 I get an honor of introducing our first keynote speaker. Would you please pull up my introductory slides? Thank you. Just a little bit about the Knights Templar Eye Foundation. I think just looking throughout the room, many of us definitely are very grateful for the support they have provided, but also the kind of instrumental grant support that's needed for starting off their career. I know I'm very thankful for having my start with their grant. As you may know, their mission is to improve vision through research, education, and supporting access to care. And since their inception in 1956, they definitely have spent tremendous efforts, monetary efforts in supporting research, patient care, and granting over 24 million in support for basic science. Now, we are very thankful that they're instrumental in helping us kick off our first meeting and now our second meeting in supporting our keynote lectures. I'm honored to introduce our first keynote lecturer, Arlene Drake. She's an undergrad degree in biology and physiology from University of Scranton. She did her international research fellowship at University of Alson, Norway, and medical school at Pennsylvania State University. Her internship and research was done at Georgetown University, and she did not one, but two, but three fellowships. In uptown League genetics, Ed Wilmer, and pediatric ophthalmology, and molecular ophthalmology with Ed Stone at the University of Iowa. Her academics is very impressive, starting as a faculty member at Emory, leading the way for fellowship as well as the children's clinic. She then became a chair of pediatric ophthalmology, children's hospital in Denver, and then returned to the University of Iowa to become the Ronald Keck professor in pediatric ophthalmology in Gen X research. She started her service there as well. She's a co-investigator in a Phase III RP-65 gene therapy clinical trial, which we all know has led to the first FDA-approved ortho gene therapy drug. She's a current investigator in ongoing clinical trial for CP290 LCA, and she focuses her efforts in really coming up with mouse models to study the human retinal degeneration, as well as the electrophysiology of the human foveal hyperplasia. She has written over 80 peer-reviewed publications and 21 book chapters. She's a genetic section editor for the upcoming third edition of the textbook for pediatric retina. She's the inaugural chair of the aposgenics disease task force, now a standing committee, and reviews for multiple professional journals. I'm very much honored to say that she's the first woman to become the tenured full professor in the University of Iowa Department of Ophthalmology and Visual Science. And without further ado, I would like for all of us to welcome our first keynote, the Aileen Draker, and talk about congenital nystagmus and pediatric retinal disorders in molecular gene X error. Thank you, Arlene, for joining us. Thank you so much for that great introduction. I do hope that Cindy is okay. I'm going to show this from my computer because I have a lot of videos, which I hope work. We'll always see. And I will try to keep on time. This is my grant support. I guess I can look up there. I don't have any personal financial interest in anything, but I have a lot of research grant support from both industry and from foundations and the NIH. And so I'm grateful for all that support. I want to also really thank the Knights Templar. I, too, had a Knights Templar grant when I was first starting out, and they've done just beautiful work in ophthalmology and eye disease. And I want to thank the organizing committee, and especially Emmy, with whom I'm working on her textbook, as well as this course. So it's wonderful. I've never been to Salt Lake before. So this is just a wonderful meeting to attend. So I'm coming to you from Iowa, and we say in Iowa we have the seasons a little different. It's almost winter, winter, still winter, and then tornado season. So right now we're in tornado season. Last week I got to spend an hour in a downtown tornado shelter with my 16-year-old daughter because we were shopping and a tornado hit, actually, just the edge of Iowa City. But that was really fun because 16-year-olds don't talk to you much. So when you're in a tornado shelter, they kind of give it all away. They think they might be blown away pretty soon, so that was good. And, you know, this is a postcard you can actually buy in Iowa. It's not made in Wisconsin or something. It's the shape of Iowa, and it says, Iowa may be a black hole you'll never escape, but it's a great black hole to raise kids in. And that's very true. And I like to add, and to do genetics in, because we can't go outside much of the year, so we stay in and we think about medicine and research and things like that. So I'm really, really fortunate to have actually a translational research lab and to be a clinician scientist. And all the images here are of my patients. This is a... I don't know if this is working. Oh, here. One of my human patients and then my porcine patient and my murine patient. I'm doing a project with the University of South Dakota because if it wasn't nice enough in Iowa, I want to go to South Dakota too to do pig ERGs for some of their work, and we have a lot of mice work, and then, of course, we have the patient. So it's basically the best job I can imagine. So the title is Congenital Nostagmus and Pediatric Retinal Disorders in the Molecular Era, and that implies that we should be doing something different in our thinking with these disorders in the molecular era. And I think that's true. And maybe we can have some discussion because not everyone agrees with me, if I can convince you. And a lot of people say that we're having... we've had a genetic revolution. But I like to say we are in the middle of a genetic revolution and we are all the revolutionaries. And so sometimes we're going to have misfires and sometimes we're not going to know exactly what we're doing, but we will get to the end where the genetic revolution has actually occurred. So I want to talk about, in this molecular genetics era, what tests should we do, which patients should we test, and then what should we do with this information? So I think what we should test, we just had a beautiful morning of talks on what we should test. It's just a perfect segue. So I'm not going to say very much about that. And which patients we should test. I think Dr. Sisk, you know, made a really good case for the kinds of things that make us think that this patient must have a retinal to genetic disorder. And absolutely those patients should be worked up and investigated very carefully. But the patients I want to talk about are the ones who maybe we are not thinking of and we should. So these groups are patients with congenital nystagmus who appear to have normal vision and normal retinas. Patients who have early onset myopia. So I mean before school age, because typical juvenile myopia starts maybe seven, eight, nine years