Lecture: Introduction to Inherited Retinal Disease

During this highly interactive webinar, we will introduce inherited retinal diseases (IRDs) and review how basic sciences and clinical diagnostics have collectively transformed this field. Dr. Stone will discuss his overall approach to work-up patients with suspected IRDs in a systematic manner and provide recommendations to help in the diagnosis and care of these complex patients (and families). The webinar will highlight free, available resources that Dr. Stone created so that attendees would prevent misdiagnosis and gain a better, accurate understanding of this salient category in retinal pathology.

Lecturer: Dr. Edwin Stone, Ophthalmologist, University of Iowa, USA

Funded by an unrestricted educational grant from Janssen.

Related Resources: StoneRounds


>> EDWIN STONE: Good morning, everyone. I’m Ed Stone from the University of Iowa. And this morning we’re going to talk about inherited eye disease. I’m just going to get my first slide up here for you. So we’re going to try to cover a great breadth of information in just about 50 minutes and have some questions, question opportunity at the end. But what I’m hoping to do is to give you a way to further your understanding of inherited eye disease even beyond today’s session by giving you access to some free web-based teaching tools that you can use to explore these diseases further for years to come. So our strategy this morning is I’m going to give you a short pre-test with three questions so that we can just kind of test your understanding of some of the basic diseases. And although we’ll show you what the audience responses are to those questions, we won’t tell you what the correct answers are, because at the end of the session we’re going to show the questions again and give you an opportunity to vote again. Then I’m going to basically go through and introduce you to the features that would cause you to suspect that someone had an inherited eye disease, and then cone down and focus on the 12 most common entities which collectively make up about almost 90% of what you’ll see in the inherited eye disease world. Then I’m going to show you this overview of a website that has a ton of information in it that you can use for further study. And we’re going to use one element of that website to actually go through three clinical cases. Then we’ll return to the post-test and have the question and answer session. Four times a month, almost 50 times a year, I give between 60 and 90 minutes of live teaching. And there’s a schedule of those sessions that’s part of the website. It just happens that one of them is tonight at 5:30 Central Time. So everyone listening today is welcome to join for that session tonight. When we get there, I’ll show you how you could connect to that if you wish. So let’s go ahead and start with the first question. And I would like to know what the most common macular dystrophy is. And this is true in all populations worldwide. So what is the single most common? Best disease, pattern dystrophy, Stargardt disease, Sorsby fundus dystrophy, or North Carolina macular dystrophy. We’ll just wait for a few seconds here to give you a chance to make a decision. Then we’ll see what the audience thinks. All right. 64% of people think it’s Stargardt disease with the second highest vote being Best disease. We’ll see what we think about that when we get to the end of the session. The second question, a similar one, is what is the most common form of syndromic photoreceptor disease? In other words, the basic disease you see clinically is a photoreceptor problem, but there are features outside the eye that are accompanying that. Would that be Batten disease, Usher syndrome, Bardet-Biedl syndrome, Senior-Loken syndrome, or Joubert syndrome? In this case it’s a similar split, about 65% of the audience think Usher syndrome, and about a fourth thing Bardet-Biedl syndrome. Last question, all of the following clinical features are suggestive of inherited retinal disease except one of them. So is it the presence of similarly affected relatives, bilateral and symmetrical clinical findings, slow progression, spots, or onset of symptoms at a young age? And I see that our Zoom setup has only allowed four of the five possible options. And so you’re going to do your best among those. So the least favored choice is bilateral and symmetrical clinical findings. And we’ll see where we go with that at the end of the session. All right. So in order to have any pursuit of inherited retinal disease, you have to recognize it in the middle of your otherwise busy clinic. So you’re seeing lots and lots of patients with this, that, and the other thing, and lurking somewhere within your clinic is a patient with an Mendelian retinal disease. What features would make you think that patient of all the patients in your clinic would have an Mendelian retinal disease? The most meaningful one, in my view, in my years of thinking about this, is bilateral and symmetrical disease. Genetic eye diseases almost invariably have mirror image findings between the two eyes. So whatever elaborate pattern you see in one eye, it’s just the reverse of that seen in the other eye. There are exceptions, of course, to all of these rules, in which the most glaring exception is a disease in which some carriers because of random activation of the X have very asymmetric findings, one eye can be much more affected than the other. With the exception of those few rare things, most inherited retinal diseases are quite