 So we'll get started anyway, but I wanted to start this off before I just kind of lecture at you on all this, but just discussing a little bit about just why anyone would want to do inherited retina diseases, okay, what are the, the, because I was thinking back about 24 years ago I answered and had to be one of the, be an inherited retina disease specialist here. I'm still doing it. So the question that I have for you is what are the pluses and minuses of doing that as a field before we talk about what it is? So why would anyone want to do this or not? So anyone of you? The expert in something. Okay, yeah, you gotta find a niche. This is more just about the principles of this. When you're looking for a job a couple years from now and you do, you know, there's a lot of, we're producing however many hundreds, if not a thousand, ophthalmologists every year. So you have to have a niche, you know, especially if you're thinking of doing something in academics as opposed to private practice. So that's one reason. What other reasons? I mean, we can do pluses and the minuses too. So what else? See the rest of it because that's mostly what you'll see. You'll see, like, whatever likes in that area because a lot of people will send you them once you get really established. Okay, yeah. So you'll be, again, it's still part of your niche. What about the patients? You know, are you, and there's pluses and minuses on this. And I can say it's probably difficult having people travel from around the world or the country with your patients since you have such a large cash bin area. Yeah. Well, I mean, it's, you know, it's the, you are, if you're a retina disease specialist, you're kind of the person of last resort. You've been the, so patients can be very appreciative coming in. You know, they've seen a lot of people. They've seen a lot of misinformation, a lot of, you know, and it's a tough disease coming in. So you are the person that they see. On the other hand, that's a lot of responsibility. That's a lot of, and it's, it can be a little bit of, you're, you're dealing with patients where you don't always have the answers on these things. And so you have to be able to take a certain mindset to actually, you know, set aside the time, talk with them. And as you can see, I don't think, you know, since you're, you're all pretty early in your careers, you are, you haven't been in clinic with me yet for retina disease. And there's a different, for inherited retina disease, there's different approaches. And, you know, there are some, some of my colleagues that have all inherited retina disease all the time. You know, that is what they do is all, all inherited retina disease. And that can have its own pluses and minuses. One is that you get very good at it, and you see a lot of really, really rare disease. It's a little bit, you know, we're all focused being ophthalmologists, you know, just a small part of the body. You're getting even more, more focused in just these degenerative diseases. And emotionally it can be a little bit hard, you know, seeing that many patients that have, where you don't have that many interventions that you can do, although that is changing. But certainly 24 years ago when I started in this, there wasn't that much. So that is one approach. When I was at Mass Eye and Ear, that's what, someone like Elliot Burson, that's all he did. You know, clinic after, you know, just patients coming through, getting their ERGs, seeing this just going through. On the other hand, I, you know, I was surgically right in the trained. I still do surgery. It's a part of my practice. I didn't want to make it my sole part of my, you know, the sole part of my practice. So I saw, so right now when you come to my clinic, the way it's supposed to be, and I'll tell you the way it really is, the way it's supposed to be is I'm supposed to have one inherited retina disease patient, new patient per half-day clinic. So that's, that's what the way that's scheduled. I even have, it took me a couple years to kind of get these schedulers to understand this, but it's just one, one in one new patient, one to two follow-up inherited retina disease patients in the midst of a 20 or 25-person clinic. When that happens, that's good, because inherited retina disease patients, as we'll talk about in the slides here, take a lot of time. It's not a 10-minute visit. It's, you know, it's not quite as bad as Neuroop, but it's pretty bad. You know, they, you know, it can take, if my 8.30 patient, I often, I often don't see until 11 o'clock, because they've had all this testing, they've gone through all the steps. So you can't, if you bring in a bunch of patients, then it throws off your whole clinic completely. The other thing is that these patients take a lot of time. Even after they, you know, they have, they're not, you, they're often not simple. They have lots of testing to go through. They've seen a lot of other patients. They have lots of questions. So it, it can easily eat up 15 or 15 to 30 minutes of your time if you don't watch out for it in your clinic. And again, you can't have that many patients to do that. So that's what they're, that's, that's the, that's the plan. The reality is, is they just told me yesterday afternoon, they were saying, well, on your Monday clinic, you've got three inherent, you've got two inherited retina disease, new patients scheduled at one o'clock. Is that okay? And then I look at my schedule, and then I actually have three, because they stuck another one in there. And, you know, the scheduler's neuroop, put in a cone dystrophy, it's just a regular new patient. They're asking, you know, we've got this other patient, 14-year-old with excellent RP, flying in from Montana with their family. Do we cancel that patient and, you know, make them reschedule? This other patient's been waiting three months. So it's a problem, and that's going to be a problem with clinic. Plus I have 31 patients, so I'm already overbooked. So it's, but that shows how much you can be in demand for doing this. So that's, that's one of the challenges. Now, why did I go into inherited retina disease? Well, there's a lot of, I mean, in addition to being kind of the niche, is for being