Senior Research Associate
Caspary Professor of Ophthalmology
|Center for Canine Genetics & Reproduction
James A. Baker Institute for Animal Health
PRA, BACKGROUND AND DIAGNOSIS
Progressive retinal atrophy, or PRA as it is frequently termed, is a long recognized, hereditary, blinding disorder. The first modern description of this problem was in Gordon Setters in Europe, in the early years of the twentieth century, but since then PRA has been recognized in most purebred dogs. PRA is a disease of the retina. This tissue, located inside the back of the eye, contains specialized cells called photoreceptors that absorb the light focused on them by the eye's lens, and converts that light, through a series of chemical reactions into electrical nerve signals. The nerve signals from the retina are passed by the optic nerve to the brain where they are perceived as vision. The retinal photoreceptors are specialized into rods, for vision in dimlight (night vision), and cones for vision in bright light (day and color vision). PRA usually affects the rods initially, and then cones in later stages of the disease. In human families the diseases equivalent to PRA (in dogs) are termed retinitis pigmentosa.
In all canine breeds PRA has certain common features. Early in the disease, affected dogs are nightblind, lacking the ability to adjust their vision to dim light; later their daytime vision also fails. As their vision deteriorates, affected dogs will adapt to their handicap as long as their environment remains constant, and they are not faced with situations requiring excellent vision. At the same time the pupils of their eyes become increasingly dilated, causing a noticeable "shine" to their eyes; and the lens of their eyes may become cloudy, or opaque, resulting in a cataract.
The big difference in PRA among breeds is in the age of onset and the rate of progression of the disease. Certain breeds, noteably including the Collie, the Irish Setter, the Norwegian Elkhound and the Miniature Schnauzer, have early onset forms. In these breeds the disease results from abnormal or arrested development of the photoreceptors -- the visual cells in their retina, and affects pups very early in life. In other breeds, including the Miniature Poodle, the English and American Cocker Spaniel, and the Labrador Retriever, PRA is much later in onset. Affected dogs in these breeds appear normal when young, but develop PRA as adults.
Diagnosis of PRA is normally made by ophthalmoscopic examination. This is undertaken using an instrument called an indirect ophthalmoscope, and requires dilatation of the dog's pupil by application of eyedrops. Broadly speaking all forms of PRA have the same sequence of ophthalmoscopic changes: increased reflectivity (shininess) of the fundus (the inside of the back of the eye, overlain by the retina); reduction in the diameter and branching pattern of the retina's blood vessels; and shrinking of the optic nerve head (the nerve connecting the retina to the brain). These changes occurr in all forms of PRA, but at different times in the different breed-specific forms. Usually by the time the affected dog has these changes there is already significant evidence of loss of vision.
Confirmation of the diagnosis can be undertaken by electroretinography. This is an electrical measurement of retinal function somewhat similar to an electrocardiographic test of heart function, but with two differences: the electroretinogram (ERG) can only be recorded as a response to a flash of light (ie: it is not a free running signal like the EKG); and accurate recording of the ERG requires that the dog be anesthetized. In all dogs showing clinical evidence of PRA, the ERG is severely diminished or extinguished.
The ERG can also be used for early diagnosis of specific forms of PRA, that is to detect PRA-affected dogs before they demonstrate clinical evidence of disease. This requires very carefully controlled ERG recording conditions, and a well defined understanding of the age of onset and rate of change of ERG dysfunction in the specific form of PRA under consideration.
INHERITANCE OF PRA With one exception, PRA in all breeds so far studied is an autosomal recessive disorder. That means that to be affected a pup has to receive one copy of the defective gene from both parents. Thus both parents of an affected pup must be either carriers or affected themselves. Similarly, because affected dogs have two copies of the defective gene, all their progeny will be at least carriers.
Three of the early onset forms of PRA -- rcd1 in Irish setters, rcd2 in collies, and erd in Norwegian Elkhounds -- are known to represent different, nonallelic, gene mutations. In contrast, several of the late onset forms of PRA (those present in the Miniature Poodle, the English and American Cocker Spaniel, and the Labrador Retriever) are known to be mutations in the same, as yet unidentified, gene.
The Siberian Husky is the only known breed, so far, in which PRA is not autosomally inherited. In these dogs PRA is X-Linked. The Siberian Husky PRA locus, on the X-chromosome, has 2 alleles: Xpra, the mutated disease gene, and X+ the "wildtype" allele present in normal dogs. Thus the normal male Husky has the genotype X+/Y, and the affected male has the genotype Xpra/Y. Similarly a normal female Husky is X+/X+; an affected female Husky is Xpra/Xpra; and the carrier female Husky is Xpra/X+.
In normal circumstances it is usual that only males are seen to be affected with X-linked PRA. This is not because females cannot be affected, but because they can only result from breeding an affected male to either a carrier or an affected female, and this is an unlikely breeding as long as the frequency of disease in males remains reasonably low, and if breeders cease breeding affected males once their disease is recognized.
Note that only females can be carriers of X-Linked PRA, males must be either affected or normal. All mothers of affected males are carriers, and so are all daughters of affected males. Because of random X-inactivation some females heterozygous for the husky XLPRA gene show a patchy pattern of lowgrade degeneration in their retina, and a modest level of reduction in their ERG amplitudes.