CEA/PRA

Understanding CEA and its inheritance by Val Brown ch. M. I. A. C. E. DBC.

COLLIE EYE ANOMALY

More usually referred to as CEA is a non-progressive congenital, present at birth, hereditary abnormality of the eye which affects members of the wider Collie family. Originally thought to be a simple recessive its mode of inheritance no longer appears to be quite so simple and it is probable that its more severe expressions involve additional gene mutations that have yet to be identified.

Usually bilateral, affecting both eyes, in its milder forms it is no more than a slight lack of pigment to, or thinning of the optic disc which does not appear to affect the sight in any way. In its more severe forms, which thankfully represent less than 9% of the total Rough Collie population, it can manifest itself as Colobomas of varying sizes and/or partially or wholly detached retina, this latter condition producing blindness.

Being a congenital condition CEA can be detected at an early age, the only method of discovering which if any puppies are clear, or only mildly affected by CEA, is to have the whole litter eye screened for the condition, by a BVA listed ophthalmologist, at the age of 6 to 7 weeks.

Many puppies diagnosed age 6-12 weeks as ‘mildly affected’ will appear to be completely free of CEA if tested when older, this is often referred to as CEA ‘go-normal’. CEA is inherited as an autosomal recessive trait and both parents must carry at least one copy of the defective gene for the offspring to be affected.

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RCD2


 


PROGRESSIVE RETINAL ATOPHY

Commonly referred to by its initials, PRA, it is a progressive inherited eye abnormality, which causes eventual blindness.

Generalised Progressive Retinal Atrophy or GPRA is of early onset and typically apparent by the time a puppy reaches six weeks of age. Current opinion is that this condition does not affect Rough Collies in their country of origin, although it is known to affect Collies in North America, which explains why the Collie Club of America’s Health Foundation funded the research into its genetic inheritance which has since established a DNA test for the condition. This has little relevance to breeders in the United Kingdom or Europe unless they intend incorporating North American blood lines into their breeding programme.

Central Progressive Retinal Atrophy or CPRA is in many ways a more insidious condition, which can not be detected until it manifests itself sometime after the first year of life, and frequently not until quite late in life explaining why breeders are urged to submit their breeding stock for regular eye screening. The condition’s development is also somewhat unpredictable often taking many years before serious loss of sight is experienced if ever. It is also considered that improvements in canine nutrition may have been largely responsible for today’s low incidence of the condition as it is known that Vitamin E deficiency can affect the eventual outcome and most modern feeds use Vitamin E as a preservative.

The possibility of a DNA test being discovered remains slim as the actual mode of inheritance is still not fully
understood, and with the number of confirmed cases being less than 0•25% of all dogs tested under the
BVA/KC Eye Scheme there is little encouragement for further research.

No cases of PRA have been reported in British Collies in several years - Optigen now offers a DNA test for the early onset form of Generalised PRA (RCD2) which affects American Rough and Smooth Collies and it is recommended that all British/American/Canadian bloodlines are tested to prevent this eye problem from entering the British gene pool.

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This artical was first writen in 1991 and has been reproduced courtesy of Val Brown.

Collie Eye Anomaly is the commonest eye disease associated with dogs in the United Kingdom, and as it's name suggests affects the Collie breeds, namely the Rough and Smooth Collie and the Shetland Sheepdog.

In order to understand what CEA is we need to be familiar with the various parts of the eye.

Figure 1 shows a section through the normal canine eye

Figure 2 shows a view of the left eye, as seen through the lens.

From Figure 1 we can see that the eye is spherical in shape, made up of a tough outer skin, the Corneo Scleral Tunic, enclosing various highly sophisticated components. The posterior, white part of this sphere is the Scleral and the Anterior, transparent part is the Cornea.

The Iris regulates the size of the pupil and in conjunction with the movements of the eyelid, affects the amount of light entering the eye. This iris is the coloured area of the eye referred to in the breed standard for eye colour.

The Lens, in conjunction with the Cornea, allows the image being looked upon to be brought into focus. It is in contact with the iris and held in position by thin strands called Zonular Fibres, which connect to the Ciliary Body behind the iris. The Ciliary Body regulates the shape of the lens to facilitate focussing and also produces a fluid called the Aqueous which feeds the lens and the cornea.

The area behind the lens and in in front of the Retina, is filled with a transparent jelly called the Vitreous. Between the retina and the sclera is a nutrient layer called the Choroid, which contains a coloured mirror like structure known as the Tapetum. This reflects the layer passing through the retina back into the eye, to double the nerve impulses being transmitted to the brain. When viewed through an ophthalmoscope this coloured mirror like segment, or Tapetal Fundus, appears as a half moon shape in the upper portion, with the Optic Disc at the junction of this and the dark area, or Non-Tapetal Fundus. It is the tapetal fundus which causes the glow at night when light is shone into the eye.

