In this interview, Ken Nischal, MD, of Children’s Hospital of Pittsburgh, talks about a study that is ongoing in partnership with the Alagille Syndrome Alliance to uncover the ocular impacts associated with Alagille syndrome. Hear more about the survey and ways you can get involved. Learn more.
Ken Nischal, MD:
Hi, I’m Ken Nischal. I’m the Division Chief of Pediatric Ophthalmology and Strabismus at Children’s Hospital of Pittsburgh, UPMC. I’m also the Medical Director for Digital Health at Children’s Hospital of Pittsburgh. I came here 15 years ago from Great Ormond Street Hospital for Children in London, where I was clinical director when I left. Previous to that, I trained at Oxford and King’s College in London. I did my fellowship in pediatric ophthalmology at SickKids in Toronto.
Question:
How did you first learn about Alagille syndrome?
Ken Nischal, MD:
I was a medical student at King’s College Hospital in London, and it had a liver unit, a very famous liver unit. Actually I knew about Alagille syndrome in my second year of medical school because there were so many children, and adults actually, who were being treated there for Alagille syndrome, and I learned very quickly, I think in the third or fourth year of medical school, that one of the key features for an ophthalmologist is a posterior embryotoxon, which is this developmental white line that you see in the periphery of the cornea, which is the window of the eye. If you see that in a child who’s jaundiced, a baby who’s jaundiced, then it’s Alagille syndrome until proven otherwise.
Question:
Can you provide an overview of Alagille syndrome for people who may not have encountered a patient with this condition?
Ken Nischal, MD:
Alagille syndrome is a form of intrahepatic cholestasis. We know that when that is the case, you’ll get jaundice. The first thing is that the conjunctiva, the whites of the eye, look a bit yellow. But really there’s much more to Alagille in terms of the eye than that. The posterior embryotoxon is the first … In fact, it’s a diagnostic sign. Before we had genetic testing for JAG1, which is the gene most commonly implicated for Alagille syndrome, the presence of posterior embryotoxon in a prolonged neonatal jaundice gave you the clue that that’s what you were dealing with. But there are other things that you can get, iris hyperplasia with what we call Axenfeld-Rieger anomaly. In my experience, these children don’t normally go on to get glaucoma very often. It has been reported.
But the more important thing that you see is in the retina, because they’ve had, if you like, the jaundice and the intrahepatic cholestasis, they can get vitamin A, D, E, and K problems. When you have a vitamin A problem, you can get changes in the retina because vitamin A is so important in photoreceptor physiology. They can get nyctalopia, which is night blindness. When you look at the retina, it can look somewhat thinned, and electroretinograms, which is a way of testing for the retina function, can be abnormal. There are other phenotypes that are more specific.
You can get a macular atrophy, which is rare, but does occur. The optic nerves, they normally look a little crowded and it turns out that they’re usually due to optic disc drusen. They get refractive errors, so they need glasses. Usually, that needs to be checked from an early age. Then they can get common problems like strabismus, but it’s not peculiar to Alagille syndrome. In fact … so my only claim to fame in the Alagille world is that I was the first author on the paper that discovered that optic disc drusen occurred in children with Alagille syndrome, and they become more common the older they get.
Question:
What is there still to understand and uncover about the connection between Alagille syndrome and ocular implications?
Ken Nischal, MD:
What we don’t know is the natural history of the disease. I mean, we all have anecdotal evidence about what happens, and some stay stable, some get worse. But in this day and age where we could look at the molecular imprint, the molecular diagnosis that they have, and then look at the natural history of what happens over years, which group or subgroup are going to go on and get, for example, macular atrophy, which ones are going to get the worst type of retinal phenotype, we just don’t have a clue. We can’t really counsel parents and we can’t counsel patients as to what’s coming down the road. I think that’s the most important thing for us is we’ve done cross-sectional studies. I was involved with a very big study in the late ’90s, I think it was 47 patients, and looking at their ocular features. But what I think is more important now is which group go on and develop problems and which don’t.
Question:
Can you talk about the work you are doing with the Alagille Syndrome Alliance in relation to ocular involvement with the syndrome?
Ken Nischal, MD:
The main thing is that the Alliance is very interested in natural history, not only of the eye, but of the liver and also of other features to do with the condition, skeletal as well. But I think my role really is down to the fact that I’m the co-founder of the World Society of Pediatric Ophthalmology and Strabismus. That’s a charity, www.wspos.org. What we have is we have about 6,000 members, and we’re all pediatric ophthalmologists. The idea was that the Alliance is wanting to do these surveys really to find out how many of the children that they are aware of, or their members are aware of, have the kind of problems that we’ve talked about. What is the percentage of children who have optic disc drusens? What percentage have nyctalopia or night vision problems? The only way you can do that is when you run a survey is to do it by approaching large groups of ophthalmologists. WSPOS is global. My role really has been to try and get those surveys to our members in WSPOS and see if we can help the alliance to get some answers.
Question:
What can be understood about the different ocular phenotypes in this patient population?
