Talk by Professor Moosajee, Moorfields Eye Hospital at Conference 2025

It is now accepted that reduced PAX6, caused by genetic changes involving the gene, does not just affect the eye (causing aniridia) but has an impact on many other organs of the body.

In this talk, Professor Mariya Moosajee explains the impact of PAX6 outside the eye, and expands on insights gained from looking at all the metabolites in the blood of aniridia patients.

Professor Mariya Moosajee is a clinician scientist, she is a Consultant Ophthalmologist specialising in Genetic Eye Disease and Head of the Genetics Service at Moorfields Eye Hospital, Professor of Molecular Ophthalmology at UCL Institute of Ophthalmology, and Group Leader of Ocular Genomics and Therapeutics at the Francis Crick Institute, London.

@MariyaMoosajee on Threads
@profmariya on Blue Sky

Transcript

[James] Right, I’m going to pause my screen sharing and hand over to Professor Mariya Moosajee for our first talk. Welcome Mariya.

Mariya has recently been appointed as our medical advisor and we’re delighted that she’s here today, along with John Brookes a little bit later, to give us the benefit of their knowledge. So over to you Mariya.

[Mariya] Thanks James. Hi everyone, so nice to see so many of you, and really nice to actually read everyone’s little bios in the chat.

So it’s my pleasure for the next 20 minutes just to talk about the role of PAX6 and how it affects the rest of your body outside of the eye.

A little bit about myself, I am a consultant ophthalmologist, I specialise in genetic eye disease, and I see children and adults at Moorfields Eye Hospital. And I have a long-standing clinical and research interest in aniridia, and so I have seen a lot of patients with this and continue to do so.

I work with a fantastic team. One of the consultants, a neurodevelopmental paediatrician works with me, Ngozi Oluonye, she’s also on this call today. But you can see there’s a picture of the wonderful team that work to look after our genetic patients.

And then I’m also a professor of molecular ophthalmology, a scientist, and I work at UCL Institute of Ophthalmology and the Francis Crick Institute. And again I have a wonderful research team, who over the past few years have done some great research into furthering our understanding of aniridia.

So when we think about aniridia, especially as eye doctors, we tend to consider it mainly as an eye disease. And it’s an eye disease that we know can affect many parts of the eye.

So the most obvious feature is that you get complete or partial loss of the iris, leading to having a large black pupil. Children often will present with nystagmus, the involuntary movement of their eyes, which can be apparent from six weeks of age.

Individuals will suffer from reduced vision and this is partly because an area of the back of the eye called the fovea – your area of central vision – hasn’t developed fully in aniridia, and we can detect this by doing various scans in clinic.

But individuals can also have abnormalities involving their optic nerve, the nerve that sends signals from the back of the eye to the brain. It can be underdeveloped or it can fail to fuse completely, called a coloboma.

Later on, individuals can develop cataracts, glaucoma, corneal keratopathy leading to opacification of the cornea, you can get droopy eyelids, and some patients can even get retinal detachments.

But aniridia is no longer considered an isolated eye condition. It’s thought now to be a syndrome that affects many other parts of the body, and certainly in the last Aniridia Europe meeting there was a big discussion to maybe change the name of Aniridia to PAX6 Aniridia Syndrome, so it reflects more correctly the involvement of the rest of the body.

So there are various different features that affect different parts of the body in aniridia patients. Individuals can suffer from obesity, they can suffer from diabetes and, prior to a diagnosis of diabetes, insulin resistance and high glucose levels in the blood.

They can suffer from something called central auditory processing disorder. So their hearing is normal but their processing of what they’re hearing is not quite correct. And I’ve given a silly example, but if I said “grab the reindeer”, they may actually hear “grab the rain gear”, which is slightly different.

Patients can suffer from problems with their sense of smell. They can actually have partial or full loss of smell. They can have brain abnormalities, so the brain structure itself hasn’t developed properly. They can have sleep disturbances, and a lot of patients develop behavioural issues such as autism and attention deficit hyperactivity disorder. And some patients can develop depression and anxiety.

So the reason this happens is because PAX6 is not just involved in eye development. It’s working in other parts of the body, such as the development of your pancreas, and particularly the cells that produce insulin. And that’s why patients have a higher predisposition to endocrine problems such as diabetes.

