Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations that affects about 1 in 4000 people. The mode of inheritance can be autosomal dominant (15 to 20%), autosomal recessive (60 to 70%), X-linked recessive (15 to 25%) and others (<1%). Most of our genetic materials are present in pairs (one copy from our father and one from our mother) except in the sex chromosomes (X,Y). Man would only get the X chromosome from their mother. Over the past ten years, researchers have found a number of mutant genes that can cause RP. Furthermore, we are starting to know why these mutant genes lead to disease.

Autosomal dominant (AD)

Each of us carries two copies of the same gene, one from the father and the other from the mother. In AD cases, only one abnormal gene is required to cause the disease, hence the word "dominant". As we only pass one of the two genes to other children and it is totally random which one to pass on. Hence, 50% of the children would be affected. The others would be carrying the normal gene and would not pass the disease on any further.

Autosomal recessive (AR)

In AR cases, both genes have to be abnormal. So if there is an affected child from normal parents, both of them must be carriers. There is a 1 in 4 chance for the next child to be affected. Recessive diseases are more commonly found in consanguinity families; however, the couple might not know they are related. It is unlikely for the affected persons to pass on the disease as they have to meet up with another carrier, unless they marry a relative or the recessive gene is very common in the community, like the cystic fibrosis gene. That is the reason, in AR, it is common to have no family history and the disease does not pass onto the next generation. However, there is no way to confirm the AR inheritance unless there is affected sibling.

X-linked diseases (XL)

As mentioned above, we should have two copies of each gene, but that is not true in if it is in the sex chromosome of a man. All women have two X chromosomes, but men have one X chromosome and one Y chromosome. In XL cases, the abnormal gene is in the X chromosome.

In man, there is only one X chromosome and if that is abnormal, there is no normal gene to counteract the problem and hence disease. In a family with XL disorder, no female offsprings of an affected father would be affected but all of them would be carriers. There is also no male to male transmission of the disease. However, if the mother is a carrier, 50% of the male offsprings would be affected and 50% of the female offsprings would be a carrier but none would be affected. The female carriers might have a milder form of the disease but could also be totally normal.

Digenic inheritance

This is a recent discovery that two unrelated mutant genes in terms of position in the chromosome if inherited together, it can cause the disease. The classical example is the ROM1 and peripherin/rds genes. They are located in different chromosomes but functionally related genes. If an individual carries one copy of either the mutant ROM1 or peripherin/rds gene, he will be normal. However, if an individual carries one copy of both the mutant ROM1 and peripherin/rds gene, he will have RP.

What are genes and proteins?

Genes are the coding sequence for the proteins of the body, and are a bit like the manufacturers manual for a car. Protein is the building block of the body and similar to the different components in the car. Different components have different degree of importance.   If you have a faulty seat, the car will still run smoothly but if you have a faulty engine, the car will not go at all. Indeed, that is the reason that some RP are milder than others.

Dominant negative effect

In recessive diseases, either autosomal or X-linked, there is no functioning gene, so disease occurs. However in dominant diseases, only one of the two genes is mutated, therefore the disease is still present. For quite some time now, researchers don’t understand why this is the case. It is now clear that most dominant diseases are due to the “dominant negative effect”. In other words, it is not the lack of the normal protein that causes the disease, but the mutant protein made by the mutant gene.

Why lack of protein causing cell death?

It has been recognised for some time that some infants are blind at birth with normal looking fundus called Leber congenital amaurosis (a severe form of RP). They are mostly recessive diseases. The concept is that the cells are not functioning from the beginning, so the infant is blind but the cells are not dead. However, most RP patients can see at birth but only slowly and progressively get worse. It is becoming clear that the lack of protein can cause a change in the microenvironment of the retina. This will lead to cell death rather than just cell dysfunction. Similarly the mutant protein in the dominant disease can also change the microenvironment leading to cell death.

Why is that important?

It is becoming clear that there might be over 100 genes that can cause RP but there might be only a few pathways leading to the photoreceptor cell death. So we might not need to find all the disease-causing genes, yet we can still treat RP. It is a bit like there being many thousands of bacteria but we only need about 10 different types of antibiotics to treat most bacterial infection.

So why finding genes is important?

At the moment, we are not sure about these pathways, finding the abnormal genes can allow researchers to discover the pathways and more importantly develop drugs to modify them. Furthermore, we can target the treatment to the individual. 

For instance, it is believed that certain RP leads to a local increase of calcium. Using calcium channel blockers might help this sub-group of patients. Another example is that some RP patients have a problem with Vitamin A transportation, therefore Vitamin A might be useful here. However, it might be inappropriate to treat all RP patients with calcium channel blockers and/or vitamin A. 

So how far on are we in finding the genes?

By the end of the year 2000, at least 7 genes have been implicated in dominant RP in which rhodopsin (30-40%), RP1 (10%) and peripherin/rds (5%) are the most common. (I don’t understand any of these terms. Are they important to know?) There are over 20 genes that have been implicated in autosomal recessive RP, but all together, they form only a small proportion of all recessive RP. There are at least 5 genes that are implicated for Leber’s congenital amaurosis, in which, CRB1 (10%), RPE65 (7%), Ret-GC (6%) and CRX (3%) are the most common.( Or any of this.)  RP2 and RPGR, are implicated for most of the X-linked RP (at least in Europe and the US). There is another gene called Rep1 that is implicated for most choroideremia patients (a special form of retinal degeneration but commonly grouped together with RP).

What are the practical issues of molecular diagnosis today?

At the moment, looking for the abnormal genes is expensive. As mentioned, about 50% of dominant RP, 25% of Leber’s congenital amaurosis, and most X-linked RP and choroideremia can be mapped.  It is likely that the test will be available in most major RP centres around the world. Indeed, some centres are already screening the mentioned genes in their patients.  It is however unlikely to be a routine test everywhere else until the test affects the management. In other words, until we know how to treat which sub-groups of RP patients with what, the test is not worth the effort, except for research only.

 
Nonetheless, establishing the carrier state within an X-linked family can be carried out relatively cheaply in most clinical genetics laboratory. They can determine whether the patient and their sisters share the same X chromosome. In the past, RP specialists were using clinical examination and electroretinogram to determine X-linked carrier state. It is often unreliable and as many X-linked carriers are totally normal, the RP specialist can only give bad news and not good news.

The future

Before 1990, we did not know what caused RP. Now we know the cause in significant numbers of other RP patients and we can start to appreciate the disease mechanisms. There are clear strategies in developing treatments for RP by researchers around the world. Although I do not have a crystal ball, it is likely that we will see drug therapies for targeted sub-groups of RP patients in the near future. The use of gene transfer techniques might bear fruit a little bit further down the line. Retinal transplantation or artifical retina may give the totally blind patient some navigational vision, but I do not think it is likely they can restore a significant amount of vision in our lifetime. Nonetheless, transplantation techniques might be useful in preventing further deterioration.