Ken Nischal, MD:
Look, the thing is … I mean, the largest cohort that I know is about 67 patients, and I think there might be one a little bit bigger than that. But if you could get a cohort that was not only large, but in terms of racial grouping or ethnicity grouping, you could see, well, it’s interesting that children of this origin seem to be getting this kind of phenotype more often than others. You could start to see what the genetic background, what effect that has on the expression of the JAG1 mutation. For me, what I want to do is get to the point where we’re personalizing the medicine that children with Alagille syndrome receive. We get to the point where we say, “Okay, you’ve got a JAG1 mutation. Interestingly enough, when we look at your whole genome, you have changes that are very specific to a particular type of geographic or racial background, and we know that when that occurs, you’re more likely to get X, Y, or Z of the ocular problems, so we’re going to focus and stop you getting those.”
Question:
What is the survey asking of ophthalmologists? Would you encourage ophthalmologists to join the study even if they only have 1 or 2 patients with Alagille syndrome?
Ken Nischal, MD:
As long as you have 1 patient, your input is valuable. I mean, it’s not a short survey, but it’s sort of like fairly straightforward questions that an ophthalmologist would be able to answer. Has a child got a displaced pupil? Does the iris look hyperplastic? Is there a posterior embryotoxon? What’s a child’s vision? Is there a night vision problems? Does the retina look abnormal? Does the nerve look swollen? The sorts of things that you would pick up in a general examination.
Question:
What are the key takeaways you and the Alagille Syndrome Alliance hope to gain from this study?
Ken Nischal, MD:
I think there are 2 aspects to it. One is we definitely want to know what proportion of patients have what ocular phenotype, and see if we can then correlate that down the line with racial or ethnic background. I think that’s important. Number 2, the bigger database you have of children with rare disease, the more likely the typical description of that ocular phenotype becomes more accurate. You see, if I write a textbook, let’s say, and I mentioned Alagille syndrome, I’m only going to write about what I know about and what is clearly published in a few papers in a few centers around the world. But now if you’ve got, let’s say, 10 times the number of patients and you see that actually posterior embryotoxon occurs in only 80% and not 99%, then it becomes a less reliable marker. If you see that glaucoma actually occurs in 10%, it now becomes worthwhile screening every child with Alagille syndrome every 6 months until they’re 8, and then every year for the rest of their lives.
These are the things that we don’t know. The reason why I say that is the papers tend to come from centers that see a lot of patients. Let’s say I see 20 Alagille patients at Pittsburgh, there may be another 20 ophthalmologists who see one each in rural Pennsylvania or rural Virginia, and their phenotype actually is different to the phenotype that I’m seeing. I might be giving a very biased view of what that ocular phenotype is. If you have 1 center in 1 area, tendency is not to see that change, that different approach. Rare diseases odyssey is really quite sad. There are children who still will have Alagille syndrome, and because people are not aware of it, they will struggle and suffer. Those are the ones I think … My belief is that when we look at children who had early intervention, let’s say within the first year of life, I think their retinal phenotype will be better and healthier than ones who had it later.
Then the question would become every child who has prolonged jaundice, because children can be born with jaundice, neonatal jaundice is well known. But if you have prolonged jaundice, every child should have this test. Either a blood test or an eye evaluation. Now, the eye evaluation only is important if we know that the sensitivity … We know the specificity is good, but the sensitivity is good. I think that’s the biggest thing to come out of this study is how much can we rely on the physical signs and how much do we need to do a genetic test?
Question:
There’s the saying that the eyes are the key to hidden truths. Metaphorically speaking, what truths do you think this work could uncover about Alagille syndrome as a whole?
Ken Nischal, MD:
This is not a chicken-and-egg situation. The problem is the intrahepatic cholestasis, which causes all the knock-on effects. JAG1, we know, has a role in the development of the anterior segment of the eye, so you see the posterior embryotoxon. I think in this instance, rather than the windows being … The eyes being the windows to the soul or the body, what we’re looking at is these children and adults have a difficult life. Some of them will need liver transplant, some of them will need quite sophisticated surgery to overcome their intrahepatic cholestasis. Imagine the number of times they have to be in hospital. Imagine then that because we didn’t pick up that they had Alagille, that they lose vision because of a retinal problem, and then imagine the quality of their life. I think in this instance, the eyes are a way of making sure the quality of life that these children have and these patients have is the best they can be under the circumstances they find themselves in.
I don’t think the eyes will necessarily tell us what’s happening in the liver. Unlike the kidneys, the retinal vasculature in the eye, those vessels are very similar to the ones in the kidney. If you have a patient with diabetes who’s got terrible diabetic retinopathy, you better be worried about the kidney because the kidney vessels are going to be behaving the same way. I don’t think that is the same in Alagille. I think in Alagille, the issue is can we make sure that we give them the maximum visual potential so that their quality of life is good? But in order to do that, we need to know what the natural history is. We need to figure out which ones are going to get the worst ocular phenotype.
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