 I'm going to go ahead and start. It's one of my favorite topics. Albinism is more like National Geographic Special, than is a discussion about ophthalmology. Pigment is probably the most consistent, the most consistent chemistry throughout evolution of anything. It precedes blood systems, classic cardiac systems and that. It's just about the same, and it's been the same, as far back as they can tell, close to a million years. Albinism occurs in all organisms, not just animals, but plants. It occurs in everything. By the way, this one is interesting. There's a private zoo in the Phoenix area. It suckers like 12 feet long. I took that picture there a few years ago. Everything. Our visual system is organized such as far as the distribution of the optic chiasm. It's not 50-50 like we tell patients, but I do too, although I know better. It's dominated still by the claustrophobic fibers of the chiasm. This is true from any of the arboreal monkeys up through humans. This is the organization and the distribution of the optic chiasm. Whereas in rodents, the variation goes from up to about 99% in guinea pigs to 5 or 10% in mice and rats. As the eyes are placed on the head of an animal, you can guess what the distribution is. As the eyes move frontal on the head, you get more uncrossed optic fibers. The guinea pig, if you think of a guinea pig, their eyes are almost on the sides of their heads, and they only have about 1 or 2% uncrossed fibers. There are differences in what happens at the optic chiasm, but a lot more detail than we need to here. You might not know the name Carl Lashley. Carl with a K. Carl Lashley was maybe the first neurobiologist. He was published in the 1920s, and he looked at things like what are the capabilities of learning if you have certain sets of optic distribution at the optic chiasm. Carl Lashley used pigmented rats like so. And then a series of studies, a series of studies in the 1930s by a guy named Chang, who showed that the optic fibers don't work in albino cat, in albino rats, but they did, but Carl Lashley said they did work in pigmented rats, and nobody paid much attention to that. If you retrospectively look at all of the studies from the early 1920s to 1965, and you can predict the outcome of the study by the pigment of the animal, so that albinos can't learn if they're limited to their uncrossed optic fibers, pigmented animals can learn, although the only ones that were examined were rats. When you look at the dorsal lateral geniculate of the rat, these are slices through a pigmented rat on the left. Instead of the laminations that are true from carnivores on up through primates, instead of laminations in the geniculate, because almost everything is crossed and there's just a little bit uncrossed, you get filling and then you have a pocket for the uncrossed. So this is the beginning of laminations. If you look at the albino rat, there is no pocket for them on the cross side, and the uncrossed, instead of being a tight organization like this, is fragmented up into pieces. And again, you can jump to any mouse or rat model that has any hypopigmentation of the retina will produce something like this. You don't have to be an albino to look like an albino. If you just have ocular albinism, or even ocular albinism in only one eye, this will be the effect. Until 1969, this was thought to be a phenomenon of rodents, animals that had very few uncrossed fibers. It had been demonstrated in rats, guinea pigs, and rabbits, and that was it. The sigmes had is a form of albinism. It's a special temperature labile tyrosinase system that allows pigment on the cold parts of the body. So if you picture a sigmes cat, if you picture a sigmes cat, they're pigmented in the cold parts of their body. When a sigmes cat is born, they are as white as a white mouse. And about the same time their eyes open, about two weeks out, they start to pigment on their feet, and their face, and their ears, and their tail. And you can actually reverse that if you would take a five-year-old adult sigmes cat and put it in the cage where it was really warm over the next couple of weeks as hair would grow in white. But their form of albinism as far as the inside of their eye is concerned, they are albinos. This is the organization of a normal cat visual system. There's a very strict point-to-point organization of the outside world onto the retina. And then this is maintaining on back to the genetic layers so that each point in the outside world is in a register and columns in the lateral geniculate. And in arboreal primates and humans this continues for six layers that you have these columns right through the geniculate that organize the outside world. And then this goes on to the cortex. And this is the underlying basis for binocular stereo vision. When information from different points of the world land in the different retinas and then the information arrives on one cell at the visual cortex, that's where you get your binocular information. The geniculate of a sigmes cat looks like this. Everything of course on to the retina is the same. But because the sigmes cat is an albino and too many fibers cross at the optic chias and they have to go somewhere. The only way they go is they invade. The cross fibers invade the layers that are normally would be from the uncross system in register like this. So when you get this invasion, what this does is it completely jumbles the outside world so that point 11 doesn't line up with point 11 at the next layer. And this destroys the binocular vision. When I first showed an albino a fly test, I was standing behind him and I was explaining like I would to you that you see how the wings come off the page and you can just, I was doing this and he looked up over his shoulder and said it's a flat picture. Because they have very little or no stereo vision. If you map the visual cortex of the sigmes cat you find that almost all of the input is to the