symmetrical. Most inherited retinal disease is also very slowly progressive. It changes over years after it’s first noticed. There are also some exceptions to that. For example, Batten disease is extremely explosively progressive between the ages of 5 and 7 years. Early onset Stargardt disease very rapidly progressive in some cases. But most of these diseases we’re going to talk about change very, very slowly. A positive family history is very valuable when it’s present, when you have a similarly affected sibling or multiple generations. But of course there are many situations in which an inherited retinal disease won’t have any infected relatives. If the sibship is small, you might not have an affected sibling. Some fraction, a few percent of inherited eye diseases come from de novo mutations. So even if it was a dominant disease, it wouldn’t have a positive family history. So this is a feature that if it’s present, it’s helpful. But if it’s absent, it shouldn’t make you not consider inherited eye disease. Most of the diseases that we think of as Mendelian have an early onset, some of them in childhood, so they really look different than the other conditions that you see. But almost all of them will have at least some symptoms before age 40, although of course there are some exceptions to that too. Some forms of pattern dystrophy and really mild Stargardt disease really have nothing visible and nothing symptomatic well up into the late 50s and early 60s. And finally, there are certain features, clinical things that are just characteristic of diseases that you know to be inheritable. And there are dozens of these. The ones just worthy of mention are true pisciform flecks, that are driven from drusen, that would make you suspect Stargardt disease or pattern dystrophy. Vitelliform lesions, or bone spicule-like pigmentation. Finally, a surprising fraction of inherited retinal diseases are syndromic. Retinal degeneration plus deafness, things like that. So the presence of syndromic findings can make you suspect Mendelian retinal disease. So in 2017, we finished this study of a thousand consecutive families seen in my clinic that basically had these features. In other words, we took a thousand people coming through the clinic that we said to ourselves, this is a Mendelian retinal disease. And then we subjected those people to just every molecular investigation we could think of to try to find the cause. And we found the cause in almost 80% of these people. And the reason I’m showing you this slide now is that because the cases were consecutive, they allowed us to determine the relative frequency in the population of all these different entities. And so the frequencies that we discovered in that study are the basis of the classification system that we now use for teaching the disease to other people. And if you want to read more about that, of course you can look at that paper. So we basically divide all inherited retinal diseases into three main categories. Photoreceptor diseases, which are about two-thirds of all the patients. Macular dystrophies that are about a fourth. And then all the other conditions that aren’t one of those two basically make up just 7% of the total. So moving down into these categories then, how would you recognize something in the photoreceptor disease branch? Now that we have OCT, we can actually look at the photoreceptors with imaging and see the loss of the outer nuclear layer, selective loss of the outer nuclear layer. But just by history, if you have rod selective disease, patients will be night blind and have constricted visual fields. If you have a cone selective disease, you’ll be photo phobic, poor acuity. Rod selective disease, that’s typified by some amount of bone-spicule-like pigment. And the arterials are usually narrowed because of the increased oxygen tension in the retina. Most photoreceptor diseases have ERG abnormalities throughout the course of their progression. Nowadays in most adult patients, you can make a pretty good clinical diagnosis without the use of ERG and then go right to a focused molecular test to get the final diagnosis. So here’s a schematic drawing of the thickness of the retina with the nerve fiber layer on top and the capillaris at the bottom. If you have a photoreceptor disease, you’re expecting the primary disease, the most obvious an atomic abnormality, to be down here in the photoreceptors themselves. And that is most seen by the loss of the outer nuclear layer, that dark band on the bottom of the OCT. Features of macular disease. Here are the primary an atomic abnormality lies under the retina, between the outer segments and the choriocapillaris. Most of the abnormalities are bounded by the temporal cascades. A lot of the diseases will have material deposited in that location between the photoreceptors and the choriocapillaris and are yellow in color. Back to our schematic, the macular diseases occupy this extremely thin an atomic zone between the very top of the choriocapillaris and most will have some sort of feature within this circle about four disk diameters in extent. And then the third branch disorders are sort of everything else anatomically. Meaning on OCT, if the real features are deeper than the photoreceptors or are more superficial than them. Just to share the schematic again, choroideremia. Retinoschisis will have big spaces in the internuclear layer. And all of the inheritable optic nerve diseases will have thinning, very visible thinning of the ganglia cell layer and nerve fiber