Canine Hereditary Ataxia in Gordon Setters – an Update
Reprinted with the permission of Dr. Natashia Olby
In the 1970s, an inherited disease that caused progressive difficulty walking was recognized in Gordon Setters and the first scientific reports appeared in the early 1980s. Dogs started to show signs of lack of coordination in adolescence and early adulthood, typically between 6 months and 4 years of age. These signs progressed until the dogs were unable to walk. The disease, named cerebellar abiotrophy at the time, was studied in detail by high profile veterinary research groups, and shown to be the result of gradual death of cerebellar neurons, in particular, the Purkinje neurons (figure 1 and 2). The disease is inherited as an autosomal recessive trait meaning that dogs had to have 2 copies of the underlying mutation in order to show signs; dogs with just one copy appear normal but can pass on the mutation, and so are called carriers. Affected dogs have appeared at a low rate worldwide ever since then.
What is the cerebellum?
The cerebellum is a part of the brain that controls the ability to move in a smooth and coordinated fashion. When the cerebellum is damaged, dogs develop cerebellar ataxia (ataxia simply means a lack of coordination; it can result from damage to many different parts of the nervous system): this is characterized by a high stepping gait, a wide based stance and exaggerated side to side swaying of the trunk (aka truncal ataxia). In addition, affected animals may show intention tremors (their head tremors from side to side when they fix their gaze on something – this is exaggerated by excitement and goes away when they are quiet), and nystagmus (flicking of the eyes from sided to side, up and down or round in circles).
Terminology – what do the names mean?
Neurodegenerative disease: This term includes all diseases in which neurons gradually die over time. Common examples in people include Alzheimer’s disease and Parkinson’s disease.
Cerebellar abiotrophy (CA): is a name given to inherited neurodegenerative diseases affecting the cerebellum in which animals are born with a normal cerebellum, and neurons die gradually over time. The term was coined to denote an intrinsic metabolic problem (a lack of trophic support), but now we know that these diseases can be caused by a wide range of defects, such as abnormal structural proteins, so the term is now used less commonly.
Hereditary ataxia: This term is an umbrella term that includes all inherited neurodegenerative diseases that cause progressive and intermittent ataxia. It is commonly used in humans, and was used by Linda Cork’s group to describe the disease in Gordon Setters (although, to be exact, they called it Canine Inherited Ataxia at the time), hence the acronym CHA – Canine Hereditary Ataxia. It is the term we have used in our publication. This term aligns well with the terminology used to describe people with similar diseases – indeed, when considering neurodegenerative diseases, Hereditary Ataxia is the third most common cause of difficulty walking after Huntington’s and Parkinson’s diseases in people.
Cerebellar Cortical Degeneration (CCD) and Cerebellar Degeneration (CD): can also be used to describe many neurodegenerative diseases of the cerebellum. The names are an accurate description of the changes found on pathology, with the term cortical included if the degeneration primarily involves the outer layers (the cortex) of the cerebellum. It avoids the implication of a problem with metabolism that comes with the name cerebellar abiotrophy.
Cerebellar ataxia: This simply means a lack of coordination due to cerebellar disease, in other words it describes a sign that can be common to any disease causing cerebellar damage. However, it has been picked up by some breed societies to mean cerebellar abiotrophy and this can cause confusion between dog owners and veterinarians.
Neuronal ceroid lipofuschinosis (NCL): is classified as a lysosomal storage disease. These diseases are hereditary neurodegenerative conditions in which a mutation causes accumulation of products that are usually broken down by lysosomes (an important disposal system within cells), causing gradual death of neurons. There is a form in Gordon Setters that causes progressive loss of the ability to walk, but also causes blindness and behavioral changes.
So to summarize – the disease we are discussing in Gordon Setters can be called Cerebellar Abiotrophy, Canine Hereditary Ataxia or Cerebellar Cortical Degeneration – all are correct, but our preferred term (to keep in line with the human classification) is Canine Hereditary Ataxia of Gordon Setters. Gordon Setters do suffer from a form of NCL but it causes different neurologic signs, and finally, the term cerebellar ataxia is simply a description of the way affected dogs walk, not the name of a disease.
