Glaucoma

Glaucoma is a painful and blinding disease associated with pathologically high intraocular pressure caused by inadequate drainage of fluid within the eye. The fluid, which is called aqueous humour, is produced in the ciliary body which is located behind the iris. This fluid flows through the pupil and drains from the eye through a sieve-like network located at the junction of the cornea and the iris called the iridocorneal angle. The aqueous humour is produced and drains from the eye at approximately the same rate, resulting in a stable pressure inside the eye. Glaucoma occurs as a consequence of inadequate outflow of aqueous humour and a subsequent build-up of pressure inside the eye. The resulting high pressure damages the optic nerve and results in blindness. Sadly, in dogs glaucoma treatment is usually unsuccessful and most affected dogs ultimately require removal of their eyes on welfare grounds.

Primary Glaucoma

Glaucoma is termed primary when the cause is considered to be inherited and is thought to affect over 40 breeds of dogs worldwide and at least 1500 dogs in the UK each year. In the American Kennel Club Canine Health Foundation's 2013 Health Poll, glaucoma is listed as a health concern by 17 different breed clubs, meaning it is ranked 37th out of nearly 300 different diseases listed.

Primary glaucoma can be further classified into primary open angle glaucoma and primary closed angle glaucoma on the basis of the appearance of the iridocorneal angle. In both forms however, glaucoma results from reduced drainage of fluid within the eye, causing a build-up of pressure which, in turn, leads to pain and blindness.

Primary Closed Angle Glaucoma

Primary closed angle glaucoma (PCAG), which is the most common form of primary glaucoma in dogs, has been shown to be significantly associated with pectinate ligament dysplasia (PLD), an abnormality affecting the iridocorneal angle that has been shown to be highly heritable.^1-3 The term PLD is often used interchangeably with the term goniodysgenesis. The pectinate ligaments are slender, widely separated fibres of connective tissue that span the iridocorneal angle. The pectinate ligaments are thought to form from a process of rarefaction of an initial sheet of mesodermal tissue spanning the iridocorneal angle (ICA) and development was originally thought to be complete by 8 weeks of age.⁴ In dogs with PLD, broad sheets of tissue are observed in place of the thin, widely separated pectinate ligaments that are present in normal dogs. Pectinate ligament dysplasia/goniodysgenesis can be screened for using a technique known as gonioscopy during which a special lens (goniolens) is placed on the surface of the cornea to enable the iridocorneal angle to be examined. It was originally believed that the degree of PLD did not progress after birth and so a 'one-off' gonioscopy test before breeding was advised for dogs of breeds known to be at risk of glaucoma. It is now known, however, that goniodysgenesis can progress with time so more frequent testing is advised.⁵ Not all dogs with PLD go on to develop glaucoma, so it is assumed that additional risk factors are involved.

The onset of closed angle glaucoma is characterised by a very rapid (acute) increase in intraocular pressure, often literally overnight, that is extremely painful and frequently leads to sudden and irreversible blindness. Breeds at risk of PCAG include the Siberian Husky, the Flatcoated Retriever, the Basset Hound, the English and Welsh Springer spaniels, the American Cocker spaniel and the Spanish Water dog.

Primary Open Angle Glaucoma

In primary open angle glaucoma (POAG), the pectinate ligaments appear normal and the opening to the iridocorneal angle is open to the flow of aqueous humour and appears normal, so there is no easily observable abnormality that can be screened for. Primary open angle glaucoma typically progresses gradually, without significant pain. Breeds known to be affected by POAG include the Beagle, the Norwegian Elkhound and the Petit Basset Griffon Vendéen.

Genetic Investigations

The development of DNA tests to identify dogs at risk of developing primary glaucoma will obviously help breeders reduce the prevalence of this painful and blinding condition. To date, only four mutations responsible for primary glaucoma have been identified, all for autosomal recessive forms of POAG. Two mutations lie in a gene called ADAMTS10 and cause POAG in Beagles and Norwegian Elkhounds, respectively.^6-8 Two additional mutations that lie in the closely related gene known as ADAMTS17 have recently been identified that cause POAG in the Petit Basset Griffon Vendéen and Basset Hound, respectively (Forman et al.; Oliver et al. Manuscripts submitted for peer-review).

In contrast to POAG, it is generally considered that PCAG is likely to be genetically complex in most breeds, and currently there are no DNA tests available to test for dogs at risk for PCAG. At the Animal Health Trust we are undertaking an extensive research programme to identify genetic risk factors for PCAG in multiple breeds with the aim of developing DNA tests to help breeders reduce the prevalence of the disease in breeds at risk. The project is being undertaken by James Oliver, who is a veterinary ophthalmologist and panelist of the BVA/KC/ISDS eye scheme and forms the basis of his PhD studies. Thus far, James has performed gonioscopy on > 1400 dogs and collected DNA from all of them. DNA samples are also being collected, using cheek swabs and following written owner consent, from additional dogs previously examined by other veterinary ophthalmologists and submitted for genome-wide analysis along with copies of appropriate Eye Scheme Certificates. DNA from glaucoma cases are also being recruited by enlisting the help of veterinary ophthalmologists across the world. We are currently undertaking genome-wide case-control investigations of each breed, to identify regions of the genome associated with PLD and/or glaucoma and to pinpoint mutations associated with the disease.

References

1.  Bjerkas E, Ekesten B, Farstad W. Pectinate ligament dysplasia and narrowing of the iridocorneal angle associated with glaucoma in the English Springer Spaniel. Veterinary Ophthalmology. 2002;5(1):49–54.

2.  Bedford PG. A gonioscopic study of the iridocorneal angle in the English and American breeds of Cocker Spaniel and the Basset Hound. Journal of Small Animal Practice. 1977;18(10):631–642.

3.  Wood JL, Lakhani KH, Read RA. Pectinate ligament dysplasia and glaucoma in Flat Coated Retrievers. II. Assessment of prevalence and heritability. Veterinary Ophthalmology. 1998;1(2–3):91–99.

4.  Samuelson DA, Gelatt KN. Aqueous outflow in the beagle. I. Postnatal morphologic development of the iridocorneal angle: pectinate ligament and uveal trabecular meshwork. Current Eye Research. 1984;3(6):783–794.

5.  Pearl R, Gould D, Spiess B. Progression of pectinate ligament dysplasia over time in two populations of Flat-Coated Retrievers. Veterinary Ophthalmology. 2015;18(1):6–12.

6.  Kuchtey J, Olson LM, Rinkoski T, Mackay EO, Iverson TM, Gelatt KN, Haines JL, Kuchtey RW. Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma. PLoS Genetics. 2011;7(2):e1001306.

7.  Kuchtey J, Kunkel J, Esson D, Sapienza JS, Ward DA, Plummer CE, Gelatt KN, Kuchtey RW. Screening ADAMTS10 in dog populations supports Gly661Arg as the glaucoma-causing variant in beagles. Investigative Ophthalmology & Visual Science. 2013;54(3):1881–1886.

8.  Ahonen SJ, Kaukonen M, Nussdorfer FD, Harman CD, Komaromy AM, Lohi A. A novel missense mutation in ADAMTS10 in Norwegian Elkhound primary glaucoma. PLoS One. 2014;9(11):e111941.