layer on OCT. Another way to sort of look at these diseases in an overview manner would just be, what are the main entities, and how many of them are there in the population? So the top to inherited retinal diseases, ones you should focus on initially, read about, look at cases of, and just be very, very comfortable that you know what the clinical features are, are nonsyndromic retinitis pigmentosa, meaning RP without anything outside the eye. That is one-third of all the Mendelian retinal disease you’ll see, is nonsyndromic RP. And the second big one is autosomal recessive Stargardt disease, the most common macular dystrophy. It makes up 18.5% of the total, almost one in five patients that you would see in an inherited retinal disease clinic will be some form of autosomal recessive Stargardt disease. With just those two entities, if you are to teach those two entities to your residents and fellows, and they became adept at them, they would be ready to go out and recognize and properly counsel half of all the inherited retinal disease patients. To get it up to 87%, we need to add ten more entities, up to what we call the big 12. Collectively, these conditions occur in about one in 2,000 people in the population. And really, all eye doctors should be familiar with these 12 diseases. They are pretty easy to recognize. They’re pretty easy to know the main clinical features and be able to explain them to patients. And why would we want everybody to recognize these things and not let them slip by us in our clinics? Well, right now, in 2023, if we recognize these conditions, we can actually tell the families what to expect, but often prevent recurrence of really bad diseases in the families that we care for right now. And then what we’re all hoping for, of course, is in the not-too-distant future, when we’re able to identify the patients and get molecular diagnosis for them, we’ll be able to provide gene and cell-based therapies. Now, I know that a number of people who are listening to the presentation this morning see patients in clinical situations in which it seems unlikely to you that you’re going to be able to deliver gene therapy in that setting. You’re just sort of overwhelmed with the number of patients that you’re asked to see and resources are limiting and so forth. When I get to the part where I’ll show you some access to some research material that you can read about, we’re working on some nonprofit ways to manufacture gene therapies that we think are going to get the cost of these things down to an extremely low level. And gene therapy is small. You could nail that really anywhere in the world. So we sort of envision a future not too far from now in which a clinician in a remote location would be able to make the correct clinical diagnosis, work with a central lab to make that molecular diagnosis, and then potentially receive a gene therapy from a nonprofit manufacturing site and be able to deliver that gene therapy anywhere in the world. So we think that, you know, this knowledge we’re talking about today really does apply to everybody. And we hope that the therapeutics are going to apply to everybody in the not-too-distant future. So just looking at the big 12 as sort of a classification scheme to see how the conditions all fit together, starting with the photoreceptor diseases, there are really three clinical questions that you use to divide these into six categories. Six categories, six of the big 12, are in the first branch. So the first question is, are there any syndromic features or not. And you might think that that’s an odd first question. You might think that syndromic diseases are really rare, and, you know, maybe you don’t have to really think about those so much. But these syndromic conditions are actually out there. They’re quite common. And if you don’t think about them right up at this first branch point, you’ll just blow right by and miss them. So Usher syndrome is the combination of retinitis pigmentosa and hearing loss. And some forms of Usher syndrome, the hearing loss is relatively mild. If it’s picked up early and people are treated with hearing aids, their speech is pretty normal. And so a patient could be sitting there with a little invisible hearing aid in their ear, and you might just think they have nonsyndromic hearing loss when indeed they have Usher syndrome. So always ask about hearing loss. That’s the number one syndromic disease, is RP plus hearing loss. And then Bardet-Biedl syndrome has a number of features, polydactyly can be on both hands and/or feet. Sometimes the extra digit is removed around the time of birth, maybe the parents never mentioned it to the patient. So always have the patient hold their hands up like this and look for a little symmetrical scar on the ulnar side. And those two things, Usher’s syndrome and Bardet-Biedl syndrome, are the most common that you don’t want to miss. What’s nonsyndromic, if you make it up here to the letter A, the next question you want to ask is when was the onset of the symptoms. You’re trying to separate congenital conditions from acquired conditions. Congenital conditions really are present at birth but they’re sometimes not really recognized at birth. So what we say is, are the features present before the fourth birthday, before the fourth birthday? Because really, none of the acquired progressive conditions present that early, like at age 3. So if you have pretty clear evidence that the features were present before the fourth birthday, you can get it down into this congenital