 Okay so we'll get started now the theme today is really is supposed to be macular dystrophies but I have a talk that's both retinal and macular dystrophies and I think it's important to cover both every every year but what we'll do and we'll just try to stay on time the retinal dystrophies which is the first part of the talk we have to get through before before we're half way through by 730 so we have enough time so that macular dystrophies doesn't get cut off all right so I've been here 22 years when I came here 22 years I was brought here in addition to be a retina doctor but really to fill the need of having someone who could who specialized in inherited retina diseases and would see the patients the number of patients that we have out here in Utah with inherited retinal diseases and it's it's a tough specialty to have but it's an important specialty to have in any academic center we're here in you in an academic center being inherited retinal disease person I'm I am you know the person that's kind of the person of last resort to these patients they've typically had things going bad in their eyes their vision is going bad they know something is really wrong it may be affecting multiple family members but for the the private practice doctors out in the community the community doctors they don't they often are not educated in how to deal with these patients they're not educated in counseling the patients they don't have enough time to come to really spend with the patients and these patients are coming here when they see me they're coming here to really learn about their their condition and understand what the implications are so when in you're now now in my clinic when you're those of you are with me in retina I have in every clinic slot and every clinic session half-day session I have an inherited retina disease spot for a new patient and one to two for follow-up patients and that's to give them enough time when they when they come in because they are not quick patients especially the new patients and they and we're trying to make things more organized so the patients understand it's just like neuro it's going to take a half day to do to get things done it's not going to be a quick in and out and it's also so there doesn't overload my clients because I do have busy clinics and it was turning into a disaster when I would get three or four new patients that were all inherited retina diseases in one half day because I couldn't give enough time so it's important I find it very rewarding to talk with these patients and yes we haven't made enough progress in 22 years but we're making some I mean we now have genetic testing available as you'll as we'll talk about today we now know a lot about these diseases on a molecular molecular level there are clinical studies that are going on and some clinical treatments that are just now starting to get into clinics so it has changed a lot we still have a lot more to do so with regard to retinal dystrophies the ones that affect the entire the pan retinal diseases we I see a lot that are that are here and the ones that you're going to see most commonly when you're here with me here in clinic are retinitis pigmentosa is by far the most that affects more than a hundred thousand people in the United States you will see fewer but they're important you'll see fewer syndromic retinopathies you'll see even fewer stationary retinopathies where there are stationary inherited retinopathies where they are not progressive by definition but they still can be visually disabling and then you'll see cone dystrophies as as I'll discuss cone dystrophies are a little more tricky because our diagnosis the diagnosis is harder to make there's a lot of cone dystrophies out there where I really don't understand what's going on yet and then you have to just remember there are toxic retinopathies that can simulate inherited retina diseases and pseudo retinopathies which really aren't even inherited retina diseases so retinitis pigmentosa is has an estimated prevalence about one in three thousand about a hundred thousand people are affected in the United States and so and this is considered one of the most common forms of inherited retina blindness there's a large variety of inheritances and that's what confuses a lot of patients and that they may have a vague family history or they may have no family history at all and why are we calling this an inherited retina disease are they going to pass it on to their kids what is what are the implications and of course there's a large variety of clinical courses and genetic causes and it's very important to understand especially the clinical courses in that you know patients go to the internet read about retinitis pigmentosa read about how devastating this is and I'm not going to minimize that it's a devastating disease but there are a lot of people that do very well or have very mild cases of retinitis pigmentosa and especially now that we understand some of the genetics and do genetic testing patients that we thought were just kind of funny retinal changes with age we're getting better at recognizing well this is retinitis pigmentosa you can diagnose retinitis pigmentosa in a 70 or 80 year old person because they just have a mild case that's going on very slowly and then there are limited retina interventions available that this is changing so when I see a patient referred with retinitis pigmentosa the the clinical symptoms are usually the first sign why they're being referred in unless they have a strong family history and pretty much universally if you take a history from a patient with retinitis pigmentosa they're going to say their first signs of this were night blindness or poor vision at night they couldn't see the stars when they were playing with kids with their fellow kid when they were