It’s also involved in how the brain develops, hence the issues with the structure of the brain, the problems with the sense of smell, and potentially the behavioural issues.

And so having only half of the healthy PAX6 gene is the reason why we have these developmental issues, and why we get this secondary disease that occurs later in life. And just to highlight that, I’ve got a diagram here.

So we explain to patients that we inherit one set of genes from our father and one set of genes from our mother. So if we can imagine we have two copies of every gene – one from mum, one from dad. So we have two copies of the PAX6 gene.

Now, in my case, I have two healthy copies of the PAX6 gene, and it produces a full amount of PAX6 protein, and that allows my eyes to develop healthily.

But in aniridia, you inherit one healthy copy of the PAX6 gene from one parent, but you can inherit a bad copy of the PAX6 gene from a parent. Or you yourself, when you were developing in the womb, may develop a mutation on one copy of your PAX6 gene.

And that leaves patients with aniridia with one healthy copy and one bad copy. And because of that, you only have 50% of healthy PAX6 protein and 50% is missing And it’s that lack of that 50% that gives rise to all the problems.

So we undertook a study a few years ago, where we looked at all patients at Moorfields Eye Hospital that had a diagnosis of PAX6-related aniridia. They had genetic testing and they had PAX6 mutations. And we looked at some of the involvement of other body parts.

And what we found was that in our cohort we identified a large number of patients with type 2 diabetes. Around 13% of patients had this and this was actually twice the UK prevalence. So an aniridia patient is twice as likely to develop diabetes than someone in the normal population.

A large number of patients, over 23%, had obesity, 7% had learning difficulties and 2% had autism. And there were other associations with hyperthyroidism, hypertension, high cholesterol levels and also asthma in the cohort.

So we wanted to try to investigate this a little bit further, by trying to see if we could detect any changes in the blood of our aniridia patients, that could explain why they were more predisposed to these conditions affecting the rest of their body.

And so we decided to do something called whole metabolomic profiling. So essentially what this means is that you can take the blood of a patient, and you can spin the blood down, and you can extract the plasma from the blood. And then you can send this plasma and you can screen it for over a thousand metabolites in the blood. And this could be proteins, it could be carbohydrates, fats, vitamins, caffeine, any metabolite that’s in your bloodstream it can detect it.

So we did this for 25 aniridia patients and 25 age and gender matched healthy controls. We got every single patient to fill out a food frequency questionnaire and this gave us an idea of what individuals were eating over a period of time, to make sure that the results were not skewed – for example, aniridia patients having a much healthier diet than their normal controls or vice versa.

But we found that there were no differences in the dietary intake between aniridia patients and healthy controls. And we had to exclude patients that had diabetes, or those that were taking statins for high cholesterol, because that would have altered the blood metabolites.

So we included seven children in our cohort and 18 adults. The mean age was 31 years and 48% of the participants were male.

Now we calculated an individual’s BMI and then we grouped it, and we found that actually the aniridia group fell into the overweight category, whereas the control group fell into the normal healthy BMI category.

So that’s a difference in itself, showing that although your diets are the same, the aniridia group was still more overweight than their healthy counterparts. If we looked at the composition of people in the cohort, 44% of the patients actually had obesity, compared to only 16% of the controls. Some of the aniridia patients suffered from gastric reflux.

There was a balanced amount of patients with hypertension. There was a slightly increased number of patients with central auditory processing disorder in the aniridia group, as with depression, anxiety, learning difficulties, ADHD and autism. There was one patient that had pineal gland hyperplasia, and three patients that reported sleep disturbances and were on a melatonin supplement.

So when we ran this experiment we found that there were over 94 metabolites that were different in the aniridia group compared to the healthy group. And the five main groups that were different were lipid (or rather fat) metabolism, oxidative stress, complex lipids, neuroactive metabolites and microbiome-related metabolites. And I’m going to explain some of these in a little more detail, just to give you some further insights.

So fat metabolism was disrupted. We found that there were disrupted markers of something called our fatty acid metabolism in our aniridia patients, and particularly some metabolites called carnitines. And when we looked into the literature, we found that patients who have increased carnitines have been linked to diabetes and heart failure.

So that’s just something to bear in mind, that having high carnitines in your bloodstream can be linked to cardiovascular disease and diabetes.