old. And patients who have albinism. So let's talk with the congenital nystagmus patients. So what I was taught was that if a child comes in with nystagmus and they're blind, they think that child probably has LCA and work it up either with an ERG or in the more current times with genetic testing. And if a child comes in with congenital nystagmus and they can see normally for their age, that's probably motor nystagmus and they're probably going to have pretty good vision and you don't have to worry about it too much. You can get a brain MRI if you want to make sure there's nothing neurologic but otherwise don't worry about it. And I was taught that vertical congenital is blind with neurologic conditions. So definitely get that brain MRI but if it's normal again reassure parents and probably the vision will be good. And that there's a shimmering asymmetric nystagmus called spasmus newtans that is a self-limited kind of immaturity of the neurologic system that will go away on its own. It can be caused by diencephalic tumors so we were taught to do an MRI in babies. But if the MRI is normal again, advised people it's probably going to go away and it's probably benign. So now I want to show you some of the nystagmus patients that I have seen recently. And you know, if you look at the kind of nystagmus these patients have, which one has a diagnostic ERG? We've just seen a beautiful example of the diagnostic ERG from the previous talk. And which patient here has a treatable condition because one of them has a treatable condition. So if we don't work them up we don't know which one. And there's a whole variety here. So this kid has vertical nystagmus and so does this kid. So are they neurologic? This person has kind of a pendulum just constant very small amplitude back and forth nystagmus. This baby has really good fix and follow and just has intermittent nystagmus if you watch kind of at the end gazes of their versions. And this kid has a very shimmering nystagmus. So think about those for a minute. I will tell you in a minute who has what. But the thing that really made me start thinking about congenital nystagmus was a child who was referred to me when he was seven years old and he had had spasmus newtans diagnosed when he was six months old. And a brain MRI was done. It was normal. He saw a really good neuro-ophthalmologist and they said this spasmus newtans it will go away and vision will be normal. He saw three more doctors. All excellent pediatric ophthalmologists or neuro-ophthalmologists and every one of them said this looks like spasmus newtans we should do an MRI they did another MRI it was normal and then they said it's going to get better and don't worry about it. He had normal growth and development everything fine but finally when he was seven they ended up in my clinic because the teachers of this kid said I don't care what anybody has told you he cannot see. He can't see what we're doing on the board so I saw him he did have this shimmering spasmus newtans like nystagmus but in my mind this is congenital nystagmus because it hasn't gone away and so I usually do an ERG and so I did an ERG in this child and he has the the classic diagnostic ERG that Dr. Lam just told us about where this is the patient on your left and this is a normal on the right the rod response in dim light after dark adaptation is barely recordable and then when you do a bright flash in dark adaptation he has this down going A wave which is a pretty normal amplitude but the B wave is tiny so the B wave is the bipolar cells we just don't have a bipolar cell response the oscillatory potentials which are inner retina are what I like to call biphasic instead of spiking and then his cones are essentially non-recordable so this is really classic for the congenital stationary ERGs and when you have cone affected also it is called incomplete congenital stationary night blindness so we did genetic testing for genetic or congenital stationary night blindness panel and he has mutation in CACNA 1F which is one of the genes in this group now CACNA 1F is very interesting and we've started to call it a synapse dysfunction it's classed with congenital stationary night blindness because it's the same ERG and some patients have night blindness other patients get a cone dystrophy this is what we were talking about before the meeting started about the different manifestations of the mutations in the same gene so this kid has more of the cone dystrophy type of CACNA 1F synapse disorder and his parents felt so bad because they had been saying for his whole life watch where you're going why are you tripping over things they've been telling his teachers oh no he can see fine and now they find out he has an actual retinal problem so if this had been diagnosed early he has 2060 vision he's not horribly impaired but everybody could have been doing the right things for him instead of kind of the wrong things so this precipitated a study that a medical student Morgan Birch did one summer where she looked at charts of 202 consecutive infantile and stagmus patients that have been sent to the pediatric clinic or my genetics clinics I have general Peds clinics as well and a lot of pediatric ophthalmologists see stagmus patients every day and when we looked at the patients who had had full workups the most common cause was albinism and next was labor congenital hemorrhosis of various different genetic types after that was non-LCA retinal dystrophies and in fourth place was motor nystagmus but there are reports in the literature that say motor nystagmus is the number one cause of congenital nystagmus but if you read them they didn't do ERG they did an MRI like we were all taught and it was normal so they said okay that's motor nystagmus so if you look at what test the patients had first the blue bar is how many patients had that test first and this is the number of patients up the side and the orange bar is how many of those showed something that was actually related to their diagnosis so the number one most common test first was an MRI and it had the lowest yield of any test almost any other test eye test you could do like OCT or ERG or genetic test or a specific eye genetic test all had a better yield and then if you divided the patients into those who had another neurologic sign sorry besides nystagmus so these patients had some other neurologic sign their head circumference was too small or too big they had some developmental delays something their optic nerves didn't look quite right if they had some neurologic finding those were the only ones who had anything positive on MRI the ones who had no other neurologic finding in this group there wasn't a single one that MRI was diagnostic and if you look about the cost of these different things at least at the University of Iowa the most expensive test is MRI and has the lowest yield so I would propose that we start thinking differently about congenital not immediately go to MRI but think that a lot of these patients