 Good morning everybody, I'm Nico Ronchile, I'm one of the first-year residents. I'm going to be talking about today about macular tilagric Asia. There's been a lot of studies, it's been a hot topic in the last several years, and I just wanted to go over natural history and the research that we are conducting to help identify genetic positive mutations that cause macular tilagric Asia. So let me start with a case presentation. This patient is a 21-year-old male that was seen last year around July. That was referred for blurry vision that he noticed especially when he was driving. A pretty healthy guy in other past medical history. His father and sister has a history of a shark or married tooth that is being followed in neurology. He has two siblings, including the sister, which has no eye problems that they report. And the father has a macular problem that he says he's had since he was 30. The rest of the history is non-contributory. His examination on this first visit was 2100 and 2080 on the left eye as a best-corrected vision. His pressures were normal, pupils were equal in no APD. The rest of his exams were normal. Just to note, he does have some slight decrease in his color plates, the three out of eight plates and the five out of eight in the left eye. His anterior segment was otherwise remarkable. These are his fundus photos. I just wanted to point out a couple of pertinent findings. The first is we can see this graying of the macular area in both the right and the left. That's one of the first things I saw. The next thing is there's this pigment comp. I don't know if you can see that very well. A temporal to the macula. And then finally, just looking at the phobia. The phobia just doesn't look normal as well. I would characterize this as having irregular pigmentation. That is probably a little bit more pronounced in the left compared to the right. But the rest of his fundus looked normal, optic nerves looked normal, and the periphery looked normal, which I'm not showing here. In infrared, what I wanted to point out is that you can see these little spots of hyperreflective spots more pronounced really in the right eye compared to the left. But you can see it as well in the left. On OCT, these top portion is the right, and bottom is the left. I just wanted to go through this. You can see loss of or irregularity in loss of the ISOS junction. The outer nuclear layer, especially centrally, is lost as well. You can see the inner nuclear layers also disrupted. And there's these little hyperreflective spots just along the inner retina as well that may correspond to the hyperreflective spots as well. Finally, there's this hyperreflective cavity centrally. The left eye shows very similar findings with loss of ISOS junctions. The outer nuclear layer, especially in the center, is also disrupted. So on fundus autofluorescence, what we can see is a hyper-autofluorescence phobia seen here that corresponds to that kind of hyperpigmented spot in our fundus photograph. And these are the top portions are FA around one minute, and this is a little later, around nine minutes. And I'd like to draw your attention in the left one. There's leakage that is more pronounced temporal to the macula in the left eye. And in the right eye, there is a little bit more diffuse leakage early on. And obviously, in the later FA stages there are leakage that is in a leaf-like distribution in both macula. So the golden visual fields show some central scatoma in both eyes, preferably looks normal. And finally, we got a macular pigment measurement. And for those of you that don't look at this every day, so this is the right and this is the left. And usually what we should see is the highest concentration of pigment in the center, so a little bit more white. And here what we can see is a ring of white, which corresponds to macular pigment. And then the center, it's absent. This is a quantification. There should be a peak early on. And the same is for the left. And I'll show you a little bit more about the normal macular pigment in literature in the next few slides. So just looking at this, the differential diagnosis, of course, includes macular telangiotesia with all of his findings. Best disease is also one of the considerations. We don't see that the teleform, the yellow lesion that we usually see in BEST. You can also see that in macular telangiotesia. But its absence really doesn't rule it out. We did get an EOG, which was low normal. And I actually talked to Dr. Creel about the results of this. Another consideration would be cone dystrophy, given his decreased color as well as that loss, the central loss of the outer nuclear layer. But it was reassuring that he had normal fulfilled ERGs. Other less likely considerations would include star guard, AMD, and medication toxicity, which he does not take any hydroxychloroquine. So now let me talk a little bit more about macular telangiotesia and its natural history and what we know and what the studies are going to be showing in the next few years. So this is also known as idiopathic juxtaphoial telangiotesia. There are really not a lot of studies. There's two studies looking at the prevalence of the disease. So historically we've always thought that macular telangiotesia is a very rare disease. But from these two studies it seems like it's not as rare as we thought. The first was the Beaver Dam study done in Wisconsin. And they enrolled around 5,000 patients and they found five patients retrospectively with the characteristics of mac-tel. Another study in Australia, the Melmore Collaborative cohort study, also showed they had 22,000 patients in their cohort and they found one patient, so a prevalence of around 1 in 20,000. And both studies did comment that they may be underestimating the prevalence of the disease just because it's a retrospective study as well. So people now think that this may be a little bit more common than what we initially thought. We do not have any data suggesting that males or females are more commonly affected. And then this macular telangiotesia is likely autosomal dominant because there is a vertical transmission from both males and females. The macular telangiotesia has been described for several years now. But in 1993, gas and a barbara of Lodi classified the different macular telangiotesias into three types, which I won't go over too