 foundation. Divisions to find cure for CODE's disease. Missions to offer patients hope and improvements as they wage a lifelong battle against CODE's disease and blindness. Goals are to build awareness, raise funds, fund research, and build patient resources. Now it is a nonprofit foundation. It was established in 2006 by parents of Jack McArna. It was our honor to actually, Jack is here today with us in the audience, as well as his mother Tina. And they promised really to find cure for disease, CODE's disease. Now it's only fitting that our inaugural keynote lecture on Jack McArna CODE's disease foundation keynote lecture is Mike Jumper being that he has taken care of Jack. Now I'm going to tell you a little bit about Mike. His medical school training was at the University of Texas, Southwestern in Dallas. He's a resident in the University of California in San Francisco. And we share passion for blue devils since he did his fellowship at Duke. He then went on to do his chief service in the United States Air Force. He's currently a Vice Chairman, Retro-Renteral Service Chief and Retro-Renteral Surgery Fellowship Co-Director at California Pacific Medical Center. He's a member of West Coast Retina Medical Group in San Francisco. No Mike from many appointments. And he's a pretty prominent role within the ASRS as a Board of Directors and also editing and leading on some of the really well-known publications such as Retina Times as well as a preference and trends survey. He has published over 80 journal articles, chapters and peer-reviewed ophthalmology literature. He's given really numerous presentations and participate in many courses. He's on editorial board for the ASRS Journal of Retro-Renteral Disease. And he has really served in many scientific reviewer as a reviewer for many journals. He has received many honors, senior honors from AO and ASRS. And he has been an outstanding teacher and you can witness that by outstanding faculty awards given by residents that he's thought. So without further ado, I would like for you to help me welcome our inaugural keynote lecture for Jack McGartin Coates Disease Foundation. Mike Jumper and his talk will be on Coates Disease, our current state of ignorance. Thank you, Mike. Well, it is really an honor to be invited to speak here and to be given this honor of being one of the keynote speakers. And I wanted to share with you a passion that I developed when I first met Jack with Coates Disease. And tell you what we know and maybe what we don't know about Coates Disease. I have no financial disclosures pertinent to this talk, but I will be talking about the off-label use of a lot of drugs. And when you're talking about a lot of drugs, it means not one works really well. So that's one of the reasons. The Coates Disease Foundation had its beginnings almost a decade ago when in 2010 the family, the McGovern family and the foundation sponsored a small retinal vascular disease meeting. You can see some of the familiar faces in the crowd that we met in San Francisco. We did it again two years later and this meeting was in 2012. And their dedication to education and getting people together and networking and learning has been really tremendous. And I very much appreciate that. And all my colleagues that made it out to San Francisco for these meetings. And now here we are today, this big meeting that Emmy has put on and they've been a part of that as well. It's been a great 10 years, really. And I didn't really appreciate the bottom-up research efforts that are needed for rare diseases until I met the McGovern family. But it's a very important thing that either a solo investigator or a family or somebody with a real vision starts working on a rare disease or else it won't get studied and it won't get cured. These are a couple of articles that highlight families much like the McGovern family regarding this effort. I'm a clinician and I'm going to give you a bunch of cases. And I'm going to throw some cases out to start with. And I'm going to come back to those cases as we're hitting on points in Coates disease that I'd like to make. The first case is an 11-year-old Asian boy who had progressive vision loss in his left eye for a month. And it was harder for him to see in the dark. He has a past medical history of asthma. No family history and his vision was counting fingers in this affected left eye. And you can see pretty amazing exudation throughout the periphery and in the posterior pole. The second case is a two-year-old who had normal birth and development, developed a right exotropia, was discovered by mom. That right eye had poor vision and on examination had a 3B coats related retinal detachment. Now just to refresh the memory of people, this is the classification scheme that had been developed over time and was finally kind of elucidated by the shields who have done so much in our understanding of Coates disease. And you can see here 3B means a total retinal detachment. The third case is a 12-year-old boy who had vision loss in his left eye for three months. No past medical or family history. And poor vision in this left eye that has peripheral telangiectasis and posterior pole exudation with subretinal and intraretinal fluid. And then the