are going to have an eye reason try to do that work up first if there are no neurologic findings so let's look at these patients again so here's a kid he has this vertical kind of upbeat nystagmus and you can see his optic nerve pictures there he has very small optic nerve so this child has optic nerve hypoplasia he had an MRI he has a small pituitary and is being followed for endocrine disorders this child has intermittent nystagmus and good fix and follow and she has that totally flat electrorhetneogram you have there and we did genetic testing and she has RPE65LCA so even though she has great vision at this age her chance of being LP by the time she's 30 is pretty high and we actually have a treatment for this but many people would have said this is nystagmus blockage she has esotropia along with the nystagmus she has good fix and follow here's another kid with upbeat nystagmus what I was taught this is going to be neurologic it's CACNA1F it's again that congenital stationary night blindness category with this CACNA1F gene this kid with the shimmering nystagmus has labric congenital amaurosis which was eventually figured out to be CRB1 related and this woman has FRMD7 nystagmus this is an X-linked nystagmus that I think about as a motor nystagmus she has 2025 vision there's many manifesting female carriers if you will and some patients have a little subtle difference on their OCT but this woman has a completely normal phobia completely normal ERG everything normal so don't judge a book by its cover or an eye by its wiggle but what does it matter well it matters because of what we've already seen this morning I'm so fortunate to be an investigator in the Phase 3 RPE65 L'Externa Therapy Trial on your left you see one of our patients prior to treatment who's trying to do this obstacle course completely with her feet she has no vision you know whatsoever in dim light and one year actually 30 days later one year later two years later three years later we're now up to four years later you can see that she can easily navigate the FDA has had an incredible improvement so we don't want to miss these patients and the FDA has approved this for down to one year of age I was talking to one of the P's retinal surgeons yesterday where Steve Russell who did these surgeries at our institution said there's no way he's doing a one year old the eye is just too different but a three year old they can have it early so we made this algorithm which you don't even have to look at really but just to know that it is back and forth you know it keeps making you think well if the ERG was normal should you do an MRI if there's no TIDs what does that mean and Brittany Scruggs did a new version of this which is much better and it's going to be in Dr. Hartnett's pediatric retina E3 book so you can look forward to that just to help you think about have I really exhausted all the possibilities in this patient and so you know I've learned that in a child with congenital nystagmus who's blind right to genetic testing because yep that probably is LCA if the child has normal vision though and no neurologic signs I do an ERG and an OCT if they do have neurologic signs I do the MRI but the most important thing is that if the brain MRI is normal and one of these congenital nystagmus kids don't stop there go back and do all the eye things because many of them have a retinal reason for their nystagmus so that brings me to albinism you know you might not think of albinism too much when you think about pediatric retinal disorders but albinism is a pediatric retinal disorder and it's really affecting the most important part of the retina the macula so AMD we think is this very big problem because it affects the macula but albinism we don't think of it much as a retina problem even though these poor people don't have a phobia so we looked when I saw that it was the number one cause of congenital nystagmus in my practice we looked at 209 charts of we pulled them based on features of albinism so they had iris translimination, nystagmus, foveal, hypoplasia, or someone had said they had albinism and 58 of these had actually had genetic testing and you can see the breakdown of the different types of albinism OCA1 is tyrosinase it's definitely the most common OCA2 is a close second OA1 is the X-linked albinism and OA4 we had several and then we had two patients with hermanski pudlak which was not suspected so it's not like these patients were bleeding or anything they just happened to have it when we did the testing and 20% of patients had no mutations found at all so we did this scoring system and a higher score meant more features of albinism and when we looked at the patients who had two mutations versus one mutation versus zero mutation their albinism score kind of stair step so two mutations that are known to cause albinism gives more full blown albinism patients who have one mutation a lot of them they have a milder albinism score and then the patients with zero mutations had a low albinism score although you did give them some points but a lot of these patients turned out not to have albinism and I'll mention briefly some of the other things they had but there's a lot of other things like trans illumination defects that get misdiagnosed the higher the albinism score the more likely two mutations the worse their visual acuity and also an abnormal appearance to the optic nerve was correlated with worse visual acuity so which of these two kids do you think has albinism? so everybody's going to say you know this guy but I'm going to tell you it's him so he has ocular albinism and so you cannot judge every blonde kid with an astagmus gets sent in as albinism and none of the kids with brown hair gets sent in as albinism you can't look and tell which one it is and so if the whole family is blonde it doesn't really matter that that blonde kid has albinism you still have to do the whole work up now if you can tell let's say they have massive virus trans illumination defects they have no pigment at all does it really matter what type of albinism they have well again I would say it does of Hermansky-Pudlak syndrome and again I was taught what it says down here in black even textbooks you can find say this these patients have moderate pigment so they're not completely hypopigmented they have bleeding gums very easy bruising it's very rare and it's mostly only in Puerto Ricans and in our series of 58 patients two have molecularly confirmed albinism and neither one of them has any roots in Puerto Rico and one of them you see here her whole heria trans illuminates she has no no pigment whatsoever and there are some types of Hermansky-Pudlak that are fairly benign but there are others that are really life threatening so there's a couple of ways that you can tell if an albinism patient has Hermansky-Pudlak one is by doing these platelet aggregation studies the PTPTT is normal that is not a diagnostic test at all but you can do genetic testing or you can do platelet EM or