Chapters Transcript Video Symptoms Associated with Dysautonomia in Patients with Primary Mitochondrial Disease and the DySSy Survey Jeffrey Boris, M.D., F.A.A.P., F.A.C.C., presents at the Johns Hopkins POTS Grand Rounds on December 2, 2021. So this is my first slide primary mitochondrial disease as a heterogeneous group of energy deficiency disorders with pathogenic variants and either mitochondrial and nuclear DNA. Um, and then again, discussed just, you know, there are 16 various symptoms at an average um from anything in these patients. The symptom time of onset can range from infancy, dilated belt hood uh and can involve either a single organ or severe multi system failure. So we talk about autonomic dysfunction uh and PMD. It's thought to occur in as many as 38 a half percent of Children with definitive or suspected PMD. Um, but the specific features are not well described in the literature. Um, it's mostly mostly in adults and mostly in single PMD disorder. So um, you know, very highly described in in a specific disease. So we came up with the dc, the disorder nomi a symptom survey as a questionnaire to assess both the features and severity of these symptoms. Uh, and um we felt or what we did was we counted symptoms that occurred at least weekly as affirmative. And then I was kind of getting into the issue of the compass 31. So, um, one of the things that came out in the latest american autonomic society meeting, um, is that a lot of people have used the compass 31 to assess autonomic dysfunction um, in a variety of disorders and that includes things like pots um, diabetic neuropathy and you know, um, scleroderma and I'll actually show some of these a little bit later as well. But Wolfgang singer who was one of the folks who was originally involved in the Creation of the compass. 31 reminded of Saul that it's really only been validated for autonomic neuropathy and nuclear nuclear nopa these. So I think we just have to make sure that we keep this in mind. Our patients sources were both Children and adults. Um and we got them from, we got four different groups of patients. Um the Children's Hospital of philadelphia, mitochondrial medicine frontier program or the mm FP. And within the mm FP group we had two different subtypes. We had those who were genotype confirmed or PMD positive. And then we had patients with suspected PMD or what we referred to as P. M. D. Negative. And then we also went outside to see the United mitochondrial disease foundation mitochondrial disease community registry or the M. D. C. R. And again we split these patients into two groups. Um those who reported that they were genotype confirmed or PMD positive and those with suspected but not confirmed PMD PMD negative. And um Our statistical analysis was was used here. One thing that to keep in mind was that we did use a bond for any kind of correction. And so um our threshold P values were a lot lower than just typically .05. And the reason for for those that are not familiar with using a bond for any correction is if you ask a lot of questions then you um then your likelihood of getting a positive answer is higher but that positive answer may not necessarily be um statistically significant. So one of the ways to correct for this is to divide your threshold Um value for significance .05 by the number of questions that you use. And that's what the bond phony correction does. Um When we were set are like an analysis for quality of life, we split out excellent, very good and good versus fair and poor. Much better, somewhat better versus somewhat worse and much worse. And then um some of the time a little the time none of the time versus most or all the time. Um and then we did multiple comparisons. You're gonna see a lot of initials and uh so hopefully I'll be able to help you kind of maintain a little sanity with this. So to remind you the mm FP is the, is the internal or the chop group. The MDC our is the the external or the united mitochondrial registry group. And again PMD positive or those patients who were Jenna typically found or reported in the MDC our case to have primary mitochondrial disease. And those who are PMD negative were either genotype negative or suspected. So we compared um the with within mm F. P P and the P. M. D. Plus vs minus and the same for the M. D. C. R. And then we also went um between groups mm FP vs mg cR in our PMD positive and negative groups. And then we also compared to those who were specifically PMD positive and Children versus adults. Sir. Let's talk about what we found with the kids first. Here's our demographics. Um as you can see, not a huge study. Not a huge number of respondents 49 in the mm FP group, 31 in the MDC our group. Um and you can see the age distribution here. Um interestingly, I think one of the things that's kind of interesting is here specifically is that the mm FP group has a lot of kids under age three years. Um and that may be potentially because the MFP is just either diagnosing it sooner or patients are not getting to the united mitochondrial um disease group until maybe they've been diagnosed later. Um And um you can also see our breakdown between MD plus vs minus patients. Um and as well as the location of the mm hmm. Of the genetic um variant um uh and it's almost split half of our mitochondria. Half of them are nuclear. Shut up. This is what we found. Um there was no difference in the frequency of specific symptoms in any between any of the PMD positive