Lecture: Analyzing Complex Inherited Retinal Disease Cases: Five Interesting Patient Cases You Don’t Want to Miss!

DR. CHERWEK: Well, I certainly want to welcome everyone to our webinar today. We haven’t done this before. We’re making Orbis history at the time. We’re taking consults that have real patients from around the world that are demonstrating not just inherited retinal diseases, but how to use our E-commerce service to help them. And I can’t thank Andy and Lawrence for their help. And start with Dr. Levin, we started Cybersight to not only teach about genetics, but to use the platform to do consults. I know everyone is on Cybersight at the moment. I think of Cybersight as CCC, just like your continuous curvilinear capsulorhexis. Everyone knows about the consults. Everyone knows about the content, and everyone knows about the courses. I find most people are not using the consult service as much as they could. We’ve had unbelievable growth since the COVID pandemic. And you can see that we now have over 100,000 registered users. So, the reach of Cybersight is just incredible. And now we’re taking talent from around the world to give webinars and to help with our consult service. Certainly one of the things that I think you’ll see more and more of over the next 10 years in our field is the concept of ocular genetics. So, certainly the field of genetics is exploding. Out of all the fields of medicine, FDA approval for gene therapy is ophthalmology. And talk about these diseases, IRDs, inherited retinal diseases, complex diseases, just like neuro-ophthalmology. The history, the differential diagnosis and the workup is critical. And certainly, Alex, Dr. Levin, has a fellowship where he’s trained doctors from around the world in epigenetics. Not everyone can get his fellowship. But through Cybersight and E-consults, you have access to Dr. Levin and other experts in ocular genetics. Really Cybersight is here to help you, those watching, with complex cases. We have courses in ocular genetics. All are free. If you complete them, and I’ll go through this when Alex starts in the chat, we have literally had thousands of people take these courses from around the world. Certainly our map, you can see now, almost every country in the world is engaged with our E-courses and our webinars and our E-library for ocular genetics. And if you want to take a minute, you can scan this QR code and go straight to those content resources and courses today. Obviously, Alex has begin other lectures in ocular genetics. He’s a pioneer in this field. But we have had speakers from around the world talking about gene therapy, IRDs, retinopathy pigmentosa. Children or adults with things like Stargardts or other problems. We’re using the webinar to talk about consults. And Alex used prior cases to create these quizzes in the library. You go to the Cybersight E-library and look at quizzes, you can see cases around the world that are now multiple choice questions and you can think about how you would work up a patient with different retinal diseases. IRDs or other genetic syndromes. And here is just an example. But what I’m really excited about, and I want to talk a minute to thank Alex, we’re now beginning to take consults from around the world and helping people with some of the most complex cases. And how we are now leveraging this incredible technology with ocular genetics to give patients and families a way forward. You can click on the QR code to submit cases. Only allowing consults from low to middle income countries and I’ll send that in the link which countries are included. If you have any questions how to register to do consults or have any questions about Cybersight in general, you can go to [email protected]. So, really today is taking some real cases that Dr. Levin has worked with some of his former fellows and some of their fellows. He’s now a grandfather to a lot of ocular genetics fellows. And one of the things to remind people, in about a month’s time, on November 10th, we’re having another Cybersight webinar on how to use our Consult service. I find that is by far the most under-utilized resource on the platform. Even though ocular genetics and gene therapy is all very exciting, submitting a consult without the fundamentals. I’m amazed at how many times people submit consults, there’s not a refraction, no notation about nystagmus. This is one of those — like I said earlier — this is one of those cases where you need a very detailed history. For example, the child’s birth history or family history or, you know, genetic counselors. Knowing things like the past medical history is very important. So, as you’re starting to use the Cybersight Consults to help manage patients with inherited retinal diseases or other ocular genetic cases, please don’t forget that like any consult, they’re only as good as the data and the organized workup. Take your time, please, if you’re going to submit these histories so that Alex and others get clear patient and family histories, et cetera. I’m going to ask Alex, after the five cases from around the world, to end his presentation and discussions about the things that he really needs from a good consult to give you, the Cybersight audience, the best possible consult and resources. So, I’m gonna stop screen sharing and pass the baton to Alex. I can’t thank him enough, not only for joining us today on another great Cybersight webinar. But really he’s been the one pioneering and leading the charge for ocular genetics, not just with Cybersight, but with our orbit program. Over to you, Dr. Levin.
DR. LEVIN: Thanks very much, Hunter. And Hunter is the voice of Orbis these days. Speaking with about two hours of sleep and lots of jet lag. We appreciate you flying in and joining us today. I’m going to share my screen, but before do I that, a couple comments. Cybersight is amazing in every area of ophthalmology. Not just for us, but for ophthalmic techs. And you have this cornucopia of webinars and quizzes. Made largely by my former fellows from all over the world in every area of content. Not just genetics. In plastics, in pathology, every single element of ophthalmology.
You’ve got course content where you can take courses. So, it’s a really powerful tool. And the Consult service is amazing. You can put in a consult, and within 24 hours you will have a response from any topic in ophthalmology from an expert in the field. And in ocular genetics, which we’re building now, we are developing mentors from around the world in your regions who can answer questions as well. So, it’s a great place to get a quick curbside consult with some good information. So, without further ado, I’m going to demonstrate some you. We’ll take questions after each case. You can ask a question about the process. You can ask a question about the content. And I’m happy to take that. We’ve got five cases lined up. As time permits, we have two backups if we need some extra time. But please feel free to put your questions in the Q&A. So, let me just share my screen. Okay. Can someone give me a this ups up? Seeing the consult for Dr. De Guimaraes.
DR. CHERWEK: It’s great.