in academics and doing inherited retina, and doing, trying to be running a research laboratory. It's a very fertile area for research, of course. You know, there's all sorts of genetics, interventions now. There's a lot of things that are going on. And it's, I've seen the evolution in 24 years from just saying, well, we know this, that your disease is inherited to, I think, let's say, I guess it was probably, it was during my PhD probably, is when the first gene for, was ever discovered for inherited retina disease. Which, do you know which gene that was, or what was produced? Anyone know? Need to see it before? Nope. Earlier than that even. But it's, what's that? ECOE. Nope. And it's an obvious one, you'll say. It's rhodopsin, actually. That was really the first one. Maybe you could argue, you know, ECOE was known, but rhodopsin was the first, what I would say is the first monogenic one, where they could really say, for retinitis pigmentosa, except for these kind of rare syndromes, they knew certainly for, say, gyrate atrophy. There were some that, metabolically, they knew what it was. But it was really a big deal to say, for retinitis pigmentosa, a disease that affects 100,000 people, that we know a gene that causes this, if you have a mutation, you get this disease. So that evolved now to the fact that we have a genetic counselor, we do genetic testing on everyone, as much as we can, and we can find the gene mutation in an awful lot of them. So you kind of take it for granted, but that just wasn't known, and that was a big deal. So that's, and for my research work, for looking at both genetics, looking at the basic biochemistry of how visual cycle works. Again, I don't know how much of you know my background, but for my PhD, going way back, my PhD was on the isomerization of all trans retinoids to 11 cis retinoids. That was my PhD. And that was basically, it was just because it was an interesting biochemical topic to do that. Now, eventually I did figure out that this enzyme activity existed. I didn't figure out that back then the technology wasn't good enough to figure out what the protein was, but it took another 20 years. That was RPE65. And now RPE65 is in the clinic. So if you look at the long picture of how all these things work, you can see that something that was just an interesting biochemical problem can be eventually translated. So that can be very rewarding. On the other hand, not everyone wants to do inherited retina disease. So you have to have the right mindset, but even if you go into private practice and you're going to see these patients coming in and you need to know some of it. And the other reason to know about this is it's on your boards, of course, too. And it's a fertile set of pictures that they can throw on there, so you do need to know it. And so that's another reason. And so anyway, that's kind of any other reasons that you would ever want to do inherited retina disease. We'll talk more about this now. But we're going to talk a little bit today. It is kind of bright. So inherited retina diseases are generally considered orphan diseases, but if you sum them up, they can be a very significant part of your of ophthalmology. Now, with the most common ones you're going to see are retinitis pigmentosa, a big kind of group of diseases. But another reason to know about inherited retina disease is that there are syndromes. These can be signs of other problems in the body. And they are inherited. And now, of course, the other thing, of course, about knowing about genetics and knowing about inherited retina diseases is a lot of diseases that we have in ophthalmology that we deal with were not thought to be inherited retina diseases, but we now know are. Genetics is a very major component in knowing the physiology. So it would be 25 years ago thinking that age-related macular degeneration would be an inherited disease where you could at least consider doing genetic testing for risk factors that was just not even on the radar. As you've heard me talk a little bit, and I think you'll be hearing more, a disease like macular telangitasia type 2 that was thought to be just totally random and sporadic disease. We now know the first genes that underline this condition we just submitted our paper yesterday on that. There's much more to learn, and genetics is important as we know. Another thing is that you need to distinguish between what are the really bad prognosis diseases and the ones that are not so bad, stationary retinopathies. There's a big difference to telling someone you have a retinal degeneration and it's going to get worse and you might eventually go blind and need huge interventions and you've got something, it's going to stay stable, if you've adjusted to it as it is, it's not going to impact your life much more. Literally, there is a patient that Nico I think was with me when I diagnosed this patient where it was a 16-year-old kid came in with a retinal degeneration referred for RP was already doing cane training, was learning braille, everything, and once we did the ERG and took the history, it was clear that he had congenital stationary night blinds. Basically, I could just tell him, you're great, go back and don't even worry about this and quit all the stuff that you're doing. It was good to finally give them the correct diagnosis and not give such a devastating diagnosis. They're very complicated, you have to distinguish between what's affecting rods, what's in cones. To think about our toxic retinopathies, you can have, some of these diseases are not inherited, some of them are literally environmental and if you can get rid of that sort of problem, you can take that, it will help the patient quite a bit. Again, this is going way back to when I first started here and where basic science can come in is when I was studying, studying inhibitors of the visual cycle and other things that I was doing for my PhD, one of the things that we had to do was, since I worked on frogs, is you had to anesthetize frogs in the way that you anesthetize, does anyone anesthetize a frog, ever? Or fish? Basically, what you do is you take a compound called MS-222 and you throw it into a, you just make a solution of this and you throw