fourth case, a five-year-old boy who looks very much the same with macular exudation due to temporal telangiectasia. His vision loss was discovered at a school screening. The vision is 2400. The last case is a patient who has distortion of vision and he was diagnosed with multiple sclerosis and currently inactive without therapy and was treated for Coates disease originally when he was 26 about five years ago and now has good vision. The macula was never affected but now has some distortion associated with exudation that's temporal to the phobia. So the original Coates description, we were talking about this yesterday these researchers that happened in the early 20th century were quite good at identifying and characterizing and showing what things look like without all the fancy equipment that we have. And Coates did a good job of identifying this condition as being in young males, usually unilateral, congenital, not familial and really not associated with any real systemic disease uniformly. But the question is usually unilateral still hold and is it really unilateral? Well, there's been some studies that have been done by members of this audience including Mike Blair and his co-workers that showed that there are vascular changes when you look with wide field angiography in the unaffected contralateral eye in some Coates patients. They are in the form of telangiectasis and micro-aneurisms that rarely exudates and are not neovascular. And in a larger multi-center retrospective study looking at 175 Coates patients they found that 19% or so had this contralateral finding, none of which progressed over time. Going back to Coates description, there are retinal vascular abnormalities which we all are aware of associated with exudation and this has a tendency to accumulate in a posterior pole and he also identified the lipid-laden macrophages that are in the sub-retinal and intraretinal space. So later on we've had some refining of the definition and the shields in one of their named lectures proposed that Coates be defined as idiopathic congenital retinal telangiectasia with intraretinal or sub-retinal exudation and without appreciable vitro-retinal traction. And this was really trying to distinguish Coates disease from the many conditions that result in either retinal telangiectasia or exudation or both. So going back to case one, this is the 11-year-old who's had some difficulty seeing in the dark. His other eye is not normal. He has peripheral retinal changes and his visual field is abnormal. In both eyes, electrophysiology is also abnormal with abnormal photopic and scotopic ERG responses. So this is a child that has retinitis pigmentosa and has a Coates-like response. Now there are systemic conditions that have a Coates-like phenotype including FSHD, Senior Locan, Turner syndrome and Alport syndrome and then there are ocular conditions that also have a Coates-like response as well. There's a little controversy in this. I think in some of these conditions it may be that they actually have a real Coates sort of phenotype such as in Turner syndrome and we might learn something from these genetically abnormal conditions that we can somehow link up and try to sort of discover what's common between the retinitis pigmentosa or say FSHD that we can kind of better understand the cause of Coates disease for which we don't at this point. There's an estimated incidence of 0.09 for 100,000 people. That was from a study by Morris in the UK. It's been diagnosed anywhere from one month to 79 years of age but the median age of presentation is around five years when you look at tertiary care centers that are getting referrals mainly to rule out retinoblastoma and other things or eight years when you did the population-based study. When there is an earlier age of presentation there's an increased disease severity and an accelerated progression and this is almost its own entity in my opinion and in an advanced Coates series of advanced Coates patients 40% presented at or before the age of two. If you don't do anything about Coates disease, it's not good and so total retinal detachment is common. Neovascular glaucoma occurs in a third of patients without treatment and HAKE reported that 80% of the untreated patients in his study developed ticis, neovascular glaucoma or both. So the treatments that we have available to us include ablative therapies as you know, drug treatments, intraocular surgery or a combination of all of the above which is what a lot of people end up doing some form of combination. Now as far as ablative therapy, I'm a big believer in the results of this paper and the Baskin-Palmer experience and that repetitive aggressive laser I think is oftentimes a good way to control the progression of Coates disease. In their study they used a diode laser and their objective was to whiten the vascular abnormalities even in detached retina. And when the retina reattached or in areas of reattached retina you can place scatter laser in the areas of ischemia. They did a medium number of four to five treatment sessions and they applied the treatments about every two months and they had very good anatomic outcomes and this is what I feel has been helpful in my practice and I employ much of the