DR. LEVIN: Thank you. Dr. De Guimaraes is brilliant and trains with me and puts through this case. You don’t have to be a world-leading geneticist like Dr. De Guimaraes to put in a case. No matter your level of expertise, you have questions. I could use a consult now and then, and anybody is fair game. No question is too low, no question is too high. We can do anything. And although we’re doing mostly IRDs today, it can be any area of genetics. Retinoblastoma, cancer genetics, strabismus-related genetics. And see what I’m reading you. This is the format. This is exactly what it looks like in Cybersight when the case comes in. The case comes in, Dr. Guimaraes tells me, started a few months ago, 40-year-old. That’s an important point. As we look at the history of how a case evolves, it also tells us. For example, it’s unlikely that this patient has retinitis pigmentosa. Might be in the macular region, may be right, we’ll see. An older sister, unknown cause, and a nephew, 40 years old, also complaining of mild distortion. That’s important information. Could this be a dominant or recessive condition? I’m trying to get some idea on that listening to the family history. Otherwise very healthy. No systemic issues and not using medications and no drusen were seen. We’ve got some key points of information. We have the age of the patient and the onset. Not only the able of onset, but also the type of onset. What were the initial symptoms? We’ve got family history. We’ve got systemic history, number three. And then we’re gonna go on to some other features, which is the phenotype. As we scroll down, it’s very simple. You put in the vision. Good central vision in each eye. That’s a little bit odd because complaint was distortion of central vision. And some basic eye examinations. Some pressure, the anterior segment’s normal. And then you get the opportunity to make a best guess. So, he’s saying he thinks it’s best disease. And we’ll get to the mentor diagnosis later, that doesn’t come on. Best disease. And here’s the question — this is a critical thing in consult — what do you want from your consultant? He’s asking, would we expect to see such an atrophic scared fundus in the right eye of his sister? And should we follow the patient up more frequently? Two clear, easy questions are asked. And let’s look at the eye. So, here is the proband, that is the presenting person. And click on this picture. And you can see we have a healthy optic nerve, healthy blood vessels, basically healthy retina with a clear form lesion in the fovea and the macula there in that eye. Look at the proband’s other eye. We see a similar picture. Now we can see the settling of the lipofuscin that’s underneath the retina. This is a kind of classic best disease presentation. We’ll get back to that in a second. The thing that’s troubling Dr. De Guimaraes. This is the sister. This is an autosomal disorder, and expect it running through the family in that way. But the sister’s left eye, first, looks like this. We see the scared, atrophic late stage disease of Best disease. Otherwise normal fundus. We get pigment and scarring where the lesion or have been. And if we go to the other eye, here’s the trouble. That certainly doesn’t look like Best. Best disease is a very focal disease in the fovea where we see a localized lesion and this is a more widespread pigmentary disruption of almost the entire macula. Maybe even some subretinal fibrosis out here. No clear flex anywhere in the retina he pointed out. Something more widespread appears to be going on. So, he’s asking me, he said, well, it’s dominant. Sister could be affected. We don’t have any information on the parents’ dominant disorder. But this doesn’t look like the disease that she’s purported to have. Why are the two eyes asymmetric? How do we explain that? My thinking is reflected in my rely. So, your consultant gets reply. Let’s read together what I wrote and discuss it as we go. Thanks for sending this in. Interesting case. You have certainly demonstrated the value of examining family members, right? A pedigree is just a story to be confirmed or refuted by your examination. There are several possibilities for disparate appearance in the older sister. Number un: She could have another disease. And a pedigree is just a story. When there’s other people in a family who have vision loss, is that vision loss due to the same thing your patient has? Her left eye certainly looks like a typical car from Best disease. Right eye is very atypical. So, I’m asking, did she have something else that happened to that right eye? Trauma in that eye? Could she have had infection in that eye? Two, best is autosomal dominant. If the sister is affected, then by definition one parent is affected. She didn’t spontaneously get from one gene. Variable expression, that is where the parent may have the disease so mildly that they don’t even know. Or variable penetrance where they have the gene abnormality, but don’t have anything on exam. Then they wouldn’t know they have the disease. These both happen in this disease and many autosomal dominant diseases. The challenge is that if the nephew is truly affected, that puts multiple intervening people in the same situation as the parent. And the odds of that is small. So, in other words, that would have been multiple people through the pedigree who are non-penetrant or expression. I ask, is there consanguinity or — the sister could have autosomal retinopathy. Instead of one change for autosomal disease, both copies of her Best 1 gene are abnormal. She gets autosomal recessive Best retinopathy, which is a more widespread disease, and the brother has dominant just one copy abnormal. Granted, she has other typical features of AR Best. She doesn’t have the multiple flex we see under the retina in different areas. This requires a detailed pedigree. And if available, DNA testing to sort it out. Now let me just stop there and make an important point: Many of you will not have access to genetic testing. That is not required to ask a consult. You’re still seeing patients. You still need to make a diagnosis and do the best you can. Here’s a case where I think we can go forward without genetic testing. If you have it, great. If you don’t, we’re going to give you an answer that works in your scenario. So, for this woman, I’m saying maybe, if I had that information, that there was a constricted gene pool, we could think she could have autosomal recessive Best retinopathy. Occipital, examining other family members is critical and helpful as well.