contralateral hemisphere and very little input and fragmented on the ipsilateral side. If you then put a single electrode like you would in a human bean where you would put an electrode on each side of the visual scalp in a pigmented cat it's so close it's only about 65-35 but still it's so close at that crude level of recording that you can't tell any difference. Whereas in a sigmes cat, you see a tremendous difference between the crossed and uncross potentials recorded from the back of the head. This is the underlying basis for being able to record this misdistribution in human beings. These are albino cats that appeared as a mutation on a ranch near Sheridan, Wyoming. The foremost cat geneticist in the world died a couple of years ago. He was well known in the world about cat genetics and the woman on the ranch knew enough about cats to know about this guy. So she wrote him a letter and said would you be interested in albino cats and he said no it's not practical I'm in London but Don Creel might, why don't you call him so my phone rang one day and this woman said hi this is Sally Springer and Roy Robinson referred you to me and blah blah blah and so I ended up getting some true albino cats. If this was a video all of them had anesthetics. They're all just looking at you like this. And I think this cat I think this cat, I'm not positive, is the next picture. That's Willie. Willie was grown up I think it's that cat but I don't remember for sure. Willie again you can see he's got exotropia and also if this was a video his eyes were just like this. This is the most extreme model that a lot of anatomy has been able to be done on because arboreal primates is very rare in primates to have albinism other than human beings. Why? Because most of them live in trees and you can't have bad vision because you can't miss a limb 100 feet off the ground so it pretty much gets selected out of the pool. So about the only place you see him are in zoos. This is the funnest photo of Willie. This is not Willie, Willie lived a very happy life as the sperm donor in a colony. This is another one of the albino cats with labeling in the retina. This shows the degree of crossing the light fibers. These are the gun cross fibers and this is the degree of uncross fibers. Never did it count. It was probably a percent or two. Unaffected were the old phylogenetically old projections up into the hypothalamic nuclei. This up here is a normal geniculate of the same sign he's got in the optic chiasm picture. This is a normal geniculate of a pigment of cat showing the laminations and this is the cat dyschiasm. This is the cross in this little tiny pocket here. This is the uncross quote lamina. Back to something at least as primitive as the rats I showed you earlier. Don't need to go through all of this. One of the interesting things of this is things are so abnormal at the geniculate that by the time you get up to the cortex, 84% of the cells are normal in area 17 and 70% are normal in 18 whereas the lyrogeniculate less than only about half of the cells are normal. Don't know why. Albinism model for a lot of disorders including this diagnostication. Very complicated. I don't even understand it. This is a sample of the connections in the brainstem that control eye movement. If you ever want to read a cure for insomnia, besides my papers, look up Roland Geoli here. Roland Geoli is now retired. He was at Irvine. The world's expert on the brainstem connections that control eye movement. Couldn't be more complicated. To this day I don't know why. I have my theory and of course I think I'm right. Albinism has a lot of features. I'm just going to skip through these. You know these just from knowing about albinism. It's a model for a number of things. There are many types of ocular botanist and ocular albinism. Currently there are 20 known forms of albinism in humans where they know the genetic loci and there's going to be more. Why? Because they've already found more in mouse models. So there's lots of rare ones out there yet to be found. This couple, Albin, the albinists have their own organization and this is their quarterly magazine Albinism Insight. This couple met when they were middle schoolers and dated long distance until they were in college and got married last year. Like Lady They're true. They have a good chance that it's the same gene and that their children will be albinists also. But in almost all of the forms of albinism you can get the same degree of expression from a lot or a little or almost no albinism. However, in reported and probably happened a lot more times than that an albino of one type has had children with an albino of another type. They're all normally pigmented. This gene is on 11. This gene is on chromosome 15 in human beings so they don't match up. This is an interesting story to me. I did not ever know them but one of the first people that got me into albinism knew this couple. They were in Tennessee and he is classic albinism chromosome chromosome 11. She used to form on chromosome 15 and this was in the 1950s and they had several children and they're all normally pigmented and the doctors told them with their superior knowledge they took the husband aside and said it's hard to tell you this but you're not the father of those children. My first response was well I am the father of the children and I can see that she's one kind and I'm another kind but it took science and decade to figure that out. So the type that you think of is classic albinism. It's now called type one way more than 100 mutations. Main location 11 q 14 to 21. This is a guy from Salt Lake lives in San Francisco now and his brainstem auditory potentials were in science. If you look at a diagram of how it's distributed as far as the eye in all of us the phobia is the zero demarcation of the outside world, the zero meridian and all the fibers temporal to that are uncrossed, the fibers navel to that cross