you can do platelet aggregation studies and the platelet EM they say you know we should have chocolate chip cookies you should see these dense granules in platelets on electromagnetic or yeah EM and they're butter cookies in HPS patients they do not have those dense granules which is why they don't clot properly so once I figured out oh my gosh I've been missing HPS patients my whole life I started getting involved with the Hermansky-Pudlak syndrome foundation and they sent these pictures and these people asked that we show these pictures because all these people have Hermansky-Pudlak syndrome and you cannot tell by looking at them you wouldn't think they had albinism to begin with and importantly these two women are both from Puerto Rico there is a founder effect actually two founder effects in Puerto Rico so if someone has Hermansky-Pudlak syndrome from Puerto Rico then we're likely to have those mutations also it is more common in Puerto Rico than in the rest of the world but it occurs in every ethnicity every population you can't tell by looking so these people have foveal hypoplasia and the stagmus and if you see anybody who looks in any way and you think they have albinism they should have that genetic testing I got really interested and I saw this article in our local newspaper because they were raising money for this guy to go to Mayo Clinic and get a lung transplant and he worked at our local grocery store his whole history is here he went to City High School in our town Iowa City he played football at City High School he was a good player and I thought that guy looks like he has albinism and you read all the way down here he does have albinism he was 40 years old when he went into acute respiratory distress and almost died people misdiagnosed it all over the place nobody thought it could be related to his albinism he has Hermansky-Pudlak syndrome and he did get a lung transplant and again I think of this guy every time I see a kid with albinism because he's not from Puerto Rico he doesn't have moderate pigment he has a deadly disease that could have been treated way better if he had been diagnosed earlier so I'm going to ask you at the end I have some other interactive patients but this fundus I know I'm showing it in the albinism section but what do you think about this fundus this child was sent to me with a diagnosis of retinitis pigmentosa she's 7 years old her best corrected visual cutie has only been ever 2060 she has known a stagmus but she has this very strange pigmentation and when I saw her I scheduled her for an ERG because she was being sent in as RP but I also did a slit lamp exam and luckily I put the light through the center and looked for TIDs because there they are you would not know it looking at her and she has no phobia whatsoever and her ERG was of course normal and we found one mutation in OCA it was a real mutation but she was one of those people who had only one mutation and she doesn't have any stagmus and her parents were just convinced she must really have RP and so she got ERGs every year because they couldn't shake this idea that she was going to go blind. Finally we did whole genome sequencing and found that she has a deletion on the other allele so we could finally tell the parents we found that second allele so it doesn't always look like we think it will look. Here's a few other phenocopies just quickly this is a 5 year old boy who was referred from ENT he had a cochlear implant from very young because he was deaf and he has finestagmus and poor vision so they thought well he must have Usher syndrome but I did an ERG and it was totally normal so I thought well that's not Usher syndrome and then I looked at him really closely he has TIDs, Iris TIDs and he has like a hypopigmented area of his iris it's a little bluish in addition to his foveal hypoplasia does anybody know what this is so this is Wordenberg syndrome and there is nothing in the literature that says that patients with Wordenberg syndrome have foveal hypoplasia and the stagmus but that MITF gene is in the same pigment cascade as albinism and Brian Brooks now at the NIH has a couple of patients with the same thing and maybe someday we'll write them up but you know this guy looked like he had albinism all his albinism testing was negative and then you know I figured out the Wordenberg angle here's another kid who was sent for Usher syndrome he has cochlear implants he was deaf since birth he does not see very well he has an astagmus I don't know how well it shows up here but he has iris translumination defects all around the periphery he has no pigment in his retina whatsoever no pigment his ERG is a little bit low amplitude but that could be because he's a minus 25 myope minus 25 and you can see how sort of excavated this is so we went through a whole bunch of stuff with him but to make a long story short he has this thing called Donnie Barrow syndrome and in Donnie Barrow syndrome surprisingly they spill retinol binding protein into their urine so they've got this weird metabolism thing however the ERG is really normal even though he's a minus 25 the ERG was almost normal but he does not have albinism he has this other completely different thing and he's a minus 25 and he spontaneously detached one retina and our people put it back on and he was Plano without any lens and his mother said okay you do that in the other eye and of course everybody was like no and then he actually did detach his other eye and now he's Plano in both eyes and he has 2150 vision which is something after all that we know about him here's another kid he has had severe lifelong photophobia his best corrected vision has always been 2060 his fine horizontal nystagmus and he has these iris TIDs all around the periphery so I thought he was going to have albinism but he's got quite a bit of pigment in his fundi and then we did OCT and it's because it's not completely extruding the inner layers but it's not typical he has a pretty small foveal avascular zone he has a pretty normal dark adapted ERG but his light adapted ERG is non-recordable so this guy has a cone problem as we heard about earlier today and I know no one will ever guess what this is because the diagnostic test for him was a chest x-ray so this is his chest and this is a normal chest and he has this unbelievably small thoracic cavity and this is Zune syndrome or asphyxiating thoracic dysplasia but he's not asphyxiating he's now like 14 or 15 years old he plays baseball and there's nothing in the literature that shows us what the foveal looks like in Zune syndrome so this was a puzzle for a very long time so the take home messages I think about albinism are it's very common so we found it was 19% of all the congenital nystagmus in our study but only if we tested them the patients may appear normally pigmented they still have an increased risk of skin cancer even if they look normal so you want to tell them that 25% in our series did not have nystagmus so you can't go by the