The Optic Nerve enters the back of the eye off centre, towards the nasal side of the head and spreads out into a very thin delicate membrane, known as the Retina. It lines the rear two thirds of the eyeball and is responsible for converting the light entering the eye into nerve impulses. Contained in this retinal layer are the sensory nervous fibres which transmit these impulses to the brain.

CEA is a disease essentially affecting the scleral and choroidal layers of the eye. The disease is bilateral, which means it affects both eyes, but not necessarily to the same degree. In it's mildest form, vision is not impaired, but blindness will occur in it's severest form. The disease is not progressive, unlike PRA, which means that whatever the degree of affliction, it will not deteriorate.

It is now regarded that CEA has four lesions, which are as follows:

  • Grade 1. Choroidal Hypoplasia, which is the mildest form.

  • Grade 2. Coloboma.

  • Grade 3. Retinal Detachment.

  • Grade 4. Intra-ocular Haemorrhage, the severest form.

Choroidal Hypoplasia:
I will deal with later as this is the most complex part of the disease, but it must be stressed that all affected dogs have this as the common lesion. The more seriously affected will have a coloboma in one or both eyes. The third lesion may be related to a severe coloboma and the fourth lesion may result from a completely detached retina.

The Coloboma:
Is a defect of the sclera, such that a hole appears in the optic disc, or next to it. A hole in the disc itself is called a Papillary Coloboma and a hole next to the optic disc is called a Peripapillary Coloboma. A thin area or very small hole next to the optic disc will not impair vision, but obviously the larger the coloboma the more distorted vision will be and a very large coloboma will almost certainly result in a partial detachment of the retina.

Retinal Detachment:
Is where the retina becomes detached from the underlying tissue, at some point or points, resulting in the retina becoming loose, possibly showing signs of multiple folding or rippling. Vision will be affected and blindness will occur with a complete detachment. Having stated earlier that the disease is not progressive, it should be said that it may appear to be so, when a partial detachment becomes complete, causing total blindness in an already poorly sighted eye.

Intra-ocular Haemorrhage:
Is the severest form of CEA, which may result from severe retinal detachment. But it may also occur at any age to a greater or lesser extent within this category. Early examinations can reveal haemorrhage in puppies which have partially repaired. However, it is extremely likely that further haemorrhage will occur.

Choroidal Hypoplasia, as I said earlier, is the mildest form of CEA, but is the most complex. It is basically an area, or areas of the choroid layer which is lacking in substance to varying degrees. In it's severest form of total lack of pigment tissue, the sclera is visible through the retina. The condition is complicated, however, by the fact that in a certain amount of mildly affected dogs the lack of pigment can fill in and appear apparently normal. These dogs are commonly referred to as "Go Normals" and it is virtually impossible to distinguish them from CEA clear dogs.

Because this filling in of pigment can occur very early, it is essential to have puppies eyes screened between six and seven weeks of age. After this age the chances of a mildly affected puppy becoming a go normal is significantly increased.

The reason why the " Go Normal" is so harmful is because it is a diseased dog showing apparently clear eyes, so that when mated, will produce the disease in it's offspring, probably more seriously than itself or the other parent, especially if this is affected as well. This is where the disease has caused so much trouble in the past. But eye testing at or before seven weeks of age can detect the disease in these go normal dogs.

The disease is further complicated in the blue merle dog, as some naturally have a lack of pigment in the choroidal layer of the eye. These are known as "Merle Eyes". This is not to be confused with a wall, or blue eye, which is a colour change in the iris. A merle eye can appear in a dog with a normal iris equally as much as a dog with a wall eye, or blue iris.

The merle eye can vary in degrees from a partial lack in specific areas, in one or both eyes, to a complete lack of pigment and because of this problem about10% of blue merles are wrongly diagnosed. With merle eyes it is possible for the experienced ophthalmologist to detect the disease, with some difficulty, by considering other features, such as the length and thickness of the choroidal vessels, but it is because of this difficulty that the odd one slips through the net.

One possible advantage is however, that if a dog showing two completely merle eyes is tested as an adult and found to be clear of CEA, then it is not possible for it to be a go normal, as the lack of pigment is due to the merle factor and not choroidal hypoplasia.

With regard to the inheritance of the disease, we know that it affects both male and female equally and is therefore not sex-linked, i.e. limited to one sex only such as monorchidism or cryptorchidism. Similarly, as the disease can be passed to offspring from normal clear eyed parents, it must be recessive in nature, being "hidden" by the normal eye. This is not to be confused with the Go Normal which is an affected dog. We will see later that two go normals mated together will produce 100% affected progeny, whereas two clear eyed dogs will only produce 25% affected.

