 And then Leah has our main talk today. She's going to discuss bad eyes and bad ears running the family, early onset vision and hearing loss. You can go ahead. OK, good morning. I'd like to present a case that I saw and found very interesting in Dr. DeGree's neuro ophthalmology clinic this year. And it was a little girl who was 12. She came in with her mom. And their chief complaint was that the bad eyes and bad ears had been running in the family. They were now affecting the daughter at a very early age of 12. And this is what prompted them to want to know what was going on. So history of this little girl's presentation, she is now 12, as mentioned. And she's had progressive complaints of decreased vision bilaterally, pretty much equally since age eight. And breaking this down, she complains of blurred vision, equal at distance and near. It's been progressively worsening. It's not associated with pain, any double vision, no ocular injection, no motility deficits that they could see. And then finally, she does have this subjective complaint of decreased hearing. Again, pretty equal bilaterally. But she hasn't been formally evaluated. So her clinical course was somewhat brief. Before we saw her, she was evaluated by a local optometrist in November of 2011. They were unable to refract her with any marked improvement. And so she was referred then to a retinal specialist in the area who concluded it was likely an optic nerve problem and sent her our way. So this patient's general history is pretty unremarkable. She's healthy. She doesn't take medications. She's, importantly, had no other neurologic history. She's had no head trauma. She's had no eye surgery or eye trauma. She's never required any eye drop medications. She lives in Idaho with her mom. She doesn't use tobacco or alcohol as she stated with mom present. So we think that's correct. She does not have, on review of systems, she subjectively doesn't have complaints that would point us to other neurologic deficits, no ataxia vertigo, difficulty swallowing, no seizures, numbness, tingling, headaches, nausea, vomiting, developmental delay, or failure to thrive. And so I left out pertinent part there, which is the family history. And as mentioned, the mom stated that a number of family members have suffered from similar symptoms. But the workup really has been minimal. But when we kind of went through the pedigree, this is as far back as we could go, but it was a couple of generations. We have our affected patient here. But going up, she has three aunts, well, a mother and two aunts, rather, who have similar subjective symptoms and that this is their age of onset. And again, our patient had complaints as early as age eight. And then her grandfather also apparently had a similar phenotype as did his mother. So we can see that the presentation is present in each generation and both men and women seem to be affected and it appears here that there's male to female transmission. So on examination of the patient in our clinic, indeed, she had a best corrected visual acuity that was 2040 in the right and 2050 in the left. But she didn't have any pupillary abnormalities. Her visual field appeared full to confrontation. And she had full extracular motility without any dybulopia or pain. Her intracular pressures were normal. She did have normal stereopsis and color vision. And we did do kind of an expanded assessment of her color vision with a D15 as well, which was fairly normal. Her anterior segment examination was normal. There was no ptosis or any other abnormality. And then as is commonly done in Dr. Degrees Clinic, we did do a full neurologic examination and that was completely normal. So when we did her dilated fundus examination, though we were struck by the marked temporal pallor that was present on both optic nerves. But otherwise there was no evidence of edema and the other retinal structures were all seemingly normal. On visual field assessment, we found that she had kind of a central depression bilaterally when you look kind of at the numbers here. And then in the right eye, she had somewhat of an enlarged blind spot. And then on retinal fiber layer assessment, you can see that her nerves are thinned and they're pretty equal bilaterally. So her average thickness is 56 micrometers. And you can see that it's most marked in her temporal nerve, which kind of fits the appearance of her optic nerves. And given these data, we obtained visually evoked potentials. And by pattern reversal, we found that they were slowed bilaterally at 108 in the right, 110 in the left. And this correlated nicely with a decreased flicker fusion of both eyes, both optic nerves as well. So putting this all together in a clinical assessment, she's 12 years old and she's had early onset bilateral visual decline. We see somewhat of a seco-central scatoma with temporal pallor and thinning of the optic nerves. So overall consistent with a bilateral optic atrophy. And in addition, she has the subjective complaint of difficulty hearing. So for the sake of my simplicity of thought, I like to take things at one at a time and break them down. So I'll start with the optic atrophy and then we'll kind of see later on how that difficulty hearing might play into things. So thinking of the differential diagnosis of optic atrophy in a child, it is more broad than what I have here, but these are some common things that you would wanna think about. Certainly autosomal dominant optic atrophy would be a consideration. And also glaucoma, you might see more cupping and more elevated intracular pressures and usually not such a strong familial component. Libers is uncommon in a woman, in a female. And usually of course has excellent transmission as a result. And generally the vision is normal and then drops suddenly first in one eye