time. Laser has long term good out of atomic results with a loan as a monotherapy and we find that using intraoperative wide field angiography can help identify the extent of the disease in the areas of ischemia that may not be so easy to see on examination alone which then I think reduces the retreatment rates. Cryotherapy has been traditionally used for stage three and four disease and I think it still has some role but I don't use it much. It may temporarily increase exudation and I would just caution that people be careful when using it with combination of drug therapies. Intraocular pharmacotherapies, the rationale is that angiogenic and bioactive factors have been found in the fluids of coats patients at higher levels than normal and you can see the list of the agents here. VEGF levels interestingly are higher in the pediatric coats patients than adult coats patients which may explain this different phenomenon that you have in the younger patients with greater exudation and problems. Steroid therapy has been used, primarily intravitural triumcinolone has been studied with mixed results as a monotherapy and there have been a lot of complications reported when it's used in combination with cryotherapy. A study by Berkstrom helped to let us understand that. They found elevated intraocular pressure in four or five of the patients that they treated with intraocular triumcinolone followed by cryotherapy some months later. There was severe cataract in three of five patients and then even long term there was development of traction and retinal detachment that was inoperable in three of five patients. So I would caution people to avoid the use of intraocular steroids and cryotherapy. Intravitural anti-VEGF therapy I think has a role. A lot of the different drugs have been used. There's a temporary reduction in exudation and much like the treatment of proliferative diabetic retinopathy or other exudative diseases that we deal with, it's not a cure, it's a temporary treatment. And so an ablative therapy is often needed in conjunction or afterward. There have been reports of improved vision but there have also been reports of vitro-retinal fibrosis and progressive traction to detachment reported with the use of anti-VEGF therapy combined with ablative therapy especially cryotherapy. So again cryotherapy and these intraocular drugs are something to be cautious about. Now intraocular surgery for coats is usually reserved for stage three or greater disease and it's been shown in this series of a large number of patients with shields that 17% of those patients ended up, 17% of the eyes ended up meeting some form of intraocular surgery in their hands. The techniques go from anywhere from placing an anterior chamber infusion with drainage and then having the reattached retina using the reattached retina to ablate it with either laser or cryotherapy more often. But then the trectomy with all the different techniques that we know to use have been employed to try to get retinas reattached with coats detachment. I'm sorry, this is an example in the literature from Stagna and his co-workers showing an anterior chamber maintainer placed with a 27 gauge needle that's poked through the sclera, through the coroid to allow drainage of sub-retinal fluid as the anterior chamber maintainer is maintaining pressure in the eye. So, colleagues in this room have gotten together and put together a series of patients who, looking at long-term outcomes of stage 3B coats, you can see here this was 16 patients, or 16 eyes of 16 patients with at least five years of follow-up but it was very long follow-up with a mean of nine and a half years. The interventions were all of the above including ablation in all of them and then the trachomy was performed in 12 eyes eight of which had the trachomy within the first year of diagnosis and four of which had what they called late which was average or mean of three years after the diagnosis. The outcomes are disappointing but what we see, what we see with no light perception or light perception vision in eight eyes, counting fingers vision to 2225%, some of the patients had some vision to begin with. There was neovascular glaucoma and tysis that developed in four eyes but 15 of the 16 eyes were salvaged. There was a thought that perhaps earlier of atrectomy, the group that received the atrectomy earlier in the course might have a better outcome as there was less vitreo-retinal fibrosis and less traction in those cases in the long run. It just makes me think that this is a disease that we can't let get to the 3B stage and so we just have to figure out I think ways of screening babies and young children better than we are now and I salute Darius Moshfagi and his coworkers who have tried screening tests and are proposing this as I do think this is something that might be a way for us to prevent blindness from Coates disease in the future. So of all the causes of permanent vision loss in Coates disease unless we can get to this early, catch it, treat it before the macula becomes involved, a lot of these are very difficult to reverse. One, though, I think is macular fibrosis where I think we have some hope and that brings up case number three and this is a 12-year-old boy