playing as kids they didn't see as well at night as their friends were seen so that's first and they and since they may have had it all their life besides knowing they're slightly different from others they may not be if they have a relatively mild case they may think that's just what they're what normal is or that's that's part of the the spectrum of normal eventually they start developing more symptoms in classic retinitis pigmentosa such as loss of visual field and that again can be kind of subtle and sneak up on patients remember with visual fields when we do the art the the goldman visual fields we all see who with normal vision we see 120 130 degrees binocular field and you can you can lose quite a bit of this before having any any real symptoms that you're that your visual field is down although we can detect it and you can still drive quite well with a 90 degree visual field 60 degree visual field is legal here in Utah and it's not until you're down to a 20 degree visual field that people are legally blind and there's a reason that legal blindness is established at that is mobility becomes very severely decreased at that point and patients are having trouble you know they're bumping into things that's when they start thinking about that they they're really effective when they're down to 20 degrees and it's amazing and sometimes disturbing how some patients can tolerate that till they're down to 20 degrees and come driving in with visual fields that are they're asking to renew their driver's license when I say you know you really have to start thinking about legal blindness not driving anymore so in classic retinitis pigmentosa cone visual acuity a cone function is preserved until late in the course of the disease and the end stage unfortunately for retinitis pigmentosa can't include no light perception so the first signs are bone spicable formation peripheral retinal atrophy waxy pallor of the optic disc and optic and also optic nerve head drusen and vascular attenuation those are the things that you need to recognize that will be on the boards those are the classic things that you find you'll also see vitreous cells which are kind of degenerate maybe degenerating photoreceptors other condensations in the vitreous they very commonly get posterior subcapsular cataracts why I don't know but they but that's what they do and they can get cystoid macular edema which is important because that starts affecting their preserved central vision and unless they get cystoid macular edema in a classic RP that's not a rod cone dystrophy or cone rod dystrophy the macula will be preserved until late in the disease so when a patient comes in with RP you want to do a clinical history what we discussed about the signs and symptoms that they have a family history is very important you need to ask not only how did your parents your siblings do but do you have cousins that seem to have the same the same symptoms that you had then of course we do a dilated retina examination photography visual field testing electro retinography so and that's very visual field testing is much more than just your standard 30-2 Humphrey visual field you want to get a visual field that really looks at every at the whole visual field so that's going to be either a manual goldmine visual field or an octopus 900 which we have here the goldmines they do pretty well here but it is technician dependent as to whether they really do a good job I don't worry in my clinic whether they're dilated or not dilated I just want to get the field and you know these patients have often come in from far away and if they're stacked up in neuro and they've got five hours of testing of other things I just say move along and we'll get the visual field later on in the session but it is important to get that get the visual field done the octopus 900 is a good machine but it's grueling it takes 20 minutes to do the visual field it's a lot of testing on that machine breaks down sometimes throws away all the data at the end of the at the end of the session so it's a problem and then electro retinography done by Don Creel I'm sure he gives a lecture on that is important on no expert on electro retinography and it but it's important it's important early on in the testing for most new patients coming in I want them to have an electro retinogram or at least a documented electro retinogram in their record if they got it done elsewhere I don't need to repeat it I find as we'll discuss with the electro retinography it's not very good in following the patients but it's good to have kind of a baseline if they have a reportable recordable electro retinogram then of course you can follow that but an awful lot of patients have nearly unrecordable electro retinograms from the start OCTs are important obviously to look for macular edema and then genetic testing is pretty much standard and we'll talk about that in the next slides or two and we're hoping to have our genetic counselor up and running she was supposed to start this week but there's been some delays so hopefully she will be starting in two weeks we hope so just going back here you can just see how the visual field see this laser can go from you know relatively preserved with patches of missing visual field to more where it's kind of goes in and then on this patient eventually it's not shown here but in some patients they'll have a classic rinse ring scatoma where the centers preserved they'll have right here's a ring scatoma here the center is preserved but they still may have some peripheral islands that eventually can go to legally blind and then tiny at that point and eventually even snuff out and electro retinography is helpful in distinguishing various classic RP from things like cone dystrophies congenital stationary night blindness all this but I'll leave that