 So the main thing I want to talk about is why do we need inherited retina disease specialists? Okay, and why so why am I why was I when I was recruited here 24 years ago that that was one of the main things So that was brought on so why do we need it Chris you're in the service now, so why? well one reason is because there's you know Implications for future generations Definitely planning another reason so why doesn't an academic center where we're supposed to be a top-10 center Why why would you every top-10 center have? Someone should have someone They're relatively rare or many of them are quite rare. So it's general ophthalmologist Practitioner didn't necessarily know much about them. We know how diagnosed them So it's helpful to have a referral center where you're for everything. That's odd Yes, you have to have someone who is somewhat knowledgeable any more reasons. There's actually quite a few another reason is that One you know a lot of people going into say comprehensive ophthalmologist Ophthalmology, I mean they're doing that to see patients to do surgery generate all that and these patients Don't generate that so you need you know They want to have a referral center that they can send someone there and so to talk about to talk with the patients these patients Take as Chris will tell you sit on the service take a lot of time They have a lot of social issues. They have a lot. They need counseling. They'll bring in the whole family They've been bounced around from specialists to special or from ophthalmologists ophthalmologists through all this process and so they They need someone who will actually talk to me and that Can mean and it's really it's a little bit more counseling. It's a little bit more oncology Psychiatry a lot of different things now There's a lot of science and ophthalmology going on too, but you have to have someone who's willing to do that and to kind of And to and to work with these patients and so there's for retina does for inherited retina disease specialist There's several different models. There's some if you go to some centers, and we don't have this that's all they do You know, they see they see patient after patient with this they run the ERG service They run the genetic service. They run everything you have to have a that's pretty specialized There are some centers that do that but not but you have to have a lot of patients coming through and it's also Kind of hard for the retina specialist for an inherited retina disease specialist because you're gonna see how many you're gonna see six eight patients in a half day, maybe six, you know, they they don't see a lot of patients and These are you're you're giving a lot of bad news in general. So you don't want to do that all too much You can also have models like mine where I do retina I know a fair amount about red inherited retina disease, but it's not my only practice. And so And I've learned through the years That you have to control your practice with that And so when you come on to the retina service, you'll see I have if if they actually followed my schedule I have one in one new inherited retina disease spot per half clinic Basically and because unlike, you know a quick new retina patient you can see in five or ten minutes I really need a half hour or so of my it'll end up eating up a half hour of my time They're here for a huge number of testing which we'll talk about a huge amount of testing coming through and It blocks up the clinic if you if you get three inherited retina new inherited retina disease patients in a row It's just going to destroy the flow of your clinic And it's so I try to do that now They're always sneaking in patients so that either they're misdiagnosed or there's something There's some there's always some excuse why you end up with two or three in my clinic And it's just and you just have to deal with that the And the so and then the other thing that I kind of insisted through all this We'll talk about it a little bit more is that I needed help just in seeing the patients and follow up and by having someone By having a genetic counselor, you know, it was And she's really a good resource if you have any projects that you want to do she really knows her stuff She's got a good database for all these patients But I needed someone who I can say why when I talk to the patients and say you need genetic testing We are going to do the new tests here I needed someone who can actually get proper consent can kind of go through in detail answer their questions And then even more importantly do the follow-up because you order these tests you draw the blood and they may the results may not come back Now I will they'll come back within two or three months It'll take a little you know, but they're not going to come back right away But someone has to track all these if you talk about 10 15 years ago. I'd ordered genetic testing and say well especially with hygiene Sometimes they've never ever come back the results when you know, they just or they come back three years later And you'd have to do follow-up and so that that didn't work on that. So having a genetic counselor is very important the the other things to have a for retina disease specialist is they these patients aren't very interesting in the biochemistry and the Pathology that you'll see and that we'll talk about today is very interesting and through the the last couple decades We've really learned a lot about the basic biochemistry. We can start to think about interventions We can genetic testing has changed dramatically from as I said before no genetic testing genetic testing in a couple to research-based genetic testing To genetic testing whenever it comes back Yes, we'll get something back and there's a more than 50% likelihood We'll know exactly what's going on and then you have to of course discuss why we're doing this and then finally The with clinical trials. We do have clinical trials there I'll talk a little bit about what is coming up for some of these diseases. The problem is as Is that there are too many genes too many genes? There's too