nystagmus and about 4% have Hermanski-Pudlak syndrome and it could be life saving to diagnose that so all that transluminates is not albinism but a lot of it is and all of these patients I think deserve a work of including genetic testing so we will just segue quickly into early onset myopia so I think most retina specialists do think about high myopia as a retinal disorder but they don't necessarily think about it as a genetic disorder or a genetically testable disorder so here's a girl who came in to me she was referred by pediatric ophthalmologist when she was 5 for intermittent next T but she had a very high myopia and she had no nystagmus I asked about night blindness other complaints nothing and then the mother brought her little sister in her sister same thing she was like a minus 10 both eyes so two sisters very good acuity very high myopia what's the differential this is what her fundus looks like basically just myopic changes but pretty impressive for a 6 year old or whatever she was at that time same thing with her OCT I mean maybe the phobia isn't quite normal there's some Staphyloma there so you know there's a differential for pathologic myopia in childhood and includes a lot of systemic syndromes as well as ocular syndromes and I basically centered to medical genetics and we tested for all of these different things and they didn't have any of the typical things like stickler syndrome and at 9 years of age she was even more myopic she was minus 13 she was still 20 30 and 20 25 known as stagmus but her mother said you know when we're in the dark I don't think she sees as well as we do so then I was thinking what could it be congenital stationary night blindness or RP we did visual fields and they were normal but her her 1 to E SOPTER is a bit small but other than that normal not like an RP field for sure and then here's her ERG so again we have a diagnostic ERG for congenital stationary night blindness because she has no rod function an electronegative standard combined response a biphasic oscillatory potentials she has a slightly low single flash cone and very mildly low 30 hertz flicker so because her cones are normal this puts her in the other category and we can look at the genes because it's combined into the incomplete and the complete and so she's now in the complete category and there's a whole bunch of genes that you can test and we sent testing and she has two mutations in TRPM one and so does her sister and each parent carries one so this is a very classic and as we talked about before diagnostic ERG well then I started ERG all the kids who are high myopes before the age of seven and we found seven patients with TRPM one mutations who have exactly the same ERG only three of the seven ever had nystagmus and of those only one had it at the time we ascertained them and only four of the seven even though I followed these kids now for like 12 years only four of them ever actually noticed night blindness and I think that's because we did an FST and the FST you fully dark it up someone and then you see how dim a light they can see and their FST is about 50% of normal so if they're in a very dark situation they're not going to be able to see as well as a normal person but if they're in a city with normal lighting and stuff they really may not notice much of a problem and so we published this and it very kindly got a commentary with it and I was really happy that Rob Kunakupu they asked to write this commentary got exactly what I was saying which was kids who are high myopes may have congenital stationary night blindness or some other retinal problem and they may not have the things we were taught to look for they may not have nystagmus or night blindness and still have congenital stationary night blindness and one important thing about this is we may someday have a gene therapy treatment for this but in addition all the kids now are being put on atropine for myopia which is great and I really hope that we will see a slowing of myopia but that is for school age myopia it's been tested for school age myopia I saw a kid the other day 5 years old minus 10 he's been on atropine for a year of course now he's minus 13 because I did an ERG he has TRPM1 congenital stationary night blindness atropine is not going to help him and the other interesting thing that we found well first there is a differential for the electronegative ERG it's not all CSNB the most important things are baton disease juvenile x-linked retinoskesis though it often is not electronegative in kids but baton disease is that's the scary one that we have to think about and cancer associated retinopathy so you have to think about it it's not always CSNB if it is you can categorize the genes as you see here but we also have to think about these kids who come in with high myopia and the ones who have axial high myopia I think we really need to think about doing a genetic or some other work up and this is from Ginny Utz who's on the APOS genetics committee with me and this will be on the APOS website we have to think about working up these kids because otherwise the parents are very concerned why are they getting more nearsighted and what we found in these kids the TRPM1 kids was when we saw them at like 3 they were like minus 10 they progressed rapidly up till about age 7 or 8 and then they plateau which is the exact opposite of the juvenile myopia kids who have onset between like 7 and 12 and then they progress and then they plateau like in their 20s so it's a different type of myopia so in the last few minutes before we do some questions and some interactive cases I wanted to just talk about something that we rarely talk about so what do we do with these diagnosed ones we find them we show many slides and we say okay I found and this kid had batten and this kid had RP but what do we do it so when we tell parents about this it's not easy because we're giving them bad news and we want to do non directive counseling which is the way in genetics you want to tell them what's available not push them to one thing or the other some people may want to use the information for family planning for treatment or for clinical trials they're very mildly affected do we want to just let them go see there's a clinical trial they have 2030 vision there's a clinical trial for Stargardt should they go into that trial do we know enough about it do they know enough about it and should we just send them to clinicaltrials.gov I give that website to my parents of kids but I'm going to show you some issues with it so one thing that's important is for a long time we've been telling people that if they can do pre-implantation genetic testing with IVF to avoid having an affected pregnancy and I have had several patients do this but it's not widely done and so I think this article is really really good it's very recent it's from Israel and they use pre-implantation genetic diagnosis to prevent kids with heritable eye disease so it's specifically about heritable eye diseases