It is therefore now known that CEA follows a "Normal Simple Autosomal Recessive" mode of inheritance. This means that it is Transmitted through a single gene carrying the disease in a recessive or hidden nature and to understand how this works we need to know a little about inheritance. Fortunately we do not need to delve the depths of genetics to be able to understand how CEA is passed from one generation to the next.

All living organisms are constructed of cells. Millions of cells in fact, which make up every minute detail, from the internal organs to the exterior skin, including the hair, bones, claws etc. Each and every cell contains a central nucleus which contains the chromosomes. These are thread like structures which carry the genes. Every cell has the same set number of chromosomes and each single chromosome has an identical partner within the same nucleus of the cell. This means that each pair of chromosomes carry the same identical genes. These pairs of chromosomes are known as "Autosomes".

The genes are the controlling agents which make up every part of the body, so that each gene, or pair of genes has it's own particular purpose or function. Some genes, or pairs of genes have a singular influence, whilst others work together to build up, say, a specific organ of the body.

In the reproductive process the autsomes divide into two in both the male and female, so that each male sperm contains half the number of chromosomes and each female egg contains an identical half. Thus when fertilisation occurs, the two halves join to form a new complete cell containing the correct number of new autsomes.

We can think of the gene as a bead on a string of beads, with each string having an identical partner carrying identical beads in the same order, so that both genes of a particular pair control the disease. As the normal eye is dominant, we can represent this by a capital letter, say "E" for clear eyes and the small letter "e" will then represent the recessive affected eyes. Thus we can see that as the genes are in pairs there are three possible combinations which the genes may pair into.

  1. E,E. Both genes being identical and carrying the clear eye condition. Dogs possessing this combination are genetically clear of the disease and cannot reproduce it in it's offspring.

  2. E, e. This combination shows the dog with one clear gene and one affected gene. As the normal gene is dominant, the eye condition is clear, but the disease is being carried recessively, hidden or masked if you like by normal condition.

  3. e,e. The genes are again identical but both in the recessive from and as there is no normal gene present the disease is visible in the eyes and so the dog is affected. Note also that this category contains the Go Normal dog.

As each offspring inherits half it's genes from each parent we can represent the theoretical outcome from possible mating sequences in a box diagram.


If both parents are genetically clear, the expectations would be as follows:

          sire      
        E,   E    
                 
  E     E, E   E, E    
dam               100% E, E. Genetically clear progeny
  E     E, E   E, E    

If one parent was genetically clear E, E and the other a carrier clear E, e then the theoretical expectations would be as follows:

          sire      
        E,   E    
                 
  E     E, E   E, E    
dam               50% E, E. Genetically clear progeny
  e     E, e   E, e   50% E, e. Carrier clear progeny

All puppies would be clear eyed.


If one parent was genetically clear E, E and the other affected e,e then the theoretical expectation would be as follows:

          sire      
        E,   E    
                 
  e     E, e   E, e    
dam               100% E, e. Carrier clear progeny
  e     E, e   E, e    

All puppies would be clear eyed.


If both parents were carrier clears E, e then the theoretical expectations would be as follows:

          sire      
        E,   e    
                 
  E     E, E   E, e   25% E, E. Genetically clear progeny
dam               50% E, e. Carrier clear progeny
  e     E, e   e, e   25% e, e. Affected

If one parent is a carrier clear E, e and the other is affected e, e then the theoretical expectations is as follows:

          sire      
        E,   e    
                 
  e     E, e   e, e   50% E, e. Carrier clear progeny
dam               50% e, e. affected
  e     E, e   e, e    

Finally if both parents were affected e, e then the following would be expected.

          sire      
        e   e    
                 
  e     e, e   e, e    
dam               100% e, e. Affected
  e     e, e   e, e    


I have deliberately referred to theoretical expectations because as we all know, luck or chance has a large part to play in practice. For example how often do we get four puppies in a litter and odd numbers crop up just as frequently. The probability of the results matching the theoretical expectancy in a single litter are 50-50, but the more a mating is repeated, the closer to the theoretical expectancy the results will be.

We must always remember that CEA itself varies in degrees of severity, which means the "e" gene has the ability to influence the disease to a greater or lesser extent. The more we use affected stock the greater will be the severity of affliction in their progeny. It is vitally important that we avoid, as much as possible, the matings shown in the final example, as however mildly affected the parents might be, their progeny will all be affected and some of the puppies may be more severely affected.

I hope that this has helped those who are unfamiliar with genetics to understand how the disease is passed from one generation to the next. It also explains how two clear eyed dogs can produce the disease in their progeny, something that has bemused many breeders to the extent that some may have given up eye testing their stock altogether. It is a disease that, with patience and understanding, we can eradicate from our breed by selective breeding and if more enthusiasts understand it, then the sooner this will be achieved.
© 1991 Val Brown, Mertrisa Collies