Canine Disease Profile – Primary Open Angle Glaucoma
Written by Dr. Marine Rullier MSc, DMV (Translation DR)
Glaucoma is a leading cause of irreversible vision loss in humans and in dogs. It is a disease that has a multifactorial origin with complex genetics and that is also influenced by environmental factors.
Glaucoma is the result of increased pressure in the eye (intraocular pressure or IOP) caused by an excess of aqueous humor in the anterior chamber of the eye (see image of the eye, opposite). The aqueous humor is the liquid produced in the anterior chamber and is drained by a structure called the iridocorneal angle. Overproduction of this liquid or a defect in it’s drainage will cause an accumulation of aqueous humor in the eye which in turn will increase the intraocular pressure.
Clinical Signs of Glaucoma
An uncontrolled increase in intraocular pressure can cause several problems. Firstly, it can cause discomfort, redness of the eye and overproduction of tears in the affected animal. The eyeball will then enlarge (known as buphthalmia) and may even exit the eye socket.
Eventually, the lens can shift, which will decrease the ability to see clearly. If the glaucoma is not controlled at this point, the swollen eyeball will slowly crush the optic nerve. The animal will first lose peripheral vision which will be followed by a loss of central vision. Severe glaucoma will cause the animal to go blind.
Primary / secondary / open-angle / closed-angle glaucoma
Primary glaucoma is caused by a genetic mutation. Secondary glaucoma refers to any case in which another disease, trauma, drug or procedure causes increased intraocular pressure. Primary glaucoma can be either open-angle (POAG) or closed-angle (PCAG) where the iridocorneal angle (see the above image of the eye) will have an open or closed appearance. Primary open-angle glaucoma has a slow and / or moderate increase in intraocular pressure and will not cause pain, while primary closed-angle glaucoma will have a rapid and abrupt increase in the intraocular pressure resulting in considerable pain to the affected animal.
Treating Glaucoma
Treatment for glaucoma depends on its origin and its cause. The goal of treating glaucoma is to lower the intraocular pressure to reduce pain for the animal as well as to slow or stop the progression of the disease. The sooner glaucoma is diagnosed, the better the chances of preventing vision loss.
Primary glaucoma cannot be treated definitively but can be managed medically (by taking medication) or with surgery. Medication is mostly used to slow the progression of the disease but it is not a solution that is sustainable in the long term. There are several surgical options that are available and can be performed by an ophthalmologist but surgery is not without potential complications. Enucleation (the removal of the entire globe) is also an economic possibility for the animal.
Glaucoma and Dog Breeds
In dogs, several breeds are particularly susceptible to primary (genetic) open-angle glaucoma. The mutations and genes involved are specific to each breed. The following table lists the breeds where a mutation has been identified and can be used for genetic testing.
In the above table, you can observe that:
- Mutations in different genes can be responsible for glaucoma in dogs with each dog breed having a specific gene affected.
- Individual dog breeds can have a different mutation within the same gene that causes glaucoma within the breed in question.
Thus it can be concluded that several genes are involved in the formation of the iridocorneal angle and that different mutations can result in the same disease.
Why does each breed have its own mutation?
Why does each dog breed have its own mutation? The answer lies in the animal’s pedigree. Several generations ago, an individual was born with a mutation in a gene that is expressed in the iridocorneal angle cells. Since glaucoma develops later in the animal’s life, this individual with the mutated gene had no clinical signs during it’s reproductive age and was therefore able to transmit its gene to its descendants.
If this individual was a champion, he was probably very prolific and was therefore able to transmit his mutated gene to an entire generation. If we extensively trace the pedigrees of affected individuals and / or carriers, we increase the chance of finding an ancestor in common.