much. But one of the things I wanted to point out is the type 2, which we now call mac-tel, is a bilateral compared to the type 1, which is usually unilateral and has other findings. But the disease can be definitely very asymmetric between both eyes. Lastly, Dr. Blody, when she moved to Wisconsin, published another paper in 2006 with Yanuzi, which reclassified the disease. And this is what we're using right now to understand the natural history. So from these studies, the earliest finding that we know from macular telangiotesia is leakage temporally in FAA. So this is an early FAA time point in this upper inlet. And later FAA finding, we can see leakage in the temporal region of the macular. The fundus really is unremarkable. The only thing is a specific loss of phobial reflex. This is another patient just showing you the early finding of FAA leakage. And so really at this point, the FAA still goes standard for diagnosis of mac-tel. In stage 2, macular telangiotesia, now we can see more characteristic fundus binase. And it doesn't show up here nicely, but there is some retinal grain, like I showed you in the patient more temporally, which can extend more in an oval-like fashion to cover most of the macula. And so this is stage 2. And the FAA here just shows you a little bit more leakage as well temporally and concentricated. Stage 3 of macular telangiotesia is really described by blunting of the vessels. And here's shown that usually they should be tapering off and have a smaller caliber, but they blunt off. And that's one of the characteristic findings. There are also these crystalline deposits that is seen in this disease that could happen at any stage. Crystals can be found in several other diseases. We don't really know the composition of these crystals, but people think that these are precipitation of several macular pigments. Lutein, Z-azine, B-z-z-z-azine, but we don't really know. The other finding is this yellow lesion, like I mentioned to you about, that could be characteristic of best disease as well that could be present in any stage of macular telangiotesia. Lastly, in stage 4, which we think is the most severe, is a presence of pigment proliferation or these hyperpigmented spots, and also accompanied by RPE atrophy. And rarely we can also see presence of a macular hole in a macular telangiotesia. Now, the natural history of macular pigment is even less well understood compared to the fundus findings. And just as an aside, the MacTel project is conducting a natural history study, which is now underway, so we'll have a little bit more data. So, but in this study, this is a normal high, so this photo here is actually from the lab of Dr. Higginman, and we can see this yellowish pigment in the center, which corresponds to macular pigment, and we can see it's highest density. Now in macular telangiotesia, we can see what we're looking at is the dark spot in here, a temporal to the macula, and that suggests a loss of a macular pigment. And that can progress from passing a little bit more of the temporal side of the macula, and even more, of course, a loss of a majority. You can see that there's maybe a little bit more left here inferiorly, and it just progresses. This is another postmortem, which really shows a difference of a macular pigment being in the center, and it's a little bit more dispersed. Now as another side, it's really poorly understood what's happening in the pigment. We know that there's definitely loss of pigment in the center. We don't know whether the pigment is dispersed and moved out, or whether this is normal pigment surrounding it. That just gets accentuated after the loss of the pigment centrally. In those studies, I've really quantified the density of the macular pigment in that ring. So now to switch gears, I wanted to talk a little bit more about mactile genetics and how we're contributing to finding the genetic mutation. But to this point, there are no positive genes for mactile. There are not even good animal models for macular telangentasia. Now just a week ago, this paper with our collaborators got published in Nature, and just to highlight a couple of things, this is the first paper that identified three independent loci with several possible genes in this. They have a nice story, but they've never really shown any causality for any of the genes that they've identified. The other point that I wanted to take is that they do have a lot of patients, but the patients are not related for these studies. And after calculating really, they only estimate 5% of the estimated heritability for these findings. And so really it's still wide open, the field of genetics. And so the real goal for the studies is to be able to recruit large, very high quality families with macular telangentasia. And we're in a great place to do that. So the Mactile Project is an international research collaboration that was founded in 2005 or started in 2005. And we are one of the centers and we are currently enrolling patients and they're family members that we think has Mactile. Most of our families are from Utah and Idaho. And when they come here and we usually screen them on a Saturday morning so we bring them here and they get a battery of tests which I've shown you. But also we get blood for them to get some basic lab work, including hemoglobin A1C, which we think is associated with a disease, as well as isolating blood, DNA from this blood and isolating lymphocytes for IPSL generation. We send all these data to the London Reading Center in Moorfield Hospital for confirmation. And all of our pro-bats that we have here has been confirmed to have Mactile to this point. So now I'll be showing you all of our families and again I think we really do have the best families of macular telangentasia in the world that we have compiled so far. So I want to talk about this M65-472 family and the names are just for the study. This is actually our patient, this is the pro-band that we have. This is our 21-year-old diagnosed with Mactile. He has two sisters. His dad, we brought him in for the study and we did show that this is his dad's funnest photo and he has this characteristic pigment pumping of macular telangentasia and we did all the tests and sent it to the Reading Center and confirmed to have Mactile. So this is very interesting of it itself. This is one of the earliest known