Number three, another possibility, she has a subretinal neovascular membrane that occurs in Best disease. And is resulting in more widespread scarring. The left eye is suspicious and might benefit from an fluorescein angiography or OCTA. You might not have the technology available, making a suggestion. If you don’t have the technology, we can write back and respond. And in later cases, we can help you in your setting come to a diagnosis. Lastly, it is possible that this is a Best mimic. Of which there are several. OCT may be helpful in confirming. And I gave — here’s a list of mimics. Many of these are obvious that she’s not affected. But I gave a list of things that cause subretinal lipofuscin deposits that look just like — or can look just like Best disease on an OCT. So, many of these we know she doesn’t have myotonic dystrophy or McArdle’s disease. No findings for retina syndrome. What you can use in the future whenever you see a lesion that is subretinal that has this lipofuscin deposit. And there at the bottom, we have Best disease, which is my leading diagnosis for this family. For now, I would try to do fundus autofluorescence if you have it. You may not. OCT on these two, the nephew, and intervening family members. DNA testing of the BEST1 gene, that’s a type to be DNA testing, if available. If the patient does have Best disease, now I’m gonna get to the other question, I would screen them every 6 months as I do for all my Best patients for sub-neurovascularization. I tell them if they have a sudden change in vision, contact me before. But every of months, get an FAF and an OCT. I want to warn you, treatment with antiVEGF drugs is not indicated unless the patient experiences a sudden drop in visual acuity with a change on OCT. Then I get back to the sister, did she have that history? Let’s look. This consult has generated, I think, an answer, at least a possibility — possible answers to the question that’s been asked. We’ve set up a plan going forward of what can be done to narrow this diagnosis, taking into account the setting that the case is in. Some things may or may not be available. And if the person asking the question wants to have a continuing dialogue, I’ll show you that on subsequent cases, we could go further. So, that’s an example of a Cybersight Consult case. So, before we go on further, are there any questions? And let me just go back to my window and see if any questions came up in the box.
DR. CHERWEK: Alex, just a few questions, what is a constricted gene pool? You use that term “Constricted gene pool” what do you mean by that?
DR. LEVIN: All of us on this call are related to each other. In the course of time from Adam & Eve or whoever to billions of people in the world, we become genetically diverse. As perfect as you all are on this call, all perfect and achieved a lot, we have mutations in our genes. When we marry someone, it’s a random chance that they have an abnormality in the same gene that we have the abnormality. It’s only then that a child gets a dose from each parent to create a double dose in the child and thus an autosomal recessive disease. The chance of your partner having the same gene abnormality as you is increased if you’re related to each other. Just by the nature of the world. And many populations of the world, marrying within families is a common thing. And therefore the chance of having autosomal recessive disease goes up because you have two parents who more likely have the same gene. You don’t have to marry a relative to do that. If you live in a constricted gene pool, that is in a — your partners are picked without knowing you’re being related, but let’s say you’re on an isolated island. Or let’s say you’re in a small population, Ashkenazi Jews are 0.2% of the world. Let’s say you come from the same tribe, even though you’re not related. And maybe geographically, a patient from Africa, married a woman from another tribe. She lived across the walking bridge on the other side, those are constricted gene pool that increases the chance that you’re partnering with someone who has a gene abnormality in the same gene.
DR. CHERWEK: Yeah. So, you’re also getting compliments in the chat about your glasses, the square and the circle.
DR. LEVIN: That’s a male and a female, it’s my pedigree on my case.
DR. CHERWEK: Okay. Another one. A constricted gene pool is a gene pool where the gene pool is con districted like in Tangier Island, where there’s Tangier’s disease. Did you use EOG for the workup of best disease? And the second thing, what should you look out for the next six months? What would you do with follow-up? EOG and ERG, what is the follow-up?
DR. LEVIN: EOG is very helpful. It’s fairly specific for Best disease, not readily available. They have to be able to take the test. Young children can’t do the test. But it can be useful in increasing your confidence in your diagnosis. Because most helpful I find in patients who have very little signs of the disease, a non-penetrant parent who has no findings on their examination may have an abnormal EOG. If you have access to it, it can be an additional adjunctive tool. As far as follow-up for this family, I would continue to follow-up the proband, the male, the brother every six months like I do for all best disease. And the same for this female. I suggested a couple tests for his sister here to maybe she if she’s had a net or had an evidence of a net, OCTA, IVFA, and continue to follow her especially now that she’s down to one eye. We don’t that want eye to have a subretinal bleed.
DR. CHERWEK: And then very quickly, Alex, before we move on to the next, would you use a grid to follow the patient at home between visits? What else can you do for this child or prenatal diagnostics? Is there anything else — we’re gonna do obviously potentially ERG, EOG, see them sequentially over time. Would you use an Amsler grid over time?
DR. LEVIN: By the way, this is a question that the person asking can go on an ongoing basis. The communication can be endless. Which we love in Cybersight. ERG is less help of because it’s normal in Best disease. I wouldn’t expect it to be abnormal. Her blood vessels are not attenuated so I wouldn’t expect any effect on the rod system. It’s less helpful. I think that, you know, a very important question is being asked about what about preventing future pregnancies? Technology is available with DNA diagnosis to do something called pre-implantation diagnosis where you in vitro fertilize and only put in eggs that don’t carry the disease. That is available. That is a high-level technique. It may not be available in many countries. But the important thing is it shows you the context, the importance — excuse the pun — the penetrance in families of intraocular disease — and how hard it is to answer the questions when we don’t have DNA testing available. How to counsel them. The risk of this man having a child is 50% for each pregnancy. Whether it’s a boy or a girl. It’s a dominant disorder. If he marries someone in the same community, they could have an autosomal — the risk goes up. All of that counseling depends on an accurate diagnosis and that’s where Cybersight consultation can come in handy. Why don’t we move on to the next case.
DR. CHERWEK: I was going to say, let’s move on to the next case and I’ll have a little bit more questions after the next case.