and it's inaphthalmic genetics and there were 35 mothers they went through 88 cycles of IVF with pre-implantation genetic diagnosis and it resulted in 18 unaffected children being born and they list the disorders here there were albinism 10 families retinitis pigmentosis 7 retinoblastoma 4 Blu-Cone monochromacy A chromatopsia aniridia Hermansky pudelac syndrome LCA norea disease so they had the whole range so obviously it's not 100% but I think if families are considering this this paper is a really really good resource to tell them it can be done and it is being done then of course we have to tell them about clinical trials so first we have to tell them about the one FDA approved treatment but then we have to tell them there's all these clinical trials and I often have them go to clinicaltrials.gov but you know there's this disclaimer that says that on clinicaltrials.gov these studies that are posted are not vetted and that's really important clinicaltrials.gov is such a great resource and I look at it for patients before each of their visits so I know what's out there but it's not vetted and so there was this really nice article from Baskin-Palmer about patients who had vision loss after intravitrial injection of autologous stem cells so there's a loop hole in the law that if you're putting someone's own cells back into them you can get by without all of the many regulations that we all have to do for clinical trials and so there are clinical trials going on where they're just trying it putting people's stem cells into their vitreous into the retrobulbar space et cetera and there were three people who went totally blind from this as you can imagine and it was very courageous for the authors to report this and just recently I had a family come in with a 16 year old boy who has dominant optic atrophy plus and his dominant optic atrophy is horrible he's got massive central scutomas he's got like 21,000 vision because he just has a little rim and it's genetically proven OPA1 mutations and he had found this this study online because he has voice to text on his computer and he's super smart and it says they treat optic atrophy and this is one of the autologous stem cell injections and they will do subtenon, intravitrial retrobulbar injection of this kid's stem cells and he was so mad that his parents wouldn't take him for this because he wants to get a driver's license and he was convinced this is on clinicaltrials.gov he's convinced he'll be able to get his driver's license if he gets this treatment so I tell patients here's the site go to it but if there's something you're interested in let's talk about it and I think that's a good thing for everyone to do so we can look at it and say does this look like a really good thing for this patient so then finally what if the news of the diagnosis is bad and in Peds Retina there are a lot of bad diagnosis and I started to wonder what is the best way to tell parents about this because I think my whole career I've mainly kind of emulated the people I trained with who were very good but there must be a way and there is actually a literature out there about how to deliver bad news and I think about our bad news in kind of grades of bad news you know like when we look into a room and a kid has come in 2200 and they need glasses we think that's good news but often the parents are just devastated and the mother is crying and stuff so we have to remember that for each parent and patient we have to kind of get to the level that they are but sometimes it's really devastating news like it's a fatal condition and there have been studies that show that doctors really fear giving bad news we fear being blamed or we fear that the person is going to get emotional so what we have to do will take away their hope and so there has been a study or two about how to do it the right way so the first thing they say is you know let the patient or family or kid express their feelings and don't minimize it don't say oh well you know at least he only needs glasses he's not going blind like the kid next door and also don't say well at least he's only going blind at least he's not going to die like the kid in the store you know doctors actually said things like that to patients believe it or not so we want to not minimize any of their concerns and just hear what they're worried about because a lot of times it's a specific thing oh he'll never be able to play football and you might be able to say yeah you know if he keeps wearing sports goggles he can play football and then that's really their main worry they also recommend talking to people ahead of time about the Walmart effect and this has become a thing that's published which means you're wheeling your kid through Walmart and he looks weird or his one eye is gone or he's got a patch on and just random people come up and say what's wrong with your kid why does your kid look weird and this has become so common that they actually recommend telling parents people may come up to you unsolicited and ask you or your child what's wrong with their eye and I always tell them these are rude questions you can just ignore the person and walk away or you can say anything you want you know I was attacked by a bear and sometimes with kids this is really helpful and they've actually shown that especially with kids if you give them something to say ahead of time they feel much better after the encounters happen so kids with white canes I say how are you doing is anybody making fun of you and they'll say yeah I hate using this white cane people make fun of me they say stuff and I said well why don't you say it's a lightsaber I don't want to lift it so I don't want to blind you or something like that you know make it something funny and that has really worked with a lot of kids or teach them how to say the whole name of their disorder that will also shut up other kids really quickly there are also ways that they have found it are better to deliver devastating news and so how many people think that the best way is for the physician to remain calm and controlled the parents are upset and obviously distressed versus the physician also becoming emotional and distressed who thinks it's better for the physician to remain calm and controlled a lot of people and that is what I was taught okay well actually there's a body of literature that shows that if the physician shows emotion it is much much easier for the patient and better for the patient and there was a study which I would not have wanted to do called the death of a child study where they actually went and interviewed parents after they had had a child die and they asked them about the ways and the people who had told them about the death and police officers got much higher rating than doctors and nurses because the parents said the doctor was just like well I'm sorry but we lost him you know and the police officer was like oh my god I can't believe I have to tell you this you know your son is gone so that was really