than the other eye. Not as consistent with our history. A compressive optic neuropathy, it's a little less likely to be bilateral. It would usually be a little bit more progressive in a rapidly progressive. And we wouldn't necessarily expect such a strong family history. The same would be true for infiltrative or inflammatory optic nerve pathology where we might expect to see more swelling in an acute setting. And then in a toxic or nutritional etiology for an optic neuropathy, we might elicit a toxin exposure. We wouldn't quite see such a strong family history. Though as Dan Bettus talked to us about recently, there can be some familial components to something like alcohol toxicity. And then optic nerve hypoplasia might be another reason for abnormal optic nerves, but in general we'd see a double ring sign and the history is not quite consistent with what we're seeing in this patient. And then finally autosomal recessive optic atrophy. But given the family history and overall presentation of the patient, I think it's safe to say that our leading differential would be the autosomal dominant optic atrophy in this case. So evolution of the diagnosis of this condition, it was originally, well a hereditary optic atrophy was originally described in the 1800s. But Lieber did kind of beat them out on this, but he, in describing an optic atrophy, but he did not distinguish what kind of, what the heritable pattern was when he first observed the characteristics. So all in all, it was in the late 1800s that we first started thinking about hereditary optic atrophy. But then it wasn't until 1959 that a Danish ophthalmologist first characterized the autosomal dominant pattern. And that is where we get kind of our diagnosis of autosomal dominant optic atrophy right now. And then it did take quite some time for us to really learn more than the heritability of this condition. It wasn't until 1994, 1995 that we did some gene mapping to show that the mutation was likely correlated with chromosome three. So autosomal dominant optic atrophy is the most common now hereditary optic atrophy. There have been some sporadic cases though due to de novo mutations. So you don't always have to have a dominant family history. And its prevalence is about one in 50,000 but interestingly it's most prevalent in Denmark due to a founder effect. And there's a particular mutation that has been traced back to the Viking era that is responsible for the increased prevalence in Denmark. It's characterized by symmetric loss of the retinal ganglion cell layer leading to the optic neuropathy. And it's associated now we know with mutations in the OPA1 gene which is the gene at that chromosome three. This was not further elucidated until about 2000. So it took us some time after we knew chromosome three was involved to understand which gene was actually responsible. Several mutations have been identified in this gene. And all in all about 80 to 90% of people with this phenotype have been shown to have a mutation in OPA1 which is somewhat interesting that it's not 100% but I'll talk about that a little bit later. So what do we know about this gene and why it might cause this disease? It's a genomically encoded gene so not a mitochondrial DNA encoded gene like in leavers and it's a dynamic like mitochondrial GTPA. So it functions within the mitochondria but it's not encoded in mitochondrial DNA. It's localized, the protein is localized to the mitochondrial intermembrane space. It's ubiquitously expressed but it does show some increased expression in different tissues including the retina. And in human the open reading frame is 30 exons. However, as highlighted in blue there are a couple alternatively spliced exons when you get to the mRNA level. So in total there are eight mRNAs that can be generated from this one DNA sequence. And so there is further processing once we have a protein in that there's cleavage events that occur such that we can generate both a long and short isoform of the protein. And so the long isoform is associated with the inner mitochondrial membrane but the short isoform is more diffusible. Beyond that we don't have a clear idea of the different roles for each of these. We know that during apoptosis we see more of the short isoform but that's more of an observational piece of data. We don't have any real functional data to how one functions over the other. So overall the function of the OPPA1 gene. It is important, it has many functions which makes it much more complicated in thinking about the pathophysiology. But firstly it functions in fusion of mitochondrial membranes. So in tissue culture cells mitochondrial fusion has been shown to be impaired when we use RNAi to knock out OPPA1. And then control of program cell death or apoptosis is regulated by OPPA1. So if we overexpress OPPA1 it protects cells from apoptosis induced by intrinsic stimuli namely cathases and oxidative phosphorylation. So RNAi's which deplete OPPA1 within cells again demonstrate severely reduced endogenous respiration. And they cannot be stimulated with addition of an uncoupler. And they also have decreased oxygen consumption driven by essentially the mitochondria. So finally OPPA1 is thought to be important in maintenance of the mitochondrial DNA. So electron microscopy has demonstrated that there are changes to the internal membrane structure in OPPA1 knockout cells and that this inhibits mitochondrial DNA anchoring to the internal membrane which is required for replication specifically of the mitochondrial DNA. So this has all been done in tissue culture cells and we have kind of a schematic of then overall you can see in general the mini functions of the mitochondria are reliant on OPPA1 it would seem but what do we see in an actual animal model is what we see in cells transferable