DR. LEVIN: Sure. This comes from a an excellent geneticist in the Philippines in Manila, Michelle Lingao. And asks about a 3-year-old with side vision problems and gradual blurring of vision. Night vision problems were noted during high school. She’s 16-year-olds, so a long-standing night vision history. But weren’t that prominent. Pre-diabetic, indigestion, no hearing loss, review of systems otherwise unremarkable. No previous history of fever, hospitalizations, she gives her pigmentary status, which will become relevant. Used to write as a script writer in films, no family history of similar eye condition. We’re getting a feel for the history over time. And there’s no family history, an isolated case. The patient sees 2500 in the right eye, 20/630 in the left eye, best corrected. No transillumination defects. Has a cataract and what we know is they were able to get genetic testing and it came back — it’s one pathogenic variant in the ocular cutaneous albinism 2, the P gene. It’s the protein change, and it’s heterozygous. And the question she’s asking is the patient is a carrier of a pathogenic OCA2 variant. But this variant is not consistent with the patient’s phenotype. OCA2 is recessive and the patient carries only one pathogenic variant. You need two abnormal copies to get the disease. She only has one. Hm. It’s possible this may be an incidental finding. Questions are: Is this possible cone rod dystrophy, or is this fundus consistent with more of a metabolic condition? However, there’s lack of systemic findings, which may point out to a metabolic cause? And number two, could whole exome sequencing be the next step? And this was on a panel test, we’ll get back to that. Look at the patient. Here’s the fundus photo. And it’s turned, but that’s fine. What we see is a lot of pigment in the fundus. Normal pigmentation. And the vessels are pretty normal, we’ll back to this in a second. Here’s another view of the fundus. And it looks like there’s flecks, doesn’t it? Looks like there’s all these flecks. At least that’s what I’m getting from the photo. Am I right? Am I wrong? The photos don’t have to be superb, high-tech, award-winning quality pictures. We can work with whatever you got and ask questions back and forth to get the answer. I’m just gonna show you a couple other things. We’ll skip the field. But we can see the — here’s from the ERG that the flicker is reduced. This should be kind of as I’m tracing here. It’s reduced in amplitude. And it’s delayed so there is some cone abnormalities. The flicker is the part of the ERG which tests the cones. Only they can recycle. We have a time domain OCT which is really less helpful, but we can see that there seems to be some atrophic area in here. And we can see the rod response here better. And let’s just get down to the gene test results. The OCT, pathogenic carrier. So, we have this information and taking this all together. I’m just gonna go down a little further. I want to show you — this is more helpful. But it’s difficult, you know? Quality-wise, seems to be some mottling of pigment. Vessels are a little attenuated on this stage here. So, let’s try and put this all together. So, what did I write? I wrote back: Yes, I agree that the OCA2 is an incidental finding of a carrier unrelated to the eye condition. So, the larger the panel you order, the more genes you test, and some of you only have access to panel testing or whole exome testing in various countries or various institutions. You’re gonna generate a lot of stuff because everybody’s carrying stuff. This was a retinal disease panel or whole exome. They happen. And find it — it’s a carrier of OCA2. Unrelated. The absence of iris transillumination, cove yay — that should be, or nystagmus and the presence of normal choroidal pigment, and getting back to the patient to check for phenotype and supports the genotype. Any time you get a gene result, ask yourself, is this important? Is this related to my patient? Well, it’s recessive disease. We only have one copy of the gene. Just a carrier. Nothing clinical to support it. We can throw that out. The patient appears to have subretinal flecks, which with the long standing history of nyctalopia and macular involvement, I suggested two other genes, RLBP1 or RDHS, or even less likely, RPE65. Focused gene testing could be tried if available. Otherwise whole exome retina panel would work for pretest and post test counseling. Always have those. Place the risk of incidental findings. Let’s see what she said. This is important. She writes back to me, oh, she already had a panel. 330 genes. Which included the genes I suggested, which are all normal. So, this patient would have a whole exome next would be the next step. The next bigger test. Her whole genome is even bigger. I wonder if targeted testing of genes might have a better chance of a better diagnosis. Now getting to the more sophisticated question. Presents the phenotype to me, it’s not the OCA2. Turns out she had a wider panel. We see there’s central atrophy and cone disease on her panel. And she’s saying, well, what can she do to dive deeper and get a diagnosis when her broad panel, which includes the cone-rod dystrophies — came back negative? Right? And I wrote — and this is where we can discuss ethical issues. Economic issues. Availability issues in your communities. I think the cost of whole exome or genome is difficult to justify as the yield is likely very low having done a big IRD panel in an otherwise well patient at this age. Provided that the panel test also included tests for deletions of duplications, which they all do, and would be missed if you’re just sequencing. Although 20% of IRD cases around the world remain unsolved by genetic testing, this may be one. I think it’s more important to consider occult systemic disease begin the late onset including Vitamin A deficiency and cancer-associated or melanoma-associated or autoimmune-induced retinopathy. Although admittedly the flecks make these less likely and the ERG is less consistent with these diseases. At least these things are treatable entities. You have done a big panel that’s got most of the genes. The added cost of a bigger panel has a low likelihood of getting us additional stuff. And I’m suggesting that may not be worth it and this may be one of the 20%. And that’s how we ended this case. So, a great case to demonstrate how we took a more sophisticated question with testing already in place without an answer. Do we want to go forward? What’s our chance of going forward? What else can we do to come to a diagnosis in a complicated case? We don’t need an answer, do I think it’s a hereditary disease in absolutely. Symmetrical involvement in both eyes. We just can’t find that gene. Let’s take some questions, Hunter.
DR. CHERWEK: Yeah, the one big question — what are the benefits of whole exome sequencing over other genetic testing for IRDs? What are the benefits of whole exome sequencing over other genetic testing for IRDs?
