WORLD ARABIAN HORSE ORGANIZATION

GENETIC DISORDERS IN ARABIAN HORSES: CURRENT RESEARCH PROJECTS

Update January 2010: The Cerebellar Abiotrophy site has recently moved to - http://www.cerebellar-abiotrophy.org/. Please visit this site for further information and details about CA and the newly available indirect genetic test.

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INTRODUCTION: Researchers have already identified over 13,000 genetically inherited traits in humans, more than 5,000 of them are diseases or other abnormalities. Many of these diseases also occur in animals including horses of all breeds, world-wide, so Arabians are not the only breed of horse to have problems with inherited disorders, which may be fatal or disabling genetic conditions. However, some genetic disorders are breed specific and in this short article we will be looking only at the most serious genetic disorders which are known to affect Arabian horses.

It is important to understand that inherited genetic disorders in Arabian horses know no boundaries. They have been reported in all blood lines of the Arabian breed and reported cases have come from almost all countries where Arabians are being bred today. It is also important to understand that there is nothing to be gained from “pedigree witch-hunts”. Through science, we can all learn to deal with facts as they are today, and not to ‘point fingers’ at individual horses from the past which may or may not have been the original sources of these genetic disorders. It also has to be said that it may not be possible or wise to eliminate a genetic disorder altogether, because by doing so an unwanted side effect might be to also eliminate other beneficial traits and diminish, rather than enhance, the gene pool.

It is to all our benefit to become more informed about the genetic disorders in our Arabian horses, to support the researchers in their work and whenever possible to take the necessary steps to selectively avoid the production of affected foals. By identifying the genes responsible and having gene tests available, these can be used as tools by responsible owners when planning breedings, so that carriers are not bred to carriers. In this way affected foals, with all the attendant heart-break that this causes to their breeders, would not be produced.

Fortunately, a few Universities around the world are still undertaking research in an attempt to create gene tests to identify carriers of the many inherited equine genetic disorders, not only those found in Arabians. The Equine Genome Project is now complete, and a full ‘map’ of the horse’s genes is now available to researchers. Universities also hold vast databanks of DNA, much of it from registered and parent-verified horses of many breeds, with known pedigrees going back generations. These databanks hold the key to the future of equine gene test research.

It is only through the collection of large numbers of samples that these genetic diseases can be studied; the location of the mutant allele established and a genetic carrier test developed, as has been done for SCID. Then, and only then, will breeders have the ability never to breed an affected foal again. This is the ultimate goal of the researchers which will benefit us all. The research teams need to obtain samples from affected foals in order to carry out their work. Owners and breeders of affected horses are being asked to submit samples both from the affected animal(s) and if possible from their related family members, together with their registered identification. It is important to note that these Research Centres all have confidentiality clauses in their sample donation forms so the identity of the affected animals, their pedigrees, breeders and owners are protected against any type of finger pointing or 'witch-hunt' against any particular blood-line, which was an unfortunate side-effect of the early research into SCID.

The main reason that this research is taking so long is financial, it is extremely time consuming and expensive to identify the specific genes which cause these disorders, especially when it is into the relatively rare conditions such as Lavender Foal Syndrome, and it will not be successful without further funding. Anyone who wishes to make a donation towards this research should contact the WAHO Office for further information. Please support this research. All communications are welcomed. All information is confidential.

GENETIC DISORDERS IN THE ARABIAN BREED: There are four known genetic conditions in Arabian horses, which usually result in death or euthanasia of the affected animal. All four are thought to be autosomal recessive conditions, which means that the flawed gene is not sex-linked and has to come from both parents for an affected foal to be born. A fifth genetic condition, Juvenile Epilepsy Syndrome is not usually fatal, but can be disabling if not treated.

These are:

1. Severe Combined Immunodeficiency Disorder (SCID);
2. Cerebellar Abiotrophy (CA);
3. Lavender Foal Syndrome (LFS);
4. Occipital Atlanto-Axial Malformation (OAAM).
5. Juvenile Epilepsy Syndrome (JES).

1. Severe Combined Immunodeficiency Disorder (SCID). After many decades of expensive and time-consuming research, the good news is that for some years there has been a DNA test available, developed by VetGen in America, that can detect whether a horse is clear of the SCID gene, is a carrier of SCID gene, or is an affected foal which has inherited the gene from both parents. A horse which carries one copy of the SCID gene is not affected and is, to all intents and purposes, healthy.