an eye-opener for me the other really helpful thing is they've done studies that show okay I gotta wrap this part up so we can have questions but they've done studies that show that if you prepare someone for bad news a second before it actually helps it helps them absorb what you say so if you walk in and say yep it's retinitis pigmentosa yep it's baton disease like we thought then they just it's just a shock reaction where if you walk in and say we have some really difficult news about the testing I'm so sorry you have to go through this it is baton disease it seems like a small difference but apparently it really helps people to to kind of process what you're saying and so there's this spikes kind of memorization thing that reminds you of what to do that's from the oncology literature not surprisingly because they have to do this all the time and you can look this up it's in a paper it's actually a really good paper and they also mention you know also talk about we're gonna help you with school stuff they might be eligible for make a wish I was really afraid to bring up make a wish but you know parents sometimes just brighten right up at that because it gives them like something oh we can do this and it's going to be a good thing so I'll just share briefly a recent case with a seven year old kid who was referred for rapidly decreasing vision he was totally normal he had no seizures he had nothing else his mother thought maybe he was a little night blind even in childhood and his ERG was very very abnormal but it was not electronegative so I wasn't really thinking about baton disease but his mother is a nurse and she had a friend who had a child with baton disease having vision problems at the same time so she was really worried about this so I sent a panel a retinal degeneration panel that included baton disease and that's another caveat look at the panels you're sending because a lot of them include baton disease now and you want to at least tell the parents there are some more serious things that are multi-system not just retinal that will be on this I don't go into detail but I tell them so we schedule the follow-up visit that's the other thing so you don't want to like call somebody and tell them to come back in if you have even the slightest suspicion that it's going to be something serious it's good to just schedule another visit so sure enough it came back to mutations in CLN 3 I was just floored so we had them come in we changed their time so it would be a quieter time of the day I had my orthoptist bring some toys in that she could play with the kid she just stayed there the whole time because as you know a lot of times the kid is coming around and talking to the parents and stuff and they can't pay attention and I also called palliative care and they said if the parents wanted to talk to them they would and it was like an hour discussion and you know I really I didn't like sobbing cry but I let myself express emotion because it was devastating and both parents were crying and you know I answered their questions and you know all of this stuff and this was one of the cases where they didn't say like so I didn't say and they usually go completely blind they didn't ask that so I didn't say it but what the father said was you know I really want him to play sports I'm a soccer coach you know and and I said well you know he's probably not gonna have good enough vision for soccer you know within a few years but there's other things he can do you know so we went through it but after this particular one that I had really prepared for I really thought does it matter you know I just gave these people the worst possible diagnosis in the world I don't even think it matters how I said it and then six months later I got this note from the mother through my chart and if you read it you know she says you and your staff are so empathetic and we would not have asked for our situation to be handled any differently first of all I thought what an incredible person that she could write this I would never be able to write that after my child was given this diagnosis but it was also so helpful to me because it told me I mean I've had other families who just didn't appear to matter how I said anything they were just so devastated but I think for some people it really does make a difference if we kind of prepare and and use this information so in summary congenital nystagmus and pediatric retinal disorders deserve a full workup in the molecular genetic era because we have some treatments in clinical trials and family planning I think that all kids with congenital nystagmus should have an ERG and should have MRI if they have any neurologic signs or even if it just makes you feel better but don't skip the ERG I also think that all kids who have high myopia onset before school age should have an ERG considered because they may have something retinal going on there we don't know about and I really think that all albinism patients should know that they are at risk for Hermansky-Pudleck syndrome that it can be picked up on a genetic test and that you can also do platelet or other studies to look at that and albinism is way more common than we think so suspect it more thank you for inviting me to your beautiful city this is just a fabulous meeting I'm looking forward to the rest of it I want to thank all the parents and patients who come to me and who have participated in research my colleagues Wanda Pfeiffer and Sejug Badari are just the best we have a ton of students also who work in the clinics and labs and I want to leave with pictures of Iowa to show you it's not always horrible there's like two days between winter and tornado season when we have a beautiful lake that we get out on and you know we have springtime and happiness and all of that's good and now we can have some questions any whenever questions considering that thank you so much for that terrific educational presentation and we we wanted to provide a little bit of Utah for you to to enjoy oh wow that's beautiful thank you so much oh wow even better so and then beautiful thank you thank you these are beautiful and I think we also have a few other little Utah gifts in there too so kind of you we can have them, thank you they are a little heavy but I think I can carry them these are just gorgeous they will have a place of honor and just being here is thank you thank you so are there any questions that's a great idea that parent dysfunction and the whole family dysfunction how do you address that yeah the question about you know there's often parent dysfunction probably because of these really difficult diagnoses I think the only thing we can do is really recommend that they get the parents get professional help as quickly as possible and one thing I found is we have a palliative care team and I always thought of that as like hospice but they don't, they take care of chronic care patients too and they will often meet with the family and they will suggest programs or