many targets now for what we're doing. Okay, so does that make sense in terms of why and then of course You have to learn some of this stuff for the boards and you'll just you'll see I'll flash some pictures of course in your in your Your books you just have to learn there's some things I'll highlight a few diseases that do show up on the boards and some that never will and It doesn't always correlate with what you'll ever see I'm going to talk about diseases that I have never seen in my life You know these patients have never shown up, but they're so characteristic and they were described so many decades ago That they are that they're expected that you know them, okay? so The retinal dystrophy is that I see coming through my clinic Very you know are quite wrong quite wide through all this So you've got the classic one is going to be retinitis, which is shown here as a kind of classic slide here You're going to see syndromic patients in my clinic not not an enormous amount But you'll see some and that and these syndromic ones basically mean that there's that the mutations that are causing these problems Not only affect the eye, but cause other problems elsewhere in the body and of course with With one of the reasons why why there's so much genetics known about this is that There are syndromic cases, but I'd say the vast majority of the kid of the case through to see are isolated to the eye So these are healthy people that have lived long enough to have kids and keep passing these genes through various generations So you still see them we can study them in exquisite detail because usually They're there for there's something unique about these genetic defects that are targeting the eye And we need to understand why and we can try to figure these out and treat them and if you can if we can Get things under control in these patients, and I'd say it's still very rare Then you know they can have otherwise good lives So you have to this is something that's a good target to try to to try to improve their lives and then As I think Nico has presented in one or in a previous Grand Rounds Some of these are stationary retinopathies. And so what stationary means they look bad. They have some visual defects, but They aren't going to get worse. That's the problem with the most of the patients that we see with inherent especially inherited retinopathies These are not going to get better. They're going to get worse and you're trying to counsel them But there are some that truly will never get worse And I've caught several patients over the last last few years young kids you know teenagers that have been identified as having inherited retina diseases and thought that and misdiagnosed as retinitis pigmentosa and they're learning Braille they're doing cane training They're going through all this stuff and told them that they can't do things and then they turn out to have a stationary retinopathy That's not going to get worse. I can definitively tell them that genetically and say Just get on with your life. If you if you're doing okay the way you are and most of these teenagers Yeah, I can't have some problems, but not that much And don't don't be worried about going totally blind Then of course we have other other diseases cone dystrophies that are going to be more affecting the macula than the than the Perforal retina you also want to pick up any toxic retinopathies There are a few out there and we'll talk a little bit about those and then of course pseudo retinopathies Which aren't even retinitis pigmentosa. They're old and burnt out inflammatory diseases or other things so But when you see in my in my clinic you're going to see patients always coming through with retinitis pigmentosa and the The estimated prevalence is really pretty good at one in one in three thousand So if you think about there's 300 million people in the United States, there's a hundred thousand people with this disease Now that makes this an orphan disease and why is it an orphan disease? Well, do you know the definition of what an orphan disease is? Think I think I'd still know it think it means that there are two hundred thousand people or less in the United States with the disease And that that's an important thing because an important designation Because for the FDA and drug companies, there's a lot of incentives for to develop diseases for orphan diseases they get fast-tracked they get all sorts of monetary incentives of their first to market and probably and I and retinitis pigmentosa was probably very Vocal community, and I think they were part of the part of getting this established in the federal government to do it this way And that's probably where the number two hundred thousand came from because if they put it a hundred thousand people would be arguing Well as RP an orphan disease or not, but if you set the number of two hundred thousand and retinitis pigmentosa is It fits into the category now With RP as we'll learn is it's it's very common It starts out patients when they're younger and classic RP have pretty good vision You know when they're in teenage years and they're young adult years, but as time goes on and the vision constricts Eventually they will go legal blindness and become you know become have big problems But that's very compatible with that time course of classic RP That you can be very successful in industry You know be a captain of industry be make a lot of money and then eventually you run into big problems And so when I deal with people at the when I talk with people at the retinitis pigmentosa foundation some of them surprising number of more billionaires you know that have had That have made it through you know done very well in business and now are going totally blind and they they have You know through the years if they're billionaires they've learned that in business money solves everything In medical research it doesn't solve everything of course, but they so they're an interesting kind of cohort to deal with They have a lot of very high expectations Often over expectations than me But they are on the other hand