SCID is known to be an autosomal recessive trait and is found in many mammal species. "Autosomal" means the trait is not sex linked, and "recessive" means that in order for a foal to be affected, it must have 2 copies of the mutated allele, receiving one copy from each parent. A foal affected by SCID is born with no immune system, and generally dies of an opportunistic infection such as pneumonia, usually before the age of five months. Breeders who suspect SCID can have the foal or both parents gene tested, and if positive may opt for early euthanasia of an affected foal to prevent further suffering.

Since SCID is an autosomal recessive disease, matings between two clear animals as well as matings between a clear and a carrier animal will never produce an affected animal. By definition, carriers of genes for autosomal recessive disorders are completely free of clinical signs of the disease. That is, carriers do not have any negative consequences to their health or performance. Responsible owners are declaring the SCID status of their stallions and generally require that mares sent to those stallions are tested as SCID clear prior to breeding. Please note there is no reason that SCID carriers should not be used for breeding provided care is taken not to breed carrier to carrier. WAHO does not at this time support any proposition that SCID carriers should be formally excluded from breeding by any Member Registry. Through responsible SCID testing and avoiding breeding carrier to carrier, owners can now eliminate the possibility of an affected foal ever being born.

The majority of WAHO Member Registries can now advise their members and owners of their nearest recognized laboratory offering SCID testing, of which there are now several world-wide, so a full list will not be reproduced here. Alternatively, please contact the WAHO Office for further information.

USEFUL CONTACTS FOR SCID INFORMATION:

VetGen 3728 Plaza Drive, Suite 1 Ann Arbor, Michigan,48108 USA Tel: +1-734-669-8440 Fax: +1.734.669.8441 Website: http://vetgen.com (There are many excellent articles on SCID available at this website)

Arabian F.O.A.L. Association Marguerite Illing, Treasurer 853 Cooley Road Parksville, NY 12768-5336 USA Website: www.foal.org

2. Cerebellar Abiotrophy (CA) also referred to as cerebellar cortical abiotrophy (CCA), is a neurological disease affecting the neurons known as Purkinje cells in the cerebellum of the brain, causing them to die off. With CA, the Purkinje cells do not regenerate and once atrophied, their useful life is lost permanently. These cells affect balance and coordination. Put simply, without Purkinje cells, an animal loses its sense of space and distance, making balance and coordination difficult. In most cases, the neurons begin to die off shortly after the animal is born and the condition is noticeable when the animal is less than six months old, though sometimes the onset of symptoms is gradual and the animal is much older before the owner or caretaker notices a problem. Cerebellar Abiotrophy is different from Cerebellar Hyperplasia. Research since 1967 indicates that CA is thought to be an autosomal recessive mode of inheritance.

An affected foal is usually born without any clinical signs, but after 6 weeks and even as late as 18 months the following notable symptoms may be observed: A palsy-like head shaking called ‘intention tremors’ affecting only the head and not the neck or body, particularly noticeable when the foal is trying to focus on something; the lack of a normal blink response although vision is correct; and an awkward exaggerated form of action with the forelimbs called ‘hyper-metric action’ similar to a military goose-step or high elevation used to cross over a very low object. Sometimes in a badly affected individual it appears that the hind legs are also affected, but not usually. This hyper-metric action involves a shooting out and up of the foreleg directly from the elbow at both the walk and the trot. The hoof is brought down to the ground with a thump, often heel first. When cantering on level ground the horse looks as if it is cantering uphill, like a butterfly stroke in swimming. It is a highly exaggerated gait. The more stressed the horse, the more exaggerated the gait. Their spinal column is not involved; they do not lose weight; they are not in pain; they are neither lethargic nor show signs of increasing weakness, or loss of muscle tone.

As these affected foals will often run into things or fall down, sometimes causing head injuries, their condition can be misdiagnosed as injuries from a blow to the head or neck, making the true neurological condition go unnoticed. A CA affected horse has little to no control over its balance and has difficulty judging distances between itself and an object. Hence, they startle easily and appear panicky and hyper-active. When maintained in a constant environment, the older the horse or foal becomes the more it adapts to the surroundings and its own disabilities, thus appearing as if it is improving. Change the environment and the affected horse will have to undergo a serious of hopefully minor 'accidents' before it has adapted to the new distances and objects. Often an older affected horse will have a 'horse buddy’, which will be their guide. Horses with CA will often be referred to mistakenly as 'Wobblers', which is a condition of the spinal cord, not of the brain, or are misdiagnosed as a head injury caused by an accident. The degree of severity varies, with some foals having fast onset of severe coordination problems, others showing milder symptoms. In theory, mildly affected horses could live a full lifespan, but in practice, most are euthanized before adulthood because they are so accident-prone as to be a danger to themselves and others. They are not safe to ride.