onset of macular telangentasia in the literature with a known parent affected by the disease. Now, we also collaborated with a Utah population database. So we have around 50 pro-bands and the question was are any of these pro-bands related and so that we can make a super family and indeed this family is related to another family that we're studying that are related up in here. And these red circles correspond to all the patients that we've already recruited and phenotype and these black things correspond that they do have confirmed with macular telangentasia. So these are very, very useful resources having big families to find a genetic mutation. One of the things that we're understanding right now is one of the exclusion of the disease of the study is we don't screen patients less than 30 years old just because we did not think that we would find macular telangentasia but now we are also getting younger children above 18 to see whether they're really affected. The next several slides is just showing you how extensive our families are not really trying to draw any conclusions but this is another family, the P40-156 and I just wanted to emphasize that we prioritize recruitment of patients in families where multiple members are affected so the more siblings that's where we try to get and the families have been very, very cooperative as you most of you know the hardest part of these studies is recruitment of families. This is another family and I just wanted to point out that we also prioritize siblings of affected family members for example this dad, we try to get the siblings and just a note in this family the pro band's father we are still trying to get his two brothers come in that would be very, very useful for our genetic studies. These are our other families showing you that it's still not complete we're still recruiting these families but most of the families we have recruited most already and have compiled all this data so one of the things that we were interested as well is calculating the penetrance of macular telangentasia which at this point was just hypothesized to be very, very low and just to summarize the families as I've mentioned we have around 50 pro bands that we know has Mac-Tel 23 we have enrolled in the study in clinically phenotype and confirmed by the disease center looking at all the genetic studies people can run into trouble by saying that this is a rare disease and most of the studies look at the penetrance to be around 10% but when I actually calculated the penetrance it's a little higher than that you can calculate in several ways you can look at a sibling analysis and if an autosomal disease you would expect a 50% rate of the siblings affected but we don't see that it's definitely less and after calculating it we see that there's around 41% penetrance when I calculated the penetrance with a parent analysis the penetrance is a little higher but at the same time we don't have a lot of families that we've recruited both the parents and the siblings as well so one of the conclusions is that the penetrance is higher than previously thought and I'll show you why this could be important as well later so just to end my talk Mac-Tel is characterized by temporal leakage on FAA decreased central macular pigment and this temporal pigment clumping that we see this case that I've shown is one of the youngest patients reported to be diagnosed with Mac-Tel and one of the clinical things that we can draw from this is when we see a patient with a Mac-Tel we can let them know if they're siblings or if they have children that the risk of developing Mac-Tel would be around 20-35% based on these penetrance estimations that we've had the last thing I'm just going to talk about is there's just a lot of studies with Mac-Tel right now there's a lot of emerging imaging modalities and I think we'll hear from one of our visitors Lydia in the next several weeks she'll be giving grand rounds on really flio and the cool things that she's been seeing with Mac-Tel injectasia I did not show our other research projects with the families but I just have to acknowledge a lot of people that is involved in this study including of course Paul Bird's theme and a lot of other people I'm working with Alan Thomas with the calculating all the penetrance and I've worked mostly with Justine and the Utah population database so with that I will take any questions that you may have Great work So I always thought Mac-Tel was one of the few conditions in the Mac-Tel in which when the blood vessels are plunged they're actually diving deep into the outer retina and I've been interested in those because it's interesting that the retina the outer retina is bored of blood vessels so when we see situations like that in rap and blood vessels flow down it may give some ideas of what's going on as far as we have to see it all Do you see that though? I mean is that I mean you didn't mention as part of the surgery so is that something to see Yeah, so let me back up So the neovascularization of a Mac-Tel is very interesting because compared to other diseases we think that it's coming from the outer retina and not from the coroid so that's in itself is very, very interesting You can see I did not show that in the natural history because it can actually in the new classification it can show up anywhere so now we call this non-proliferative or proliferative but you do see it more commonly in later stages of disease but there's some reports showing it as well in like stage three or stage two where there's just retinal grading and maybe just a neovascular memory So and to answer your question in our families many of our families do not have neovascular complexes so I really can't comment much more about that So you said that the program's father gets a Charcomery tooth and you've been looking at these other families did you see that greater incidence of CIT of those? No So I think that's just a red herring and from the genetic studies actually we know their mutation for Charcomery tooth already but the associations that we know of that are strongest in a Macro-Telangia is a high A1c Diabetes is one of the common but there are also papers suggesting that the initial studies were just were confounded high BMI and smoking but no other really interesting associations That's a good question Thank you Any other questions?