your fish or your frog in there and then they go to sleep. Okay. It's not a big deal, but people realize and it was known then that this caused all sorts of abnormalities in the ERG and you had to be very careful if you used this for doing ERG abnormalities and in my first year or two I was referred to retinal degeneration patient from a Kathleen degree and I saw this thing written in that she had taken a history that was written MS-222 and I said, why is this even there? I didn't know what this was and it turned out he was a fish pathologist and what did he do? He would take his fish when he had to study them, throw them in the vat of MS-222 then go to sleep, then he would grab the fish out and study it. I asked him, do you wear gloves when you do this? He had RP and he had all these ERG abnormalities. He said, of course not, he had to just grab it and I do and so the intervention I said is try wearing gloves and he got better and that was it and his ERG got better and his symptoms went away so you can look this up, we did publish this as the toxicity of MS-222 clinically again, you know, basic science and again saved his vision just by knowing this and doing the right history and there are some of the other things that can and then of course there's pseudo-retinopathy things that aren't RP so the common ones you're going to see in my clinic and in clinical practice is retinitis pigmentosis so it's estimated prevalence and I think this is a pretty good number is 1 in 3,000 so there are 3 million people here in Utah if you cover that so there are about a thousand people with RP out there it's not insignificant it does mean that there's about a hundred thousand people with classic retinitis pigmentosis in the U.S. so does this qualify as an orphan disease? Does anyone know what the cutoff is in the FDA? 200,000 so it is, it's definitely an orphan disease it's the most common inherited form of blindness and as we'll see there's lots of inheritances, clinical courses and genetic causes and there are limited interventions available but it's getting better this kind of reminds me as we return to this another reason to be studying inherited retinitis is if you're and I don't know how many of you even have an interest in academics and research is a fertile area of research and it's actually a reasonably well-funded area of research it's a priority both at the National Eye Institute and there are some foundations that are very well-funded like the Foundation Fighting Blindness because some very rich people get inherited retinal disease and I think, someone was pointing out to me I think it's true that the number of people who are billionaires and leaders, captains of industry that have RP and are legally blind is surprisingly big so not only, because people can be successful if they don't earlier on and can compensate for many, many years but people like Steve Nguyen who's had his own other problems but have it, Gordon Gund there's a whole series of people that are billionaires that are out there with really poor poor vision and they put their money into the research so they can put this money back so there is it can be helpful in terms of doing academics and I've seen a lot of evolution of this from a totally very bad, bad disease to at least being able to offer some hope to patients so with RP your first symptoms that my patients have is night blindness and that's the first thing that they usually complain of if you take the history there's always some exceptions but if you ask them what did you first notice they'll say I just didn't see as well as my compatriots eventually they start developing loss of visual field so remember that when you're doing certifying legal blindness in these patients if they get down to 20 degrees or less that's when they're legally blind what do you need to drive I'll ask you this when you're filling out the forms what's in Utah how many degrees of vision do you need to drive is the absolute minimum there some people in 90 and 120 you start getting at least some restrictions on it but 60 is the lowest limit so there's a reasonable gap between 60 degrees and 20 degrees and I can tell you that the patients who go that the department of motor vehicles misses a huge number of patients there's a number of patients that are much lower than 60 degrees that are out there that are coming in that are asking for both a driver's license form and a legally blind letter for their taxes which is really not compatible if that's really true central acuity and cone function are often preserved but not always that's the thing you want to check on these patients is their central vision really as good as it should be because what else if someone comes in with RP they have to think about that are treatable and again these are not hard questions so they can have cystoid macular edema that is potentially treatable they can have cataracts they get cataracts early so those are things that you have to at least think of if they're vision, if they're not coming in 2020 and they have classic RP but of course this is a devastating diagnosis in these patients or can be a devastating diagnosis to think about the worst of the worst and the answer is yes this is a disease where if we don't have effective treatments they can go to no light perception in patients that does happen so that's not true for many other diseases like AMD so we need to know just what are the classic signs and symptoms of this we've already talked some about the symptoms in terms of the signs that we've seen, not always seen those are the pigment clumps that you see in the periphery of the retina typically in mid periphery you can have just a few they can be along blood vessels it's basically a pathologic reaction of degenerating retina and RPE where the RPE kind of migrates into the retina and clumps there peripheral retinal atrophy is common but that can be missed especially in people who are in the pigmentation of their retina they have waxy powder of the optic disc and they may have optic nerve head drusins that's always worth looking at vascular attenuation occurs very commonly vitreous cells or at least clumps of degenerating cells in the retina are common and then