The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
So last question because we're running up on time and this is actually a question I've been struggling with as well. Knowing that testing panels are changing, your thoughts on if someone has had a negative panel but now that SMAD2 is being offered, like, should we be offering just that as a single gene? Like, what are your thoughts on pursuing that? Now that it hasn't been on panels and can you talk a little bit about Loeys-Dietz type six potentially?
Yeah, so people should take a careful look at you and say, you know, "What there is?" "This new gene available on a panel?" "Does that gene make any sense for you as an individual?" you know, "Does it match with your features?" "Is it plausible that your condition would be caused by a change in that gene?"
The answer is yes, then it may make sense to do that testing and to be honest I would choose the method that's most reliable and least expensive, you know, if you can get if it's only that one new gene that's available on the panel and it costs less to get that one gene sequence than to repeat the whole panel. I would choose to just get that one gene sequence.
If, however, since the last time that you were tested there are five new genes on the panel and three of them could make sense for you it probably would make sense to get the panel repeated rather than to have each of those three other individual genes done.
So Loeys-Dietz syndrome type 6 or whatever someone is referring to it as caused by mutations in SMAD2, can have skeletal and craniofacial features that overlap with Loeys-Dietz syndrome. It can have aortic aneurysm although there are people, there are quite a few people that have inherited the familial SMAD2 mutation that for reasons we don't understand, are not showing aneurysms early or even late in life. It's not uncommon to see people with a SMAD mutation that never got the aneurysm that was seen in their brother or sister or aunt or uncle that led to the initial testing.
What also is not seen in people with SMAD2 mutations to the same extent as TGFBR1 or 2 or SMAD3 mutations is aneurysms elsewhere throughout the circulation or aneurysms that are tearing at small dimensions, you know, so that's, you know, that's what's making people, you know, giving them incentive to collect more information before deciding what proper management principles are, for example, in people with, with SMAD2 mutations.
Certainly in some of the cases when you see the an individual with a SMAD2 mutation there's little doubt in your mind that it's in the Loeys-Dietz syndrome spectrum of disease. If you just look at their face and look at their skeleton and even look at their aortic root but then there are these other factors that suggest that this is at a new mild end of the spectrum, milder than what we've seen before in other forms of Loeys-Dietz syndrome.
You know, we have to consider that the clinical spectrum of severity in aortic aneurysm conditions is very broad in all the conditions we think about. You know, we see young children with Marfan syndrome, who at birth have really striking skeletal and facial features, have very severe and rapidly progressive aortic enlargement and valve dysfunction within the first few months of life, who may require surgery within the first two or three months of life to try to save their lives and then there are other people with Marfan syndrome. No one would argue that they don't have Marfan syndrome, who you would not pick out of the crowd at age 75, who perhaps have some very mild scoliosis and some nearsightedness and an aortic root at age 75 of 4.0 centimeters.
So, you know, the the issue of wide variation in clinical severity is not new to us and, you know, I think that there are good practices and rules in place to make sure at every possibility that you're not making recommendations based upon the average person with that condition but rather are making recommendations based on everything that you can learn from that person sitting in front of you so that's what you should be challenging your doctors to do.
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
So someone is asking your thoughts again on the variability within one type of Loeys-Dietz-like syndrome if you think it's more likely to be caused by the kind of gene variant, other genetic factors, other external factors-like. What are your thoughts on the variability and the causes of variability?
Yeah, so as we've discussed the, the gene that's involved contributes to variability. As we've discussed the precise mutation that's present influences disease severity and therefore variability between families but as we've also discussed there can be dramatic variation among individuals in the same family with the same underlying Loeys-Dietz syndrome mutation, so therefore, there in that circumstance, we can't blame it on the gene of the variation. We can't blame it on the mutation. All those people have the same mutation.
So we have to start thinking about other variables, other factors and when we think about those other so-called modifier factors there are two broad classes: one of them is the environment, you know, what has been the experience of that person over time ―― "Did they do a lot of weight lifting early in life" and also "get into a couple of car accidents" and "have high blood pressure that was poorly controlled," whereas their more mildly affected relatives always took meticulous good care of themselves and, you know, didn't partake in any of those risky behaviors.
We think about medication use, "Did one person start medication at a young age to try to modify the rate of aortic growth?" and another person "Either never took medication or wasn't very compliant with taking their medication when they were supposed to?" So there's a whole big list of potential environmental modifiers that we think about.
But now there's another category of a lot of interest to many researchers and that's something that we call genetic modification. So we talked about we all have 20,000 genes we talked about we, that we all have variation in all those genes and most that variation is innocent ―― it dictates what we look like, what our hair color is, what our eye color is. Sometimes that background normal variation can either make a disease worse, something that we call protected, and I'm sorry aggravating modification, or can make an underlying genetic disease better something that we call protective modification.
You know, those, as those normal variants pass throughout a family. It's like dealing a hand of cards, you know, is this person with Marfan syndrome, for example, or Loeys-Dietz syndrome going to get a good hand of those normal variants from their relatives just by chance or are they going to get a bad hand or are they going to get dealt the variance in those other genes that make things worse or, or simply fail to protect.
So there's a lot of research now to try to understand those modifiers to understand especially how the protective genes and variants work because if we could understand how nature has learned to protect some people with Loeys-Dietz syndrome perhaps we can use a medication to try to mimic that protective effect to try to duplicate it in someone that did not get dealt the favorable hand of variance.
So I think that it's a combination of what genes involved, what variants involved but also what our life's experiences are and the protective variation that we inherited from from our parents.