group. And the two conditions that made it into the big 12 are Leber congenital amaurosis. LCA is congenital disease that affects both rod and cone photoreceptor systems. Usually the ERG is nonreportable. Many of these patients have profound vision loss, no light perception, light perception, things like that. And so the diagnosis is pretty evident. But amazingly, some of the genes that cause these profound diseases have mild abnormalities in them. And you can have vision as good as 20/40 or 20/50 and have really good ambulatory vision and really fall into this same clinical zone with a nonreportable ERG. So LCA is the most common congenital inherited retinal disease. And the second most common is achromatopsia in which the cone photoreceptors selectively don’t work. And those patients are generally quite photophobic and have poor acuity and poor color vision. If you have normal vision up to your 4th birthday and then have a photoreceptor problem, your final question is, is the disease rod selective or cone selective. So does the person have night blindness, constricted visual field, in which it’s retinitis pigmentosa, the most common inherited disease of all, or are they more light sensitive and is photophobic, in which they would have a selective cone disease. The macular dystrophies, there are three that made it into the big 12. Incidentally, how do you get into the big 12? You have to be 1% or more of all inherited disease. So in that study, you had to have at least ten families represented in order to be on this list of 12 entities. So the only macular dystrophies that were that common were Stargardt disease, Best disease, and pattern dystrophy, and Stargardt disease was far and away the most common of those. Then the third branch disorders, which I mentioned to you when I was showing you the schematic of the retina, the three that are 1% or more in the population, are choroideremia, X-linked retinoschisis, and dominant optic atrophy. Now I want to give you a quick overview of a website that you can use to help do further study of these conditions. I’m just going to switch my share hear to a different screen. And here you’ll see the overview of the StoneRounds website. This is a completely free thing. I do encourage you, when you go to the website, to sign up, create a log-in and sign up, because if you create a free log-in, it will open up some of the features that aren’t available to people that don’t have a log-in. But if you go to the start screen, there’s actually a little video tour that will take you through all the elaborate features of the site that we don’t have time to go through this morning. But I just wanted you to know that that tour exists. The heart of the site is the atlas. So what the atlas has is, a precedent has about 400 different cases in it. These cases are organized according to the classification scheme that I’ve just presented to you. So you can either navigate through the branches themselves and go down and look at the various diseases and then finally get down to a whole list of patients that have that disease, or you can type a gene name in or the disease name. Let’s just, for example, type in ABCA4, if I can do that while you’re watching me. And then it will show me all the Stargardt patients that we have in the site. If you want to see them in thumbnail view, you click on this little blue squares thing, that means the light box view. And that will actually show you all the cases that have Stargardt disease in the set, in these sort of thumbnails. And then if you click on one of them, it will take you to all of the images this patient has ever had at the University of Iowa. And some of the patients here have been seen for over 40 years. And every single image ever reported from this patient is visible to you in full resolution. And you can even download them to use them for teaching, if you like. So the next section I want to show you is, there is a section with all sorts of learning tools in it. And they have various tutorials similar to the talk that we’re doing this morning. Here’s an introduction to the main diseases. And there’s both a video version that you can listen to if you like your teaching material that way, or a textbook version that you can just read sort of like a textbook. This is only 15 or 20 pages long. And some of these sections actually have little self-assessments where you can go through and first take a test to test your knowledge, then read the material and go through and take the test again, sort of like we’re doing in today’s session. There’s also a section that we call additional resources. And that has all kinds of different movies and thing in there. One thing it has in there are actual lectures. And one that I want to specifically draw your attention to here, the first one under the audio and video section, is a one-hour talk by my stem cell colleague Budd Tucker which was the Kogan lecture given this year and in that one-hour talk he goes through all of our thinking about how we’re going to make this nonprofit gene and stem cell therapy to make it really accessible to people that have inherited retinal disease regardless of the rarity of the disease and regardless of its severity. In this section of the website there’s a whole series of writings about basically how to succeed in academic ophthalmology, how to succeed in science. For those of you who are interested in one person’s ideas about that, you’re a welcome to rummage around in there. Down at the bottom you’ll see the SRLive schedule. This