who has poor vision like a stage 2B. You can see here before treatment he has quite a bit of exudate in his macula and serous detachment and some intra-retinal edema and three months after treatment it's looking better as far as the OCT is concerned but you can see there's increased exudation or increased lipid deposition in the macula the vision's improved somewhat. Three months after that, now six months after the original treatment something has changed in the macula there was no leakage to begin with in the macular area and now there is. Well, what's gone on? You can see here there's a fibrotic scar in the center of the macula there's a pigmented spot in the center of the fibrotic scar it looks like vessels are diving into that area where the pigment is and this is all centered in the area of the greatest exudate deposition earlier. So what's happening with the angiography you can see here it looks like a retinal retinal anastomosis has formed and there looks to be abnormal blood vessels and choroidal neovascular retinal angiomatous proliferation happening within the retina here and with leakage late. So we call this or it's been described as macular fibrosis and Coates disease. I looked at the patients in our practice over the time our practice was in existence at the time and 47 patients who had adequate imaging were sort of looked at and the conclusions were that this is very common in Coates disease this macular fibrosis that it occurs at the point of the exudate accumulation and it's a neovascular process and it portends a worse visual prognosis. So this is another example of a case in which we have neovascularization happening right in the center of the macula and it turns out that of the 47 patients in our series we had 23% or 11 eyes who developed this exact phenomenon and it's always sort of at the area where the exudate was most dense there's usually within and underneath the retina and there's this intraretinal vascular anastomosis that had been identified in seven of the 11 eyes. There was hyperpigmentation oftentimes at the point of anastomosis and this is something that was reported originally in 2010 and it's been some other coworkers or authors have found similar findings in their Coates patients and Eric Sigler and Dr. Calzada both they found that their rate was around the same as ours 24% of the patients that they studied had the same macular fibrosis. The lower author Darius has proposed that the presence of a sub foveal nodule be included in the Coates classification that was proposed by Shields. So what is the pathophysiology of this fibrosis? Well it seems that phospholipids are a stimulant for inflammation that are there and that this inflammation is a stimulant for angiogenesis. This is my sort of guess on all of this. This is Larry Yanuzzi's paper on retinal angiometous proliferation and I think the same sort of thing is happening here from the top down in our case and you can see in our patient this area where the anastomosis is occurring much like a retinal angiometous proliferation lesion. Now this is not isolated to Coates disease this can happen in any exuded process this happens to be a patient that Albert had reported on with von Hippel disease who developed macular fibrosis after severe exudation. There's also macular fibrosis that can occur in diabetic retinopathy and it's kind of interesting looking back at the ETDRS study that 1.8% of patients had choroneovascularization or anovascularization process happen during the course of the ETDRS and it seemed that the extent of the heart exudate was the strongest risk factor at the time they proposed that this had something to do with the laser treatment that the laser was creating choroneovascularization in these patients but 34 of the eyes 34 of those 109 eyes who had this process had not had any laser they were in the control arm and of those patients who were treated with laser 92% did not have the choroneovascularization kind of associated with the actual laser mark so it's, I think this is a case where the exudation is creating neovascularization. Well, in more recent diabetic research they have been looking at the effects of anti-veget therapy on retinal heart exudate in diabetic macular edema and in the exploratory analysis on ride and rise study patients monthly intravitral randobizumab resulted in significantly greater reduction in the heart exudate as compared to sham and in contrast to the rapid decrease in edema this was a much slower process reduction in the heart exudate but it gives me hope that maybe there's something that we can do to reduce the heart exudate which is the nightest in my opinion of the neovascular process well this brings up case 4 so I've already dealt with case 3 he came and went and he's got just as much exudate in his macula as case 3 and so and just as much sub-retinal fluid and all so what I did on this patient was begin anti-angiogenesis injection therapy during the course of the exudate resolution which usually happens that I've seen over several months and usually requires about five injections about every six weeks to sort of get through that period and you can see here as the exudate is going away after six weeks and then 23 weeks and then 32 weeks