In 2021, the results of a significant study were published by Vivienne Kit, Dulce Lima Cunha, Ahmed M. Hagag and Mariya Moosajee.

It assessed 86 aniridia patients with a variety of mutations in the PAX6 gene, through the retrospective review of their clinical notes and imaging.

The study explored the prevalence of vision loss, iris hypoplasia, cataracts, glaucoma and aniridia-related keratopathy, to see if there were any patterns in relation to different PAX6 mutations.

That detailed analysis resulted in the largest in-depth clinical description of PAX6 genotype-phenotype correlation and natural history of aniridia in the UK to date, which therefore provides valuable insights for patients and clinicians.

Vivienne shared a summary of the results and answered questions at our 2023 Conference in Birmingham in September last year. You can watch her presentation in the following video, below which is the transcript. The full results are available online if you wish to find out more.

Transcript

[Vivienne] Hi, good morning everyone. My name is Vivienne, I’m a junior doctor specialising in ophthalmology in London. During my training I took a year out to do some research with my supervisor, Professor Moosajee, at Moorfields and the Institute of Ophthalmology.

So one of the research we’re going to talk about is a paper that we published in 2021. I’ve taken out what I think are the interesting bits of it, because it’s quite a long paper, but if it’s something that you’re interested in, it’s something that you can access online, it’s open access to everyone. So if you search these words online, you’ll hopefully be able to find it.

So before I begin, I also want to give thanks to my supervisor, Professor Moosajee, who couldn’t make it today, Ahmed Hagag, who helped with the paper, and Dulce, who will be our next speaker as well today.

So our paper, published in 2021, looks at the natural history of aniridia, looking at genotype-phenotypes of 86 patients with a confirmed PAX6 mutation. So a bit more information about it.

So aniridia is truly a panocular condition. And what I mean by that, is aniridia, the name, means without an iris, but actually patients with aniridia don’t just have a lack of an iris. They have problems that affect the front of the eye through to the back of the eye.

So the cornea, the front of the eye, you can have something called an aniridia-related keratopathy, which affects the front surface of the eye.

Iris hypoplasia – So the iris is either missing or partially missing, or in some cases actually appears full in some patients with aniridia, which we’ll come onto later when we talk about our results.

Glaucoma – So glaucoma isn’t something you see from the outside, but something that affects patients in how they see. So things like increased pressure in the eye can affect the nerve at the back and cause a gradual loss of vision.

Cataracts – So cataracts is something that everyone with eyes will develop, but they’re probably a little bit more difficult due to the other complications of aniridia to operate on in patients, but also something that we’ll talk about in terms of our study.

And then other things are foveal and optic nerve hypoplasia, so underdevelopment of the fovea and the optic nerve.

Okay, and a bit more about the gene. So the first bit was more about what you find clinically in a patient, and this bit is more about what you find genetically in a patient.

So aniridia results from a mutation in the PAX6 gene. Now, the PAX6 gene is important because it underlies the development of different parts of the body – the eye, the brain, spinal cord and the pancreas.

Now, two-thirds of patients who have aniridia have it inherited, so from a family member, and in a third of patients it occurs sporadically, So you may not have a family history of aniridia, and then it develops in that person because that mutation has occurred.

So when you go for genetic testing, they find out do you have or do you not have a mutation in your PAX6 gene. But how many of you actually know the type of mutation you have in the PAX6 gene? So just one.

[Lady] I’ve got it written down.

[Vivienne] You’ve got it written down. Okay, exactly.

And the question is actually does the type of mutation you have in the PAX6 gene affect how your vision is going to be like? As in, if you were a child who was born with aniridia, yes, you get diagnosed with having a PAX6 gene mutation, but does the type of mutation you have affect your long-term visual prognosis?

So, on a whole, around 40% from the literature that I found online have a nonsense mutation, and around 10% have a missense mutation in the general literature. But actually in our study we found out amongst the 86 patients we had a fairly good reputation amongst the different type of mutations.

Now, without going into too much detail, but the different type of mutation you have on the gene will affect how much of it is expressed, and missense mutations tend to have the least detrimental effect of the PAX6 gene in comparison to the others. And that we’ll demonstrate or discuss in our following slides.

Right, so I’ve sort of summarised this bit already, but basically I worked at Moorfields and I went through the database, I found as many patients as I could who had aniridia, and I then sorted out those who had aniridia, and then have also had genetic testing to find that they do indeed have a mutation in this gene.