posterior subcapsular cataracts are really really common in these patients does anyone know why? probably not because I don't know why either you see that quite a bit and then as I said cystoid macular edema can be hard to manage but it's worth knowing that they have that they have that's why we get OCTs very commonly again we used to miss this all the time before the OCT era but you want to do that because that's something that you can try treating with dimox you can try treating with dorsolamide topical dorsolamide you have steroids can work but sometimes just nothing works but there are other patients managing this can make a big difference for this and then of course late in the course the macula is preserved so when someone comes in to my clinic on there if they have just one patient they my techs know what to do or supposedly know what to do right sort of but not always because they're always switching around but of course in seeing any patient you want to do a clinical history you want to know what is anyone else in the family affected when did this start what are the symptoms so you want to do that first then you want to do a retinal examination and the techs are supposed to but they shouldn't check color vision I would say that happens only about half the time because typically it's not going to affect the cone system but sometimes their cone rod dystrophies are more common or more complex things and so they should be checking that they should be checking an absolute grid they usually don't do that either but at least they know to get to dilate the patient and to send them initially for visual field testing is the thing that I want first now as an inherited retina disease specialist I find automated visual fields worthless those are for screening glaucoma they don't go out very far right they go 24 degrees or 30 degrees in the back of the eye that is not going to pick up what's going on in the periphery and seeing what's really going on for these patients so I like doing a golden on visual field if at all possible the problem is neuroop clinic is running at the same time as mine they want golden on visual fields so one of the things and this is just my preference and the texts say well we have to it slows them down because there's an hour of wait for this and we can't dilate the patient it's like I really don't care for a visual field I don't care whether they're dilated or not I just want to get at least a decent visual field so I'm pretty for a clinical study that would not be allowed but for my clinic I have to move them along so I do that they need a dilated retinal examination we get OCT of course in terms of photography my standard battery is what I call them non-invasive imaging so they know to get this they'll order color photographs we have to get montage and I have to remind them on that because they'll come back and I'm seeing an RP patient they give me just a picture of the macula going on in the retina so they're gradually learning that we want montage I like auto fluorescence although I would say auto fluorescence is a little bit controversial in some retina especially because of the intensity of the light and it's blue light is a bit much for the patients and there's some people that are convinced that's making the patients worse I still think it's worth getting that information I like getting since we have the option of getting a flio getting fluorescence lifetime imaging and that's more for academic interests but we see a lot of changes in the auto fluorescence infrared imaging those are kind of the basics of that I don't get fluorescing angiography routinely on the patients unless there's a reason that I'd want to and then let's see what else did we and then electroretinography I do like getting a baseline of what's going on in the program on patients coming in it can help diagnostically it can help understand it can help understand what's going on at least initially rule out other problems once they've had an ERG or if they've had it elsewhere especially if it's really abnormal and almost down it's lost 90% of the of the vision of the sensitivity in looking at that there's some more mild patients where it's down 25% or 50% so potentially you could get that every couple of years on the patients I do like getting visual fields if possible every year on the patients there's a lot of variability on a goldmine field but it's still worthwhile and this is just showing an example of how a patient can progress with time I don't know if this is going to work here showing down in the bottom left corner where you get the paracentral scatomas eventually they kind of complex wrap around until you eventually get this is a very common field where you have central preservation and some temporal islands of vision over there and eventually if you lived in this particular patient becoming affected in 20 years going to 50 years or 60 years you can see down to just a tiny vision at the very end so electrorhetnography I leave to Don Creel we have a great electrorhetnographer who can typically do it on demand and so but we're using this to distinguish between what's normal what is typical RP as shown in the bottom versus how much is the cone system involved and how much is and then there are other things like congenital stationary night blindness or something that's a little bit different or that you want to see is behaves differently from RP so then the important thing now is genetics there's almost every patient now I will try to get get some sort of genetic testing on them if possible and the reason is to get them into the right clinical trials to and to give them better prognosis to inform the family of what are the other risks in the family the problem is it can be complex it can take a lot of time to do genetic counseling properly it's not well covered by insurance in fact most insurances won't cover it these days but we can try and currently we do have we do have access to free genetic testing the programs kind of come and go and I asked some some companies where they were the company spark when it was trying to find patients with RP 65 mutations was offering a limited panel of 31 genes for free that was pretty good it found a lot