after and then we get into six years and seven years there is a reduction in the kind of fibrotic but not complete resolution of a nodule underneath the retina but it does not appear at least clinically as far along and as bad as what happened without treatment but I am completely open to this being just the natural history and that I didn't do any good with the anti-vegeta injection therapy but I'm hoping that we are doing something to help these patient's eyes and he this patient had a good outcome you can see here not a big scar and no retinal-retinal and I can see on examination of this patient now almost eight years later this is another example of a patient who received five Bevacizumab injections over about six months over about eight months and this is a picture taken at one year after initiating therapy so the other interesting thing about this kid this kid has an unaffected identical twin brother so it sure would be nice to get genetic analysis on this patient and his family and we did and so this just is a segue into the genetics of coats which I don't have any answers for you but I'm intrigued as most of you all are as well it all started with me with a paper that was by black and his coworkers out of England who found that they happened upon a patient who had coats a woman who had coats disease and a coats phenotype who gave birth to a child with Norie disease and then in looking back at the genetics it found out that her mother had an NDP mutation she was a carrier so then they then looked at archival coats tissue from their tissue bank of coats disease patients and they found that one of those nine they could find an NDP mutation a somatic mutation in some of the tissue it was present in the in the ocular tissue and the retinal tissue but not a non-retinal tissue in this eye that they studied so maybe there was sampling problems and they couldn't find it in others maybe there was a sampling problem and they found it where they shouldn't I don't know but it's intriguing that we're talking about the possibility of a somatic mutation I think it's much more complicated than this but it started with the idea of genetics in my mind at least there has been developed a coats disease registry and this is a multi-center effort and thanks very much to the efforts of Emmy and Drs. Lee Rekia we have partnered with the Jack McGovern Coase Disease Foundation and Genentech and have performed whole exo-em sequencing and gotten data on 61 unrelated probands 12 first-degree relatives and we have complete trio data on 26 families at this point and this is what we're working very hard to get kind of mother-father proband data on more of these patients and the collection has yet to be completed but we're very excited that we now have one of the largest whole exo-em databases for coats disease that we hopefully will learn something from here in the future alright Case 5 is our 32-year-old man who at age 26 5 years previously had been treated for coats disease and has new distortion but good vision and these are images from 5 years earlier in which there is some mild exudation in the superior temporal periphery but when you look and this is not easy to see but on the screen there is the original area which then turns out to have the new coats lesions and exudation later now 5 years later it's not very impressive you wouldn't have treated it back then and I don't see much in the way of leakage at that time there's another example of a patient I saw just a couple 3 months ago and retreated is a young boy who has again retreated in 2011 and now here going on 8 years later he has an area where you can see on angiography by the arrow really not much going on that turns in to be a real exudative component there so late recurrence in coats disease after initially complete therapy has been described in up to 7% of coats patients in the meantime to recurrence is as long as 10 years so that's why we need to keep following these patients remind our patients that they need to keep being watched because there is a chance of a late recurrence so in conclusion our cause remains unknown for coats disease the vision loss is too common and we definitely need more effective screening and it's going to be the people in this room that will make that happen we need further study to prevent this macular fibrosis and I'm excited about the possibility of pharmacotherapies to do so that macular fibrosis is a neovascular process and fairly common I think potentially a way of preventing vision loss in patients with coats disease and I think that the phospholipids may have something to do with promoting this inflammation and angiogenesis it seems that peripheral ablation of abnormal vessels and ischemic retina is the main form of therapy still lasers effective and even in detached retina and multiple sessions may be required if you do that and I'd say be cautious when using cryotherapy and coats can recur in a previously normal appearing part of the retina so long term follow up is needed now I want to give special thanks to Emmy Layla and Cindy this has been a wonderful course and you know I can tell it's really been a big part of your life for the last year and a half or so and I know that it's really been a