DR. LEVIN: Let me just rephrase that question — what’s the benefit of genetic testing, period. Patient know what is their diagnosis is. 99% of people would rather have a bad diagnosis than not know what they have. It helps them plan for the future, family planning. It tells us what other things to look for. You know? If you have Marfan you got to look at your heart. And what to expect in the future. This patient is driving in 10, 20 years. And is there a treatment? RP65, externa. There’s many things that genetic testing does for us. But genetic testing, the yield of genetic testing is dependent on your phenotyping. So, I can do genetic tests on any of you on this call and get a positive result. But without knowing what your eye exam is, I can’t help you. And the more narrow your testing, if you say, “I think this patient has Stargardt” and test that one gene, ABC4, and that’s positive, the likelihood that have being correct is much, much higher than if I look at your fundus and I get a whole big panel and a bunch of things come back. We try and narrow our testing. When we don’t have narrow testing available, panels are designed to give us the highest yield at the lowest cost. The add-on of exome and genome is minimal. A genome tests 40,000 genes. In fact test the whole chromosome. It’s 98% of your DNA is not covered in an exome. You have many more genes. But it’s very hard to look through all the data and know what matters. That 2% on the exome gives a lot of genes, but we’re only gonna look at the genes relevant to the patient. You’re not gonna make a new discovery. It has to be a recognized gene. And that’s why the recognized genes are all on the panels. And you don’t get much added value from whole exome and whole genome until you get into the research mode of really digging deep, if you have those resources, to make a new discovery.
DR. CHERWEK: And so, Alex, one last question before we move on to the next case — how old you approach a patient who is the only affected member in the family, but genetic tests suggest an inherited condition. Family members show up, no other family member affected and when you do the history and analysis, but there is genetic testing that shows it’s an inherited condition. How would you approach that?
DR. LEVIN: Remember that a sporadic disease, it’s a disease that occurs for the first time in a family can be inherited from a parent that is affected and either doesn’t know they’re affected or fails to disclose. Or from both parents who are carriers. Recessive disease. A mother could be a carrier. That’s one possibility. It can also occur because that’s the first person in the family to have it. But it could still be genetic that they could pass on. So, when we have inherited retinal disease, that’s when we start to examine other family members where applicable based on the history to see if they have something. I have a patient in my practice who had aniridia. And her mother was never examined. She had two kids. And lo and behold, see she has complete aniridia with 20/40 vision, no nystagmus, just thought she had dark eyes. No one asked about her parents. Turns out her parents met at the school for the blind, one of them had aniridia. So, unless you look at family members, you never know. And examining parents is the first place we start. With DNA, we do the same thing. You get the DNA on the patient. We find the result. Then we appropriately test family members, what’s call cascade testing to evaluate them. Each patient is connected to a family and we want to evaluate that family for their risk and affectation.
DR. CHERWEK: Great answer, Alex. I think we’re ready for case number three if you are.
DR. LEVIN: Here we go. Another one from the Philippines. 10-year-old, blurry vision since she was 4 years old. Describes broken vision. Some night vision problem. But not so significant. No hearing loss. Review of systems unremarkable. Basically, unremarkable pedigree as well. No other family history of note. When we do down, see she’s 20/31 and hand motion in the other. And right there, I’m saying, is this genetic? Because genetic disease is often symmetric between the two eyes. Everything else is normal. And I’ll get back to these genetic testings later. But she did a wide panel and a bunch of stuff came back. We’ll get back to there. Let’s look first together at this. Here is the patient’s eye. That is a pretty remarkable fundus. Some attenuation of vessels. The kind of pattern of atrophy is a long, vascular tree in multiple directions. There’s some pigmentary disruption elsewhere in the fundus. If we look at the other eye, we see more of a diffuse pigmentary retinopathy. Involvement in the macula as well. Again, vessel attenuation, which tells us the retinal photo receptors are involved. If we look at her OCT, it’s a little small. But we see the loss of the outer nuclear layer there. If we look here, we can really dramatically see in the fundus fluorescence this black area with a hyperautofluorescent ring corresponding to the findings in the fundus. And other information was provided for the sake of time, I’m going to skip over except to show you this fundus image right here. And you can see the pigmentary retinopathy. Let’s look at the gene test results. Then we’ll go back to the question. You did a big panel. You get a lot of variance. Variance of unknown significance. We don’t know what they do. Two in the same gene. One in another gene. One in the gene for Usher’s syndrome. But the patient isn’t Deaf. Type 1A, recessive disease, we’ve got one allele, not the other copy. Maybe just a carrier. So, let’s go back up and see what’s being asked. They identified the genes, insignificant, did not seem to match the phenotype. He’s absolutely right. The asymmetry of the vision between the right and left eye is significant. Absolutely right. Also known as a prominent retinal change along the vascular arcades. Should we consider other conditions? In other words, is this even a genetic condition at all? I chose this case because it demonstrates that it doesn’t have to be a genetic condition for you to put in a genetics consult if genetics is still in the question. That means genetic testing was done, what does it mean? And I wrote back: The striking asymmetry tells us this is almost certainly not genetic. Two eyes look very different from each other. Etiology such as infectious, immune or vasculitis, vascular, are much more likely I would suspect in an otherwise well child that it would be difficult to find the cause. Perhaps a basic rheumatology lab panel. And tests for titers for common cause of infectious retinitis in your country might be useful. I agree that the genetic test results are mismatch with the phenotype and likely reflect his chance of finding such advanced disease a person who has a large enough test even with those with normal exams. And to the last question, asking about other family members, I would not worry about testing other family members because the gene tests are to the important in this case. At the very most, although there’s an absence of family members affected, any family member with unexplained, uncorrected vision loss should be examined. It came back negative, it’s asymmetric. It doesn’t look genetic. Let’s give up on the genetic idea and go forward. She writes, and here’s the dialogue. In the case rheumatology tests come out unremarkable, would testing for autoimmune retinopathy be considered and could I see how they could access it? I write testing for retinal antigens is challenging. High false positive rate. Cancer-associated, melanoma-associated retinopathy are extremely rare in a child like this. Even autoimmune retinopathy are rare. Fundus changes are atypical. Suggest observing every 6 months for a while to study if any progression may be more helpful than retinal antigen testing. We took a case that was thought genetic, genetic testing, stuff comes back that’s not related and redirecting, reflecting, this is not genetic. I think this is some other systemic disorder. vasculitis or immune-related. Let’s do the appropriate workup and follow the patient with a differential diagnosis suggested. Go ahead, Hunter.