PMD negative mm FP or M. D. C. R. Groups. And we and we sort of assessed all of them in different directions and there were no statistically significant differences. I think the reason for that though. And as I go over the specific symptoms, you'll see a range of percentages of, of occurrence of these symptoms. And that's probably because our sample size was fairly, was relatively small, but one of the things, but some of the things that you can see here um in the patient's, um, nearly half were able to perform mild exercise, which means about half were not able to okay. Um There was a wide range of patients who had skin color change. Um and a quarter to a half of them had heat intolerance. Um, there was a range for patients having brain fog and insomnia as well. Uh, I think the other thing to keep in mind is look at the taco cardia, skipped beats and Ortho static symptoms. Those are relatively low and certainly much lower than we would expect. And as as compared to patients who have postural metastatic tachycardia syndrome. Other symptoms that were found included a fair amount of gi symptoms, early satiety, bloating, nausea, abdominal pain, very little um issues from a bladder standpoint. Um, There were there was some aspect of pain and nerve pain and very little um, Ocular symptoms. When we looked at the overall number of or the overall amount of symptom Atala ji, anywhere from three quarters to 100% of patients reported any symptoms. A third to two thirds had at least five symptoms, and then very few had at least 10 symptoms, or at least 15 symptoms. And the reason I bring this up is I want you to compare this to the next slide, which is what our symptom Atala Ji that we published in our demographics paper in 2000 and 18. Which which was a study Of our pediatric pots database. And at that time it was over 700 patients. Um where two thirds of patients reported at least 10 symptoms. Half of patients had at least 14 symptoms and 30% reported over 26 symptoms, so um much lower overall uh symptom reporting when we looked at the quality of life um findings in the mm FP group, three quarters of PMD positive patients really had uh positive quality of life. Um As compared to about 41% as compared to about 2 41% of the PMD negative patients. And that actually turned out to be significant otherwise, there was no difference between groups in their change of health. Um 3/3 quarters of them felt that there in the last year their symptoms had had for either the same or better. Um Um up to 2/3 felt that there was minimal interference with their activities of daily living, And almost 2/3 felt that there was minimal interference with their social activities. When we looked at the NBC, our group, um They also had up to about two thirds of them felt like their general health was good and um three quarters to 100%, 3 quarters to 100% of them felt that their change of health in the last year was the same or up to better. Um Almost half though felt that there was minimal interference with their activities of daily living. So they did demonstrate more interference with activities of daily living and as well as um although their interference with social activity was relatively minimal too. Then we looked at the compass 31 and two to remind you that 0-100 score with a higher score meaning more being more affected. We broke it out by domain and there was really, there were really no significant differences between mm F. P. And M. D. C. R. In the Ortho static Visa, motor secreto, motor G. I. Bladder and pupil of motor um scores. Although one of the things to to look at overall is how the G. I. Um scores are much greater than the other domains. And then total scores were uh were relatively well 10 to 17 for the mm FP and 16 to 33 for the NBC. Are groups um which would be essentially mild, mild impairment. When we looked at by various analysis, there was no differences in gi bladder or eye symptoms between groups. So from a summarization staying over the pediatric findings, there were really no differences when comparing the mfp groups with the mm DCR groups or the PMD positive or negative groups. They had an overall symptom burden um versus pots that was lower. They had more G. I. And temperature intolerance complaints with fewer cardiovascular symptoms. But they did demonstrate some aspects of pain, brain fog and exercise intolerance. Their quality of life was overall good. Um and their compass, 31 scores were relatively low. Um and mostly demonstrated um findings in the G. I. bill right now for the adults. So here is our demographics for this group, um a lot more adults in the NBC our group. And um again, you can see the breakdown of PMD positive and PMD negative um as well as their genetic locations. Interestingly enough, a lot more mitochondrial, a lot more patients with mitochondrial DNA variants than nuclear DNA variants in the in the adults. Um When we compared the PMD positive and negative groups, there were no differences in symptoms on on the Dc. In the mm FP group. Um However, in the NBC, our group, there were more um there was more skipped beats in the PMD positive group and there were and in the N. MFP group, um When we compared PMD positive versus NBC rpm D. Positive, there was more insomnia. In the MDC, our group, um looking at specific symptoms again, relatively lower overall um cardiovascular symptoms, but a higher amount as compared to the the pediatric patients. Again, about only half were