tremendous success I also want to thank the Jack McGovern Coats Disease Foundation including the McGovern family Debra Marin and the board and I want to point out to the people in the audience that there's a website CoatsDiseaseFoundation.org and there's a couple things that I'd like to direct you to on the website number one is that there's a place in which you can sort of identify yourself as somebody that takes care of Coats patients those who are on this website and this website is indeed frequently visited by patients and families and then also there's a patient registry that I would encourage your patients to consider being a part of as this genetic efforts get going further that would be a good way for us to recruit patients so thank you very much for your attention yes time for questions yes sir hey there's a twin study on Coats and they didn't find any genetic association between the twins do you want to comment on that? yes so there have been some genetic studies looking because there's some sort of candidate genes that were people were looking for and even in the the wind signaling pathway there has been nothing really shown to date that indicates this is a genetic problem just a germline genetic problem I still hold hope that there's got to be some sort of downstream thing that's helping with the maintenance of vessels in general and I do think that Genentech has taken this project on and done a lot of whole genome sequencing and I think that they're doing so because they have a hunch that we could learn something from this little disease about vascular maintenance that might pertain to diabetes or other vascular diseases Nina oh I'm sorry yes here I'm Dr. Ozek from here with the moderator site I was looking hard you have shown a very nice case with antivirus where you don't have any nodules nodules didn't happen I mean in the form with just anti-vegeta injections is that correct well they were treated with a blade of therapy in the periphery but they were treated with anti-vegeta together well yes I mean the blade of therapy I think of as being the thing that stops the peripheral exudation and the anti-vegeta what I think of is that the idea is to keep the that exudate from turning into neovascularization in the peripheral I have not seen great results with anti-vegeta in causing sort of exudation to dry up without laser but that was my idea that was just five injections or you continue to it was five injections done over about a six or seven month period done about every six weeks and I feel so when you combine the injections with the laser it helps but it's difficult for the children to give injections under anesthesia so that's why I'm concerned how many you did thank you Mike? great talk yes great talk but you know the most interesting patient I have with Coates is a 70 year old guy now who came to me I followed him for 20 years and in those 20 years he pops little areas that we treat with laser and he also had a slight vitreous hemorrhage when he had a PVD but throughout 20 years it's been great to follow him because and geographically he just pops little areas that we treat yeah I mean that's something that makes no sense to me I don't I don't get it so yeah the nasal retina so I think I'll repeat that for cases of late recurrence what I've tended to see is under treatment of the nasal retina the tensions on the temporal retina I think that using ultra-wide field either ret-cam or obtuse imaging to try to identify all those vascular changes and nuking anything that looks even slightly abnormal gives the best chance at avoiding late recurrences I agree with that you can get late recurrences in the novo areas but you can also get you can get what he's saying I think is just progression in a sort of quiescent area that had vascular changes to begin with and you really do have to look for those yeah and it keeps that VEGF drive going maybe Mike this disease and familial x-ray when it gets ahead of you I think are the perfect examples of that penis-satotic leakage that I mentioned when I talked just saying about the VEGF anti-VEGF therapy didn't seem to add that much it's kind of instinctive that with this type of leakage we would think anti-VEGF therapy would be something to do because we think of anti-VEGF therapy and control of leakage but this is a perfect example of why normal healing fails to treat really severe leakage it's a really fantastic demonstration yep Leila that was just a beautiful lecture thank you very informative and very interesting intriguing questions we recently did an institutional review of all our cases of treatment over the period and over the decades in terms of how our management has changed and very much along the lines of what you've talked about but we also did some some indices of OCT findings what we can see in codes and it was interesting to find out in cases where they show an intranetal just like in mimics and diabetes and other disorders that intranetal exudation typically does not limit visual acuity down a road but sub-retinal definitely tends to clump like you showed and potentially creates the nodule but I think UK's very well illustrates potential use of anti-VEGF to limit the nodule of formation or at least vascularization