of my patients it was nice to have that option of free testing currently if the patients are willing to go online and sign up for something called my retina tracker run by the foundation of blindness they can get free genetic testing and that's a complete panel of 200 genes and what that involves though is that they have to be instructed to go online and they give away a little bit of personal information they're supposed to I think they're asking them to go online once a year enter their visual acuity enter their fields do a little bit of something so that you're getting into the registry for the foundation fighting blindness and it gives them something to informally track how people are progressing just in natural history I would say most of my patients are willing to do that that's not giving up that small amount of information in a confidential manner is fine for them so that gets them the availability to have genetic testing a panel that's worth somewhere between $1,000 and $3,000 now they're slow and it really really is helpful to have a genetic counselor like Emily Spoth I don't know if you've met her yet but we now have a genetic counselor she's here three days a week and she handles all that because as a physician I didn't have time to teach the patients how to do this how to kind of shepherd them through all this process but she's doing that and fortunately although it's currently we even get reimbursed about $300 if she does the genetic counseling so that actually helps pay some of her salary this program might go away at the end of this year might go away in nine months it's an expensive program but it's a great thing to have right now and even for those of you at the VA we can probably for patients who really want this we might be able to coordinate this because the genetic counseling at the VA doesn't know how to do this right now so when we talk about the genetics it can be we've learned from RP and we were all excited 20 or 30 years ago when we found the gene for RP that was going to be RP or that was going to be Rodopsin well it's turned out there are literally several hundred different genes that can cause what we call RP there's all these inheritances so we should have known it was going to be a lot of different genes and within every gene there can be many many different mutations so it's complicated a good genetic counselor will do like I believe will take the time and will draw out the pedigree which can be very complicated here in Utah and figure out and we can sometimes tell or think we know that it's autosomal dominant or recessive although we've been fooled you can have X-linked diseases that in a few patients in a few cases will show up in the females and that throws everything off you can have you can have or I mean the X-linked that shows up symptomatic in the females and that can be just a little bit of lionization we have the X-treme case that I just published a year or two ago of a patient with carotideremia who actually turned out to have Turner syndrome at the same time so she only had one X chromosome so that that was literally a one in 250 million chance that she had these two diseases together so it can be complicated and can be kind of humbling to understand as you try to figure out what's going on and then there's a lot of patients where there's no family history and that just means it's either recessive or a new mutation or maybe it's not even RP so for autosomal dominant is reasonably common here in Utah about 20 or 30% of my RP patients coming in are autosomal dominant they're often more mild cases and that means mainly because they have a normal copy of the gene and they have a bad copy of the gene so something's going wrong that's either mislocalization of the protein or it's causing aggregation with the normal protein but something's going on that initially the photoreceptors are probably normal when they're young and eventually start dying off so there can be variable penetrance so in an autosomal dominant pedigree it can look like it's skipping generations and that's but if you go back and look carefully at the parents maybe there is some sort of mild form of the disease the most common defect is rhodopsin the other one we see are RDS periferin ciliopathies are very common as autosomal dominant we see a lot of splicing factors which are things like that go by the initials PRPF 831 all sorts of things like that that are splicing factors that are abnormal everywhere in the body but for whatever reason the retina does not have the back up to handle this sort of genetic defect and that's the only expression of this and just shown here is an example of rhodopsin just showing the number in red this is probably way out of date just showing where the various mutations can be found so you can see as it's going through the membrane it can be interactions with the transduction pathway it can cause misfolding they're just all over the place and there's a lot of founder effects with dominant disease so if you trained in the east coast if you were at at wills or anywhere else if I talk to the retina specialists they say the most common the common one is p23h is the mutation and that one has been because it was common and that's where the first mutations and the first mutation found people developed all these animal models and became this is the most important form of our people it's just one form if you ever ever see a p23h here in utah families never moved here it just doesn't exist and people say that's while I talk to people in Tennessee they say well that's half of my patients so here in utah everyone is a g51v that is the most common one that you see and no one studies that but I would say literally half of my rp patients are g51v and that has to do with the fact one founder here probably an early Mormon pioneer had that mutation and has had lots and lots of kids so you just have to be aware that there's a lot of regional differences recessive is not as common and it's more common in cultures with a lot of consequentity even though we have the reputation of being an inbred population here in utah we are not like the Middle East where people are marrying cousins that's where it really comes up a lot it's