able to perform mild exercise. Um and a significant amount of heat and cold intolerance. Again, brain fog and insomnia are are seen here as well as as well as some headache. Um Also again, g. I symptoms, there's uh there's more findings from a bladder standpoint as compared to the kids as well as the ocular standpoint and a lot more pain. Um Para seizures are theologies and nostalgia's um are also seen in the adults as compared to the kids. When we look at their overall symptom reporting, Um 86-100% had any symptoms. Um and then um Up to 83% had at least five, almost half of at least 10. And then a small amount had at least 15 symptoms. So again, um this is a greater amount of symptom, Atala Ji or symptom reporting as compared to pediatric patients. Um And in the adults, the MDC, our patients had more symptoms than the MFP patients and the PMD negative patients. So those who did not have who or who had suspected but not confirmed um primary mitochondrial disease had more symptoms as compared to the PMD plus patients. When we looked at quality of life in the mm FP group, almost half felt that they had uh well, sorry, so there was no difference between the PMD positive and negative groups, Almost half felt they had very good good, very good or excellent. General health. About three quarters of patients felt their health in the last year was much better, somewhat better, or the same about that same amount felt that there was anywhere from none to only some interference with activities of daily living. Um Up to a third were told that they were making up their symptoms and a little over a third were told that their symptoms were all in their head. When we looked at the MDC, our group with from the quality of life standpoint, the PMD positive group um had a 44% demonstrated excellent, very good or good general health versus only 14% of the PMD negative patients. Um And yet no one and yet this was still less than half of patients. So these patients definitely had more of a negative impact of their mitochondrial disease on their general health. And then the rest of the groups were no different um in their change in health. Um Their interference with activities of daily living, interference with social activity. Um And then a little bit less than half were told they were making up their symptoms and about half were told that their symptoms were all in their head. Um So again, so looking at just getting back to the interference with activities of daily living and the interference with social activity. Um Most patients felt that there was that there was insignificant interference with with these two, these two issues Looking at the compass. 31 findings, the scores by domain um were were there were no different between MFP and NBC are except in the G. I. Group. Um The MDC our patients had a significantly higher score uh than the in N. B. C. Are than an MfP I think. But I want you to also look at the Ortho static scores. If you recall from the pediatric patients, those were much lower. And now the adult patients are reporting more Ortho static symptom Atala ji. Um They're also reporting more bladder and people in motor symptom Atala ji. So when we look at their total scores, um they're totally, you know, whereas um the kids had the lower scores and I'll do a comparison side by side comparison a little bit. The adults with compass 31 um had definitely demonstrated higher higher scoring. Um Up here and again, by burying analysis showed no differences between gi bladder symptoms. So now this is a graph demonstrating comparison between the blue is healthy controls. Red is small fiber neuropathy, Green is diabetic neuropathy, purple scleroderma, lupus, fibromyalgia. And then the orange is looking specifically at adults who were in the mm FP program and who were PMD positive. So this is comparison with published data from several studies that you can see down in the lower right corner and overall you can see that the mm FP um Patients with the PPD positive patients scored pretty similarly to um from a compass 31 standpoint to these other disorders. So um what was so what was felt to be statistically significant from an Ortho static standpoint was the healthy controls were we're less in the vase. A motor stand scores on the scleroderma patients had more, and by the way, um the PMD score, there was the senate was zero. So that's why you're not seeing a bar for the PMD plus folks um in the secret a motor patients, everybody, but they accept the healthy controls. And PMD positive patients were felt to be significant. And then you can see the breakdown from gi bladder people in motor and total standpoint total score standpoint. So now we broke this out um looking at pediatric patients versus adult patients with, and we looked specifically combined the MFP and the NBC our patients, but used only the PMD positive. Right? So we used the chop and the external patients, but only those who had um oh confirmed or reportedly confirmed mitochondrial disease. And when we looked, we found that the adults had statistically significantly higher scores from the Ortho static standpoint. From a headache standpoint, from a brain fall with they had more brain fall. Almost half of them had brain fall. Um My algebra, um zero Fail Mia and and Blurry Vision. All the rest were not considered to be significant, but again, you can see the relatively low numbers, so it it's more difficult oh, to uh, to discern a significant difference. Um