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
So say that there is someone who has an aortic root or ascending aneurysm, there's no known family history, their genetic testing has thus far been normal but we've kind of given them a clinical diagnosis of Loeys-Dietz syndrome because we feel like they fit in that spectrum. How do we as clinicians make decisions about aortic surgery in those cases?
So that's a really excellent question, so whenever we're making a clinical decision about whether to move forward with some form of treatment including a surgery we're always trying to weigh the risks of doing the procedure versus the risk of not doing this procedure, so you're, you're assessing at every moment in time the risk that would be imposed by moving forward but also the possible benefit to that individual of moving forward at that moment in time now.
If somebody definitely has Loeys-Dietz syndrome types one and two and particularly if they have mutations that a mutation that we've previously seen in people with early onset and severe vascular complications, you know, we feel very confident in saying you should go ahead at four centimeters and sometimes even smaller than four centimeters.
If someone has LDS type four or five and they have six family members that also have LDS of the same type and all of those family members are in middle to late age and either have not required surgery or only needed surgery very late in the game and never, never had an aortic dissection now we feel comfortable saying you can wait to at least four and a half centimeters before that risk-benefit ratio would favor moving forward.
So, you know, what we're going to be doing in the circumstance where you're describing where we don't have a precise answer regarding diagnosis is we're going to do a deep dive into family history, try to learn everything about every relative that we can, we're going to monitor the rate of aortic growth really carefully and look for some warning signs like a sudden change in the rate of growth of the aorta. That's something that we pay attention to: something changed, the tissue quality has changed, you know, we need to adapt.
We're going to take keep a careful look on the performance of the aortic valve as the aorta gets large. It can stretch the aortic valve and cause it to leak and we, you know, our goal now for most patients is to do something called a valve sparing procedure that would allow them to avoid the need for lifelong anticoagulants. We know that we have to intervene before there's severe valve damage and severe valve dysfunction, so, you know, the same principles would apply for the circumstance that you're describing even if we don't have a diagnosis. We're going to use every other bit of information that we can collect to try to make the best decision for that individual.
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
The Loeys-Dietz Syndrome Foundation, a division of The Marfan Foundation, did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, loeysdietz.org.
The Marfan Foundation の一部局である The Loeys-Dietz Syndrome Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、 loeysdietz.org にアクセスしてください。
What type, this is kind of a clinical question, but we'll take a detour. Is there any specific type of eye muscle disorder present in LDS, specifically type 5?
MacCarrick:
具体的な特徴に関する質問です。LDS5型に特に多い眼の筋肉に関わる疾患はありますか？
So I do not know of eye problems that are unique to any specific type of Loeys-Dietz syndrome. I do know that in various types of Loeys-Dietz syndrome you can have weakness of eye muscles that cause a condition called strabismus where the eye and eye will look inward or look outward will have a hard time looking straight forward. That is actually a quite a common finding in Loeys-Dietz syndrome types one and two but we have observed that and I've talked with ophthalmologists who've observed that problem in other types of Loeys-Dietz syndrome.
Other issues that we think about in people with Loeys-Dietz syndrome related to the eye would include a fortunately rare circumstance called retinal detachment where the nerve layer in the back of the eye peels away and can lead to a serious loss of vision if not treated urgently.
Again not particularly common but certainly described in people with Loeys-Dietz syndrome, as Gretchen mentioned, peach, people with Loeys-Dietz syndrome do not have the strong predisposition for eye lens dislocation that's present in Marfan syndrome.They can have nearsightedness but it doesn't, it's not as frequent and does not tend to be as severe as what's seen in Marfan syndrome so aunt, long answer to a short question ,you know, I do not know of any eye problems specific to Loeys-Dietz syndrome type five.
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
Can the mutation happen anytime in life or is it from birth only? I have a son with LDS2 and a healthy older daughter. My son is de novo so they had parental testing, I guess
Year, so, mutations can be passed from parent to child by virtue of that change being in the cells that are making the egg cell or the sperm cell that are giving rise to that child that's what we call an inherited mutation. Mutation can occur during the formation of the egg cell or the sperm cell that go into the conception of a child so the parent doesn't have the change in any cell of their body but it was that one egg cell or one's one sperm cell that developed the change and then gave rise to a child with new Loeys-Dietz syndrome for that family.
Very, very, very, very rarely someone with a genetic condition has a change that occurred later in development typically not after they were born but when they were still forming in their mother's uterus but you know somewhere later on in the developmental process so they may only have the mutation in their blood and their skin where they may only have the mutation in their cardiovascular system but not in their skeleton that's something that's called a somatic mutation. It's exceedingly rare and unlikely to explain the situation that you're describing in your family. It's, if I understand your family correctly your affected child likely has a new change that was caused by a mutation or a DNA change in the egg cell or sperm cell that went into their conception and your other child, you know, did not develop that same change.
You know, a good question, a good follow-on question is if I have a child with a new mutation that's causing a new case of Loeys-Dietz syndrome in my family is there any risk that I'm going to have another child affected with Loeys-Dietz syndrome with the same mutation?
The answer is yes because occasionally a woman has the mutation in a population of cells just in their ovary or a man has the mutation just in a small population of cells in his testes so they don't have Loeys-Dietz syndrome themselves but there is a higher than zero risk that they will have another child with that same mutation because another egg cell or another sperm cell would be made that has that change that's something that's called germline mosaicism. It has been described for Loeys-Dietz syndrome but also rather uncommon.
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。