often severe early onset and then one form of recessive rp is labors congenital amerosis which is basically just rp that occurs very very early in life mutations are often in the transduction cascade or in the visual cycle they can be multiple genes two different pathways kind of interacting so this typically in an autosomal recessive family if you have a large family like they do here in utah two or three out of eight kids might be affected and no one else in the family that at least is a sign that you may be looking at a recessive rp and there's it's much different to an autosomal recessive rp tell the patient there is no chance you're going to pass this on to your children that they're going to be affected except that they're going to be carriers of the disease as opposed to an autosomal dominant diagnosis means there's a 50% it's going to be passed on X-linked typically males are going to be affected females are the carriers these can be variable severity X-linked the X-linked rp syndromes tend to be pretty severe affecting kids often before age 10 carotideremia on the other hand can be much more variable now we know the natural history people's vision they lose vision early in their teenage years but they often are very functional and don't have loss of central vision until they're about 20 or 30 years old X-linked is becoming more important because that's a target for a lot of the drug companies right now because they tend to be large families again we have some very big founder effects here in Utah for caroteremia and that's one that you need to know what caroteremia looks like that shows up all the time on the boards because it has such a characteristic drop out of the carot less bone specules X-linked those on my boards it'll be on yours too they always do that and there's a lot of things they can ask about with the inheritance and how you manage it and so but these are a little more amenable thought to be more amenable to gene therapy so there are a couple companies that are coming up with that are in clinical trials they've approached us so we will probably within the next year or two be starting gene therapy either with sub-retinol or intravitrile injections for this and so in advance of that you'll see in my clinic you'll see a lot of patients coming through because these companies do natural history studies first so they collect all the patients to see how many we really have follow them for two years and then as we'll run into some of their trials mitochondrial is much less common maternal inheritance they often have a lot of associated neurologic disease I don't see a lot of mitochondrial patients they tend to be more in the neuroop realm but you need to know it's going to be a little bit more difficult to diagnose and a lot more variable and then of course there's syndromic RPs and these are usually recessive multiple organ systems are affected the number one that I see that's syndromic would be usher syndrome so you want to look at the association of deafness and blindness how do we know lots of people have hearing problems and I know to really suspect separate that from real usher syndrome does anyone know on that it's really the thing you want to look for is with usher syndrome typically the deafness is early and profound so these are patients who said that we're born deaf they often have speech problems etc. they may have cochlear implants and so you want to distinguish that from someone who just said well I'm 30 years old and my hearing is going bad too that doesn't cut it as usher syndrome usually but it's common we have natural history trials you'll see a fair number of usher syndrome patients coming through my clinics Bardet beetle another one that shows up on boards just because it has interesting and unique associations they have polydactyly the intellectual impairment their obesity there's a number of these it was interesting I went to they had a Bardet beetle convention last summer and so to have literally 100 of them in a room all of these patients the Bardet beetle syndrome has turned out to have dozens of different genes so it's a very difficult disease to deal with so then you'll see other things, Nico has been studying organ syndrome so that's there's a lot of association of kidney disease and retinitis pigmentosa has to do with the fact that they're all ciliopathies so they affect similar sorts of structures in both the kidney and in the photoreceptors and then the rare things Goldman Favre disease refsome disease, gyrate atrophy that you at least need to be aware of that are testable potentially are treatable through dietary interventions but are certainly not common they don't show up much on genetic testing and then finally there can be sporadic which means they can be recessed with no family history they might be a new founder of mutation or they might be something else so that's why we have to talk about toxic diseases consider vitamin A deficiency Creole is pretty good and picking that up those patients get referred in with they have some their cone physiology is typically very well preserved and usually well preserved that tips them off what's the number one cause of vitamin A deficiency here in Utah and you get it from the history it's bowel resection so it's some sort of bowel disease and we pick those up periodically it's very hard to make yourself vitamin A deficient on a western diet here in Utah it is possible I've had one patient again with that who literally ate no fruits or vegetables ever and still took him 20 or 30 years to do that to make himself vitamin A deficient but once once we diagnosed this he was fine he took his vitamins and he was better the problem would be the problem would be still no fruits or vegetables still no fruits or vegetables I think he just took it his dietary history when he gave it I eat a half a banana every other week sometimes that was it then he stopped and that's all he ever consumed and his wife confirmed that yes he all he had was meat and potatoes that's what he had every day for every meal it was interesting yeah he but really mostly here it's the bowel resection the problem with people with bowel resection is that they're not giving them a big dose of