and then in symptom reporting, um the adults again, had higher groups of patients with at least five symptoms and at least 10 symptoms when we compare them side by side with, from a quality of life standpoint for general health. Um It was right at the level of the threshold of significance for the pediatric PMD positive patients having about two thirds of them versus a little bit less than half for adults, feeling that their general health was excellent, very good or good. Um Back for the pediatric patients had a change in health over the last year, that was significantly improved three quarters of them versus a little over half. Um There was no difference between the reporting of interference with their activities of daily living or interference with social activities. But interestingly enough, adults were much more likely to be told that they were making up their symptoms or that their symptoms were all in their head When comparing the compass 31 scores. And again, you can see the, the corrected p value threshold at the bottom. Adults had a higher Ortho static score, higher secreto motor score, um higher pupil a motor and higher total score. So when looking at the adult findings, they had higher overall symptom reporting versus pediatric patients, Most patients had at least one symptom but still a lower overall symptom burden versus versus patients with versus at least pediatric patients with pots as listed before. But truthfully, if you look at the um the paper written by shaw, the face of postural and postural tachycardia syndrome Lauren styles is also a co author, um that symptom Atala ji is fairly similar as well. The MDC, our patients and the PMD negative patients reported more symptoms than their counterparts. They had mostly exercise intolerance, temperature, intolerance, brain fog and pain. Um They did have moderate GI and some more ecstatic symptoms and they had more bladder and i symptoms as compared to pediatric patients. They still had a relatively good quality of life, though slightly lower than pediatric patients and from a compass 31 standpoint. Um their impairment was low to moderate. Um there they had higher scores, which was worse than pediatric patients with higher Ortho static and GI domains as compared to the others. And um this appears to be comparable with other autoimmune disorders with recorded autonomic dysfunction with the understanding, again that the compass 31 is not validated for these for these disorders. So you can, you can ask, you know, why are the pediatric symptom scores lower and there could be several reasons for this. Children may not report their symptoms. The parents may not notice the symptoms as much. Um adults might just catch more and that and that might just be that they're more aware of their bodies. Um, they're more aware of themselves and this is something that we see a lot in pediatric pots patients where um they they don't they're not necessarily as aware of some of the symptoms that that might be abnormal. Another thing too, I think to keep in mind is with mitochondrial disease, there may be some aspect of a cumulative deficit in adults that Children just don't have. And obviously this depends on the mitochondrial disorder or the nuclear DNA disorder, but this might be something that could factor in here as well. I think one of the other things to keep in mind is, you know, do some PMD negative adults actually have pots and that, you know, that may be considering that they have more Ortho static symptoms. Certainly their symptom burden is is probably less as compared to POTS patients. But this, you know, this could still uh this could still be something to consider. So in summary, patients with PMD have symptoms about an army of dysfunction. Adults report more symptoms, patients without proven PMD seem to report even more symptoms as compared to those who have proven PMD. The symptom Atala ji includes more G. I. And temperature intolerance, brain fog and pain. The pain is much more so in adults, the quality of life is reasonably good. Um with Children having somewhat better quality of life is compared to adults. And the compass 31 shows uh, suggests low impairment in Children and low to moderate impairment in adults. Um, and uh so this lets us know that providers really should be a query ng middle patients regarding symptom Atala ji number one, just for the simple acknowledgment that these symptoms exist and for validation that these symptoms exist and they're not just making them up. And also that there are non pharmacologic and pharmacologic therapies available for for some of these things, you know, something as simple for patients for something as simple as a cooling vest for patients with heat, intolerance can make such a difference for them. Um, and you know, we know that obviously double blind, um sorry, that's serving double D. B. Double blind. Randomized placebo controlled trials of therapies are certainly needed, not just in pots patients, but also in in the middle of patients. Um, and we do need to really better understand the underlying process in the P. M. D. That leads to symptoms of disorder. Somehow, I just wanted to acknowledge the folks that I've been working with at the chop including Marni Falk, um and Shady, Jack, Elizabeth, McCormack, laura McCullen and uh and George. You just all right, okay, that's it, folks. Thank you so much, Jeff, but really box Created by
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