Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

PersianPersian

Chediak-Higashi Syndrome (Blue smoke (Maltese) only)

Related terms: CHS

Outline: Chediak-Higashi syndrome is caused by impairment in the process by which the body manages waste substances within cells.

Affected cats exhibit partial albinism of the hair and eyes and are sensitive to light, and may develop cataracts. Cats with Chediak-Higashi syndrome also have impaired immune function and have an increased susceptibility to bacterial infections. Blood clotting times in affected cats are abnormally prolonged

Affected cats should be kept in a sheltered environment to reduce stress from photosensitivity, sunburn, injury and infection. Affected cats with mild to moderate clinical signs usually live a normal lifespan, but they continue to show clinical signs throughout their life. The gene responsible for Chediak-Higashi syndrome is inherited in an autosomal recessive manner with complete penetrance. Cats with two copies of the defective gene, one from each parent, will be clinically affected by the condition.


Summary of Information

(for more information click on the links below)

1. Brief description

Chediak-Higashi syndrome is caused by an impairment in the process by which the body manages waste substances in cells and is characterised by a build-up of vesicles or granules in the cytoplasm of the cell. In affected animals, there is a defect in the normal functioning of lysosomes, which are membrane-bound, fluid filled sacs that act as the waste disposal system of the cell. Lysosomes fuse with unwanted/worn-out cell organelles or other large molecules within the cytoplasm and break them down into their basic building blocks in cats with Chediak-Higashi syndrome, there is a genetic defect which results in lysosomes being unable to bond with other cell vesicles during normal fusion and fission activities. This leads to a build-up of lysosomes in the cell, usually accumulating around the cell nucleus, which disrupts the normal functioning of the cell. 

The Chediak-Higashi syndrome causes partial albinism in the hair and eyes, due to a build-up enlarged melanin (pigment) granules in cells. This results in a lighter or white coat colour. Light reflecting from the retina of the eye of affected cats also appears a reddish-orange colour. Cats with Chediak-Higashi syndrome are sensitive to light, and may show aversion to bright light (photophobia). Some may also develop cataracts early in life.

Affected cats also have impaired immune function, with enlarged granules present in their white and red blood cells, and in the cells of the kidney. This causes an increased susceptibility to bacterial infections. Blood clotting times in affected cats are abnormally prolonged, eg with prolonged bleeding seen after surgery or injury.

2. Intensity of welfare impact   

Due to their albinism, affected cats should be sheltered from direct sunlight to avoid sunburn. They may also prefer shady environments due to increased ocular sensitivity to light. Cats affected with Chediak-Higashi syndrome are likely to repeatedly develop infections, due to their impaired immune system, and these may be severe and life-threatening. Affected cats have a tendency to bleed profusely, and may regularly have minor haemorrhages from the mouth, nose and other moist mucosal surfaces or from the skin, or more major bleeding following injury or surgery.

There is no curative treatment for the condition; its effects can only be managed. Owners of cats with Chediak-Higashi syndrome may restrict the environment that their cat is allowed access to, eg by keeping the cat indoors with the aim of reducing the risk of infection, injury or sunburn. Such restrictions may impact on the cat’s welfare since they may not be able to fulfil some natural behavioural activities, eg hunting, socialising.

3. Duration of welfare impact

Affected cats will suffer complications associated with the condition throughout their life. Those with mild to moderate clinical signs will usually live a normal lifespan. Affected cats are predisposed to infections, and severe infections may cause sudden death. Severely affected cats have a poor life expectancy, due to the severely compromised immune system.

4. Number of animals affected

The prevalence of Chediak-Higashi syndrome in Persian cats is not known, although it is a rare disease.

5. Diagnosis

Chediak-Higashi syndrome can be diagnosed by a veterinarian from a blood sample, and/or tissue biopsy. These will shows giant granules in cells, and a reduced number of immune cells in the blood.

6. Genetics

Chediak-Higashi syndrome is observed in cats bred for the combination of yellow eye colour and "blue smoke" hair colour only. The gene responsible for Chediak-Higashi syndrome is inherited in an autosomal recessive manner with complete penetrance. Cats with two copies of the defective gene, one from each parent, will be clinically affected by 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 will pass it on to half of their offspring.

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

To our knowledge, there is no DNA test to detect Chediak-Higashi syndrome, but affected cats can be diagnosed using a blood smear test. If a cat only has one copy of the mutation (a heterozygote), it will not be affected and will show no sign of the condition, but will be a carrier passing on the mutated gene to half of its offspring. If two cats, each carrying one copy of the mutated gene are mated together, 25% of their offspring are likely be clinically affected (having two copies of the defective gene -homozygous) and a further 50% will be genetic carriers of the condition.