and albinos human albinos is something like this for one thing they don't have a phobia and up to 15 degrees in the temporal retina also crosses the optic chiasm. There's never been a count done on a human and only one human brainstem looked at and it was just a normal postmortem where they could see the geniculate issues. I've never seen a chiasm of a human. You all know what a normal OCT looks like. The reason I used a colored one is to accentuate the nerve fiber layer which stops about a millimeter before the phobia. Here is the phobia of an albino. Not again. Here's a comparison to normal abnormal the nerve fiber layer running right over it. Huge variation. Some albinos do have a little bit of a foveal pit. These are four that we're seeing here over the last few years. And they're colored OCTs. This is not mine. This is a study of McAllister. It's a group of Minnesota. Oh, it's a group. Whole all the authors are several different places. Showing the variation different albinos. Again, this is another one of the other paper showing variation. Another big difference is albinos have invasion of the abascular zone. Are abascular zones look similar to this? This is the abascular zone quote unquote or lack of in an albino scene here. Here's a comparison. Here's a normal and three others. Is it from Milwaukee? No unique program there. Again, reminding the distribution to detect these in humans, occipital pole. The best location for recording is a little more lateral to the traditional 0102 that's used in neurology for occipital pole. A little further more lateral these are called H3 and H4 on the international system. So H3 and H4. So if you compare across the back of the head like so and then have the patient look at either a flashing light or a flashing check pattern in us you would get very little difference between the hemispheres. The best stimulus is a pattern onset offset like so. The reason is the traditional pattern reversal stimulus exaggerates their nystagmus and it decreases their ability to focus on either a flash of light or a pattern that flashes off and on gives you the best potential. If you record across the occipital scalp like this and you stimulate one eye the polarity the potential you'll get goes one direction and it reverses 100% polarity in the first couple of hundred milliseconds. So interpreting is not calculus. I call it Where's Waldo? You can also see it in their multi focal evoke potentials. You can see the cross is the blue, the uncross is the red and sometimes you get polarity reversals completely like this one. This is about the central 35 or 40 degrees of the visual field This is interesting. This is a patient that was seen here about two weeks ago 17 year old girl had no visual symptoms. She was just picked up in a routine eye exam by Petty and that her fundus looked funny and so he ordered an occipital evoke potential. Here is her oct and she was 20-30 both eyes. Here are her actual evoke potentials just recorded two weeks ago showing the polarity reversal for each of the components. I've seen I saw a little boy that was similar to this that had no albinism characteristics. He was at least as dark as me or darker. He had no observable nystagmus and his vision was about 20-30 20-40 and he had a similar he showed the misreading. He was a form of autism that's frequently found on chromosome 15 although no genetic testing had been done on him for it. There's evidence that there is linkage with nearby sites in some of these and I assume that's why he has the albinism characteristics of characteristics. The type 2, the type that do produce pigment. Let's see if I have a picture. No, type 2. I just want to run through these to show some of the genetic loci. Type 2 is those that in a European person would have blonde or reddish hair but all the rest of the symptoms was the same. Type 3 is on chromosome 9. This is an African girl that I saw in Africa years and years ago and the paper that came out of this was the first description of it but it's turned out that they're everywhere just that they're pretty rare in this type 3. Type 4, different cause chromosome 5. Most of the type 2's look similar to this but some can be very, very light. Type 5 very rare Pakistani family. 6, Chinese family but again on 15Q. This is limited to an isolate on the Faroe Islands on chromosome 10. Regardless of the type of albinism of I think the representatives of all 20 forms have been tested. I'm not sure because the Hermansky-Budlak syndrome, maybe some of them but I've never seen them have been tested but in general all types have the same phenomenon as far as their optic distribution is concerned. It seems to be the most common characteristics across all the forms of albinism. It's the most reliable and measurable other than doing genetic testing which is a pretty expensive panel. Cheapest or you know if it's this cheap anymore it was about 1200 for it and I think Minnesota charges a couple of thousand. So it's the most discriminating. The worst stimulus is pattern reversal. As I mentioned earlier even any form of hypopigmentation that happens to affect the eyes also going to affect the distribution of the optic chiasm and the organization of the central projections. These are just some of the unusual ones. I'm just going to race through them. This is real. It's not a black contact lens. Those are my hands. Ok, ocular albinism also shows that you don't have to have ocular cutaneous albinism as long as the retinal pigment epithelium is reduced in melanopigmentation during the first trimester you're going to end up with this phenomenon. This is an ocular africanocular albino. This is this irstrands illumination. This is this fundus. Some female carriers of excellent albinism have the model retina but they don't have the optic chiasm and central abnormalities. When I was in Amsterdam studying albinism a woman came in that this was the mother's fundus. Came in