What do we know about Canine Hereditary Ataxia in Gordon Setters now?
We have studied the genetic mutations underlying neurodegenerative diseases in dogs, including Old English Sheepdogs and Gordon Setters. Old English Sheepdogs have a neurodegenerative disease that causes identical signs to the disease seen in Gordon Setters. We started by mapping the disease in Old English Sheepdogs to a particular region of the 4th chromosome, and then we studied the DNA sequence of that region in detail and identified a mutation in a gene that was associated with the disease. By this we mean that every affected dog had 2 copies of the mutated gene, and normal parents of affected dogs each had 1 copy of the gene. The gene, Rab24, codes a protein that likely assists in disposal of waste proteins and cell organelles within neurons. We then looked at the same region in Gordon Setters and found that affected dogs also had 2 copies of the same mutation proving the both breeds, although very distinct, shared the same mutation. This tells us that the mutation has been around for a long time and was probably inherited from ancestors of both breeds of dog. A full account of this work can be found at: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003991
What does this mean?
This finding is exciting for several reasons. First and foremost, we can test for the mutation – our genetic testing service does offer a test – more details about the test below. This allows breeders to test their breeding stock and avoid breeding 2 carriers of the disease, thus allowing gradual elimination of the mutation from the breed.
Second, this was the first report of an autophagy gene (a gene related to a particular disposal pathway) being associated with a neurodegenerative disease. This finding will allow us to study how neurons die in neurodegenerative diseases (eg Alzheimer’s Disease) and develop new therapies for these devastating and common conditions that afflict us as we age.
How prevalent is the mutation in Gordon Setters?
When we identified the mutation, we looked at a cohort of 90 Gordon Setters within the breeding population of dogs. We found the mutated allele at a frequency of 22.2% in this study population that included dogs from the US and from Scandinavia. Since then we have tested an additional 275 dogs, again worldwide, and we have identified the mutated allele in an additional 46 dogs – so 16.7% of dogs tested since our research carry the abnormal allele. The vast majority of these dogs were just carriers with no signs of the disease, so testing provided important information for their owners when it came to making decisions about breeding. This mutation is not at a very high frequency within the breed and it should be possible to eliminate it altogether by testing before breeding. Once a breeder has eliminated it from their kennel, further testing of their dogs is not necessary as long as they are bred to confirmed clear dogs.
How good is the test?
So far, the test has accurately detected 100% of affected dogs, including dogs that did not show signs until a bit older than typically seen. These dogs had reached breeding age well before developing any signs, so the test results were important to the owners. Based on the data we have so far in Gordon Setters, the test has been 100% specific and sensitive. The test is recognized by OFFA. As this research is ongoing, there are still questions that can only be answered with further studies. It has yet to be determined with 100% certainty whether we are testing for the mutation that actually causes the disease or just one that is linked to the disease. In order to prove a mutation causes a disease, it is necessary to do a functional test of the mutation – in other words quantify what the mutation does on a cellular level. It is rather difficult to test the process this mutation may affect and we are currently investigating this further.
How do you test for the mutation?
All information about testing your dogs can be found at http://www.ncstatevets.org/genetics/ The test currently costs $51 and all proceeds beyond the cost of providing the service go back into our canine research.
Offer PRA9rcd4), Coat Colour and CA testing and offer 10% discount to Assured Breeder Scheme members. ABS members must send a photocopy of their ABS Certificate with their order and deduct 10% from their payment.
Progressive Retinal Atrophy - "Moving On"
February 2009 it was confirmed that the Gordon Setter could suffer from
a autosomal recessive mutation of a gene which causes PRA. In the
Gordon Setter this has been found to have "late onset" that is it is
unlikely to be displayed until 10 years of age, although ophthalmic
testing could show early clinical signs from 7 years of age.
Identification of Mutation for Progressive Retinal Atrophy in the Gordon Setter
A mutation responsible for the development of Progressive Retinal
Atrophy (PRA) in the Gordon Setter has been identified by geneticists
working in the Kennel Club Genetics Centre at the Animal Health Trust.
Setter Breed Council
AHT also offer a discount for
PRA(rcd4) testing obtainable by following the link to their site via
the KC website, My KC area under Special Offers