June 2010

DNA Test for Ceroid-Lipofucinosis (CL) (Storage Disease) in the Border Collie

Many of you will look at the title of this article and say “Not another DNA test for these dogs. What about working ability? We should focus on that.” That is a true statement to some extent. But the one thing that breeders must keep in mind is that knowledge is power. Whether it is a DNA test for CEA, TNS or CL, these tests are nothing more than valuable tools. Tools that can be used to the breeder’s advantage to breed genetically sound working dogs. Tools that if used sensibly can eventually eradicate these dreadful diseases from the Border Collie without the loss of the working ability.

Many of the greatest working Collies have been carriers for CEA and appear in many of the modern day pedigrees. Without their genetics the breed in general would suffer. One must remember at all times that a carrier of any of these diseases can still be used successfully for breeding if done with knowledge and awareness of how these diseases are inherited. If you have an exceptional working dog who is a carrier determined by DNA testing, this individual can be bred to a DNA tested clear dog. The pups will not be affected, but a certain percentage will be carriers and a certain percentage should be clear of the disease. This can be determined by the DNA testing of all pups. Granted this is an added expense but one worth it considering the long term benefits and goal of breeding genetically sound working dogs.

I have been on a personal mission for the last two years to establish awareness and push for funding for a DNA test for CA (cerebellar abiotrophy) in the Working Australian Kelpie. One of my best Working Kelpies is a carrier of this devastating disease. He has produced some top working pups but bred to another carrier he produced four out of five affected offspring. His genetics are valuable with regards to working ability, but without the ability to DNA test the carrier status of bitches or his offspring he cannot be used for further breeding. Will I neuter him? No. I will keep him intact with the hopes that a test will be developed in the near future and his good working genetics can then be passed on without the consequences of CA.

Fortunately you as Border Collie breeders have the option to DNA test for these anomalies which puts you far ahead of the Kelpie breeder at this time. Use these tools wisely and you can only improve upon an already great breed.

What is Ceroid-Lipofucinosis?

Ceroid-Lipofuscinosis (CL) is a metabolic disease which affects the nerve cells of the body.  Commonly referred to as Storage Disease, CL appears in cats, cattle, horses, sheep, mice and humans, as well as several breeds of dogs. Besides Border Collies, a type of neuronal ceroid-lipofuscinosis disease has been described in English Setters, Tibetan Terriers and American Bulldogs. 

This condition is inherited recessively in the same manner as CEA and TNS. Early this century, F.E. Batten studied and described the disease in children, hence the name Battens Disease. This is the same disease now being diagnosed in dogs and known as Ceroid-Lipofuscinosis. It is hoped research being conducted on the disease in dogs will benefit the children suffering from Battens Disease. As in dogs, there is no cure and no treatment yet available. The life span of children with Battens Disease is approximately 7 years.

Ceroid-Lipofuscinosis is caused by the lack of an enzyme, which allows a waste product (ceroid lipofuscin) to accumulate in body cells. Ceroid lipofuscin is a wax like liquid waste product of cell metabolism, which is normally removed by body enzymes. In cases of CL one of the enzymes is missing. The ceroid lipofuscin is deposited predominantly in the nervous system, particularly the neurons.  Brain cells are rather compact in their nature, and have very little space for the build up of any waste product.  As the waste deposits accumulate in a specific area of the brain, the build-up tends to lead to compression and eventual destruction of healthy brain cells. This leads to progressive neurodegeneration (degeneration of brain and eye cells) and results in severe neurological impairment and early death.

Dogs do not develop ceroid-lipofuscinosis; they are born with this condition.  At birth, however, they do not show symptoms.  It takes time for ceroid lipofuscin to accumulate in the cells, to the point where it is detrimental to the cells. For this reason, most affected dogs will not display signs until they are approximately 15 to 18 months of age. Affected dogs appear normal at birth, but begin to exhibit symptoms early in life - around 1 - 2 years of age. The age of onset and severity of the disease can vary greatly among individuals. Due to the severity of the disease, affected Border Collies rarely survive beyond 26-28 months. There is no treatment or cure at this time.

What are the symptoms of CL?

Affected dogs will appear normal until around 15 months of age. One of the first symptoms usually seen is hyperactivity with aimless wandering. When the dog first starts showing symptoms of abnormal behaviour, these displays can be episodic. As the disease progresses, the episodes become more frequent and severe.