8. Methods and prospects for elimination of the problem

The condition can be unknowingly spread in the population due to the breeding of heterozygous cats, that each carries one copy of the defective gene; so creating homozygous affected cats and more heterozygous carriers. Breeding practices to produce blue smoke Persians with yellow eye colour traits in Persians should be carefully monitored. The best advice that can be offered to prospective breeders is to avoid breeding between affected cats or from cats with affected relatives, including grandparents, siblings, previous offspring and siblings of parents. Owners of cats with affected relatives are encouraged to test for Chediak-Higashi syndrome in their cats, via a veterinarian, before breeding.


For further details about this condition, please click on the following:
(these link to items down this page)


1.  Clinical and pathological effects

Chediak-Higashi syndrome is caused by an impairment in the process by which the body manages waste substances in cells and is characterised by the build-up of enlarged vesicles or granules in the cytoplasm of cells. In affected animals, there is a defect in the normal functioning of lysosomes (Nagle et al 1996), which are cell organelles that consist of membrane-bound, fluid filled sacs containing enzymes. Lysosomes function as the waste disposal system of the cell, fusing with unwanted/worn-out cell organelles or other large molecules, such as proteins, carbohydrates and lipids, and breaking them down into their basic building blocks. They may then split into smaller vesicles and redistribute their contents to other parts of the cell, where these are then used to form new structures (fission).

In cats with Chediak-Higashi syndrome, there is a genetic defect which results in lysosomes being unable to bond with other cell vesicles during normal fusion and fission activities. This leads to a build-up of lysosomes and interferes with the normal transport of materials to the appropriate site of action within the cell. Excess vesicles accumulate in the cell, usually congregating around the cell nucleus, and these disrupt the normal functioning of the cell.

In affected cats, Chediak-Higashi syndrome causes partial albinism, due to the build-up of abnormally enlarged melanin granules and abnormal distribution of melanin pigment in the skin, which results in a lighter or white coat colour. The iris of the eye may also appear whiter and light reflecting from the retina of affected cats eyes appears a reddish-orange colour. Cats with Chediak-Higashi syndrome are sensitive to light, and may show aversion to bright light (photophobia) and some may also develop cataracts early in life (Kramer et al  1977). A cataract is disease of the eye, in which the lens of the eye becomes opaque and loses transparency; taking on a cloudy or bluish-grey appearance. Cataracts cause blurred vision and eventually, when the entire lens becomes cloudy, result in blindness.

Affected cats have impaired immune function, due to enlarged granules in leukocytes (white blood cells) and in red blood cells and in the cells of the kidney (Prieur & Collier 1981). This leads to impaired white blood cell function, eg of T-cell cytotoxicity and natural killer cell activity and a loss of bactericidal capacity, resulting in an increased susceptibility to bacterial infections.

Blood clotting times in cats with Chediak-Higashi syndrome are abnormally prolonged eg with extended bleeding seen after surgery or injury. This is because clumping or aggregation of platelets in blood – which form blood clots to stop wound bleeding – is impaired in affected cats, due to a defect in storage of serotonin and adenosine diphosphate (ADP) which are responsible for platelet aggregation (Meyers et al 1981). Haematomas (blood-blisters) may also form as a result of minor trauma etc.

Return to top

2. Intensity of welfare impact

Due to their albinism, affected cats should be sheltered from direct sunlight to avoid sunburn. They may also prefer shady environments due to increased ocular sensitivity to light. Affected cats that develop cataracts will experience a loss of vision and may eventually become blind, which can cause confusion and possibly anxiety in cats and may make them more prone to injuring themselves. Cats affected with Chediak-Higashi syndrome are likely to repeatedly develop infections, due to their impaired immune system, and these may be severe and life-threatening. Affected cats have a tendency to bleed excessively, and may have minor haemorrhages from the mouth, nose and other moist mucosal surfaces or from the skin, or more major bleeding after injury or surgery.

There is no curative treatment for the condition; its effects can only be managed. Owners of cats with Chediak-Higashi syndrome may monitor and restrict their cat’s environment to increase shade, avoid injury and minimise infections, eg by keeping the cat indoors. These restrictions may impact on the cat’s welfare since they may not be able to fulfil some behavioural activities, eg hunting, socialising. Infections are treated with antibiotics and anti-inflammatories.

If the cat is injured and the injury results in severe prolonged bleeding then a transfusion of platelet-rich plasma may be needed to promote blood-clotting. As the effects of such transfusions are only transient, cats that require repeated transfusions may experience poor welfare, from the stress associated with repeated visits to the veterinary clinic and the pain and distress caused by the procedure itself.

Return to top

3. Duration of welfare impact

Cats with Chediak-Higashi syndrome will suffer complications associated with this condition throughout their life although those with mild to moderate clinical signs usually live a normal lifespan. Affected cats may develop cataracts early in life, from as early as 3 months of age (Kramer et al 1977) and are predisposed to infections, and severe infections may cause sudden death. Severely affected cats have a poor life expectancy, due to the severely compromised immune system.

Return to top

4. Number of animals affected

The prevalence of Chediak-Higashi syndrome in Persian cats is not known, although it is a rare disease. A full diagnosis in truly affected cats is often not reached because the main clinical signs are often just non-specific recurrent infections.