is what I was telling you earlier, four times a month we give 60 to 90-minute teaching sessions, sort of like what we’re doing now, but they’re more interactive because there are fewer participants. There may be 40 to 60 participants. And people actually are live and ask questions and give descriptions of the diseases and so forth. We usually do about six cases per session. And it just happens that one of them is tonight, about nine hours from now. And if you have a log-in, all you have to do is click on the meeting link, and it will take you right into the Zoom session. And everyone on the call today is welcome to join us for that tonight. The last part of the site that I want to focus on today is a thing called the clinic simulator. And the clinic simulator was created realizing that many people who are interested in these diseases live in a longitude that isn’t really favorable for coming to a teaching session at 5:30 p.m. central time. So this thing is designed to allow people to have a similar teaching experience to what we do in the StoneRounds live sessions with the person being able to do that on their own without any sort of interaction with a live person. So we’re going to do three cases now, go through three cases using the clinic simulator, so that we can both sort of solidify the knowledge of the diseases that we’ve presented so far, but also give you an idea of how the features of this clinic simulator work. So the way it begins is similar to, you’re in clinic, one of your colleagues comes up to you to tell you that there is this patient in an exam room, and they’re going to give you a sort of one-line summary, they say there’s a 48-year-old woman with constricted peripheral vision. And your initial information is the fundus photographs and the visual acuity. So you see that this lady has 20/30 vision in the right eye and 20/20 vision in the left eye. You click on the photograph and it will allow you to see a higher magnification view. And if you want to go to other photographs in the set, you can go previous or next. But here, I think really all of the clinical features that you need to have a suspicion of what branch it’s in are present here. So I’ll just let you look at the photos for a second and be thinking about which of our three branches would you think that this patient might belong to. So the way the thing is set up is we want to train people to follow the diagnostic tree. And so I think it’s pretty evident that this patient belongs in the first branch, the photoreceptor branch. Why? Because there’s constricted visual fields as the first symptom. And you see narrowed arterials, in fact the vasculature is almost invisible nasal to the disk, narrowed arterials, and just visible out on the periphery here, we’ll look in the other eye too, just visible out in the periphery is some interretinal kind of spiky pigment. That’s the so-called spicule-like pigment. The narrowed arterials, constricted visual fields and bone spicule-like pigmentation all suggest photoreceptor disease. So we’re going to put this person in the first branch. Now, the cool thing about this clinic simulator is it reminds you as you go of what are the other — what’s the next branch, so to speak, what’s the next question. So by clicking on that you see that you need to make a decision of whether it’s an isolated disease or a syndromic one. And so this allows, just like you’re in the clinic, you can see what all things you can ask. And for when you’re in the photoreceptor branch, the system gives you the opportunity to ask all of the syndromic questions at sort of no cost to your ultimate score. This thing is kind of set up like a game, and you get the most points by getting the right answer with the fewest questions. So we’re going to go over here and ask all. And we see that most of the answers are no. But notice up here at the top, she had hearing aids at age 6, and her hearing has been stable since then. And so hearing aid level vision, we’re going to say she has syndromic disease, and hearing aid level vision is compatible with not only Usher syndrome writ large, but that would be type 2 Usher syndrome. The final question it’s going to ask you to do is to say what gene you think it is. You might be thinking, how in the world am I going to what gene that might be? But over time, by thinking about the in this way, you can learn the major genes that cause these diseases. Here in the simulator it actually lists the genes in the order that they are in the population. So unless you see a clinical feature that makes you suspect one of the rarer genes, you would select the most common one here at the top, USH2A, submit your diagnosis. And you get this very satisfying green box telling you that you were correct. Now, if you weren’t correct, if you had missed the diagnosis for some reason, this box will give you very specific feedback about why the answer you chose was not correct. So every possible incorrect answer has its own customized information back to you. So that’s why it’s a great teaching resource to do just by yourself whenever you have time to do it. So now let’s do the second question. Here we see an 11-year-old who has reduced acuity in both eyes. He’s just failed school screening, 11-year-old male. We’ll mag up on this thing. We go, okay, that abnormality is in the macula, but it looks on the fundus exam there are sort of cystic spaces in the retina. It doesn’t look deep, it doesn’t look down at the level of the RP where the macular disease would be. What we’ll