I then gathered all their notes. I started looking at their first presentation when they first came to Moorfields, be it as a child, our youngest patient was just a few months old, and our oldest patient presented to us for the first time was 66. So we had a full range of different ages of patients with aniridia.

And then I went through their notes in their entirety, so I started from their first visit all the way to their last visit, and I wanted to see things like did they develop cataracts, did they then develop glaucoma, at what age did they develop these different conditions that are linked to aniridia. And we’re going to look at the results.

So vision. Vision was one of the aspects which we looked at. So how we divided it was we looked at all their vision, and then we divided it into patients who then had surgical intervention, and those who had no surgery whatsoever.

So we found that eyes who had no surgery whatsoever had maintained better visual acuity, so better levels of vision for the first five decades of life, compared to eyes who have undergone surgery.

So you have to take that with a pinch of salt, in the sense that if you’ve not had surgery, yes, your vision is better, but does that mean you have milder symptoms, compared to someone who needed surgery to begin with.

We also found that in both patients who did have operations, and didn’t have any operations for their eyes, patients with the missense mutation, so the milder type, which I mentioned earlier, maintained better visual acuity compared to all the other groups.

So actually, this is why I’m going back to the type of mutation being important, because those with missense mutations, regardless if they had surgery or no surgery, actually had better visual acuity, better levels of vision, compared to all others with the other mutation groups.

Another aspect that we looked at was iris hypoplasia, so the underdevelopment of the iris. What we found in these patients was the majority of patients who had iris abnormalities had a symmetrical amount of iris abnormality in both eyes.

And when we looked more closely, we actually found some patients who were documented to have a normal iris architecture. So actually, when looked at by an eye doctor, they actually couldn’t see any underdevelopment of the iris, and the iris looked quite present and normal.

And we found that the missense group, amongst all the mutation groups, were more likely to have a full normal iris, but interestingly, the C-terminal extension and the frameshift mutation groups also had normal iris architecture compared to the other groups, which didn’t.

Another aspect we looked at was cataracts. So a cataract is the lens in the eye that’s become cloudy. So we all have a lens in the eye, and when it becomes cloudy, it can blur your vision.

Now, we found that the mean age diagnosis, so amongst all the patients with aniridia, cataracts was identified in their eyes around 17.4, which is quite young compared to the general population of patients without aniridia. And amongst those, we found that patients who had the missense mutation and the frameshift mutation had a lower prevalence of cataracts.

So actually, amongst all those who had cataracts, patients with missense and frameshift mutations actually didn’t have it as much as those in the other group. And also, interestingly as well, the mean age cataract surgery was younger in the missense group, which is interesting.

Now, the next thing is glaucoma. So glaucoma was identified in 37 of the 172 eyes that we looked at, and the mean age of diagnosis was 25. We didn’t find any significant difference between the mean age in diagnosis between the mutation groups, and 18 eyes, so around half, who did get diagnosed with glaucoma, eventually needed surgery.

Now, the interesting thing here of note, clinically I suppose, is that the mean age of diagnosis is around 25, so it’s one of those things that is worth monitoring from a young age and not neglect.

So aniridia-related keratopathy. So this relates to the cornea at the front part of the eye. So 118 of 172 eyes in our studies were diagnosed with aniridia-related keratopathy, and we found that patients with a mutation in C-terminal extension and nonsense mutations had a high prevalence, and it was significantly lower in patients with a missense mutation, so in the missense group.

Okay, so I’ve thrown a lot of results at you, what does this really all mean?

So, to date, it’s the largest in-depth description of PAX6 genotype and phenotype correlation in the UK to date. We found that patients who had a missense mutation had better long-term vision, a lower prevalence of aniridia-related keratopathy, and milder iris hypoplasia.

So how does that translate to how we practice looking after patients with aniridia?

So it gives us some information about how we can predict the long-term prognosis of patients who get a genetic diagnosis of PAX6 mutation, and it helps us in the sense that it gives us better knowledge of how we can plan future trials and management of these patients.

Yeah, that’s the end of my talk. Do I have any questions, or if we’re running late you can find me at lunch?

I hope that was something interesting. And if you do want to read more about it, it is open access, and it’s something that you can get hold of if you wanted to read about it for a bit more information.

[Man] Just a quick one. I was treated at Moorfields Eye Hospital many years ago. At the time I didn’t know anything.

It took 47 years before I found out that I’d got aniridia, and that was because we were fortunate enough to get an ophthalmologist who was interested in genetics. And he had a colleague who was a geneticist who was interested in ophthalmology. And that’s how I found out 47 years later.

