Comparative Neurology Program

Neuronal Ceroid Lipofuscinosis (NCL)
in Golden Retrievers

Yellow fluorescent storage material in the brain of an affected Golden Retriever.
From Gilliam et al. Molecular Genetics and Metabolism 115:101-9,2015

Researchers at the University of Missouri, College of Veterinary Medicine have used the latest gene discovery strategies to identify the mutation causing a fatal, hereditary degenerative disease of the brain in Golden Retrievers. A DNA test is now available to aid in the diagnosis of affected dogs and to identify carriers of the mutation so that responsible breeders can eliminate the disease from the breed.

What is Neuronal Ceroid Lipofuscinosis?

Neuronal Ceroid Lipofuscinosis (NCL) is a degenerative disease of the brain characterized by the accumulation in brain cells of material called ceroid lipofuscin. This material is unusual in that it glows a flourescent yellow when examined under the microscope. It is one of a group of hereditary diseases called lysosomal storage diseases which are caused by a failure of the system that recycles amino acids in cells.

Amino acids provide the building blocks for all the proteins in a dog's body. You can think of the amino acids like the toy plastic blocks that a child uses to build something like a toy house. Eventually, the proteins in the body get damaged or worn out and need to be replaced. Structures within the cells in our bodies called lysosomes function as the recycling centers for the cell. They can break the proteins down into their amino acids which can then be reused to build new proteins; the same way a child can take apart a plastic block house that they no longer want to play with and use the block to build something new. A specific enzyme is required for each step in the breakdown of a complex protein into its amino acids. A hereditary deficiency in one of those enzymes sets up a road block in the breakdown of the protein. It is as if you were trying to take apart the block structure in the figure, but could not remove the red blocks. You would get stuck half-way through taking it apart and not be able to go any further. The fragments of protein then build up in the lysosome, hence the name lysosomal storage disease. Over time, either the buildup of the partially degraded protein, or the lack of the recycled amino acids interferes with the function of the cells and progressive disease results.

   

The lysosome is the recycling center of a cell. It breaks down worn out proteins to their component amino acids which can be used to build a new protein.

 

In lysosomal storage disease, a deficiency in one step of the breakdown of the protein stops the process at that point. The remaining part of the protein that cannot be broken down gets “stored” in the lysosome and causes disease.

 
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What happens to dogs with this disease?

Because lysosomal storage disease only affects the recycling of proteins, affected dogs can intially produce all the proteins that they need and thus they develop normally for a period of time. It is only when enough storage material builds up in the cells to interfere with functions that the clinical signs become apparent. Thus Golden Retrievers with this disease did not show signs of the disease until they were about 1-2 years old.

Typically the first sign of a problem is a loss of coordination. Affected dogs may have difficulty climbing stairs or stumble, particularly when excited. Behavior changes often follow with affected dogs becoming anxious and agitated. They may pace or circle for prolonged periods and forget previously learned behaviors. They may show compulsive behaviors and have occasionally become aggressive. As the disease progresses, these changes in coordination and behavior become more dramatic. The dogs lose their vision and can develop seizures. Most affected dogs are euthanized by 2-3 years of age due to the severity of their impairment.

A DNA test for this disease is now available

More common diseases such as infections of the brain, toxins, or liver disease can cause some of the signs of NCL. If your dog is showing these signs, see your veterinarian. They will be able to look for common causes of these sypmtoms. If necessary, they can refer you to a veterinary neurologist that is Board Certified by the American College of Veterinary Internal Medicine who who specializes in brain disease. If you or your veterinarian are concerned that your dog may have this lysosomal storage disease, please, CONTACT US. We will be able to help your veterinarian understand this disease.

A DNA test for the mutation is now available through this link to the Orthopedic Foundation for Animals. The DNA test can aid your veterinarian in diagnosing the disease. It can also be used to identify carriers of the trait so that responsible breeders can avoid producing affected pups in the future.

What if my dog is a carrier?

This disease is inherited as a recessive trait. In a recessive disease, both parents of an affected pup are carriers but do not show any symptoms of the disease. All animals have two copies of each gene, one that is inherited from the mother and one inherited from the father. A dog that has one normal gene and one gene that causes the disease is a carrier of the trait. They show no symptoms because the one good gene is enough for their bodies to function normally, but they will pass that bad gene on to about half of their offspring. If a carrier dog is bred to another carrier, then some of the pups (25% on average) will get a bad gene from each parent. Without one good gene to carry the day, the lysosomes cannot function normally and the unlucky pup develops the storage disease.

The DNA test can identify carriers of the mutation so that breeders can make wise breeding decisions. While the initial response is often to eliminate all carriers of a mutation from the breeding pool, this is not the recommended approach. If the bad gene is common in the population, eliminating all the carriers will narrow the gene pool and limit the breeding choices available. This reduces desirable genetic diversity in the breed and may inadvertently increase the incidence of other hereditary problems that may be lurking the lines that are free of the storage disease mutation. There are often highly desirable traits in the lines with a mutation that made them popular to begin with. Eliminating those lines can eliminate those desirable traits, throwing out the baby with the bathwater.

The best approach is to test breeding stock and ensure that two carriers are never bred together so that no affected pups are produced. A carrier that has desirable traits can be bred to a dog who is tested clear of the mutation since no affected pups can result from such a breeding. When selecting future breeding stock, the gene status can be considered in deciding which pups to keep but does not have to be the sole factor. Over time, the prevalence of the mutation in the breed will decline while a genetic bottle-neck is avoided. The key is to ensure that carriers are never bred to each other so that no affected pups are produced.

Questions?

If you have questions about this disease or our research, please CONTACT US. While we cannot make a diagnosis or treatment recommendations, we can provide general information and direct you to a veterinary specialist who could help

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