do there is suspect that it’s a third branch disorder. And then we’ll ask a question. We’ll ask for the pedigree. And we see that this affected male has an affected grandfather through an unaffected female. So that might be making us thinking of one of these X-linked conditions in the big 12 that we talked about. Just to convince ourselves of that, we’ll click on the OCT and look. We’ll see that the photoreceptor layer there is pretty intact, but there are these huge cystic spaces in the internuclear layer which is characteristic of X-linked retinoschisis. Now we’ll go down, choose X-linked retinoschisis. There’s only one gene for that, RS1, and again, we’ll get the green box. Then our next and last patient in the simulator, we’re going to look at this 14-year-old person who has normal vision in the left eye but reduced vision in the right eye. We’ll mag up on that. Here we see yellow material in the macula. With our criteria that we have introduced this morning, we would say that’s pretty suggestive of macular disease. Now, unlike the photoreceptor branches where you have to ask all this stuff about what age it is, whether they’re syndromic and so forth, the ten Mendelian macular diseases we focus on are really mostly separated by their inheritance pattern and by the clinical features that are there. So usually the best question to ask if you suspect a macular disease is the pedigree. And here you see male to male transmission, multiple generations affected. So this is compatible with autosomal disease and the yellow stuff is very characteristic of Best disease. So we’ll choose Best disease. The most common cause for that is the gene BEST1. And again, that’s the right answer in our clinic simulator. So there are about 50 different entities in the clinic simulator now. And if you sign up over here and have a log-in, we don’t store your data or share your data with anybody, but it will remember what you did in the clinic simulator so that if you get one right, it won’t show you that one again. But if you get it wrong, it will put it back in the stack and show it to you again a few patients later until you get it right. And so just as your time allows, it will allow you to go through these 50 cases until you sort of teach yourself all the nuanced clinical features of these inherited eye diseases. So now I just want to switch back over to the actual PowerPoint here. Which I think is there. There we go. And so now, we have come to the point in the session in which we’re going to see whether we’ve changed our minds about any of the test questions that we had before. So our question, our first question for the day was, what is the most common macular dystrophy? Is it Best disease, pattern dystrophy, Stargardt disease, Sorsby fundus dystrophy, or North Carolina macular dystrophy? And so now we’ve moved up quite a bit since this morning to 73% of the participants think that it’s Stargardt disease. And that is my clinical experience, that Stargardt disease is far and away the most common Mendelian disease. Best disease is number 2. And pattern dystrophy is number 3 in north America. What is the most common form of syndromic photoreceptor disease? Is it Batten disease, Usher syndrome, Bardet-Biedl syndrome, Senior-Loken syndrome, or Joubert syndrome? So 87% of the audience thinks it’s Usher syndrome. I do believe that’s correct. Bardet syndrome is the second most common in north America. That disease, devastating, fatal disease that you really hope you never see is sadly the third most common form of syndromic photoreceptor disease in north America. And then finally, the third question, we’re going to list some features of inherited retinal disease. And which one of these clinical features really isn’t suggestive of an inherited retinal disease? Similarly affected relatives, bilateral symmetrical clinical findings, slow progression, cotton wool spots, or onset of symptoms at a young age? I agree with that. Certainly the presence of a cotton wool spot doesn’t mean a person doesn’t have an inherited eye disease, because somebody might be diabetic and have Best disease or something like that. But ischemic retinal disease in the inner retina is not really a common feature, certainly not as much as any of the other four choices in today’s poll. So I wanted to save plenty of time to respond to questions from the audience. So I’m going to stop sharing now, and look over at the question screen. Please answer questions that you would like me to try to address and I’ll do as many of them as I can in the remaining time. So I don’t believe that you can see the questions. So I’m going to read it to you. So the first question is, in your opinion, what will be the most important clinical indication of adaptive optics in diagnosis or tracking the progression of inherited retinal disease? I think that adaptive optics will play a role in the management of inherited retinal disease. I think the most immediate thing that I can see it helping us with is in showing the utility of a gene replacement therapy sooner than we would be able to detect it with clinical means alone. So for example, let’s say that you want to test a gene therapy for a disease, some type of photoreceptor disease. And, you know, the earlier you deliver a gene therapy, the more likely it is to work, when there’s more normal anatomy, lots of salvageable photoreceptors, it’s going to be a lot more likely to work than near the end stage of the disease when, frankly, the remaining photoreceptors are the ones that didn’t care