Symptoms that will start to appear can include any or all of the following;

Seizures, loss of coordinated muscle movements, dementia, visual impairment, blindness, fear of familiar objects and surroundings, mania, hyperactivity, rage, disorientation, fixations, abnormal behaviour, snapping, biting.

All symptoms are progressive The dog will steadily and rapidly continue to deteriorate and medication cannot improve the condition. Affected animals have all been euthanized by the age of 3½ years. CL symptoms can be confused with other brain disorders.

How is CL inherited?

CL is not contagious, it is inherited. CL has an autosomal recessive mode of inheritance, i.e. both the sire and dam of an affected dog must be either carriers or affected themselves. A mating of a carrier animal to a clear (non carrier) animal can produce carrier offspring.

Reliable identification of dogs that do not carry disease genes is the key to controlling autosomal recessive diseases. The CL DNA test enables accurate identification of these dogs. Called "genetically clear," "noncarriers" or, more formally, "homozygous normals," such dogs can pass only the normal gene on to all their pups - which means that none of their pups can ever be affected with CL. These "clear" dogs can be bred to any mate, even to a CL carrier which may be a desirable breeding prospect for other reasons. 

Homozygous means both copies of the gene in your dog are the SAME - both normal or both CL. A carrier has one normal and one CL gene, referred to as heterozygous.

Because the CL test is a mutation-based gene test, it accurately and specifically identifies normal dogs, carriers (heterozygous dogs) and affecteds. Possible test results are listed in the table below. 

The following table highlights all the breedings that will not produce affected pups. These breedings include at least one parent proven "normal" by DNA CL test. All other breedings are at risk of producing CL-affected pups. (Note these charts can be used in reference to calculating any autosomal recessive disease including CEA and TNS.)

How common is CL?
       

This is a rare disease. Among lines of Australian descent, it is estimated that up to 3% of Border Collies are carriers and about 1 in 1000 matings will produce affected pups. CL is often referred to as a disease that only impacts Australasian Border Collies. This is not true. We can only speculate that CL was believed to be associated with the Australasian Border Collies because CL was originally identified and diagnosed in Australia more than 25 years ago. However, since that time, in the United States, the Texas A&M University reported that it had diagnosed CL in several Border Collies located in Texas. Although the University never released the identity of those dogs, this occurred several years prior to the importation of any Australasian dogs to the United States. Therefore, these dogs had to be from American and/or British lines. Approximately 10 years ago, a Border Collie located in Great Britain died of CL. A post-mortem examination confirmed the diagnosis. Again, the identity of the dog was never released. However, the dog was known to be from 100% British lines.

Should I test my dogs for CL and where can I get the test done?

Quite simply the test allows you to control the CL gene frequency in your line so you can prevent producing puppies affected with the disease. The CL test is done on a small sample of blood obtained by your veterinarian. Pups can be tested to distinguish carriers from normals as soon as they are old enough to have a small blood sample collected.

OptiGen now offers the CL test for Neuronal Ceroid Lipofuscinosis in Border Collies. This test was developed in the laboratory of Dr. Alan Wilton, University of New South Wales , Australia , with support and encouragement from the Border Collie Club of NSW and others. The CL test detects the disease-causing mutation and identifies each dog as Normal/Clear, Carrier, or Affected. OptiGen has been granted an exclusive patent (pending) license to this test for the market in the U.S. and Canada , and a non-exclusive license for all other regions. The OptiGen CL test will be performed on DNA extracted from a blood sample, which is generally considered the most reliable and verifiable DNA source for genetic testing. 

If you submit a new blood sample to OptiGen, you may order both the CEA and CL tests on this same sample. 

If you tested your Border Collie for CEA/CH previously, in almost all cases they have stored DNA that can be used for the CL test. OptiGen is allowing use of a stored sample only for the new CL test. (This is separate from "Long-Term Storage.") You may order the CL test online on a stored sample. Link to "Order Test" and complete the order form as usual. Be sure to indicate that this dog's sample already is at OptiGen by selecting "Blood sample is already at OptiGen under a long-term storage agreement." Mark this choice even if you did not specifically pay for Long-Term Storage.

In Australia the test is available at Genetic Technologies and through Dr. Alan Wilton, School of Biotechnology, University of NSW, NSW 2052

The research leading to this discovery was undertaken by scientists at the University of New South Wales, Sydney, Australia. Data are published in Genomics, July 18, 2005 (Electronic Publication). The patent-pending technology underlying this test is under exclusive license to OptiGen for the U.S. and Canada, and non-exclusive license elsewhere.

by Kathy Gooch 

(as first published in the International Sheep Dog News)