Although the clinical signs are distinctive, until recently the only way to confirm a diagnosis of CA was to examine the brain after euthanasia. There is now an indirect genetic test for CA which has been developed following extensive research in USA and Europe, during which time UC Davis and the Swiss Genetics Institute exchanged data information on gathered samples, thus expanding knowledge for both research centres. The genetic test for CA is not completely finished, as the specific mutation that causes the disease has not been found yet. However, a group of genetic DNA-markers next to the disease gene can be used as an indirect test. The CA test is based on a specific set of DNA-variation which is co-inherited with the disease. As a result, the indirect test predicts the status of the actual mutation and can show whether a horse is Clear, Carrier or Affected. Because the genetic test for CA is not completely finished yet, additional pedigree information or samples from a parent may be required to complete a test. This test is now being made available to Arabian horse owners world wide. All results are fully confidential between the horse owner and the laboratory concerned. Full details of this new test can be found at the Cerebellar Abiotrophy website, www.cerebellar-abiotrophy.org.

CONTACTS FOR CURRENT RESEARCH INTO CA:

Dr. Cecelia Penedo PhD., Geneticist. Veterinary Genetics Laboratory University of California One Shields Avenue Davis, California 95616-8744 USA Tel:+1-530-752-2211; Fax:+1-530-752-3556 Email: mctorrespenedo@ucdavis.edu Website: http://www.vgl.ucdavis.edu/genomic/cerebellar/ Dr. Penedo is carrying on the research started by the late Dr. Ann Bowling, well-known author and geneticist, whose studies in 1984 were unable to be published prior to her untimely death. Dr. Penedo has very recently identified the chromosome (locus) which holds the mutant allele and is now researching the genes within that area.

3. Lavender Foal Syndrome (LFS), also called Coat Color Dilution Lethal (CCDL). Lavender foals are characterized by an unique coat colour and neurological dysfunction which leaves them unable to stand. The mode of inheritance has not been established although some researchers feel that it is an autosomal recessive. Because LFS is relatively rare, there is little in the veterinary literature about it and there is currently no genetic test for LFS. Some research appears to indicate this syndrome may be due to a biochemical lesion of the central nervous system involving the release of lower motor neurons but this is not yet certain.

The most striking feature of LFS affected foals is that they are born with a coat color dilution that lightens the tips of the coat hairs, or even the entire hair shaft. Coat color is a dull pinkish-gray, the hairs may be somewhat silvery and the skin tends to be an unhealthy pink color. In a few cases, the coat colour is a very unusual iridescent silver to pale lavender blue. Some affected foals do not exhibit this particular colour, but are unusually pale compared to normal foals. Hence the description ‘lavender’ refers to this unique colour at birth, but Coat Colour Dilution is probably a more accurate description.

In many cases, foals have had a difficult delivery (dystocia) and all LFS foals are never able to stand and nurse. Foals may therefore be misdiagnosed as having neonatal maladjustment syndrome, also known as "dummy" foals, due to a lack of oxygen from the dystocia, or the symptoms may appear similar to spinal cord injury, but the LFS affected foal is generally distinguished from these by the peculiar coat colour.

The neurological dysfunction is characterized by opisthotonus, a position where the head and neck are drawn back, with the body and legs rigid, and is accompanied by convulsions or spasms. This condition is due to a disturbance of the central nervous system. Although unable to right itself, an LFS foal may have a strong suckle reflex and may be bottle fed, however this is usually to no avail. Nystagmus or involuntary, rapid eye movements are a secondary sign of opisthotonus and is present in some LFS foals. Foals with LFS often have seizures, and if they do not die they are usually euthanized within a few days of birth on humane grounds as they are incapable of survival.

LFS should be considered a possibility in the differential diagnosis of any newborn Arabian foal with a markedly dilute coat colour exhibiting a seizure-like disorder at birth.

Research to find the LFS gene is already underway at Universities in USA and Australia, but urgently needs further funding. By comparing the clinical signs of Lavender foals with similar syndromes in other species, several genes have been identified as good candidates for harboring a mutation that might cause Lavender Foal Syndrome. The researchers would welcome submission of any samples.