DR. CHERWEK: That is great. And Dr. Shetty had a question I was having. I think this is not genetic, but is rubella retinopathy in a differential diagnosis? If you saw in the Orbis or in clinic, would you include rubella retinopathy in the differential diagnosis?
DR. LEVIN: A very timely question. Not just around the world, but in the United States where vaccines are being eliminated. You’re going to see more and more rubella. And call attention to one of the things I wrote in my reply. And titers for common causes of infectious retinitis in your country might be useful. So, when we’re thinking about immune-related or infection-related diseases, each country has its own commonalities. And I would definitely put congenital rubella. The problem is that congenital rubella retinopathy in my experience, and granted, I see a lot less than some people in this call do, doesn’t occur that often in the absence of cataract or congenital delay. You rarely get the syndromic of rubella syndrome with just this. That’s less likely. Just looking at it, could it be possible? Sure. The kid is little bit old now to make a titer-based diagnosis. I’m thinking that’s less likely. And look locally at what is common in your country to arrive at the appropriate workup.
DR. CHERWEK: That’s perfect, Alex. And I think we’re ready now for case number four.
DR. LEVIN: This one comes from Thailand, a former fellow, Dr. Wangtiraumnuay, a wonderful geneticist. What we are doing with Orbis, visiting countries to do a hospital base program. Many are familiar with the flying eye hospital, we do surgery. But we made our first ever hospital genetics ocular-based program. Where we went to Thailand and my genetic counselor came with me and we spent a whole week seeing patients, doing consults, teaching didactic genetics and working with the community to develop resources for genetic testing. So, that’s another thing that’s available through Orbis to interested companies. Countries. This is a 3-year-old child. Difficult seeing objects in low light for the past year. And looks at things close. And poor sight at night. Otherwise healthy. Family history unremarkable. Vision, you can see, she’s got unsteady, poor fixation. The rest of the anterior segment examination is normal, but subretinal fibrosis in both. Show you these pictures, they’re quite dramatic. We have this pattern of subretinal fibrosis. That’s pretty striking. Very symmetric between the two eyes suggests a genetic disorder. What could this be? And we look here. We can see on OCT these patches of subretinal fibrosis. Notice the photoreceptors are pretty on the nuclear layer, and peter out over here to the left as well. And she tells us, the genetic testing — so, they already did genetic testing, and you do not have to do genetic testing to get a Cybersight Consult. Came with two pathogenic variants in this gene, PNPLA36 compound heterozygous means there’s a different mutation on each copy of the patient’s gene. Here’s what I wrote, the symmetry of the two eyes certainly speaks to genetic disease. Subretinal fibrosis can lead to the gene — I listed genes which are known to be characterized by subretinal fibrosis, one of them is this gene. That your genotype matches the phenotype, increases the certainty that your genotype is correct. In other words, you got the right disease on your test. And they tested using a panel or a whole exome. If the patient has two different mutations and support to test the parents to ensure that both mutations are actually on opposite copies of the gene. Because if they’re both on the same copy of the gene, for an autosomal recessive disease, then you’re missing the copy on the other chromosome. And sure enough, if you test the parents and each one carries one, then you know that the patient’s got different mutations on different copies of the gene. And then I go on to write the PNPLA6 often presents with chorioretinal dystrophy with a systemic condition. And I list the diseases. The reason we do genetics testing, look for ataxia, paraplegia, short stat cure, polyneuropathy, and developmental delay. Your case illustrates the importance of genetic testing to inform you as to what systemic workup is needed. I would suggest a neurological consultation. This gives a look at the testing that was done. But the question is: Do the results match the patient. After genetic testing, always go back to the patient. And sure enough, this is a match. This is what the disease looks like. The gene testing tells us what else to look like, test the family members and so on how this disease affects the family. Take that away, Hunter.
DR. CHERWEK: No, that was fantastic. There’s a question in a chat. How do I explain to a patient why peripheral field loss in RP feels different than glaucomatous field loss? When you have a patient with retinopathy pigmentosa, and trying to explain cataract or peripheral vision loss, how do you use the visual field to educate the patient and the family? And how do you differentiate that from glaucomatous field loss which can have segment or segments that are not necessarily that of RP? How do you differentiate and educate the patient and the family there?
DR. LEVIN: That’s a great question. Keep in mind, having a genetic disease like retinopathy pigmentosa does not make you immune from disease. Common things happen commonly, and rare things happen rarely. Glaucoma is rare, this is one in 4,000, but they still get Glaucoma. Be on guard for the cross-over of diagnosis. And obviously with glaucoma, taking the pressure and you have other signs of glaucomaous change in the optic nerve that helps you sort out one from the other. But the field loss issue is difficult. And there are characteristic ways that the field is constricted in one versus the other that help you to differentiate the two. For example, in RP, you get a central isotropic constriction, often with a temporal island of field that’s left. The progression is the centralized opters constrict. You get a donut scotoma and last lose your temporal island. That can help you. I often use the visual field — we use Goldmann Visual Field, I know are not available in many countries, but are best for these diseases. I put the field up, and look at the patient. Say it’s a driving question. Here’s your field. Both eyes open. And I draw on the pedigree. Here is a woman pushing her baby carriage and she gets to this blank spot in, you don’t see her. You kill her with your car. I use that to help patients understand what they’re seeing and its impact on their safety and the environment around them. So, the field could be useful, not only to make a diagnosis by watching patterns over time, but also in explaining to patients what’s going on and why they see what they see.