to what we can see in an animal model. So there have been two OPPA1 mutation mice generated and so one is a frame deletion and one has a premature sub codon. But the data from these is fairly similar and in that a homozygous mutation is lethal and a heterozygous mutation which is really more similar to what we see in the human condition anyway does demonstrate what we would expect based on our cell culture and to some extent what we see in humans. So we see progressive loss of retinal ganglion cells and reduced number of axons with an abnormal shape and myelonization of the axons. And so that is pictured here and generally you can just see these bundles of axons look distorted in this picture with the OPPA1 heterozygote and it's quantified here you can see there's just fewer axons overall and then structurally as we mentioned with the electron microscopy in cells the mitochondria were very disorganized in appearance and we see that also in the mice. So here's a normal mitochondrial structure in a wild type mouse and then the mouse that has the mutation you can see the mitochondria just don't look appropriate there and so they have correlated this with function to some extent in the mice where they use the patterns to have the mice track and see how well they can, their visual function is performing but so they do believe that as in a human in the mice these aberrances result in decreased vision. And finally with respect to reduced overall cells of the ganglion cell layer we can see here that over time extending down in the OPPA1 mice in this column versus the wild type mice when we label the retinal ganglion cells we can see that there are fewer when we go out 13 months in the OPPA1 mutation mice versus the wild type mice. So how does this correlate to people and it seems to me that it correlates quite well these are some of the classic findings of autosomal dominant optic atrophy and it's very similar to what we saw in our patients so we see optic nerve pallor that's most marked in the temporal aspect of the nerve and there are varying degrees of color vision abnormality but this is what you might expect with optic nerve pathology and then on visual field we have kind of central or seco-central scatomas but there is a spectrum of what we see within humans and so overall we see this insidious mild to moderate vision loss it does generally start in school age children which does fit our patient quite well and it does progress throughout life but the degree of progression is really unclear at this point there have been a number of studies I'll touch on one here and then a few others later but over a 10 year period an Australian population with autosomal dominant optic atrophy and known opowan mutations was studied and you can see that 62% of the 30 patients that they looked at did not have a change in their logmar scores over a 10 year period but they did not stratify by age so they kind of they had age range from 10 all the way up to 60 and so we don't know, you know, does the progression occur earlier in life and level out? They were not able to assess for something of that sort in their study but overall it's kind of striking my understanding of this disease prior to preparing for this talk was that it was just kind of progressive throughout life and they would have really bad vision in the end but all in all the progression is variable and it doesn't necessarily mean that they're going to progress to a significant degree and then what's their final visual acuity? It is also quite variable but in general 40% are about 20, 60 or better 45% are between 20, 60 and 20, 200 and then the remaining are below 20, 200 so it really is the minority of people that have severe visual impairment from this condition and then as we mentioned essential or seco-central visual defects are most classic but some individuals have demonstrated altitudinal defects this chromatopsias often seen both within the blue, yellow and red, green spectrums optic nerve pallor is kind of evenly dispersed between just the temporal aspect or the entire nerve and many times what you will see peripapillary atrophy and this makes it a little more difficult you can see an enlarged cup to disc ratio and glaucoma can be on your differential so though it can be present in this condition so why the variability and one thought that came to mind was maybe it was just more for residents to memorize but all in all I think it's more likely that it's due to incomplete penetrance and the reason for that is again unclear but you could imagine environmental factors play in the genetic background might have a role and then the mitochondrial DNA background itself might have a role and there is a study in support of this where they found a threefold over expression of the mitochondrial haplogroup J in the autosomal dominant optic atrophy patients compared with control patients but the functional significance of this is not known but it's interesting that there is this over representation and then in addition there are just a lot of OPA1 mutations so we can see here that throughout the gene these are kind of schematizing the different regions of the gene and then you can see the frequency of detected mutations in that area of the gene and then overall what that results in in terms of what the protein looks like so there are proteins that just have misins mutations versus premature truncation which is the most commonly seen mutation result but we don't understand really exactly how OPA1 is performing its different roles that we've detected in both our cell culture and in the animal models. We don't exactly know the mechanism and so it makes it difficult to correlate all of these mutations to what we see in the clinical setting but we have kind of observed and categorized some of the variability