We found that aniridia patients had reduced levels of something called plasmologens. Now, what are plasmologens? Plasmologens are a type of fat that are found in our cell membrane.

So our body is composed of billions of cells, and the outer protective layer of our cells is called a cell membrane, and it has lots of fats in it, and plasmologens are one of them.

So these plasmologens normally provide our cells with stability and fluidity. It allows them to move properly as they should and it also gives them the ability to protect them from something called oxidative stress.

So oxidative stress is something where when you have lots of chemical reactions going on within the cell, you can generate metabolic byproducts like charged oxygen molecules, and these can whizz around within your cell and cause damage.

And so our cells need to find a way to protect themselves from these charged oxygen molecules, and that’s called antioxidants. So we need antioxidants to counter oxidative stress. And when you have reduced plasmologens, you reduce your ability to provide an antioxidant protection.

And interestingly patients with other rare diseases, for example a condition called Zellweger syndrome where patients develop cataracts, also have low plasmologen levels. And so it could be that these low plasmologens may be predisposing our aniridia patients to cataracts.

We also know that patients who have diabetes and higher fat levels in their blood and cholesterol can also have reduced plasmologens. So again this is a very interesting biomarker that points towards aniridia patients having a predisposition again to diabetes and cardiovascular disease, and cataracts in this case.

We then found that ketone bodies were high in our aniridia patients, there was an accumulation of them. Now we tend to see high levels of ketone bodies in patients that have uncontrolled diabetes.

Now remember, our cohort did not include diabetic patients, none of them were taking any diabetic medications. And interestingly there were other markers linked to high ketone levels and ketones leading to our blood being more acidic. And so taken together this suggests that our aniridia patients are in a pre-diabetic stage, possibly in an insulin resistant stage.

And so that’s something that we need to think about in terms of making sure that our aniridia patients are referred to endocrinology, that they’re monitored either by their GPs or endocrinologists, potentially in case they are going to go on to develop some form of diabetes, and if they need to put dietary or drug treatments in place before they get to the point where they need to have, for example, insulin injections.

So we also found that oxidative stress was high in the blood of our aniridia patients. Now I explained to you what oxidative stress is and there are certain markers in our blood that indicate that.

So there is a compound called taurine and this is actually a natural antioxidant. And we found that taurine was reduced in our aniridia patients. And its precursor – so the chemical compound that makes taurine in our bodies – hypotaurine, was also reduced. And so you’ve got antioxidants reduced in our aniridia patients and oxidative stress markers increased in our aniridia patients.

So what can we do about that? Well taurine, the antioxidant, is really important in our bodies. It helps us to make our bile acids and it also stimulates insulin release. Now that’s important, because we know that the cells that produce insulin in aniridia patients are already not functioning very well.

So if you’ve got something that doesn’t help stimulate the insulin production, that’s going to have an even more knock-on effect on the predisposition to diabetes. So in other conditions such as depression, schizophrenia, autism spectrum, hypertension and obesity, patients are also found to have reduced taurine levels.

So one thing that we would like to now investigate in our lab is potentially giving our aniridia disease models taurine supplementation. Because if this shows that it’s a benefit, it may alleviate a lot of the problems that our aniridia patients are facing. So this is a body of work that we want to take on going forwards, but taurine supplementation may be something that really could help the aniridia community.

So neuroactive metabolites were also found to be slightly deranged in our aniridia patients. So particularly a component called N-acetylaspartate. This was found to be increased in our aniridia patients. And interestingly N-acetylaspartate is one of the most common what we call neurotransmitters in patients.

So when you have a nerve ending and a junction between nerves, and it wants to send signals between two nerves, one nerve has to release a neurotransmitter which passes across a junction, so the other nerve can detect it and then start to send the signal onwards.

And so when there are very high levels of this neurotransmitter, it has already been found to be associated with neurodegenerative disease, but also it’s being detected in the brain of female children that have been diagnosed with attention deficit hyperactivity disorder. So just something also that could explain some of the behavioural issues that we’re seeing in our aniridia patients.

So, just to summarise, PAX6 does not just affect the eye. It does have an influence on other systems outside of the eye – obesity, diabetes, brain function and structure, sleep, behavioural issues, depression and anxiety.