willing to fund a lot of research for this the there's a large variety of inheritances the clinical course and genetic causes are diverse we'll call it to cover that in the next slides and Unfortunately, there's only limited Clinical interventions, so the next slide I won't put up yet, but what is someone with RP? What are the classic symptoms that they're going to have and what are what are the chief complaints the patients are going to come in with? One night vision or night vision is almost always the first thing though if you take the history They say when I was a kid. I didn't see as well as it as anyone else. So that's correct anything. What next? It's more advanced you're going to get like decreased visual acuity as well with some peripheral field changes So you get like the ring skatoma, right? So even so the acuity is often late in classic RP That stays pretty good. They can still read, but yes They will start noticing constriction of their visual field They have like CME right so CME and that's important. We'll see that in the next slide that CME is important because that's potentially Okay, so that's that's correct and You know eventually if they have it long enough, they'll have no light perception other problems the So those are are truly those are the main things that you're going to see progressive visual field loss Exactly what we said right here. That's going to be the main things that they that they talk about and the They may have a family history so they may know about it. They may not they may be able to do You know function pretty well Some people can be and the onset I didn't hear age and that's you know, there's classic ages But there's a huge diversity in in RP. There's something you know, well There's some where the kids are debilitated in there You know when they're five years old, but I I diagnosed RP You know not infrequently in patients were 70 80 years old or who are doing Functioning pretty well. I've got gotten again high very high level jobs But are now starting the visual the visual field starting to constrict in and they're starting to have problems So one of the ones that probably the more one of the more disturbing ones that I diagnosed was someone who came in Who was a commercial airline pilot? Okay, and so he Made it through and you'll see this even at the VA here. How did these patients get in to be become soldiers? eyes and With the commercial airline pilot. What do you think his chief complaint was when he came in? Yeah, but in doing what function do you need a lot of peripheral vision to fly a plane? Right even that didn't bother him so much But yeah for when you fly a plane you're looking straight ahead. You got the gauges. They're all really bright They're all close to you and you don't even look to the right or the left You're looking straight ahead. You got all this so his hardest thing to do was walking through the airport terminal Okay, when you go through the airport terminal people are coming in darting in front of you from the right and left crossing there And he was bumping into people while trying to get to the plane That did not inspire a lot of fun And his field was bad enough that I said you can't you know There is no way that your employer will be happy about you're flying so But he made it a long time. He was in his fifties by this time I was surprising. He didn't seem to have any problems flying a plane at night either Anyway Yeah, a lot of it a lot of it's automated, but I think he learned anyway Okay, so that's those are the symptoms now. What are the signs? What are you when you look in on these patients and occasionally they have no symptoms at all, right? So what do you see that's going to tell you I think this is RP. What are the classic signs? Okay bone specules are classic. Yes, what else? Raterial attenuation and optic nerve like a waxy pallor. Those are all the classic descriptions. Yes Sometimes there's vitreous cells just debris that's floating around in the eye What about an anterior segment anything that you might that is common not gonna be diagnostic Rare where I see You see cataracts are common and we don't know why they get that but they do get cataracts anything else We already mentioned CME So I think we got most of them. We'll see bone specules peripheral retinal atrophy just in general You have waxy pallor of the optic nerve attenuated vessels vitreous cells both psc. So you got most of them there right there and then the macula is relatively preserved So that's but this is again classic and you're gonna see but not all these patients present classically and they're gonna be all sorts of exceptions and then you've got the patients so they've been referred in from the outside and What diagnostic tests are you gonna do and this is where again? I run my clinic and Chris will know all this I've got kind of a standard protocol at the patient if they come in an inherited retina disease spot They have a bunch of testing before I've even seen them and that's another reason I don't want to have too many patients because this is Almost as bad as neuro. It's a couple hours of testing They have to go through before they even see me So if they and so I don't want to have too many they got that's my my inherited retina disease New patient slot is always early. So what do you what are they gonna have done? They'll always have an OCT why are you getting the OCT well, they may have seen me we want to know that To you can actually see some of the atrophy and we'll talk and what else so OCT everyone gets an OCT ERG they'll be scheduled for that I like getting an ERG just it's diagnostic it can't it unfortunately goes bad early in the disease So it isn't always good for following them, but I like to have patients that if they're Truly coming in with RP or similar conditions You want to be you want to do at least a baseline ERG if you can get them to do it. So that's they'll be scheduled for an ERG That's correct. What else? Visual field is very important. What kind of visual field do I order? Goldmine, yeah, they because the standard Visual fields