 Great. Can everybody hear me? Apologies for my voice. I'm fighting a little bit of a cold. So, as Lloyd just said, I'm going to be talking about the ocular manifestations of Fabry disease, also known as Anderson Fabry disease or Fabry's disease. In this talk, I'm going to start by describing a case. It's a hypothetical case, but it's very illustrative of the natural course of the disease. We're going to go over the basics of Fabry disease, the epidemiology, the pathophysiology, the signs and symptoms, especially as they pertain to ophthalmologists, and the interventions, again, focusing on where the ophthalmologist can come in. So we have a 14-year-old Caucasian male who presents to his family doctor complaining of occasional tingling of his hands and feet at times progressing to moderate pain. On physical exam, they note 40-50 small dark red-blue macules on the lower abdomen, buttocks, scrotum, and thighs. Some simple laboratory tests come back normal. He returned several years later for just a regular physical. He has the same peripheral neuropathy, but also occasional abdominal pain and diarrhea. On physical exam, more macules are noted. They send some more labs. Everything comes back normal, except the UA demonstrated some mild proteinuria. We'll jump forward to age 22. Our patient was hospitalized with swelling of his hands, feet, and around his eyes. He was told that his kidney function was at about 50 percent, and an eye exam by the internist demonstrated cloudy corneas. Further workup went on, and at age 23, finally a kidney biopsy was done. They were light microscopic changes, including glomerular, interstitial, and vascular disease. On electron microscope, you could see inclusions in the puttycytes, and the endothelial cells, and mesangial cells within the lysosomes. They sent a lab for alpha-galactosidase A, and the activity of that enzyme was markedly low at 11.9. Thus, diagnosing him with favorite disease. He went on, by age 40, he was on dialysis, had a stroke at age 50, and died at 55. So this case, it's very classic in terms of the timeline. The average length of time between first presentation of symptoms and diagnosis is about nine years. It's easily missed. So this patient presented at 14, and by 23, finally was diagnosed. Some basics on favorite disease. It's a rare lysosomal storage disease caused by a deficiency in the alpha-galactosidase A activity, or alpha-gal-A. It causes a deposition of globo-tryaso- tri-A-o-sulceramide, or GL3, in the cells causing endothelial dysfunction. The onset is in adolescence and leads to periodic acroparesthesias, which are the pains and tingling in the hands and feet, angio-keratomas in a bathing suit pattern, also hypohydrosis, or anhydrosis, or lack of sweating, and characteristic corneal and lenticular opacities, which we'll go into later, in addition to protein area. These patients usually die of end-stage renal disease, average age of 41, unless dialysis is started. If dialysis is begun, then you get cerebral vascular accidents, heart disease, and eventual death, usually in the fifth decade. It's an excellent, possessive disease, so it affects males mostly, but due to lionization, females can also have display a range of severity in the disease. Population-based studies have shown that worldwide it's seen in about one in 80,000 to one in 117,000. However, a recent paper in Italy found that the incidents, just looking at newborn screening of the alpha-gal-A enzyme activity, it was low in one in 3,100, and however, the predominance was toward the non-classic type of fabric disease, and so those would be people who have a cardiac or renal variant, so they lack the classic findings of the acroparasthegias, the young childhood or adolescent onset, angio-keratomas, hypohydrosis, and the corneal and lenticular opacities. It's thought that actually a larger proportion than was originally thought of patients that have end-stage renal disease in their between their 60s and 80s may actually have this non-classic renal or cardiac variant of the fabric disease. The mutation in the GLA gene on the X chromosome, as I mentioned, causes a deficiency in the alpha-gal-A enzyme, leading to the deposition of GL3 within the lysosomes, and you can see in this electron microscopy image, this is endothelial, an endothelial cell, sorry, in glomerular epithelial cell, and all of these, they're called zebra bodies. These are the lysosomes that have been filled with the GL3 material. This is just the pathway that the glycosfingolipid metabolism follows. So if you're missing the alpha-gal-A enzyme here, you can see you develop fabric disease. If it's lower down on the pathway, you can develop Gauchat's disease. The GL3 material deposits largely, well, it deposits in all the cells of the body, but it causes the most dysfunction within endothelial cells. So you have, as I mentioned, kidney problems in the heart. You can get cardiomyopathy in addition to ischemic events, cerebrovascular accidents in the brain, in the peripheral nervous system, you get the acroparasthegias. In the GI tract, you get, due to deposition within the blood vessels and the nerves, bouts of diarrhea and abdominal pain, and in the skin, the angiocaritomas and anhydrosis. So we'll