DR. CHERWEK: Alex, two other quick questions I would love for you to address. One is about RP, and one is a more general question about genetic eye diseases. For RP, is the X-linked RP fast, worsening, or more rapidly progressing than the autosomal recessive? Talk us through briefly, I know we have one more case to go and limited time. If you could talk about the different types of RP with X-linked and recessive, and then one more question before the next case.
DR. LEVIN: And by the way, you can ask questions like this on Cybersight in a consult. But yes, X-linked RP is more severe. Earlier onset, more progressive than some forms of autosomal recessive RP. Now, there’s well over a couple hundred forms of RP. And all separated by different genes and each family. Different progression. Some other forms of RP are very aggressive. Early childhood onset RP. Others are slower. There’s autosomal recessive RP that’s late onset. So, it depends on the genotype. What I would say is if you see a male with pearly, progressive, classic retinitis pigmentosa, it’s due to the mutation of the RP gene. That can help you narrow your phenotype. The pedigree, the history, narrow down gene suspicions and give more genetic interpretation. And the other question?
DR. CHERWEK: Yeah. And the other question is a little different. This is going through your differential diagnosis and how you think of these cases. Must genetic defects or do ocular genetics diseases have to be bilateral? Are they always symmetric? Are they always bilateral? Or can you find presentations where there’s asymmetry or even a unilateral presentation?
DR. LEVIN: The answer to any question that asks something if something always happens is always no. Because there’s nothing that’s always true. And there are rare cases of unilateral aniridia, unilateral. From mutations that occurred just in the one eye as opposed to in your bloodstream that affects both eyes. So, yes. The symmetry paradigm that we talked about today it not a be all, end all. Sometimes we have asymmetric disease. Sometimes we have unilateral disease. Cataract, posterior lenticonus can affect the family member in one eye. There are many reasons this may occur. We’re doing research to try to understand that. But it doesn’t absolutely rule out genetic disease. And we have to keep a broad differential.
DR. CHERWEK: And then the last question, Alex, is a little more different. With climate change, environmental changes, do you see any of that stress — let’s just call it a diathesis-stress model, an underlying genetic condition? are you seeing more and more genetic diseases because of mutagens in the environment in your career, or even in utero, there’s not a clear case example of environmental health issues causing a genetic disease?
DR. LEVIN: Let’s first take the premise that everything is genetic. Every disease in ophthalmology is genetic. Even trauma is genetic. Response to trauma is determined by our genes. How we heal. The environment does affect our genome through a process called epigenetics. Some of that is permanent changes, some can be transient changes on the genes. I don’t think I’m prepared to say there’s been an overall change in our epigenetics influenced. But it’s happening. One example may be autism. The incidence has gone up very, very high. We know there’s genetic factors. People are very interested in what environmental factors may be contributing. We don’t know the answer to that. It’s led to a lot of political controversy. But yes, the environment does impact the genetic fate of humanity. And how that’s gonna play out is yet to be seen.
DR. CHERWEK: Yeah, they’ve shown how much the environment is gonna a health crisis for the generations ahead of us. And I think it’s an important question. That’s why I wanted to ask it. I certainly want to get you to your last question. You have been answering the questions, a lot of compliments on your glasses and compliments to this webinar. So, keep going with the eyeglasses and the cases. I think we’re on the last case presentation. But you said it best, Dr. Alex, if there are more questions, if you, the Cybersight community, are in your clinic and would love a second opinion like Dr. Alex, submit an E-consult. And Dr. Levin has done dozens over the past few months preparing for this webinar. I’m sure he would love to see the complicated cases in our community. And the last case from a former fellow.
DR. LEVIN: This is from India, Dr. Chattannavar runs — and a wonderful geneticist. You cannot send us too many consults. You can send us thousands and we would be happy to do them. That’s what we’re there for. We are dedicated to do this for every country on the planet. And we realize that we can’t make enough ocular geneticists to populate every country. But we can offer resources to help fill the gaps. And everybody sees genetic disease every day in your practice. And many questions you go home with at night, you could take 5 minutes to put in a consult, pop in some images, and get information back within 24 hours. This is a way of filling those gaps. She tells about a 1.5-year-old, kid, a boy. Eye poking behavior since birth. Otherwise generally well. Another key feature. Nothing in the family. No consanguinity. But they belong to the same community. And that constricted gene pool we were talking about earlier. We see poor fixation and following in the other eye. He’s a 8 diopter hyperope, and we’ve got myopic. We’ll look at the pictures. We’ll get back to her genetic testing in a second. Let’s look at the fundus. What do we see? Kind of an RP picture. We’ve got these mid-peripheral spiculate pigmentary changes. Definitely retinal vessel attenuation, especially for a kid this young. Macula looks pretty good. Maybe some crinkling of the internal membrane. Reflex, representing perhaps some surface gliosis. Something we see in patient’s juvenile retinal dystrophies. And test results come back and here’s what she writes: The genetic report identifies two variants in this gene, GUCY2D, often called juicy-2D in the proband, this heterozygous, likely pathogen pick and a duplication in the gene that causes the gene to be misread, also heterozygous, but if it’s of unknown significance. I know I need two copies — two copies of the gene we mutated and one is not a slam dunk pathogenic. What do we have here? Tested the parents, a brilliant geneticist. The mother who has nothing has both of these variants. The father has the other variant. So, in other words, this variant here, each parent has a copy from the same community. The mother also has this one. But the mother doesn’t have the disease. What’s that tell us? That mean she’s got these two copies on the same chromosome. And the patient got a third copy from the father. Pretty complicated. So, she’s saying, since the mother carries both variants and the father carries only one, we are