that you see in glaucoma are only going out 30 degrees We need to I need to know the whole field going out way out. So visual fields are very important Auto fluorescence, let me just step back with the visual field So the goldmine we do have automated octopus visual fields that are wide field to the octopus 900 The problem with that is it takes forever to do and the techs hate it the patients hate it It's actually probably faster to do a goldmine manually to do it. The other reason that I do a goldmine Is it's required for driving and especially when you get teenagers or even adults They have to get re-certified for their driving and if they don't have it done Then and they and they need to have it done binocularly at least with the three four e That's what I need to know for driving. And so I really am very insistent and they still Disregard me. I'd say one percent of the time and don't give me a binocular and I send it back the other thing that Just in personally the way that I do visual fields is There's so much worry about flow in my clinic to get these patients through That I don't care if they're dilated or not I know you're taught do visual fields when they're undilated but for my clinic and for following these patients I don't really care and I try to emphasize that just to get a visual field in and get it done I'm willing to to say when they say when they're backed up because otherwise they'll wait and sit there undilated for two Hours waiting for the goldmine field and I'd rather have some other tests done The the autofluorescence the color photo is all the other things so Autofluorescence yes, and that has to do somewhat a little bit more research than clinical than clinical management But it is it can't be a way to follow the disease So the autofluorescence is true I'll get a flio just because we can do that and we're following following them I'll get a macular pigment just because again. It's a research Tool, but and it can be useful for future studies that I'm doing It also gives you some idea of the of the health of the retina because Especially in classic RP the macular pigment is actually preserved pretty well Okay, so what else any other tests that you want? Like that's most of it Okay, and that's so they're gonna have all this battery of what I call non-invasive testing coming through They will and then when they by technicians should be at least getting the clinical history How long they had this what is the family history is very important? They need to have a dilated retina examination and Photography and they also are going to get color vision is very tends to get forgotten in my clinic But it's important to have the electroretnography I often save until after I've seen them just because it takes so much time to Get that arranged OCT and then in the end my my genetic counselor will meet with them Or if she's not available, we at least draw the blood and say that they will they will be coming through So that's that's enough to keep them to keep a patient busy through an entire half-day clinic that's that's plenty right there and Of all these things that we do I think the visual field testing is the most important for following patients and so this See if I can do this right Yeah, so you can see this is this graph is just showing how a Visual field can progress from 20 years to 50 years you know to just a tiny visual field But potentially this patient at least at 40 or 50 was could have been potentially 2020 still here and still able to read but not able to function with that without the visual field and then with that visual field in terms of mobility and then of course They'll get a an electroryptogram and Don Creel is much more of an expert than I than I would ever be but you know We're looking at Unfortunately with RP. They'll have just a flat flat scotopic ERG the cone flicker will be attenuated and Delayed in various other things and you can distinguish it between cone dystrophies Stationary night blindness is of course very important to distinguish because that is stationary and all that so but I get we get that and then Then we work on the genetics and the genetics of RP comes in all different flavors. That's the that's the challenge with this disease So you've got dominant or excessive excellent mitochondrial everything has been described and so I I don't have time to draw a whole genetic tree like this my genetic count Emily will and we'll give some You know and so you can figure out this one clearly is these are examples of dominant disease here and so Dominant is fairly common 20-30% of patients will come in with autosomal dominant disease and It's it's important to know that dominant is one of the more mild forms of RP and so usually They then that can make some of the the genetics a little bit challenging because occasionally You know, it's dominant someone is an obligate person should have the because they have children with the disease They have parents and siblings with the disease and they say I do just fine And that's sometimes because they truly are fine But usually they just have such mild disease that they've adapted and don't seem to have any problems so it's later onset milder variable penetrance and Commonly the and the reason why this is important is the first gene for RP was radopsin, you know found in the 1990s And so and that makes sense. It's it's a unique photoreceptor specific protein It's dominant in some way. It's not clear why it should be dominant But the reason why it's dominant is often some of these compounds are some of these mutations cause misfolding of the protein and with misfolding they then They then start accumulating abnormally in the cell and eventually the cell dies So that's that's the one that we see the most we got very excited when this first happened that we're going to figure out You know that ever that this was going to be the major gene and we can treat this the problem is It's only it's one of only many many different genes And we know that dominant can also be RDS peripheral and we see that quite a bit Which is another structural