about the gene anyway. So let’s say that you had a form of RP that you knew to have a selective expression in the nasal retina. A great clinical trial design might be to detect some very young patients who are very early in their disease, and put 300 microliters of gene replacement therapy in the nasal retina, and none in the other eye, and then follow those patients over time to see whether the treated eye ended up doing better than the untreated eye. So one way you could follow that would be with Goldmann visual field. Frankly in order to eventually fully deploy the therapy, you would want the treatment to actually make a big difference in the progression of the disease so that one eye was clearly better than the untreated eye. But what if you just wanted to know whether the treatment worked well enough that you had confidence that you could progress to the next stage of the trial and actually put some in the macula? Well, if you had adaptive optics and you could look anatomically in great detail out in the nasal retina and once yourself just after a year or two of followup that the treated eye was better than the untreated eye, that might actually accelerate the progression of clinical trial by having that super sensitive anatomical outcome measure. The next question is, there are certain areas in the world where electrophysiological tests are not available, and in such situations, how do you confirm the retinal dystrophy and differentiate it from the other phenotypes? They point out that this might be really important where there’s no family history. As I sort of touched on briefly in my previous remarks, I think now that we have OCT, which is pretty widely available, I think the need for electro physiology in adults and older children is actually much, much less than it was before. I think if you follow the diagnostic algorithm that I sort of laid out for you today, you can get down to a few-gene hypothesis solely on clinical standards. I think most people don’t have Mendelian disease, they have a normal retina, and I want to convince myself that they have normal electrophysiology. It’s useful to figure out what’s going on in visually impaired infants. That will be challenging if you don’t have ERG and you’re trying to diagnose visually impaired infants. Is the disease atlas an application that can be downloaded or is it available as a PDF? The answer to that is no. One of the patients in the atlas has 10,000 images. So I just briefly flipped through it, showing, you know, the exemplar images that we’ve chosen. But as I mentioned in my remarks, this atlas has the full resolution image. So it’s just as though you’re down in my clinic, looking at the OCT on the screen. That same OCT that I would see in the clinic, full resolution, is in the atlas. And you can click on the advance button and go through the OCT line by line, just like you can in the clinic. So there really isn’t any way to download the whole thing. It’s just gigantic. The atlas is designed to interact with through the website. But again, the website is completely free to anyone who wants to use it for a noncommercial purpose. And you can actually — again, you’ll see this feature if you go through the StoneRounds tour, but there’s actually a way to display the image in a download format so that you can go select certain ones that you want to download for teaching purposes, and you can even — there’s even a button that says create PowerPoint. So after you click on the ten or 15 or 20 images that you want, if you click on create PowerPoint, it actually makes the PowerPoint for you and puts it into your download folder to go use for giving a talk. The next question is, how does one differentiate between late onset Stargardt disease and age-related macular degeneration? It’s a great question. And those two entities are very similar. But the main difference between late onset Stargardt disease and ARMD are the absence of drusen. Stargardt disease doesn’t really have typical circular drusen scattered about the macula. Stargardt disease, even their late onset stuff, has pisciform deposits, angular, little boomerang-shaped things. If you really discipline yourself to look along the arcades and outside the arcades, age-related macular degeneration doesn’t have pisciform flex, Stargardt disease does. Foveal sparring, what happens is you’ll get an eccentric patch of geographic atrophy, and then those patches sort of coalesce such that there’s a little peninsula of preserved retina going down to include the fovea. If you look on OCT, you’ll see outer retinal tubulations in the remaining retina. That shows us the pathophysiology is actually choroidal loss, it’s actually death from below. I would say the presence of pisciform death along the arcades and frequent peninsular sparing of the fovea are the main things that would make me suspect late onset Stargardt disease. Even though this can first appear in somebody 65 or 70, it’s a little bit more likely to appear in the late 50s or very early 60s. And so that would be pretty early age-related macular degeneration. That would be the third feature, would be a little earlier than average AMD. And if they have siblings and they have a similarly affected sibling, that would be a fourth thing that would make me suspect it. Okay. So the next question is, in developing countries, where we don’t have access to gene treatment, what alternative treatment option do we have for RP? Well, I would argue, in developed countries we don’t really have any real treatments for RP