therapy for the parents because I think all we can do is say it's really, I mean I tell them this is really stressful it will strain your marriage it will strain many relationships it will help early and I think if we're not afraid to say it then it makes them less afraid because I've seen the same thing in reality I tell them get a computer get them whatever they need and make that happen I totally agree so the question about screen time because computers are going to be their lifeline to the world but you can get a little film that goes over the computer that blocks blue light I think really blue light if we could reduce that would be good but I agree with you we don't have any evidence that that's going to make them worse faster and it's definitely it's going to be a lifeline yes Dr. Seaving Arlene that was a beautiful talk thank you very much I just want to make a comment on the administration of a person's bone marrow derived stem cells yes that is a travesty just a little bit of background on that the FDA asserted that it had authority to control that and the way the law was written it was ambiguous whether in this case the patient is having bone marrow cells their own bone marrow cells extracted they're screened or not screened and then they're injected into the vitreous cavity and well sometimes Havok ensues and the FDA asserted that it had regulatory authorities over that the company of course strongly denied that and persisted but last week there was a federal court ruling saying that the FDA does in fact have oversight of that process if I could just make one heretical statement however on the flip side it is interesting to consider that there are probably 400 cases of these cells being administered and there are only a handful of cases of misadventure and one can perhaps begin to think that in fact under the right conditions this could be a safe procedure obviously it would need some better rigorous testing and whether it has the magical effects that people are looking for is a different question thank you so much for those comments exactly right I mean just because it's not being done in a controlled manner and there are untoward effects doesn't mean there's nothing at all there so I think you're right if it were studied appropriately there might be something there thank you Arlene I had a question for you among the cases that you had the pie chart for which showed the majority having some sort of a retinal diagnosis do you think that that's influenced by being a tertiary referral center or do you think that when we look at nystagmus as a whole that really about 50% are attributable to some sort of a genetic retinal cost so that's a really good question and of course I don't know exactly but those patients were from our general Peds clinics as well as genetics clinics however we're still at a university so it's not like a private practice clinic so I think it probably is a bit skewed but let's see Brittany Scruggs is here who just looked at the data for the textbook what was the percent that were retina was it 70% roughly yeah so about 70% were retina so I think it's at least 50-50 let's put it that way yeah I wonder if there is legal issues concerning about gene tests because we do have some cases where the gene test tells the mutation is from mother and it got blamed and even divorced so in other words like prejudice toward the mother if it's an X-linked thing or do you mean the mother is a carrier and the father isn't so it's non paternity I see so blame so these are issues that are really sensitive issues in genetics so I always when I have an X-linked disorder and I'm telling the parents okay this boy has X-linked retinoschesis it's X-linked it's on mom's X chromosome but what I say is it's really a combination of both parents because dad passed on the Y chromosome okay if dad had passed on an X chromosome that bad X would have not caused any problem so it's a little bit you know gamesmanship but it at least puts in their mind it's not somebody's fault and I always also say none of us would pass on a bad genetic trait if we had a choice in it it's not a choice and I also look at the child and say and plus he's got your beautiful curly hair he's got all these good things from you so I do that multi pronged thing it's nobody's fault it's really a combination and you know he got some good things from you too but it's very difficult and people struggle with that and again having some kind of a social worker palliative care person who can refer the parents for further counseling I think it's really good yes thank you for that lovely talk and I want to especially thank you for talking about how to deliver bad news that's something we don't discuss enough in ophthalmology and we do have to do that from time to time and the other thing unrelated a question is regarding albinism testing if it's difficult to get testing because of financial limitations or logistical limitations should we just focus on just getting a Hermanski pudlak test well it's hard to just get a Hermanski pudlak test and because a lot of times in albinism even with Hermanski pudlak you only get one like a lot of people only have one mutation found so the problem is if you get just a Hermanski pudlak test and they have just one mutation in the Hermanski pudlak or in a Hermanski pudlak syndrome gene you might be tempted to say oh well they must have it but yet they may have two mutations in tyrosinase that explains their albinism so it's much more accurate to get the whole panel it might be less expensive to get the platelet EM depending on their insurance and they do the platelet EM at the Mayo Clinic and so you can do that I mean I had a couple of kids where insurance was kind of valking and they were going to have surgery like a lot of albinism kids have this I mean have stra business right they go for surgery and so you can get a platelet clotting test pretty easily and pretty quickly and pretty cheaply and most kids with albinism look like they bruise a lot because they don't have much pigment and so they parents can see the bruise so it's pretty easy to document they've seen a lot of bruises they're going to have surgery and I would get the platelet clotting test or aggregation test before I would get just a Hermanski pudlak syndrome gene for genetic panels is there a nice stagmas panel because based on your talk I think it's so useful and I also think cover lab would be the one that can develop it but I don't think alike and I have suggested that however my suggestion has been rejected so there maybe someone has a pull with some other lab because I think it would be very helpful very helpful to just get all the most common genes and put them in there. I'm going to wrap up this session I want to thank Dr. and all of our speakers in this session and the audience for their questions thank you for making this a great first session I am once in a while judge of that ball I've got a comment I don't know that's kind of what I was I cannot