talk about the angiocaritomas a little bit more. So it follows this classic pattern, bathing suit pattern. The name that was given to it is angiocaritoma corporeus diffusum. This isn't used so much by general doctors, but the dermatologists like it, and you can see their small punctate. Sometimes they coalesce into a larger group, like you can see on the hip here. Ocular signs, this is probably why we're here. We're looking for the corneal verticillata, which is an epithelial deposition of the GL3 in a whirl-like pattern. The whirl generally centers just below the axis of vision, and spirals until it's linear as you move outward. This is actually a very common finding. It's seen in between 70 and 90% of patients with febri disease. However, it's not completely specific. The most common medications that are quoted, they also cause this type of corneal verticillata, or amiodarone and chloroquine, but quinocrine, chlorpromazine, endomethacin, chlophazamine, ceramin, naproxen, and tylerone also can produce a similar finding on the corneal surface. Another ocular sign is congenitival vessel abnormalities. You can see the tortuosity of this vessel here. They can also become aneurysmal and fold over themselves, bulging outward. Here you can see the classic lenticular opacities. This cataract on the right side, this is the classic fabri cataract. It's a posterior cataract, stellate or spoke-like in appearance. However, this is only seen in between 10 and 20% of fabri patients. This is much more common. This is an anterior cataract. Both are caused by deposition of the GL3 material. The vessel tortuosity can also be seen on the fundus. It can be seen using an ophthalmoscope, but more dramatically using fluorescent angiography. You can see the tortuosity of the vessels in the superior and inferior arcades. The vessel tortuosity has some prognostic value as well. You can see that patients that had the vessel tortuosity in this study, on this side, this is the fabri outcome scale of the maze symptom severity index. The folks that had vessel tortuosity had more severe presentation of the disease than those that did not have vessel tortuosity and those statistically significant. Even more significant perhaps is that vessel tortuosity is also associated strongly with cardiac size. This was looking at the thickness of the left ventricle as a marker for cardiomyopathy. Most importantly for ophthalmologists is that the ocular presentation is much earlier than the rest of the problems. So if a doctor were to pick up the corneal signs especially which can present as young as three years old, you could get the patient started, intervene and prevent potentially many of the problems that will show up later in life. Interventions that we have now which are relatively new, fabrizyme and replica, that's FDA approved in the US, replica is used in Europe along with fabrizyme. There were several studies on fabrizyme in the past decade since it was released. The first one here by Aang in 2001, this is actually the stage four when they were trying to get the drug approved, stage four trials. They found that when they looked at the microvascular endothelial deposits of GL3, it actually was cleared within six months in 20 of the 29 patients that were in the treatment group. And none of the patients who were in the placebo group. Beck at all in 2004 was able to demonstrate that the renal kidney disease that the patients were suffering from stabilized once they were put on fabrizyme. And then Hughes at all demonstrated that the cardiomyopathy actually reversed and the left ventricular mass actually decreased as measured by MRI. So in summary, fabri disease is an excellent recessive deficiency in the alpha-gal A activity. If you see cornea verticillata and you see angio keratomas in a bathing suit pattern, you can practically make the diagnosis. And finally, early diagnosis and intervention frequently by an ophthalmologist could set a patient on a course with less morbidity and increased quality of life and possibly increased lifespans, though the medications haven't been out long enough to be able to show that yet. Special thanks to Alicia and Canon for helping me out on this. And these are my references. Are there any questions? Yes? Sure. Urinary findings usually show up in the adolescent years as mild protein area and gradually increase heading toward end stage renal disease by the third or fourth decade. In terms of the UA findings, well, I know that the protein area is usually out of proportion to the azotemia, so the patients are relatively compensated until the end, but I couldn't tell you exact figures. There are also, well, I know that they can find the multis cross lipid findings, but that's not specific. I'm not sure if there are specific urinary tests. Generally when they want to do the confirmatory diagnosis, they'll just go straight for the alpha-gal A activity. No visual symptoms at all, so it would take a pretty astute clinician to send them off to the ophthalmologist. Yes? Yes, so you can test the blood. Tears are frequently checked as well. And then also, well, not frequently, but you can also go for a mutation analysis. That's another way to make the diagnosis. All right. Thank you very much.