Return to top

5. Diagnosis

A full diagnosis in truly affected cats is often not reached because the main clinical signs are often just non-specific recurrent infections.  Chediak-Higashi syndrome can be diagnosed in a histopathology laboratory using a blood smear taken by a veterinarian, which shows giant granules in white blood cells that are positive with stains for peroxidases. Tissue biopsies eg in skin or muscle, can also be taken by the veterinarian, and examined in a histopathology laboratory where giant granules can also be observed. A red reflection of light from the eye can be seen in cats with Chediak-Higashi syndrome, due to the albinism. Blood tests will also show abnormal immune cells eg reduced neutrophil count (Kramer et al 1977).

It is also possible to diagnose Chediak-Higashi syndrome prenatally, by measuring the characteristic enlargement of lysosomes associated with the syndrome. In one study, the diameters of the largest lysosomes in cells of normal foetuses ranged from 0.5 to 7.0 μm (means ranged from 0.9 to 1.8 μm), whereas the diameter of the largest lysosomes in the cells of foetuses with Chediak-Higashi syndrome ranged from 0.5 to 30 μm (means ranged from 6.4 to 12.8 μm; (Kahraman & Prieur 1990).

Return to top

6. Genetics

Chediak-Higashi syndrome is observed in cats bred for the combination of yellow eye colour and "blue smoke" hair colour only (Kramer et al 1977). It is not understood how the gene/s responsible for the syndrome are linked to coat or eye colour.

The phenotypes of Chediak-Higashi syndrome in 245 cats from 67 controlled matings of affected, carrier or normal cats were analysed, and it was determined that the gene responsible for Chediak-Higashi syndrome was inherited in an autosomal recessive manner with complete penetrance (Prieur & Collier 1981). Cats with two copies of the defective gene, one from each parent, will be clinically affected by the condition. Cats that inherit one copy of the defective gene, from one parent only, will not be clinically affected but will carry the gene and will pass it on to half their offspring.

A genetic mutation in the CHS1/LYST gene, which expresses a lysosomal trafficking regulator protein causes Chediak-Higashi syndrome in humans and mice (Nagle et al  1996, Certain et al  2000), and this may also be the case in dogs, since the clinical features are the same across all species with this condition (Windhorst & Padgett 1973).

Return to top

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

To our knowledge, there is no DNA test to detect Chediak-Higashi syndrome, but affected cats can be diagnosed using a blood smear test. If a cat only has one copy of the mutation (a heterozygote), it will not be affected and will show no sign of the condition, but will be a genetic carrier passing on the mutated gene to some of its offspring. If two cats, each carrying one copy of the mutated gene are mated together, 25% of their offspring are likely be affected (as they are homozygous - ie have two copies of the defective gene) and a further 50% will be carriers of the condition.

Return to top

8. Methods and prospects for elimination of the problem

The condition can be unknowingly spread in the population from breeding of heterozygous cats, which carry one copy of the defective gene, to create homozygous affected cats and more heterozygous carriers. Chediak-Higashi syndrome is a recessive condition which only affects blue smoke Persians with yellow eye colour, so breeding practices to produce these traits in Persians should be carefully monitored. The best advice that can be offered to prospective breeders is to avoid breeding between affected cats or from cats with affected relatives, including grandparents, siblings, previous offspring and siblings of parents. Owners of cats with affected relatives are encouraged to test for Chediak-Higashi syndrome in their cats, via a veterinarian, before breeding.

Return to top

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.

Return to top

10. References

Certain S, Barrat F, Pastural E, Le Deist F, Goyo-Rivas J, Jabado N, Benkerrou M, Seger R, Vilmer E, Beullier G, Schwarz K, Fischer A and de Saint Basile G (2000) Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome. Blood 95: 979–83

Kahraman MM and Prieur DJ (1990) Chediak-Higashi syndrome in the cat: prenatal diagnosis by evaluation of amniotic fluid cells. American Journal of Medical Genetics 36: 321–7

Kramer JW, Davis WC and Prieur DJ (1977) The Chediak-Higashi syndrome of cats. Laboratory Investigation 36: 554–62

Meyers KM, Seachord CL, Holmsen H and Prieur DJ (1981) Evaluation of the platelet storage pool deficiency in the feline counterpart of the chediak-higashi syndrome. American Journal of Hematology 11: 241–253

Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, McGrail SH, Dussault BJ, Perou CM, Boissy RE, Duyk GM, Spritz RA and Moore KJ (1996) Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nature Genetics 14: 307–11

Prieur DJ and Collier LL (1981) Inheritance of the Chediak-Higashi syndrome in cats. Journal of Hereditary 72: 175–177

Windhorst DB and Padgett G (1973) The Chediak-Higashi Syndrome and the Homologous Trait in Animals. Journal of Investigative Dermatology 60: 529–537

© UFAW 2016


Credit for main photo above:

http://depositphotos.com/search/persian-cat.html?c71e50fd026bb860b25c36d2f6376e82

© Depositphotos.com/ifeonwhite