And by investigating the blood, and potentially having an even more closer look at the general health of aniridia patients, not just early on but in some of our patients that are later on in life, we might get some more insights into how PAX6 affects individuals throughout their lifespan.

So just a bit of general advice on what you can do to maintain good visual function and general health.

Well, it’s always important to have your regular follow-ups with your ophthalmologist. If you are experiencing any of, or some of, the features that I’ve mentioned today in the talk, but you’ve never seen anyone for it or raised it with your eye doctor or your GP or anyone else, then I would suggest that you go to your GP, ask for a referral to a specialist like an endocrine doctor. But also bring it up with your ophthalmologist and they can refer you directly to hospital specialists as well.

But please don’t be sitting in silence. Think about the features that may be affecting you that you may previously not have thought were linked to your aniridia in your eyes, but this might be enlightening for you.

Think about your diet. It’s always important to have lots of fresh fruit and vegetables. Green leafy vegetables are incredibly good for you – spinach, kale, broccoli, salad, anything green, they’re rich in antioxidants. And fresh fruit, and fruit specifically that is blue, black and red in colour – so strawberries, blueberries, blackberries, black and red grapes, pomegranate. Anything of those colours are very rich in antioxidants so you should have loads of those in your diet. Eating fish twice a week is incredibly good for you, it’s got omega oils in there. It’s important to take regular exercise

You guys all know that it’s important to wear your UV-protected tinted or dark sunglasses in bright light. Try to get yourselves blue light screen protectors on any devices you’re using, especially if you’re holding those phones or iPads very close to your eyes. It just prevents the blue harmful light from entering in, which can also affect your sleep as well.

And then make sure you’re getting all the support that you require. So if you haven’t been sight registered, when you next see your eye doctors just make sure you raise that as well, so that you can get all the support that you need.

For any of you on the call that want to participate in aniridia research. you can register with something called Research Opportunities at Moorfields, called ROAM.

Stay in touch with Aniridia Network. Anytime we need aniridia participants we always get in touch with James and the team and send out emails, so we’re always thankful to you guys for that.

And please help fundraise, because the more funds you can raise, it means the more work that we can do, and the more research we can do to advance our understanding and knowledge, and go on to develop treatments for our aniridia patients.

I draw your attention to Gene.vision, a website we created which is fully accessible to patients. It’s got a whole page on Aniridia / WAGR Syndrome, all in lay. It’s also got information on the latest research and any other information that you need to access relating to sight loss.

So to conclude, aniridia can affect many organs in addition to the eye. We need to make sure that you are looked after holistically and we get the correct specialists in place to optimise your care. Please do visit your GP or tell your specialists if you’re experiencing any systemic problems that require any further investigation or input.

If you want to get in touch with me, you’re always welcome. We welcome you to come visit our clinic, even just as a one stop to say hello and making sure that you’ve got everything that you need. My email address is m.moosajee@nhs.net.

And a big thank you to Aniridia Network, to my clinical team and my research team. Thank you so much.

[James] Thank you very much Mariya. We’ve got time for one very quick question, and others we will pass on to Mariya and get you responses to those later. Katie.

[Katie] Florian has asked about whether there were a correlation between the different symptoms. Say, could a sleep sleep disturbance in itself cause some of the other symptoms that you found in the patients, and is there any progress towards quantifying these symptoms more, and screening for them even?

[Mariya] Yeah, so we’ve actually conducted some more work. We still have to analyse all of that. But following on from this work… because that was just 25 patients, which is enough to make a comparison between healthy and aniridia patients, but actually what we need to do is actually reach out to many, many more aniridia patients and actually find out exactly are there any correlations.

But to answer, yes of course, if you have a sleep disturbance and you’re not sleeping well, that can lead to, for example, low mood. And if you start to suffer from depression, then you start to eat more, and then you can put on weight. And so there can be vicious cycles that go on.

But what we found was that actually when we took diet out of the question, there were still things going on and our metabolism was showing that it was different between the two groups. So PAX6 I think is the underlying cause.

However, of course there’s going to be confounding factors, depending on your mood, on your sleep, etc. So a lot more work needs to be done to tease those correlations out.

[James] Marvellous, thank you very much Mariya, much appreciated. As I say, we’ll pass on the other questions that have come into the chat onto you and will get those back to the relevant people.

[Mariya] No problem, thank you everyone, thanks.