protein in the cell and the important thing about RDS peripheral is that it can look like anything It can look like classic RP. It can look like macular dystrophies. It can look like pattern dystrophies So it's a little more complicated, but it's reasonably common And then a number of them are ciliopathies that have to do with the cilium structure of the photoreceptors They can be RNA splicing factors, which doesn't is not totally obvious Why RNA splicing factors which are found in every cell in the body But if you have a defect in this only the eyes affected and basically it says that there's no backups in the eye the photoreceptor is such a specialized Specialized cell that it doesn't have backups that a norm that a regular cell would have that can take the place of the defective protein And as I mentioned, there's a lot of protein misfolding in misdirection Recessive is the next one. It's I would consider it relatively uncommon here in Utah at least And that's because we don't have a lot of despite our reputation We still are not a consanguine as population here in Utah with the Mormon population. They're diverse enough and But in cultures where where they are where first cousins are marrying a lot or when I was in South India last year Where a very desirable marriage to keep the money within the family was to have a niece marry her maternal uncle was it's just way too close and you get a lot of you know, a lot of Unusual rare autosomal recessive diseases and they are often severe early onset and The ones in the consanguine as population are going to be primarily You know are going to be homozygous mutations what I see here in Utah on these recessive diseases They're compound heterozygous, so they have mutations in the same gene, but different mutations. So the parents are not related One of the more common ones that we see is labors congenital amaurosis, but you're going to see that in the pediatric clinic They are severe early onset and many of these are going to be mutations that are Enzymatic somewhere in the visual cycle and the classic one for labors congenital amaurosis is rp65 and why is that important? Yeah, we have a treatment, you know it is the problem is and you can see if they picked a disease that's just plain too rare I Have I do genetic testing on all my patients I have exactly two patients with rp65 mutations and both of them are in their fifties Now it totally burned out. So they they would not benefit from the million dollars of gene therapy So you want to catch them when they're very young But in our population is there's just not enough here. And so even though they're charging $420,000 and I the company's never going to make its investment back Even at that price because they just picked something that's that's too rare But and it may be diagenic, but you know these patients Are severe the patient the two patients. I have saved rp65 mutations One I saw recently and he is literally the first patient I saw when I started practice here 24 years ago and He you know he was 20 years old then you know could read a little bit then Got himself into law school became a lawyer It's still practicing as a lawyer with with essentially light perception vision So he's intelligent functioning as best can the other one is an Iraqi refugee who's Consent, you know definitely from a consang with his family and had you know was just too far along But she had but had several siblings that were affected Then you're going to have x-linked rp. And so that means males are generally going to be carriers Are you going to be affected females are carriers? This can be severe And they but it or they can be laid on set You know there's a lot of different ones the one that's shown here if you see this on the boards What's the answer for what this is? That's coroed oremia you need to the reason you see this as you can see that the court doesn't look like classic rp Does it right? You just you can see the coroidal vessels. They're severe atrophy And they'll have kind of clumped pigmentation round clumps of pigment rather than bone spicules So it's a little it looks different They can also be due to rp gr And that's more that gives you a more classic rp. These are important one because they're fairly common To because they are x-linked they often come in with a whole family history It's known and so the family knows not only do you know if you diagnose someone with this disease But they know they know that their uncle or whoever you know They know what the natural history is in the family and they're worried that they're going to get You know that at that age 50 they're going to be Severely blind too And the other thing that's important is this is the next the next frontier of gene therapy A lot of them we are part of the natural history studies for both coroed oremia and x-linked rp Where we're bringing patients in you'll see them in my clinic. They come in every six months Which is way too often for an inherited retina disease patient, but for a clinical study we bring them in every six months This is the drug companies are flying these patients in from all across the country just to see me at our site So I get patients that are flying in every six months from Hawaii from Indiana every they're all it's kind of it's kind of unusual, but that's the way that it works on this and Their goal is to have gene therapy because these are single gene mutations typically that again gene replacement may be useful for and the coroed oremia should be starting by Next summer we think for gene therapy and unlike classic gene therapy where you have to do a fairly invasive sub-retinal injection the the vector for coroed oremia is being designed to be Intravitrally Administrative and to penetrate through the retina they've genetically selected for it at least they claim and we're going to be One of two phase one sites. So we're going to be truly the first doing these These intravitural studies. So that's that's another reason why you'll see a fair number of these patients in my clinic Then there's uncommon or mitochondrial diseases