vitamin A orally they're not going to absorb it so you have to give them intra muscular vitamin A and at least as a couple of years ago a full course of that was $10,000 the price has dropped it's now $1,500 but it's still not cheap it's better to improve so it's it's kind of it's uncomfortable how much even in charge $1,500 it's not a difficult compound to make or produce then of course there's stationary retinopathy as we talked about that that you want to distinguish if you can make that diagnosis the patients are going to do okay they just need to they just need to be to pick the right jobs there was so and to they've done quite well I would say I don't see them very commonly but I diagnose maybe one or two a year that are stationary retinopathies they have very characteristic ERG changes they have loss of the B wave and preservation of the A wave and so a good electroretinographer like Don Freel will bring that to my attention he knows to talk about that and to give the patient the right diagnosis for treatment there's been a lot of evolution on this it's still a tough disease you're going to tell the patients that we don't have truly effective treatments in most cases for the patients so it's going to be supportive you don't want to give them total loom and doom there's some patients that say you got my general ophthalmologist he diagnosed with me and said you're going to go blind and marked out of the room I hope that's not really true that that really happened but you want to give them hope you want to try to say that we're working on the trying to develop new treatments that we are going to do genetic testing we'll get you into clinical trials as best we can and then technology changes but it really has come to the clinic for rp65 mutations the problem is there are very few patients with this I have exactly two out of all of my hundreds and hundreds of patients that I've sent for genetic testing both of them were between 40 and 60 years old had light perception vision they don't do well with gene therapy that's not going to restore things you would love to pick up patients with rp65 when they're eight, ten years old or younger it's approved the part of the gene therapy is approved as young as one year old but you have to have the mutation and that's been a big problem for spark is that they picked a disease that is too damn rare and they charge you know they charge a half million dollars per dose it's expensive they've had a couple really good success stories but it's not a viable viable economically for them the next generation of gene therapy is going to be coridoremia, excellent rp that's going to be that will at least start working there's also gene therapies for rp but for dominant rp but you're going to have to knock out the bad gene and possibly put in a good new gene so that's even more complicated on all this one of the problems with gene therapy is the approach, you have to put it you have to inject underneath the retina and so that's a subretina you're doing surgery on compromised eyes that subretinal injection is not a trivial process we're involved with 4D that's developing they think through directed evolution AAV vectors that can be injected intravitrally and will supposedly penetrate into the retina that would be great if it really works but that hasn't been proven yet clinically to work it's shown in monkeys that it works well the then there's there's stem cells people are looking at can they introduce replace the cells underneath the retina either degenerating RPE or degenerating photoreceptors they've the proof of principle is yes you can inject cells underneath the retina and they seem to live there do they do anything do they do any up and do their correct function not well proven yet so people are looking at scaffolds and then you have to ask when should you be intervening too late on this that's probably true in most cases some of the work done by Robert Mark here and by Brian Jones has shown when you get fairly significant RP yes your photoreceptors are dead and yes you still have an inner retina but it's all starting to miswire at this point and once you get miswiring and that's then even putting in your photoreceptors there putting in RPE cells is not going to restore what's going on if you've got totally jumbled up retina so we probably need to be intervening earlier in the stage when that's happening but then you better have a very safe and effective intervention because you're operating on an eye that is still functioning pretty well so that's your problem some of these either stem cells or implants that we're looking at those factors that helped sustain the retina better that hasn't been proven out that's good in principle it works in animal models that hasn't been proven to really be effective yet in humans then there's all sorts of people will throw on different or throw in different drugs that might preserve oral drugs so we've been involved in there was a velproic acid was being pushed for a little while by some researchers that would be very good and then all the patients RPE patients on their social networks that let's start taking the VPA because it's an approved drug finally the foundation fighting blind the step forward and put in a couple of million dollars and we did a randomized trial it didn't work so you know VPA is not a benign drug so we took a couple of million dollars to prove that it didn't work people are looking at Tudco which is synthetic bear bile from the Chinese traditional medicine it works a little bit you have to take grams and grams a day of very expensive drug and it still hasn't made it through clinical trials and then people look at retinoids we do one of the actually the only nutritional factor that's gone through randomized clinical trials and shown any effect is vitamin A taking large doses of vitamin A but the effect is so small and the risk of toxicity is enough I don't usually encourage my patients to do that plus those trials were done before any genetic testing was done we know there's some forms of vitamin A of RPE that vitamin A should make worse there are others where it shouldn't cause problems so it's it's not a very good way to treat RPE and then patients