for dog real to talk about this but typically in classic RP they're going to have terrible terrible scotopic ERG's but they have relative preservation of the photopic ERG so RP comes in all genetic flavors and it's one that geneticists love to study because it can everything is possible in this disease and it's a disease that literally now I think we're up to a count of 350 different genes that can cause this literally thousands of different mutations so no longer can we test on the boards do you know each of these but you do have to know some of the key some of the key genetics of this disease and a few of the key genes so autosomal well is one of the more common ways that RP presents and the problem though is that in autosomal dominant is that it's the relatively mild form of the disease which makes the genetics a little more tricky in that patients will say I have a few cousins with this and uncle had this disease but my parents are just fine well it turns out autosomal dominant can have reduced penetrance so it may mean that in a in a classic autosomal dominant family it may mean the parents have no symptoms but if you look hard enough test them genetically or look at more subtle electrophysiology that they are affected so here in Utah we see a number of these pedigrees that are like this large pedigrees that show in classic highly penetrant disease it'll be a 50% chance of the past generation to generation autosomal recessive is about 20 or 30 maybe 20% it's also a lot of sporadics because if you don't have a large family you may not know you may not it may look random within the family if you have a large family with 10 siblings then yes if you start seeing a few siblings affected no one else in the family you think about autosomal recessive it's a little more common or it's certainly more common in in communities where there's a lot of inbreeding basically marrying cousins and that's not so true here in Utah except of course on a few of the polygamist enclaves do do have inbreeding but it's not not as common as the as it is in other populations X-linked is another one that could be a little bit tricky because that means that the females are carriers the males get the disease classically but there are exceptions there are females that can be affected that or get late onset versions of the disease it's just that the males are more are more severely affected and but both X-linked and autosomal recessive tend to be the more severe forms of the disease and then you may get mitochondrial syndromic and then sporadic which means we just don't it's the only person within the family so for autosomal dominant we said it's more common it has a mild clinical course variable penetrance and the most common defects that you should really know about is probably is probably rhodopsin is the number one that's the most common mutation you're going to see that was the first first one found in autosomal dominant RP and that has to do with the fact that it's it's rod specific and it's and it's not found anywhere else in the body and that's and it's a key protein that that forms about 80 to 90 percent of the protein in the rod outer segments so if you have a defect in rhodopsin that's a pretty severe problem either the rhodopsin is dysfunctional or more commonly there's a misfolding effect and it tends to cause long term eventually in a dominant form it will cause degeneration of the photoreceptors because it's mislocalizing within the photoreceptors other ones that we commonly see are rds periferant which is a structural protein and how they form the discs in the in the eye and the photoreceptors and then you'll have ciliopathies which have to do with the cilium the connecting connection between the outer and the intersegment Wolfgang Behr here and Jun Yang are experts on ciliopathies and so that's a very there's a number of different mutations but you just need to know that it tends to affect the connecting cilium is a very key part of these proteins and then for reasons that we don't understand a lot of RNA splicing factors why this kills off your photoreceptors when this is a defect that should affect every cell in your body it probably has to do with how specialized the photoreceptor cells are and that they don't have as much backup as other cells in our body and as I mentioned protein misfolding and misdirection is important and shown here is rhodopsin and you can see just the number of this is old but you can see the number of mutations and just where they are all through the protein recessive RP is relatively uncommon except if there's a lot of consecutivity it's often severe and early onset and often has to do more with the metabolic cycles within the retina either the visual cycle or the transduction cycle and these are severe in a lot of them make up where the family of diseases known as labors congenital amaurosis so these are diseases where the kids are born essentially severely visually impaired and this is one of the first ones where diagenic was inheritance was established where you can have a mutation in one gene and another in an associated gene but together that gives you our piece that just makes the inheritance even more complicated and then there's x-linked which means the males are affected the females are carriers these are usually very severe this is as this is a classic coridoremia patient here and classically you'll either have mutations in coridoremia or in the coridoremia gene or in things like RPGR or some of the other ones that are that are found on the X chromosome and then mitochondrial in my practice is pretty rare it's there's a maternal inheritance it's often associated with neurologic disease so you're just as likely to see this in neuroop clinic and cease and they have so many other things going on that this may that this may be