of it I think in that particular case it looks like the kind of fibrosis did form but luckily a little more phovial locusia release versus sub-phovial now the question for you is any pointers how to decrease the amount of sub-retinal excitation as it takes place as we're treating because sometimes we find out that treatment actually provokes it and what are your pointers to limit that because that's actually again the limiting factor in visual acuity benefit so I think that the exudation when you see it increase like we did in the third case when it was there it's just now falling out of solution and so it does increase the amount of exudate which you see that's present and when it falls out of solution like that I don't know that there's anything more that can be done there's been talk that I don't believe maybe others could comment on this that perhaps if you laser somewhere out in just a barrier to where the actual vascular changes are that you might decrease that migration of exudation but I don't know that I don't believe that another thing that has been shown that Golan Payman who is such a fantastic mind he has done actual sub-retinal surgery to remove exudate in coats patients but I don't think that's that wise either Mike that was a terrific talk you know when you showed the images of the where there was vascular where there was a recurrence and then you went back and you said this is where it was and we were all like oh my gosh I wouldn't have seen that or treated it you know as the resolution and some of our imaging improves right or the ability to see better whatever the optics are we might be able to pick up things like that earlier I agree I think that OCT angiography could be a very good way of picking these up when we get swept source more wide field OCT angiography we're probably going to see a lot more things and I think just like Mike has pointed out and taught me about fever this lapel area you know you can see that in coats disease where you have you know there are vessels going through it the retina right there and to me I think that that's an area that may be driving further exudation that we have to pay attention to and do something about maybe give norigen TM Mike you said you give six injections so at what point is your decision to stop it's a very easy end point when I feel the exudate is cleared enough that it's not going to turn into neovascularization and that's a a lot of exudation has to go away you know but I I feel like over time with coats disease I've gotten a feel for how much exudate it takes to create this fibrotic scar and so if it starts breaking up and thinning out I feel like you're in pretty good space Hi Edward Wood Royal Oak Michigan Dr. Jumper great talk one thing I was thinking about for your twins is it could be interesting to look at epigenetic sequencing in addition to whole exome sequencing provide some good information I think we have I actually have two twin boys which are affected both identical and so that is one of the things that we're working on with the Genentech and the Jack McGovern Coase disease people I have a question here I have to admit I'm not a Coase expert but I would like to ask you talking about the macular fibrosis what histological evidence are there that there's actual fibroblast involvement and I ask that mainly because the imagery that you've shown is I guess it reminds me of the processes that we've our lab has been doing some work which we haven't reported at this stage but we've been looking at drusen formation in infants like from a a series from I guess an eye bank series and we've seen drusen from age nine years onwards and I guess I'm trying to differentiate the pathogenetic genetic process in Coase disease between and the separation and the exudate deposition underneath the RPE and then the caroidal neovascularization it's reminiscent to me of possibly a slightly different like as the RPE separates you've lost the I guess the digestion that RPE role of digesting the photoreceptor outer segments so I'm trying to sort of think about the pathogenetic processes in terms of slightly different to you know I'm a angiogenesis person so I love that mechanism but I guess I'm also asking you in terms of drusen formation and the separation of the RPE and how that affects the deposition that you're seeing in Coase yeah I mean I feel like the separation of the retina and the retinal pigment epithelium shouldn't be enough of a drive in itself to create neovascularization in this situation we have people with central serous retinopathy and have you know separation for months that don't get this kind of a complication I really think that the lipids sort of between the retina and the pigment epithelium have something to do with this we know that that recruits macrophages and we know that macrophages have an angiogenic component so I'm not sure if I am following your question other than what I just said I know I actually do agree with you and part of the drusen contents that we're seeing is that there are lots of fatty lipids as well as the macrophages so I guess that there is an overlap in the pathogenetic processes that's all I'm saying I think you might be right excellent thank you very much thank you