go on the internet and tell me about all these electro stimulation all sorts of things stem cells a lot of unapproved treatments that are available in the US and outside the US I just have to tell patients they may potentially put themselves at risk they may be spending huge amounts of money and not getting much for it so I'm a big fan of doing proper clinical trials and you always have to be suspicious of people who advertise on the internet I did this I'll only charge you $5,000 or $20,000 for your stem cell treatment or your electrophysiology but if they're not willing to do the trials in action and just rely on anecdotal data it's probably not going to be good and then there's the artificial vision we've been part of the of the Argus II implant we're supposed to be doing some the problem is these chimp implants the current generation it's a big surgery it's going to be a five hour surgery to implant this it's $100,000 of equipment of ancillary equipment to do this insurance companies have been fighting it tooth and nail they don't want to spend it and we retina specialists at least the ones that have put this in and I haven't put any in say the benefit is modest at best some patients you know they try it they don't like it well they've just spent $100,000 of someone's money on this the and the kind of vision that they get out of this is with the current generation is 6 by 10 pixels so they're living on 60 pixels and their perception although they can kind of vaguely make out shapes some of them just describe it as kind of sparks so they see sort of flashes so it's not nice generations will be better but there's a lot of work that still needs to be done some people are looking at even cortical implants and the first cortical implants just bypass the whole the whole eye that's going to take that's going to take another years if not decades to see if that can be so we're not going to cover everything I usually break this talking up into macular dystrophies and retinal dystrophies so we'll just kind of finish up today about cone dystrophies and a couple others more pan dystrophies this can have a wide range of manifestations certainly the most common cone dystrophy is just color blindness which is 3 to 6% of males have this so have defects in the cone in cone pigments there this can be a little bit of a challenge because I see a lot of what I what I call macular cone dystrophies just seem to be limited to the macula the cones their vision kind of goes bad centrally but there aren't a lot of genetics that really are very fruitful in figuring out what these patients have but there can be progressive cone dystrophies cone rod and rod cone dystrophies and then the most severe one is achromatopsia where you really have no functional cones there's some gene therapies that are coming up they're trying to recruit for them I rarely ever see an achromatopsia it's just not common here it's just not common in my practice but people with cone dystrophies have loss of color vision loss of central visual acuity so this is kind of the opposite of RP very commonly they have a lot of photophobia they have preservation of visual fields if they have it really bad they'll have nystagmus and bullseye maculopathies the most important things to know about cone dystrophies is family history the workup is very much the same this one I respected I worry about cone dystrophy diagnoses in young kids at least because that can be a sign of really bad things does anyone know what I'm really referring to and it's the batten's disease and I've picked that up in a couple of kids when you do the genetic testing in batten's disease it's a really devastating diagnosis to be the first and sometimes as an ophthalmologist you're the first line person that has to tell the family well this is a condition that not only do you have a visually impaired kid but this this kid may die in the next 5 to 10 years and that's tough and so fortunately we don't see it too often but it does happen and I've also seen in the days before genetic testing it was clear I was missing this to see the kids at 7 years old and say well he doesn't see all that well and then they come back at age 14 with seizures and all sorts of other developmental problems and that but I think now with genetic testing we usually pick it up earlier and the reason again for this is there are some clinical trials there are for rare forms of batten's disease there are some interventions for that now but in terms of treatment low vision services genetic counseling and then as we said gene therapy and stem cells are kind of the future the last thing is just remember to tell you about toxicology remember not all RP is RP so there can be pharmacological agents this is canthazanthin maculopathy where people who are taking a tanning agent basically were crystallizing the carotenoid in their retina that's treatable by just telling them stop taking the drug fortunately someone with canthazanthin maculopathy usually doesn't have a lot of visual symptoms tamoxifen is another one that we see that you need to look at for you know that can cause other problems that can cause problems and then we have chloroquine and hydroxychloroquine can cause bullseye maculopathy so it can be confused with cone dystrophy and other ones thambutol that leads back to alcohol etc so and it just kind of goes on and on you know there's you know ranium from viagra there's lots of things that we consume that are that can be toxic to the retina and so and then just remember not all RP is RP that can be post inflammatory post traumatic idiopathic some patients have if it's unilateral if it doesn't if it doesn't make much sense you may at least think about other possibilities so that means asking past ocular history might be unilateral or the electrophysiology may be surprisingly good I think the patient in the bottom right I think is rubella retinopathy I've had that referred to me in the past you know patients are they going to go blind the answer is no it's totally stationary it just looks bad but the damage was done when they were born it's not going to get any worse so I think it's 8 o'clock we will stop at retinal dysrophysic any questions or comments at all