kind of left that they may not be noticing it as much or that may not be the focus of the patient and then there's syndromic RP that you just have to be aware of that multiple systems could be affected they do like to ask this on the board so you need to know classic ones like deafness plus RP gives you usher syndrome there are many different usher syndromes but they're going to ask about it they're going to show you pictures with extra digits Bardet beetle syndrome that's they'd like to ask about that that also has obesity mental mental slowness other things like that and then their senior locan syndrome so that's there's an aperit so kidney disease can also be involved and then there are other ones that are really rare but they like to ask about it because they've been around for a while ref some disease gyrate atrophy which some of which I've never even though I've written papers on ref some disease I've never seen a patient with it yet gyrate atrophy has classic pictures of it but again you just I've tested for it many times it's just not here but it's been known for decades and then there's sporadic RP which may be recessive with no family history this could this happen when you may have a new founder mutation it may not actually be retinitis pigmentosa it could be autoimmune or cancer associated or melanoma associated and also think about other things that maybe modifiable or treatable think about toxic retinopathy is think about vitamin A deficiency it does happen out there either self induced which is really rare or people who've had gastric bypasses or other other reasons that they could have now absorption that's that's at least treatable and you can cure the patient and then rarely you're going to see stationary rep retinopathy is I see no more than one or two of these a year coming through and that means they have no clinical progression they may have night blindness but visual feel is often preserved and some of the ones include fundus albic punctatus where you get all sorts of little white dots here they have night blindness but they function reasonably well now with the treatments clearly you want to give them the social supports the genetic counseling but the newest thing that's coming is gene therapy so RP 65 one of these recessive diseases that's really rare is as you may have heard I think when we've had the reps come through here is going through the approval process and has has they've spent 10 literally tens of millions of dollars if not a hundred million dollars to bring this to market they've been able to show that by using sub retinal injection of an AAV replacement for the gene RP 65 that you can get better mobility some slowing of the disease but you do not cure the disease and you really when this comes out we're going to have a lot of patients coming in asking well why can't I have this why can't my kid be cured well it took you know essentially a moonshot type project to get one of these to the market it's going to cost probably a half million dollars per eye and it's super rare I have the first patient that I finally found with an RP 65 mutation here in Utah and I've got a big practice and that patient is 40 years old and is looking to get an argus to implant it's way too late for him to be getting any gene therapy so and interestingly he was the very first patient I ever saw here 22 years ago came in so the so that's coming it's good it's our first step hopefully more of these will come along down the line the next one for gene therapy is going to be and we're going to be part of some of these clinical trials it's going to be coratoremia and then start our diseases also coming down the line these are not easy trials to do we're also looking at growth factors stem cells the the patients know a lot about them but there's a lot more height than actual than actual progress in this disease and then there's all sorts of small molecules volt valproic acid Tadka which is Toro ursi deoxicolic acid retina retinoids that have been gone through clinical trials have been tried there's a lot of anecdotal evidence that they're that they might be helpful but when they go through rigorous rigorous trials uniformly they failed so they're not very good and then electro stimulation artifice all sorts of things that patients find on the internet that I have to just say they're on their own there's no good science why this would work but if they want to spend their money they can it's probably not going to hurt any other way and then artificial vision is coming down the line that's the argus to implants which again are super expensive and are not commonly used yet I had one of my patients come through recently who's had one implanted in Minnesota she's they see mild improvements but the newest thing is to actually go to cortical implants because they the technology is not that great comb dystrophies I'm going to go through I think we'll skip that we're going to skip ahead to macular dystrophies and toxicology because I do want to have enough time so here okay so we talked a lot about a lot about or we just talked about retinitis pigmentosa which are rod dystrophies things that are pan retinal diseases but just as much I will see in my practice macular dystrophies and that's really the focus of what we need to cover the last half and that means you know the macula is the unique part of the primate retina that is involved in central vision reading driving recognizing faces we have a lot of age-related macular degeneration but I see a very significant number of inherited retina diseases that focus on the macula as opposed to the peripheral retina now we've learned that some of these disease we're going to talk about do affect the rest of the photoreceptors but for reasons that for whatever reason they tend to be focusing on the cone-rich regions