The Primary Open-angle Glaucoma Genetic Mutation
Primary open-angle glaucoma in the dog breeds mentioned in the table above follows (more or less) simple mendelian genetics. Given the fact that each individual has two versions of each gene (since we have two parents), an individual will have the genetic status (genotype) clear, carrier or double mutated. A clear individual has two copies of the normal version (allele) of the gene is said to be N/N. A carrier individual will have a non-mutated version (allele) of the gene plus a mutated version (allele) of the gene and is M/N. An individual with two copies of the mutated version (allele) of the gene and is M/M.
The different mutations that cause primary open-angle glaucoma are autosomal recessive, that is, it is only individuals who are double mutated (M/M) that are at increased risk of developing the disease and both sexes can be affected. Carrier individuals (M/N) are not at risk of developing the disease but may transmit the mutation to their offspring.
The Transmission of the Glaucoma Mutation
Let’s look at how the mutation for glaucoma is passed on to the offspring according to the different genetic statuses (genotypes) of the parents:
If a parent that is clear (N/N) is crossed to a parent that is a carrier (M/N), there is a 50% chance of having a puppy that is clear (N/N) and a 50% chance of having a puppy that is a carrier (M/N). These puppies (both N/N and M/N) will not be at risk of having the disease.
If both parents are carriers (M/N) there is a 25% chance of a puppy being clear (N/N), a 50% chance a puppy being a carrier (M/N) and a 25% chance a puppy being double mutated (M/M). The animal that is M/M is at risk of developing the disease.
If a parent that is a carrier (M/N) is crossed to a parent that is double mutated (M/M) then there is a 50% chance of a puppy being carrier (M/N) and 50% chance of a puppy being double mutated (M/M). The puppies that are M/N are not at risk of developing the disease but if used for reproduction will pass the mutation to half of their offspring. The puppies that are M/M are at risk of developing the disease and if used for reproduction will pass the mutation to all of their offspring.
A Genetic Test for Identifying the Glaucoma Mutation
A DNA test to identify the mutation responsible for glaucoma in several dog breeds allows for the identification of carrier animals. This helps breeders in their breeding choices with the goal of eliminating the disease and reducing the frequency of the mutation over time.
References:
- OMIA link: [001976-9615]
- OMIA link: [001870-9615]
- Forman OP, Pettitt L, Komáromy AM et al (2015) A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17. PLoS ONE 10(12) :e0143546. [pubmed/26683476]
- Komáromy AM, Petersen-Jones SM. (2015) Genetics of Canine Primary Glaucomas. Vet Clin North Am Small Anim Pract. Nov;45(6):1159-82 [pubmed/26277300]
- Kuchtey J, Olson LM, Rinkoski T et al. (2011) Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of Primary open angle glaucoma. PLos Genetics 7(2):e1001306. [pubmed/21379321]
- Kuchtey J, Kunkel J, Esson D et al (2013) Screening ADAMTS10 in Dog Populations Supports Gly661Arg as the Glaucoma-Causing Variant in Beagles. Invest Ophthalmol Vis Sci. 54(3):1881-6. [pubmed/23422823]
- Komáromy AM, Petersen-Jones SM. (2015) Genetics of Canine Primary Glaucomas. Vet Clin North Am Small Anim Pract 45:1159-82. [pubmed/26277300]
- Oliver JA, Forman OP, Pettitt L. (2015) Two independent mutations in ADAMTS17 are associated with primary open angle glaucoma in the Basset Hound and Basset Fauve de Bretagne breeds of dog. PLoS One 10(10):e0140436. [pubmed/26474315]
- Graham KL, McCowan C, White A. (2017) Genetic and biochemical biomarkers in canine glaucoma. Veterinary Pathology 54(2):194-203. [pubmed/27681326]
- Oliver JAC, Rustidge S, Pettitt L et al (2018) Evaluation of ADAMTS17 in Chinese Shar-Pei with primary open-angle glaucoma, primary lens luxation, or both. Am J Vet Res 79(1):98-106. [pubmed/29287154]
- Jeanes EC, Oliver JAC, Ricketts SL et al (2019) Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma. Canine genetics and epidemiology 6(5). [pubmed/31131111]