those you may see in In neuro more often than in mind they they're often associated with neurologic disease They're going to have a maternal into inheritance. They're going to be rarer syndromic things like Kernsayer me loss and other diseases like that Then that leads into syndromic rp and so what's What is this disease here if you again if you see this on the boards and they just have a picture like that What's wrong with this patient first? What extra toes? Yes Extra fingers and toes. So what what is the answer? What rp syndrome gives you extra fingers and toes? Beetle. Yeah, Bardae beetle. So it's shown right there that one will show up Okay, and again, it's trigenic. We know the genes. What else in Bardae beetle? What else do they have? Don't they tend to be Are they big like how you're said, you know these they're not very bright they Have hearing loss and it's it's interesting. I once a year or two ago I guess two years ago now. I was invited they had a Bardae beetle convention here in Utah And it's there. It's seeing a whole room full of them. It's very interesting But so they can have that other one other syndromic ones that you need to know about our usher syndrome, of course, right So what's usher syndrome? What is that by definition? Right, so rp and hearing loss it's autosomal dominant almost almost always Our I mean sorry recessive. It's recessive And there's different types, but that's another one where gene therapy is coming soon They know it's a big gene, but people are working on that senior. Locan is rarer, but Anyone know about that who's written that the definitive review on senior Logan's Niko did right Niko did his phd and senior. Logan's Know that Aperts is rare golden fava is rare I've written a paper on ref some disease. I've never seen it in a mouse in a Cell culture models. I've never ever seen ref some disease in my life yet But I got a paper out of that, but what's important about ref some and gyrate atrophy Is that they're very They were described long ago. We knew the genetics long ago And they are treatable with diet. That's the thing. So that was Gyrate atrophy you go on it It's a defect in ornithine amino trans race. So you go on a ornithine diet ref some disease Is phytanic acid. You have to avoid phytanic acid in the diet. So that that's why those those are known Then of course, there's plenty of them that are sporadic No history at all That might mean because there's a new mutation in the person might be that it's just recessive and oh, they're the only one in the family But they also might be a pseudo retinitis pigmentosa. It might be autoimmune You got to think about other things that are going on that might be treatable So it could be you'll hear probably from the uveitis people about cancer associated and uh melanoma associated retinopathy We get uh gene gene or anti antiretinal antibody testing But you also have to remember we talked about toxic etiologies So I have picked up toxic, uh retinopathies. And so The the one paper that I published long ago more than 20 years ago Patient came in with a funny-looking retinopathy The dr. Degree had done a just a kind of history and he Was just noted when he was referred to me that he had exposure to ms 222 Which you've probably never ever heard of but in my phd thesis I had worked on this compound Which is a toxic compound in animals that cause that's a fish anesthetic That causes problem that causes ERG agramalities in fish This patient happened to be a fish biologist and what he did Is when he threw the fish in the ms 222 for them to go to sleep And then he would reach in with his arm and grab the fish out And was getting it all over his arm and basically was exposing himself to this toxin and We Basically we told him wear some gloves for god's sakes and so and he did and he got better And so that's that's a possibility and then The other thing that you will see occasionally in my clinic is vitamin a deficiency so What causes vitamin a deficiency in the develop in the in the united states? number one cause probably Right bariatric surgery and those patients are out there and they may have had it 20 or 30 years ago because it takes forever to make yourself vitamin a deficient But you got to catch these patients and they are um Don krill is pretty good at picking them up by ERG and you just If you take a little bit of a history and find out you know if they've had this bariatric surgery Get a vitamin a level the patients are Eternally grateful and i've cured several patients by this by just Either giving them you know high doses of world vitamin a to get past their their Their deficient uptake or by giving them injectable forms which unfortunately are very expensive, but You can cure them again Set a rare complication that i've seen with someone who just was such a picky eater That he did not eat any fruits or vegetables at all ever And gave himself vitamin a deficiency and he He came in with classic. He couldn't see at night. He had to get He had to wear it use a flashlight to get around his house and when i took his dietary history Of fruits and vegetables. He basically says i i sometimes eat every two weeks. That was it That was done, you know in terms of what he ate his wife confirmed. Yes, he only eats meat and potatoes. That's it so And once he started taking Changing his diet. I never saw him again except we we called him up. He said he's doing fine too busy to come back in so um And then there as we talked about stationary retinopathies They don't have clinical progression. They often have very prominent night night blindness, but the visual field is good Other things you want to look at are that is are these congenital stationary night blindnesses And there are certain mutations that just don't cause a lot of problems rdh5 Can give you all of these spots written out as Fundus albipunktatus right here and that can just be a problem, you know that If you can diagnose them with this then they don't need to worry so much And then in terms of treatments basically you want to do social supports Um, so, you know, they