of the retina or that they are that they're focused or that there's something unique that that gives primarily a macular phenotype the most common macular dystrophy you're going to see in my practice is Stargardt disease but and we'll cover that in a little more detail best disease is common and then you'll see a lot of just many other you know things that are rare things that I've never seen in my life and then of course there's age-related macular degeneration and we've learned that some cases of late of age-related macular degeneration once you get enough imaging is actually maybe just late-onset Stargardt disease something that and so you have to have an open mind about what patient but when things don't look typical so Stargardt disease is the most common inherited juvenile retinal dystrophy it's estimated in incidence is one in ten thousand as opposed to one in three thousand we talked about for retinitis pigmentosa so that means it's not going to be as common in a general inherited retina disease practice but it's common enough that you will see it when you come on the retina rotation you will see a number of patients coming through it's and these patients do you know can be legally blind in terms of their below 2200 vision but they tend not to be it doesn't go to total blindness and it doesn't get a whole lot worse typically than 2200 vision which means the patients can still read with large print they can be very successful in a lot of tough specialties I've seen positions with it I've seen I've seen patient patients who are successful lawyers scientists etc. so they can do very well about this means about 25,000 to 30,000 people are affected in the United States and this is a disease unlike retinitis pigmentosa there are very few there's really one disease you need or there's one gene you need to know about for the for the recessive disease and that's ABCA4 but there are rarer dominant forms that you will see in my practice and there is some evidence although it's still controversial that heterozygotes may have some increased risk of age-related macular degeneration so there is some of the dysfunction that you see that causes Stargardt disease in its milder form may also cause some problems in age-related macular degeneration so what is the typical clinical presentation of Stargardt disease well in this case typically they have totally normal vision at birth and and early childhood these patients there was everything was going just fine and then they noticed a decline in central vision most typically in the teenage years but there's huge variation it can be but before age 10 and I've diagnosed certifiably patients and in their 60s and 70s where that's the first first time they've ever been diagnosed with Stargardt disease they the pic the pictures that you will see classically have macular atrophy that may have a little bit of a sheen what's called beaten metal with and they'll have little flecks little yellowish spots here that kind of radiate out their pits of form which means they look a little bit like fish tails and in the more severe cases they will go beyond the arcades in the more mild cases they may be within the arcades of the macula here and typical typically the end stage about 2400 vision with preserved visual with preserved peripheral visual field the when we're looking with the patient with Stargardt disease we want to know the clinical history again you know the the most typical clinical history is patient who was doing just fine in school but suddenly their school their school performance dropped they're not seeing well they're complaining they're just not they're sitting in the back of the class and have no idea what's going on in the front of the class anymore reading goes way down the they may have a positive family history especially here in Utah with large families and you want to do an eye exam and fundus photography and the problem is that this is easily missed by even good retina specialist when you look in the flex can be fairly subtle the the atrophy can be can be mild in the beginning on the other hand we're now in the age of imaging and as long as you get something like an autofluorescence you'll see this increased hyperfluorescence from the deposits associated with stargardt disease you'll see these little flex this this is picked up very well in the imaging and then when we did a lot of fluorescent angiography they have was classically a dark chloride where it just was more highly contrasted again because of the lipofusin deposits if they do a full field ERG it's usually normal or only mildly affected and genetic testing is very important now I mentioned before about I didn't go into genetic testing for RP when someone comes in with classic RP we have a I have a panel that we get from spark that we send away that has 31 genes it's missing you know I told you there were more than 250 genes so it's missing a lot of genes but if you send a panel for free panel they'll get back within a month and more than half the time they will tell me what the what the mutation is in a patient with RP in for stargardt disease it's not free right now the testing costs about $500 but it will I'm pretty good at finding that selecting the patients I'd say that 70 to 80% of the time they will find the mutation in the ABCA4 gene the problem with ABCA4 is it's a huge gene it requires a lot of sequencing there's there can be complex deletions and other mutations and it's they do miss things in this disease but especially since you're trying to find two mutations the chances you're going to find at least one in a classic stargardt patient is 70 to 80% at least and it's important yes I don't the year even the multifocal is not very useful so I follow them with imaging more than anything else and visual function but I don't order a lot