currently unable to determine whether the two variants in the proband are on the same chromosome or opposite chromosomes. How are we gonna prove that? In other words, did the patient get this one on the same chromosome as this one, or did the patient get it on the opposite chromosome from dad? Hm. Should we determine whether the two variants in the proband — I’m sorry, should we consider segregation analysis of other family members to see which these chromosome these copies are on? And then there’s also a variant in another gene, CRB1. Phenotype doesn’t fit. Can this be ignored? And there’s a variant in the LDLR gene. We’ll talk about that and what is the recommended approach for managing incidental finding. What do you do, and the all the of the testing is done, the whole exome, that’s just the way it is done there. Working with them to study if we can change that. But when you do that, you’re gonna get other stuff, right? What I wrote is I agree that GUCY2D is the most likely cause. In other words, that’s the disease. The phenotype matches the genotype. So, we can highly believe the genotype, but we need to prove it by showing that the mutations are on different copies of the gene using other family members. If her variants are in opposite copies, this would rule out this gene as the cause. Okay? In other words, if the mother — I’m sorry. If her variants, meaning the mother or the child, are on separate copies of the gene, this would tell you that the gene is the cause. Essentially, fundus tells us that the mom having it on the same doesn’t matter. Large panel exome testing is a high likelihood of turning up unrelated variants and incidental findings. It’s a recessive disease, and requiring the other variant. And the phenotype doesn’t matter the kind that it causes. It usually has a macular lesion, intraretinal cystoid spaces and pigmentary changes. The LDLR variant as this is an finding, is actionable. That happens to be a cholesterol gene, right? Has nothing to do with the retina. But it’s important because if this kid has high cholesterol, then we have to deal with that because we don’t want this child to have a heart attack over time which is associated with LDR. Now we’ve got an accidental incidental finding. We want to tell the patient about there so we can take the health interventions it prevent subsequent disease completely unrelated to the retinal findings. When you do whole exome or whole genome, there are 74 genes which we are obligated to tell families like Marfan and whatever, unless they sign off that they don’t want to know. That’s the reason we have to do genetic counseling before testing. So, parents know what might come back. And they have to decide whether they want to know that information. If this parent said they want to know this information, here’s an incidental, unrelated finding that has great systemic significance that we would need to take appropriate interventions so this kid can be treated for that as well. So, we learned something that we didn’t expect that’s important for the family. So, just in summary, this is a case where we had a phenotype done well, a wide panel, we got a genotype of unknown significance or some complications and make sure it’s correct. But it sure sounds correct. And some incidental findings that we can rule out. So, before I take questions on this last case, I just want to add that, you know, one of the things that are important to put in when you do a consult? Number one, we want to know the basic demographics. Age, sex, and the history. How did this happen? What were the symptoms? When was it noted? Number three is complete the phenotype. With not only the — but the systemic features. Is there anything else going on with the kid? And number four, the family history. Or at least is there consanguinity. Whatever you can give those four things. And lastly, if you have DNA, great. If you don’t have DNA, don’t worry about it. We can sort out the problem without that. So, you don’t have to put in a Cybersight Consult with all this highfalutin — these were four consults put in by really smart geneticists. They still needed help. That’s okay. You can know nothing about ocular genetics and we’ll teach you ocular genetics through the Cybersight Consult process. That’s the whole reason we’re there and happy to help. Hunter, over to you.
DR. CHERWEK: I think you ended perfectly, Alex. Obviously, I think you went through some cases to show people how you think. What information you would like to have on cases. There are some small questions which we’ll get to. And we can answer offline. I do want to remind the listeners and people on the Cybersight Community, if you’re interested in learning more about consults, there will be a designated webinar November 10th. I certainly want to thank you, Dr. Levin, for joining us today and all that you’re doing around the globe for ocular genetics. Is there anything else you want to add? I know there’s a few things in the Q&A, Alex, we’ll take those offline. Is there anything else you want to conclude with today?
DR. LEVIN: To take those questions offline, anybody can send me an email. There’s great questions about unproven supplements and CMVs. My email —
DR. CHERWEK: Let’s have them contact you through Cybersight Consult.
DR. LEVIN: Perfect. Great idea.
DR. CHERWEK: Yeah. Let’s do this. Obviously the whole point of today was not to answer every single possible genetic testing or, you know, every possible scenario with every possible disease, it was to let the Cybersight Community, especially those who are seeing a lot of interesting and complex cases, to let people know about the IRD, the inherit the retinal disease and the ocular genetic consult service, which you lead. And certainly I encourage anyone after this webinar to go through the chat and make sure you know how to submit consults. And if you have further questions for Dr. Levin, we can certainly get those to him, okay? Alex, anything else you want to say? Obviously you’re getting a lot of compliments. I like this format where you’re taking real cases, real challenges from around the world and answering those. Are there any other things you would like to say before we wrap up? Had
DR. LEVIN: I would just like for all of us to recognize Hunter and all the amazing work he does for Orbis. There’s a whole wealth of information out there. Orbis is there for you. It is free, f-r-e-e — everybody looks free. And there’s no better way to get information. So, please use it, pass it on to your fellows, your residents. Pass it on to your ophthalmic nurses and techs. Even your bio med, there’s something for everyone out there. Dr. Dan Neely needs to be recognized as kind of the person after Eugene started Cybersight. And COVID helped us and we got up to well over 110,000 users. There’s plenty of room for everybody. We encourage you to use it. Thank you, Hunter.