that we've seen in the phenotype into specific syndromes and then from that we've made some correlations between specific syndromes and specific mutations in OPA1. So you can see here there's just kind of straight dominant optic atrophy without any other factors or phenotypes. There's a reversible condition that was described only in one patient by only one person and so it's in the field it seems like people might not believe that but it remains to be seen and this has been correlated with a specific mutation and then importantly here there's autosomal dominant optic atrophy and deafness and that's what this D stands for and it's thought to be an optic neuropathy with an auditory neuropathy as well plus and minus perhaps some extraculomotility deficits and TOSIS but this has been correlated with a very specific mutation in OPA1. In fact, this is the highest correlation between any specific dominant optic atrophy phenotype and a specific OPA1 mutation. So I'd like to speak a little bit more about that since our patient did as you remember present also with some complaints of subjective decreased hearing. So in 1974 actually there was the first description of dominant optic atrophy with deafness and then there are some strong ties to Utah which I also thought was pretty interesting. In 1984 a researcher named Treft described this syndrome where there was a dominant optic atrophy and also hearing loss with TOSIS, extraculomotility deficits, ataxia and myopathy. But still at this point it wasn't quite known what the genetic basis was but this syndrome was again described in a Belgian family and then in 2003 there were a handful of patients identified with this phenotype who had extensive genetic testing and we identified this particular mutation R445H which is just a change in the amino acid at this position in the OPA1 gene. And subsequently to that Dr. Warner and Dr. Katz and Dr. Zong did additional testing on the Utah family and the Belgium family with respect to this mutation and identified this mutation in all members of those two families. So providing very good data that that mutation was in fact responsible for the phenotype we were seeing. And then finally another Ohio family was reported more recently. Again in collaboration with the Cleveland Clinic in Utah that showed an autosomal dominant optic atrophy with just deafness and this mutation. So it didn't have all of the other phenotype. So even within this very correlative data there is some variability but that seems to be kind of the rule with OPA1 as I've learned through my studies but some of the sentinel work which was described by Payne et al in 2004 here at the university shows that these are the patients that were assayed. And you can see that their visual acuity is really quite varied as we mentioned. Their optic atrophy in terms of appearance is somewhat varied. Their hearing loss while present is somewhat varied not present in all. Their color testing again somewhat varied but generally diminished. And then many of these patients had the extraculomatility deficits and the ptosis but not all as you can see here which kind of correlates more with our patient. And then this is the mutation that they mapped in the DNA of these patients. And in addition they did a comprehensive audiology studies showing hearing loss versus control which is listed here and this is just some representative patients. So further characterization has been somewhat minimal of this mutation in terms of really understanding exactly why it's correlated so closely with this phenotype but what we do know is that it's mutation located in the GTPase domain which is kind of the, you know all domains are technically important. You know we have a mitochondrial targeting sequence if you don't have that you're not gonna ever get to the mitochondria to do your job. But you know the GTPase is kind of the business part of the protein and what actually gets the job done. So it's a very important location for mutation. Resultant change in protein and function is not really confirmed or definitively known but what we have seen is through phosphorus magnetic resonance spectroscopy we were able to see that the rate of ATP production was significantly impaired in skeletal muscle and this was taken from the patients. It wasn't done in tissue culture. So they have less ATP which you could imagine would be important for nerve cells. And then the mitochondria from fibroblast taken again from these patients demonstrated that the mitochondrial network was very fragmented and we would have expected that based on our animal studies but it's nice to see that in an actual patient but it's quantified here based upon the total size of the tubules but you can see here that this is another OPA1 mutation and this is the mutation found in this particular phenotype and it's even more severe in terms of how fragmented the mitochondria are than this other mutation which is fairly common. And finally with respect to why the hearing might be decreased fluorescence imaging has demonstrated a high concentration of OPA1 in the cochlea and with co-labeling of cytochrome C which we know is present in mitochondria and these are cochleal hair cells here we see that there's co-localization within the mitochondria of the OPA1 and the cytochrome C not within the nucleus which is what we would expect. And so functionally it's still not definitively shown what role this would play but we can draw a correlation from these data and in fact in patients we have continued to draw correlations with specifically cochlear function not just overall hearing and so this is a tracing of two individuals who are shown to have this particular mutation as well as the phenotype of optic atrophy and hearing loss alone and we can see that specifically their