with two sons one of which had been diagnosed as an ocular albino since he was an infant and the other son was perfectly normal. Quite dark, you can see. There's the fundus of that guy though. His brother came along just for fun and since he was along we thought we'd test him while he was there. His brother had no visual symptoms at all. No trans illumination and there's his fundus and they both showed the optic chiasm starting with using the visual ago potentials. Give you an idea of the variation you can see even between siblings. Hermansky-Pudlak though referred to. Hermansky-Pudlak has been found on all of these locations and there's a tenth that's an abstract but they never published a full paper on it. They published an abstract about two years ago and so there's ten forms of Hermansky-Pudlak described in human beings and seventeen in the mouths. So it's one of the yet to find forms of albinism in humans. Hermansky-Pudlak mild living diethesis not a good thing. Is it true that that happens more in patients of Puerto Rican descent? Oh yes, yes. In fact that Puerto Rico has the highest incidence. It's almost an isolate because of the island. I don't know if they've done the genetics to date back to the prime individuals how many hundreds of years it might have been there. If it's been there for a few hundred years the isolation factor, yes that is true. The first ones I saw were in 1973 and all of them were related to Puerto Rico. But then over the last 40 years again they're everywhere too but just rare but that's true. This is a European because the bleeding diethesis they look like battered children. If they just bump into anything they bleed. There have been a couple of cases I don't know that was in a couple of cases I think of deaths where they didn't know because they were in a northern European family where they were very light anyway and they didn't suspect that they were a form of an albinism and given some medications they bled at. Kegashi syndrome is another real rare one. It's on one cue. It doesn't look like an albino at all. When I first got into this business, the albinism business 50 years ago this was considered a lethal disease of childhood because medicine didn't have the capability to keep these people alive. They were so susceptible to any fever producing infection that usually if they weren't diagnosed in the first time they got sick with a high fever they died. Several of them have come through here but they were on their death bed. I've never been able to get to test them or see them or anything. I don't mean here or Mariana. I sent her through the University of Utah. They have an unusual sort of grey silver hair. This is a girl I tested in Indianapolis. These are littermates. To give you an idea of this is a blue small Persian cat and these are littermates. This is the normal this is the one of the Kegashi syndrome. They had a colony of these at Washington's at vet school in where is it in Washington? Holman? Holman in Washington I think? They had a colony of them there and I got to do their visual anatomy on their brains and they just had geniculates like a sinus cat. In fact this is the fragmented geniculate of one of those showing the poor lamination of the geniculate. How are we doing on time? What's the time? 7.40. Prada Willie syndrome which one comes through Pete's clinic maybe a couple of times a year. It's on chromosome 15 overlapping with the same spread as the type 2 type of albinism. Half of them are hypopigmented and have a high incidence for business and high incidence of infant astagmus. If you select for those that fit that among them many of them have the albino have normality of the optic chiasm picture of one I tested at Minnesota another one is Angelman syndrome also in the same chromosome distribution those albinism type 2 have also shown some have been reported to have the optic misogyny it's not common at all really rare. Another syndrome I've never seen one. These are all probably due to some kind of linkage issues because of being within the same spread on chromosome 15. The child I mentioned to you that came through here had Asperger syndrome the one that is not the same as me. Asperger syndrome is do I describe it here? Like it's 12 or 13 year old and he has the vocabulary of an Oxford English graduate or something. It's very unusual about jumped out of the chair when I cleaned his earlobes for them. Continuously the mother had to tell him to shut up because you wouldn't stop talking during the test. This is that individual's visually vocal potential that otherwise didn't look like an albino. And here's his OCT This is a very rare syndrome only two have been reported in the United States and one was here. We didn't know what it was at first. We did an exam under anesthesia because of a genesis of the corpus callosum and still didn't do the visually vocal potential test and this is their MRI. This is the fundus photo of the individual. This is their OCT it's poor because it had to be done with the handheld and this is the phobial area and this was her visually vocal potentials. They don't know the etiology I think it's genetic determination in interacting with the timing error during ontology and people have been looking for over 40 years for an active role at the melanin in the chiasm or retina to explain it and although it works, theories have worked in some models nothing has been found to work across all mammals. By the way, it's a phenomenon just in mammals. You can see how important pigment is. Here's a 5-week human embryo It's probably all set by 40-50 days in humans. My theory is that the lack of pigment in the retinal pigment epithelium causes the genetic throwback to an 8-deficit expression of visual anatomy or embryo genesis but I have no idea what nobody has beaten me up about it nor agreed with me. Any questions? No? See you tomorrow morning. I'll finish I'll do EOGs and visually vocal potentials.