they have problems at school. They maybe have problems with jobs That's why we have social work staff You want to do genetic counseling that and our we have that under control now nutritional interventions Rare but are important to have they'll ask about lutein and zeaxanth. I say it's not bad to take it But that's not going to really cure them. Um gene therapy is coming You know is here in for luxterna more of them will be coming, but they're going to be research based Stem cells patients read up on the internet. There's a lot of promises, but There's no good stem cell studies that have been done yet that have really cured patients that you know that are fda approved And or even fda, you know sanctioned for clinical trials So that's still coming, but I obviously tell patients that You know five or ten years is a long time, you know, there a lot of things can happen in In technology in five to ten years And then people are we're looking at various other more generalizable interventions either oral or injectable growth factors antioxidants Velproic acid we were part of the studies here where you know, there's always a lot of promise on these pre-clinic People may give antioxidants or some other intervention to a mouse. They get better and they say well, let's give it to humans They'll do it if they're if they if the drug is available. They'll give it Some patients may see a little bit better or not But and that happened with velproic acid There was a lot of buzz and people started because it was already on the market people started taking Started prescribing it to their rp patients But it wasn't until the foundation fighting blindness stepped in And invested millions of about probably eight million dollars to do a proper clinical trial that it didn't work We were part of that trial And then it's kind of faded away So you gotta be careful about false hope And all these things you'll see on the internet for electrostimulation stimulation other things that just are taking people's money away And then artificial vision with the argus-2 implant Was a great tour to force that they could make an implant chip implant that got them a little bit of vision The problem is that the intervention cost a hundred thousand dollars And the the quality of vision was still so poor That it didn't have a great patient acceptance and insurers blocked at it So the next step is going to be to do cortical implants So the company argus the argus-2 implant even as we were gearing up to start Implanting it was pulled off the market In two weeks or so Mark rmeyan who's the one who's the father of the of the argus-2 implant will be giving a talk here Tuesday afternoon at four o'clock You should go and if you can't you can get away And that's the betting he's a very good lecturer So okay And then i'm going to go through other things just so we A little bit faster now on this and so Other things that i'll see are cone dystrophies. They have a wide range of manifestations The most common cone dystrophy is color vision deficiency. That's in three to five percent Of males have that They can have macular cone dystrophies progressive cone dystrophies a chromatopsia is the most severe that's that's less common And they of course will have loss of color vision loss of central visual acuity Very Characteristically they'll have photophobia much more than a classic rp patient would And their visual field is often really pretty good But they may have bullseye maculopathies and the way that we've diagnosed cone dystrophies Almost the same as rp. So you can do clinical history Family history dilate examination all the same things that that are doing that we're doing they just have to have But they're going to come they're going to have different findings. They're going to have a preserved visual field They're going to have macular problems much more genetic testing will Distinguish that And so cone dystrophy it's the same Genetic counseling Maybe stem cells maybe gene therapy And of course remember that there could be ocular toxicity numerous Agents can mimic retinal retinal dystrophies. These include the tamoxifen This is kind of catazanthin where you get these crystals depositing in there the other things We look at plaque when L which can give you a macular dystrophy here And tobacco alcohol Thabutol all the other other things Other toxicities that we've picked up here in clinic are chromium Chromium cadmium toxicity and why would someone come in with that anyone know that one? There was a small outbreak a few years ago. I had to do with hip to bad hip implants That were that were sending That were leaking out all the ions in there and that that caused a pretty bad macular problems too And then there are other ones, you know digitalis the Viagra can cause transient color vision problems. And then there's other other ones there And then finally, uh, remember pseudo retinopathies. These can be post inflammatory After trauma idiopathic and the main thing one of the more And also think about, uh, rubella retinopathy can often get misdiagnosed. All these are stationary And you don't need to you don't need to work them up as as a normal As a regular retinal dystrophy and typically sometimes they have good electrophysiology I can talk briefly either we can stop or I'll talk briefly about macular dystrophies All right, we'll see if this comes back up. Yeah, okay So in macular dystrophies, you're going to see the things that you need to think about our star guard disease. That's going to be common Um, that's about a one in 10,000 disease. So it's not as common as rp But there's plenty coming out there best disease and then various other ones listed here And I'm just just we'll talk briefly about those. So star guard disease One in 10,000 so 25,000 to 35 30,000 people infected in the u.s It's 95 percent autosomal recessive But there are dominant forms too And there's thought that you know because it's involved in Deposits of lipofusin that there may be some increased risk of amd, but it's not a major amd gene, unfortunately Because because it would make things