cochlear function is impaired in both cases. So as an academic point though it seems that our patient is fitting very nicely into the dominant optic atrophy with deafness. We don't have genetic information on her to know if she has this mutation so in thinking of what other things this could be there are other syndromes that involve optic atrophy and hearing impairment. So this particular syndrome which I won't attempt to say is X-linked and it's characterized by deafness, dystonia and optic atrophy. So in our patient we didn't really see dystonia and certainly the pattern was not an X-linked pattern. Again we can find an X-linked Charcot-Marie II disease number five we can see optic atrophy with deafness and a polyneuropathy which our patient did not appear to have at this time and again the X-linked pattern was not consistent with our history. In Gustoven syndrome I think it's another X-linked syndrome but it's also characterized by mental retardation and seizures and our patient did not have that and then there's a Wolfram syndrome that has two types and it's an, classically it's an autosomal recessive mutation in this particular gene which is important for calcium transport and it causes diabetes mellitus as well as insipidous optic atrophy and deafness. So our patient did not have evidence of these other conditions and it didn't appear that it was a recessive transmission. There's a second type with a different gene involved but the syndrome is the same and then of course dominant optic atrophy but interestingly I did mention that not all of the people with dominant optic atrophy have been shown to have OPPA1 mutations so there is I think still a lot we need to know about this condition and maybe there are other low side that modify OPPA1 either transcription or translation such that a mutation in that site would have an effect on OPPA1 expression and that could be a reason why we're not picking up the mutation in our current studies but also perhaps other genes that don't affect OPPA1 could have a similar phenotype and one such gene is this WFS1 gene which is the Wolfram syndrome gene but recently a novel mutation has in this gene has been shown to have autosomal dominant inheritance pattern with optic atrophy and hearing loss and these are some of the eight probands from that study and you can see that diabetes was not really prominent as with the other Wolfram syndromes but you did see quite a bit of color vision deficit optic atrophy and hearing impairment so there's still quite a bit we need to learn about this condition and I think that really plays into what we tell patients in terms of prognosis and treatment considerations so prognosis is really varied I mean we've seen several examples of the variability of visual acuity. There was a nice study that was done in 1993 and it was 20 individuals but they were studied over 16 years which is the longest study I was able to find and their visual acuity range from 2020 which was in several people but it was kind of within the same family a man with affected father and three affected children and then to 2400 and some of the other individuals but the median initial visual acuity was 2060 and the average age of enrollment was in the mid 20s actually for this study so we don't know at onset necessarily what their visual acuity was but the median final visual acuity was 2080 which I think is pretty interesting I mean it's not a significant change over a 16 year period and you can see here that in really an approximately 65% of the patients they were unchanged or only decreased by one snel in line and in 15% though you did have more drastic visual decline and this is really an agreement with the initial findings the sentinel data of the 19 families that were described in 1959 that were followed over a 10 year period and visual loss progressed in only 50% and was moderate but we don't have such nice delineation of data from the sentinel literature so there's no treatment though I mean we can discuss with the patients what we think will be their course but there's no treatment at this time I think more work on OPA may help us to understand the path of physiology and develop treatments in the future but at this time we don't have any we certainly should be helping people to access low vision aids we can offer genetic analysis which we did in the case of our patient and so she has been enrolled in hygiene because if we detect a specific mutation in the future we're able to target that mutation therapeutically may be helpful either to the patient or to their family and finally abstinence from alcohol, tobacco and a vitamin regimen as Dan again talked about a couple of weeks ago is important just to minimize other risk factors for optic nerve injury and then in patients who have hearing loss cochlear implants in the final study I showed you where it was a cochlear dysfunction of their hearing loss the cochlear implants have been shown to improve their hearing exponentially so that's a very good option for these patients it was interesting in our patient we did send her for audiology and it was normal she still felt like it was decreased and everyone else in her family did so maybe down the line she'd have measurable decline in her vision and then another thing to think about some of the cases that treft and pain initially presented in the literature some of that ophthalmoplegia was onset within middle age and none of her family members had had that that the mother knew about but I think that's another good reason to follow this patient she may develop something like that which would be very unfortunate but that might be why there's a spectrum maybe some of the aspects of this phenotype are more late onset so with that I'll take any questions and then I'll take any opportunity to put my son up