CONTACTS FOR RESEARCH INTO LFS:

The Arabian Horse Society of Australia is actively promoting the LFS research project getting underway at the University of Queensland. There are also ongoing smaller research projects in USA. Anyone interested in helping with these projects, either through funding donations, or by submitting samples from affected foals, should contact:
Harold Williamson, Secretary AHSA Locked Bag No. 6. 226 George Street Windsor, N.S.W. 2756 Australia Tel: +61 (0) 2-45-775-366 Fax: +61 (0) 2.45.877.509 email: registrar@ahsa.asn.au and ask to be put in touch with: Dr Glen Coleman at the University of Queensland, Australia (email: g.coleman@uq.edu.au)	Or contact: Dr. Samantha Brooks Brooks Equine Genetics Lab, Cornell University 437 Morrison Hall Ithaca, NY 14853, USA Tel: +1-607-254-8217, Email: equinegenetics@cornell.edu
The American F.O.A.L. website (see above under SCID contacts) also has an interesting article on Lavender Foal Syndrome.	The Onderstepoort Veterinary Genetics Laboratory University of Pretoria Faculty of Veterinary Science Old Faculty Building Room 2-8 Onderstepoort 0110 Tel: +27 12 529 8240 Fax: +27 12 529 8310 Contact email for NON African Arabian horse LFS testing is: vgl@up.ac.za

4. Occipital Atlanto-Axial Malformation (OAAM). This is a condition where the cervical vertebrae fuse together in the neck and at the base of the skull. Symptoms range from mild in-coordination to the paralysis of both front and rear legs. Some affected foals cannot stand to nurse, in others the symptoms may not be seen for several weeks. This is the only cervical spinal cord disease seen in horses less than 1 month of age, and a radio-graph can diagnose the condition. There is no genetic test for OAAM, and the hereditary component of this condition is not well researched at present. There are some researchers who feel that it is also an autosomal recessive.

Any breeder with an affected foal should contact their own Registering Authority or Breed Society or nearest Veterinary College in the first instance, to find out if there are any research projects known of in their region. At this time WAHO Office has been unable to locate any specific research projects.

5. Juvenile Epilepsy Syndrome (JES), sometimes referred to as "benign" epilepsy or "idiopathic" epilepsy, is not usually fatal. Foals are born normal and appear normal between epileptic seizures, usually outgrowing the condition between 12 and 18 months. Affected foals may show signs of epilepsy anywhere from two days to six months from birth. Most foals will have what is called 'cluster seizures'. Usually occurring before the third month birthday these are multiple seizures over a three day period with signs of confusion, blindness, head rubbing, depression, inability to eat, nurse or even drink. Affected foals may suffer serious injury as a result of falling to the ground, against hard objects or into fences. The more severe Grand Mal seizures may cause the horse to lose consciousness and the eyes roll back into the head.

Researcher Dr. Monica Aleman at UC Davis in California has pointed out that a foal cannot be considered to have epilepsy unless it has had more than two seizures. Close observation is essential as some seizures may be slight. The mode of inheritance for Juvenile Epilepsy Syndrome has not yet been determined. However, there are different theories at present; one suggests that, like epilepsy in humans, multiple genes may be involved. Another theory suggests that it could be an incomplete form of LFS, and a third concern is that it possibly is an autosomal dominant trait. A “dominant” trait means that an affected foal only needs to inherit one copy of the mutated allele to show clinical signs. An example of a dominant trait is HYPP in American Quarter Horses.

CONTACT FOR RESEARCH INTO JES:

Dr. Monica Aleman, MVZ, PhD, Dipl. ACVIM. Email: mraleman@ucdavis.edu Neuromuscular Disease Laboratory, University of California One Shields Avenue Davis, CA 95616-8744 Tel: +1 (530) 752-1170 or +1 (530) 752-7267

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NEWS UPDATE ON CEREBALLAR ABIOTROPHY RESEARCH. SEPTEMBER 2008. INDIRECT DIAGNOSTIC GENE TEST NOW AVAILABLE.

Research on Cerebellar Abiotrophy has been ongoing since the mid 1960s by geneticists at the Universities of Cornell, Michigan, Iowa and UC Davis in the USA and the Universities of Bern and Zurich in Switzerland, of Ghent in Belgium, of Cordoba in Spain, and in Australia by Professors Dr. J D Baird and Dr. C D Mackensie.

In August 2007 it was announced that locus of the mutant allele had been located. This was a major breakthrough.