of I don't order a lot of ERGs on stargardt patients I the reason why stargardt stargardt disease happens is it's a disruption of vitamin A processing within the eye so that normally when rhodopsin bleaches the Ultrans retinoids have to get in get into the disc membrane they're pumped out there they pass through and get out of the disc membrane by the ABCA4 with this is an old slide it used to be called ABCA ABCR but it passes the retinoids are then kind of transported out of the disc space and on through the visual cycle and to the retinal pigment epithelium to be reisomerized in a in class in recessive stargardt disease this gene or this protein is defective the retinoids sit in the membranes too long they then start reacting because they're react their reactive aldehydes start reacting with lipids the phosphatidolethanolamine in the lipids here in the lipid layer and eventually you start generating a lot of these end stage products this retinoids that are two vitamin A's condensed together that are stuck there and they these become in court and accumulated in the retinal pigment epithelium and are ultimately toxic to cells that's kind of the basics it's a much more there's a lot of research it's a much more I could talk for an hour on this but it takes but that's kind of the basics is that you get a lot of these bis retinoids and for whatever reason whether complement activation whether they're detergent possibilities or whether they're generating free radicals that are damaging but these eventually these are the bad actors in this and the goal is to try to in treating this disease is to decrease the formation of these toxic dis retinoids so how are you going to try to do this well we talked about that vitamin A the retin the bleaching of 11 cyst retinoids to all trans retinoids let's see what's going on here so the 11 cyst retinoids on Rodopsin you get the all trans retinoids these are the toxic compounds that start forming or these start forming the bis retinoids so how are you going to decrease this formation of these bis retinoids well one is to just say well don't use the visual cycle so much so you tell the patients where sunglasses stay out don't or avoid excessive sunlight that doesn't work very well because there's more they're still cycling going on in the visual cycle there's still vitamin A processing another thought is to do visual cycle inhibitors is to give an oral inhibitor of RP 65 these inhibitors we've tried in age related macular degeneration and they didn't work they didn't slow down geographic atrophy but the company is now the companies that have these are now seeing will this work in Stargardt disease and we recently in my clinic we've been part of early phase trial where we've done it given a given a month a month dose of these RP 65 inhibitors and see do the patients tolerate it and we had five patients in the trial they get a lot of side effects they get night blindness from these compounds they see all sorts of bizarre colors and we and we don't know what dose they were on three different doses but of our five people in the study to swore that to stuck it out for two for a full month and said they would never ever take the drug again at least at that dose they could not tolerate the side effects to said yeah I noticed my color vision was off a little bit my dark adaptation wasn't so bad but sure I could do this for two months if this potentially could help me and one was right in the middle so hopefully when the code is broken it's the height it's the real high doses just means it's too high in these patients and there are lower doses that could be tolerated if it's kind of random and that some patients are going to drop are going to be just disabled even at low doses that boat doesn't vote well for the trial but ultimately if you're going to do these small molecule therapies you're going to have to these are going to have to be taken for years at a time and it's going to be big trials and there's a limited number of patients out there gene therapy sounds obvious just replace the bad ABCA for gene the problem is it's a huge gene it's very difficult to package it it's very difficult to deliver it there are companies that are trying this there and they're starting to contact me so we may be doing gene therapy in the next few years on some of these some of these patients stem cells again try as a restorative but it's not yet ready for prime time and of course you want to do genetic counseling especially since this is a recessive disease if in a family if they're what if a 10 year old has it and they're still having more kids they at least need to be warned that they may get the get the disease that they may have more children with this disease on the other hand a patient with Stargardt disease you tell them as long as you don't marry a close cousin or as long as you don't pick the one in 20 random people that are carrying a mutation your chance of getting your children being affected is low but it does happen and I have you know one I have one kind of ticking time bomb family where a patient with Stargardt disease married the the son of a of a Stargardt patient so they now have 50 but if you calculate out they have a 50% chance that their kids are going to be affected but we may be able to catch those kids early through genetic testing and put them into these trials and then of course there's low vision services that have to be done but not all Stargardt disease is ABCA for there is a dominant form of Stargardt disease that looks every bit the same in a lot of these patients but is much more rare I do have one family of 18 family members with this disease that we discovered and characterized there and so this means there's only one or two thousand affected patients in the in the United States and this is a completely