinary Medical Science 77: 743–6

© UFAW 2016


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