Now Dr. Cecilia Penedo from UC Davis has identified the chromosomal region which harbours the causative mutation and is continuing with her work in analyzing the genes within this region. She and her team of researchers have sufficient "markers" in their database and with their knowledge of carrier lineage are offering an indirect diagnostic test as to the status of the presence of Cerebellar Abiotrophy (CA) in Arabian horses. This test, using hair root samples, may be requested direct from the laboratory by owners or breeders who feel the need for this test on their stock. Sufficient DNA is extracted from hair root samples to help establish carrier status.

Initially offering a free service, the overwhelming response necessitated implementing a fee of $50 USD to offset laboratory costs by March 2008, as the process is extremely costly. In August 2008, the newly formed Arabian Horse Foundation in USA contributed a $5,000 gift to the UC Davis Veterinary Genetics Laboratory from their donors for use on further research on Cerebellar Abiotrophy. This generous donation and any further gifts will aid tremendously in diminishing or eliminating this neurological problem in breeding herds as long as two carriers are not bred together.

For those who wish to know if their horses are carriers or not , please send a request to Cecilia Penedo at mctorrespenedo@ucdavis.edu with full name, registration number if applicable and parentage of each individual horse. Providing a full pedigree will facilitate matters and assure a more speedy response. All requests are treated in the strictest confidence.

If you wish to contribute Hair Follicle samples at the same time, request the Cerebellar Abiotrophy Screening Test (CA) on line at: www.vgl.ucdavis.edu/services/horse.php

Or Contact: Cecilia Penedo

Horse Research – CA, Veterinary Genetics Laboratory

University of California

One Shields Avenue

Davis,

California 95616-8744

United States of America

AS OF 2010: In the European Union all the following laboratories are testing for Cerebellar Abiotrophy in unison with Dr. Penedo and VGL at UC Davis and submitting their samples to VGL for analysis.

The Netherlands:

Dr. Van Haeringen Laboratorium BV

P.O. Box 408

6700 AK Wageningen

Netherlands

Tel +31 317 416 402

Fax +31 317 426 117

www.vhlgenetics.com/vhl/webcard.php?artnr=P802

A combination of CA and SCID testing is available upon request at VHL, Netherlands.

Belgium:

PROGENUS LABORATORY

Dr. Olivier DURERME, scientific researcher.

PROGENUS, SA.

Gembloux - Belgium

Email: duterme.o@progenus.be

Web: www.progenus.be/index.php?lang=english

England:

LABOKLIN GmbH & Co, KG (UK)

Veterinary Diagnostic Laboratory (UK)

61 Mouldsworth Ave.,

Manchester M20 1GG - UK

Tel. 0161 282 3066

Fax: 0870 160 6981

Email: info@laboklin.co.uk

Web: www.laboklin.co.uk

Germany:

GeneControl GmbH

Senator-Gerauer-Str.23

85586 Grub - Germany (DE)

Tel: 089 / 9 44 19 69-0

Fax: 089 / 9 44 19 69-501

E-mail: genlab@tzfgen-bayern.de

Web: www.genecontrol.de/main.html

The following laboratory in Germany is doing independent testing on CA with an occasional sample sent to the VGL at UC Davis for clarification.

Institut für Tierzucht und Vererbungsforschung

der Tierärztlichen Hochschule - Hannover

z.Hd. Prof. Dr. Ottmar Distl

Bünteweg 17p

30559 Hannover (Germany)

Tel.: 0511/953-8875; Fax: 0511/953-8582

E-Mail: ottmar.distl@tiho-hannover.de

Web: Web: www.tiho-hannover.de/einricht/zucht/index.htm

Web: Web: www.tiho-hannover.de/einricht/zucht/index_e.htm

LAVENDER FOAL SYNDROME. MORE GOOD NEWS:

The University of Cornell has reopened their research on Lavender Foal Syndrome and identified the LFS gene. Public availability to testing is waiting Peer Review in 2010. For further information on sending in samples please contact (note new email address):

Dr. Samantha Brooks

Brooks Equine Genetics Lab,

Cornell University

437 Morrison Hall

Ithaca, NY 14853

United States of America

Tel: +1-607-254-8217

Email: equinegenetics@cornell.edu

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WAHO would like to thank Lisa Goodwin-Campiglio, Life Member WAHO, SZED Spanish Arabians, Mallorca, Spain, who contributed this article and who has been campaigning tirelessly to raise awareness of the research into genetic disorders in Arabians, especially CA.

The WAHO Office
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