different gene in the ELOVL for gene here and we have even Utah is even more unusual than we have we have our own kind of founder mutation here but they get Stargardt disease with these flecks again they can have a pattern dystrophy and this is different because it has a whole different pathophysiology instead of a targeting the visual cycle in this it's a lipid metabolism disease and that's just shown here where it's the it's the enzyme involved in making what are called very long-chain polyunsaturated fatty acids these are special fatty acids that are found in the retina that seem to be important for for constructing the discs in the rod outer segments and in this family it's more a nutritional problem if you can if you can give them high doses of fish oil or if they consume it in their diet they tend to be relatively protected against this disease we did try a clinical trial of fish oil in these families and they were so non-compliant that we never could prove that it was really affecting them but I still recommend it within the families the other common one you're going to see in clinic is best disease and it's dominant and they typically present in young age the classic best disease with these the telephone lesions these yellowish lesions and it's these can eventually lead to choroidal neovascularization or macular atrophy here but best disease has a lot of different presentations again you I've diagnosed patients in adulthood with best disease there's it's incomplete penetrance is almost the rule not the you know not the exception in this disease I've even seen incomplete penetrance even between eyes or one patient has a full blown case of best disease in one eye and the other eye is totally normal so and you can have multifocal lesions instead of just the classic ones that you'll see in the pictures in your textbooks so they can have little yellowish spots here and they're all mutations in the bestophen gene and that's an RPE specific ion channel protein and so and there's some evidence that atypical age-related macular generation can also be associated with this disease so how do you test for this one and how do you manage it as you see classic lesions that to raise your suspicion they are loaded with lipofluorescence so they're highly fluorescence so again autofluorescence you know is part of the standard workup when my patients come in for in any sort of inherited disease and there's widely variable visual acuity someone like this could be 2020 and asymptomatic with this disease or could be could be very heavily affected and how do we diagnose it clinical history family history eye exam photos especially getting autofluorescence and then electrophysiology a electro retina electro oculogram is the classic abnormal finding in these patients and that Don Creole will tell you about and they typically will have a normal ERG and so with these diseases you want to do monitor for carotone abascularization give them low vision services as necessary again it's kind of like stargardt disease they will probably not not go to they may hit legal blindness and then just stop and then you want to do genetic counseling gene therapy if it's available when it becomes available genetic testing then after that we start getting into the rare things things that I've said that I don't see in my practice but are going to be but are at least in the literature because they've been known for so long their source we fund this dystrophy which is a very rare form of of macular dystrophy associated with carotone abascularization they have abnormal dark adaptation and peripheral drusen it's found in the British populations as source be as a British ophthalmologist and the the mutation though this is important because the mutation is known in the 10 three gene this is definitely associated with some forms of AMD in the genome wide association studies there's no current treatments it's a rare enough disease that there are people are not working on this disease it's not it's not going to have gene therapy very quickly then there's other things like malatial of anti-nazi or doins honeycomb dystrophy which are dominant drusen the things this will show up on some of them on your O caps and boards with these large numbers of drusen here and the the key thing that people talk about as they tend to be found in in this disease that's unusual as they often have drusen nasal to the optic to the optic nerve and they have a radiating pattern for whatever reason this can be compatible with good vision and its mutation is pretty well established the monogenetic disease and it might be associated with AMD and then there's North Carolina macular dystrophy this was one of they tend to have what are called macular colobomas here and they can be they can have surprisingly good acuity this might be a 2020 I and this was the first gene first macular dystrophy to have its gene found to have linkage and be established there was an inherited disease dominant inherited disease but only in the last two years did they identify the gene it turned out to be a very hard gene to identify and and when they finally figured this out it turns out this is probably a congenital disease and not progressive there's no treatment for this disease but hopefully they can continue to see well so I think that's we have that's what I've gone through here and we can either have discussions or I can talk about cone dystrophies which I kind of skipped through so what questions do you have about macular dystrophies or retinal retinal degenerations and how I handle it in my my practice what you should know any comments or questions I mean I think it's a it's a very fascinating part thing to know and to learn about these diseases when you're in my clinic there's a lot of kind of thinking about how these diseases are affecting