yet, sadly. And I think that the two things I’ll say to that very good question is, the first is that I mentioned that we’re very hopeful that the gene therapies that are going to be developed in more economically developed countries, I’m very hopeful that those will be manufactured in such a way that they’ll actually be inexpensive and be able to be shared with the world philanthropically. That’s the goal of our program, is to do that. And I’m optimistic that that’s going to happen. But, you know, the other thing to think about is that treatment of patients with RP is not solely molecular. So in other words, a lot of patients when they first show up and have a few bone-spicule-like pigment clumps and some constricted vision, people who don’t know better tell them something awful like, you’re going to be blind in three years, go home and sell your business, or something like that, and many of these patients do very well for many years. And so just being more knowledgeable about the disease and reassuring the patients that they’re going to do well for a long time, helping them have various types of aids to help them at work and so forth, all those things are forms of treatment. If a patient has a recessive disease and their likelihood of passing it on to their child is almost zero, that’s incredibly reassuring to the patient. That’s treatment. So I would argue that there are all kind of things we can do for our patients right now with — you know, it all requires excellent knowledge of the disease and experience, so that we’ll talk to the patients appropriately in a reassuring manner. But right now, before we can even deploy these treatments, I think greater knowledge of the diseases are going to help us help our patients. And then for the really terrible diseases, I’ll just stick this in, you didn’t really ask about this, let’s just say Batten disease, for example, it’s a fatal disease, awful. If you could recognize Batten disease in a 5 or 6-year-old, correctly recognize it, and get the proper genetic counseling for the family, they might then avoid by some means having another child who will die just because you made the correct diagnosis in the first patient. Conversely, if you don’t know what it is and you think it’s Stargardt disease and you fool around for a while and whatever, and the family has two more children while this is going on, and both of those other children are affected before the older child has their first seizure, that’s just — that’s just a catastrophe. So these are the kind of things that just with clinical knowledge, just with clinical knowledge and your ophthalmoscope and asking the patient the right questions, you can already make a huge difference in people’s lives without any type of molecular treatment. The next question is — and it seems like we have time for maybe two more questions. I really, really appreciate everybody asking these great questions, and attending the session this morning. The next question is, if I’m encountering a novel mutation which I believe has a founder effect, what evidence should I be gathering in order to confirm this hypothesis and get it published? I think the main answer to all questions like this is more patients. More patients. So go back to the families, go back to the families. If there really is a founder effect in a given region, then you should be able to go follow — you know, do pedigree analysis basically, go sit down with the older members of the family, track down everybody you can find. And what should be true is there should be additional individuals related to that family all over the place. And, you know, if you can get back up to ten, 15, 20 affected individuals instead of three individuals, and then show that this allele is rare enough in your population that the frequency in the population sort of matches the expected frequency that you’re seeing in this little ethnic isolate or something, that would be very convincing to me. Then this will be our last question for this morning. I want to be respectful of everybody’s time. I know many people have to get off to clinic. What if someone has features of both photoreceptor and macular disease? That is a great question. And what is the most likely situation for that? Stargardt disease. Because the more severe parts of Stargardt disease are basically an autosomal recessive cone-rod dystrophy. If you see somebody that you think has autosomal recessive cone-rod dystrophy, the most likely gene for that is A4. The combination of photoreceptor and macular disease, to think of it another way, it’s where the branches of our classification system actually touch, is they touch at Stargardt disease. Very severe Stargardt disease, the stuff that onsets at age 6 or 7 years, those people get bone-spicule-like pigmentation and constricted visual fields and it looks sort of like RP. The reason you know it’s not RP is, they lost their macula first and it’s really early disease and that’s what tells you it’s ABCA4. Again, I want to thank all the attendees for sharing their time with us this morning. And I invite all of you to come back tonight at 5:30 central time and join us for six cases of StoneRounds if your schedule will allow you to do that. Thank you very much.

3 thoughts on “Lecture: Introduction to Inherited Retinal Disease”

  1. To Cybersight

    Thank you very much for the excellence of the produced webinars and for making them available recorded and as in PDF format for later consultation.


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