easier in the diagnosis The star guard disease normally they have normal completely normal vision at birth when when they're young They decline in central vision typically in their teenage years, but there's really wide variation Classically they'll have macular atrophy Described as be metal and they have these Piece of form flex going around so but not all star guard disease looks like this not everyone we've learned There's a huge diversity in this You'll see in my clinic. I've diagnosed people 60 or 70 years old with star guard disease that are still You know that are functioning still pretty well because if it doesn't knock out their central vision They may not notice much change on the other hand. They could be debilitated at age seven also The end stage typically just stops at 2400 vision and there's preserved central vision So you can see the flex right here. You can see the atrophy here Um the way that we diagnose star guard disease clinical history family history I exam They will have your classic dark chloride Shown here, but I don't get fluorescent angiograms very much anymore on these patients because auto fluorescence Works just as well on this I don't routinely get ERGs Because that's usually normal or only mildly affected and genetic testing is very useful on this The problem is it's a very large gene. So it's we still miss even though we know that Uh, essentially every patient with star guard disease will have a mutation in the abca for gene They still miss them because of large deletions. It's it's just a hard gene for them to sequence But I'd say they're missing only 20 of them now. So it's relatively they're getting better at this And we don't have time to go through the the biochemistry in this but it has to do with abnormal The abca for gene is important in moving all trans retinal after bleaching out of the out of the cell and if it doesn't if you If you have all trans retinal if the all trans retinal is there too long It starts generating a whole series of toxic compounds that are fluorescent And that's what you see when you see the increased fluorescence Um, the way that you treat it is that we have patients avoid excessive vitamin a avoid excessive sunlight We are part of many different several different clinical trials that are looking at either vitamin a or visual cycle inhibitors things that cause Vitamin a antagonists is another reason the way that they're looking at that We're also part of a trial looking at complement inhibitors and how they may be Slowing down the disease. So there's you'll see a number of clinical trials coming through and they need genetic counseling, but You know, it's it's a recessive disease. So again, if they don't if they're not marrying close relatives, the chances are One in 20 or one in 40. They'll find just a random carrier because there are lots of carriers out there Um Dominance stargarten disease is really rare, but I do have a family of about 18 Patients that I've been following here in from california. It's a completely different mutation in el ovl 4 It's a completely different mechanism, but it can look just like stargarten disease or pattern dystrophy And I'll kind of skip through that that'll be That I sometimes gives a research talk Other things that you'll see in macular dystrophies are best disease. That is dominant We don't know the exact incidence and but it's well known It's a mutation in the vmd2 or best one disease gene and it has these classic The teleform lesions that That can be associated with best orphan mutations And that you know can progress Get these scrambled egg or pseudo the teleform lesions They're loaded with lipophiesin and some patients do really well and some patients do very poorly It's just and I've even seen such variable expressivity that I've seen one patient with Full-blown best disease in one eye and the other eye is totally normal as an adult So it's just it's it's really kind of a bizarre disease And the way that you do that The way that we have assessed that is clinical history family history Autofluorescence and then the classic things that you need to know is they'll have it an abnormal electro oculogram And a normal erg classically, but there's always exceptions and we do genetic testing for that too And I don't know I don't know where gene therapy is right now. It's I don't think it's it's progressed enough to be anything important Then finally there's going to be the very rare diseases that I've never seen in my life But that are written up well Swarovski's fundus dystrophy The reason why that comes up is it is a model for amd and some of the same mutations And the temp 3 gene are also can also cause macular degeneration And typically they get these macular changes. They get carotoneobascularization, which is unusual for a lot of these other dystrophies And that's found mainly in england And then malatia levantanese also known as doin's honeycomb dystrophy Shows up on the boards. The main things you need to know is they've got these radial flecks here And it's a well-known mutation And it is Associated it some of the same genes can cause age related macular degeneration again, that's Too rare for you to ever see in my clinic And then north carolina macular dystrophy is one other one that I'll just kind of which I it took me 20 years of practice before I finally found one patient with this and the main things to know about this Is it's dominant? They have horrible looking maculas But this is compatible with 2020 vision these patients have can have really good vision surprisingly And it turns out this is actually congenital and non-progressive Even though it was only and it was the first macular dystrophy to have linkage But it was the last one to have the gene identified. So that's the that's just kind of interesting with that And there's no treatment yet So that's it Okay, so when you come to my when you rotate with me You know, I always encourage It's christ to say, you know the see the inherited red disease you go in and see them first really try to work them up See what you can learn. Okay All right