the families both socially what kind of biochemical approaches can be used with regard to things like stargardt disease there's a lot of real fascinating biochemistry that can be done when you go back even I'll go back here when you attack the visual cycle for this the one of the other studies that we're working on is to figure out you know you're trying to restrict the vitamin a going through this pathway well what if you replaced your vitamin a with a different form of vitamin a that would just work fine in the visual cycle but not form these toxic compounds and so there's a company called alkias that has come up with a deuterium labeled form of vitamin a that can be administered orally you need to go on to you don't have to stop consuming all the vitamin a in your diet but you don't want to overdose it you don't want to overdo your your dietary intake of vitamin a but we can give enough of this drug so that 70 to 80 percent of it of your body's vitamin a now becomes the drugs the drug form of vitamin a and this one because of having three deuteriums in a select spot in the on these molecules will will not form the toxic compounds but will still work just fine in the visual cycles so we have a couple yeah I'll talk to you in a second but so we have a couple patients in that trial and they do just fine you know they don't have any visual complaints they don't you know they're on the diets not overly restrictive on them and they supposedly if they if they behave like the mice will not form any of these toxic compounds anymore so it's I would consider a well-tolerated drug you know of course if it makes it to market is going to be a ridiculously expensive drug but it's it's I think a very elegant bio chemical approach to this disease that doesn't have all the side effects so I'm hoping it works but it's they're they're going very slow and getting this to try out through the trials they're not enrolling a lot of some patients so yes that's probably not significant enough to cause problems it's not absorbed enough to be a big problem basically you tell patients with start-up disease don't go out of their way to take a lot of preformed vitamin a supplements and that's been that's been fine let's see so with regard to genetic testing and and just talking with the patients it will be very helpful in having a genetic counselor on board right now it's you know I really think genetic counselors learn a lot they know how to give reports to patients they know how to how to interact with these patients it's been very hard I've found trying to do that myself you know we all have busy clinics patients need a lot more time to discuss this it's hard to keep up on which are the proper labs to be sending tests to you know who will get back quickly how do you select which tests should be done how do you consult patients whether it's worthwhile to spend the money out of pocket or to fight with the insurance companies to get these genetic testing done right now with that I found is that in genetic for genetic testing the insurance companies will often cover for it cover it but they require they make it difficult you can't just order I want to get genetic testing for start-up disease and get reimbursed for it they want a letter from me a genetic counselor a letter from the physician explaining why you want it they just make you jump through a lot of hoops and that's for a $500 test if you're asking for a whole genome sequencing or a whole genetic panel for macular dystrophies or retinal dystrophies you're talking about $2,500 or $3,000 and that's harder to get approved many patients are willing to pay out of pocket for genetic testing if you tell them why it's important that it will get them into clinical studies that it might help diagnose in the family but it's very obvious you can tell what the price point is $500 many patients will pay as soon as you get near $1,000 they stop at $2,000 to $3,000 almost no one will pay out of pocket. Yes. So right now it's a good question right now we have our own local database that we're keeping in hope and that it's kept in clinical studies right now we then we update that and so when when we're approached and I get a lot you know I get people writing to me you know how many we're coming out with with a treatment that's targeting p23 age road ops and last how many patients do we have well we can give that number there is no national database right now out there registry people have tried to do that but that has not happened yet on the other hand some of these companies are developing their own so why is spark doing genetic testing well they want to find they want to find every patient in the United States with RP 65 so that they can have they can offer their treatment that they have they now know that they're developing their own database first that is there that is theirs they're a proprietary database that knows all the genetic profile and there is a huge variation just by region in the United States there's all these founder effects it's really it's very real yeah I don't know but I think they're providing a service and I think it it's you know there is still confidentiality they're not contacting the patients but they at least know they can target where they're going to you know which diseases they want to go after but they still if they want to get the patients they still have to what the current standard is is to contact inherited retina disease specialist around the country ask well what do you have at your site and then and then go from there because they they won't do anything more beyond that ethically they can't go they can't go from there but that's that's the price we pay we give up a lot of do we give up some privacy but to get there they are providing a service that's valuable to patients I will let people go all right