But up until then, they were telling us that what I had was cataracts. In the meantime, I had 19 corneal grafts. And then eventually they said: “Oh, we shouldn’t have done that, because there’s no point in doing it, because as the body grows, the cataracts grow back.” And this is from the age of seven after I’d had an accident. And they just did all sorts of things. Basically, they didn’t know what they were doing.

So how recent have health professionals been aware of aniridia, and as well as health professionals, like other professionals who deal with benefits and things like that?

[Vivienne] Okay. So aniridia is something that is still not seen commonly.

I have done a rotation. So as a junior doctor, you rotate around different hospitals. And Moorfields I’ve been at for a few years. And even then, until I became involved with the research in aniridia, it’s not something that, as a general ophthalmologist, you would see that common. But it is something that we know about and we’ve learnt about and seen about.

But in terms of having very detailed care that’s appropriate for a patient with aniridia, then you do have to find certain doctors who are probably more experienced in managing these patients. And you do have those at Moorfields.

[Man] How much training goes into, like, when people are in training to be health care professionals, whether it be doctors or not… because when my son was born, his mother noticed straight away that there was something different. And they were trying to discharge and say: “No, no, this is normal.” But she’d had three children before then. And this was the first time that there was anything.

Eventually, because she refused to leave the hospital until they did something, he had an eye scan and we were brought onto a consultant that knew exactly what he was doing.

But there just seems to be very little knowledge given to people in their training as doctors or nurses, or even people who assess benefits nowadays. Because they know the common eye conditions, but there seems to be very little knowledge amongst professionals about aniridia.

[Vivienne] No, that’s interesting. I can’t talk on behalf of the other subspecialties or other people who work in the health service. But certainly I agree, from a medical school perspective, it’s not something that we’ve come across often. But I think doctors that work with patients with aniridia may have more understanding of it, because you see it more often.

But I think overall, I can’t really speak amongst all different specialties in medicine, because some specialties won’t come across it per se. So if you’re specialising in bones, like an orthopaedic doctor, then you probably wouldn’t come across or be very aware of someone who has an eye condition, because they spent most of their years in training just looking at treating bones and fractures. So I think it’s individual and down to the exposure.

[Man] And the last thing is, I can’t remember if it was yourself or one of the earlier speakers that said, aniridia can also have other offshoots. And my son has had problems with his ankle, his knees and his back from a very early age, and nobody seems to be able to diagnose what it is. Could that be something that’s connected with the aniridia as well?

[Vivienne] Well, the PAX6 gene is expressed in different parts of the body, and aniridia itself isn’t just purely affecting the eyes. We do know it’s linked to other things, which I think other speakers are speaking today, like auditory associated issues. And there is research going on in different aspects of it, but I’m not specifically sure about the ankles and such.

But PAX6 is expressed in different parts of the body and so it’s possibly linked, but I don’t have that evidence or information to give you. But I’m sure research is being done and it’s something that we can have a look at.

[Man] Thank you.

[Vivienne] Hi.

[Woman] Hiya, just one question. Did the study describe or suggest any link between aniridia and age-related macular degeneration? Obviously we know something about the macular is going to be a little bit more exposed without an iris in front of it. Is there anything there at all or is there any suggested evidence there?

[Vivienne] So we didn’t look specifically at age-related macular degeneration.

But one thing we did find was when I did try to look at the macula in a lot of patients with aniridia, because of things like the aniridia-related keratopathy and the previous cornea changes, because of the presence of cataracts, it does make looking and evaluating the macula a lot more difficult.

Because one of the other things that’s separate to this was I wanted to look at patients who had diabetes and aniridia, for example. If you had diabetes, in the general population, everyone’s invited to have annual monitoring to see if there is any damage to the back of the eye because of diabetes. But I found that in patients with aniridia, it’s quite difficult to look at the back of the eye.

So, sorry, that’s going slightly away from your question. But yeah, so looking at macular degeneration, you know, you can’t do it otherwise. You need to look at the macula. But I think it is probably harder if a patient does have aniridia and does have all the other things like cataracts and aniridia-related keratopathy, which compromises our view and ability to do things like scans at the back of the eye.

Things like nystagmus as well. So if your eye is not stable, the scan that we often use to check for macular degeneration is a little bit more difficult to perform.

Yeah, good. So I’ve got a few more questions, but I think I can answer it during the break time if you wanted to come to me. OK, thank you.

[Applause]

Thank you to Glen for the video editing and write-up.