Episode #3 ADOA podcast: Clinical geneticist Dr. Astrid Plomp on genetic research

Below you will find the transcript of this podcast.

00:00:03 
Maud: Welcome to the ADOA Podcast. ADOA is a very rare hereditary eye condition. My name is Maud van Gerwen and I am here with… 

00:00:11 
Lion: Leon Augustijn. Together we will talk to professionals and experts about their view on ADOA. Welcome to this podcast. Welcome Astrid and Lowie. Lowie is here now because Maud can't. 

00:00:27 
Lion: Yes, that's right, I'm replacing Maud today, and I'm also one of the people with ADOA, so I'll be playing the role of Maud in this podcast today. 

00:00:36 
Lion: Yes, great! Today we are sitting with Astrid. Great that you are joining us for this podcast recording. And who is Astrid? 

00:00:45 
Astrid: My name is Astrid Plomp. I am a clinical geneticist at Amsterdam UMC. A clinical geneticist is a doctor who specializes in hereditary diseases, and I am involved in hereditary eye diseases, including ADOA. 

00:01:03 
Lion: But what are you investigating then? 

00:01:06 
Astrid: I don't do scientific research myself, or at least, I do participate in scientific research, but that is not my main task. So I mainly see people at the outpatient clinic in Amsterdam UMC, people who have questions about hereditary conditions - and that can be a hereditary condition that they themselves have, or a condition that occurs in the family - that they want to know whether they can get that themselves or whether they can pass it on to possible children. But also people who are referred by other doctors who think of a certain genetic condition and then ask us whether we can confirm or exclude that with DNA research, for example. 

00:01:48 
Lion: Yes, and if you look at ADOA, how can that be transmitted? 

00:01:55 
Astrid: ADOA, the full name, is autosomal dominant optic atrophy. So the name says it all, that the inheritance is autosomal dominant. And that actually means that it can be passed on from generation to generation, and that children of someone who has that condition have a 50% chance of also getting that predisposition. Most people who get that predisposition, also get the condition, although that is not always the case with dominant optic atrophy, there are also people who have the predisposition, but never suffer from it. So yes, ADOA is autosomal dominant, but there are also people with optic atrophy who have a different way of inheritance. Autosomal recessive, that is when both parents are carriers of a hereditary condition - they do not suffer from it at all - but if they both pass that predisposition on to their child, then a child has the predisposition twice and does get the condition. That way of passing on is usually only seen in children in one family, so in brothers and sisters, but not in other generations like with ADOA, with dominant optic atrophy you really see that it occurs in multiple generations, is passed on from parent to child. And with autosomal recessive you don't really see that, then you probably have carriers in the family for generations, but you don't notice it at all. And you also have another form of optic atrophy; Leber's disease, many people who have optic atrophy themselves have probably heard of that. And that is inherited in a completely different way, it is inherited mitochondrially, that is to say that the error is actually in the DNA of the mitochondria of the cell. Mitochondria are, as it were, the power plants of the cell, and they have their own DNA, their own hereditary material. That can only be passed on by women. So you see that the condition can only be passed on by women, but it is actually more common in men, but men cannot pass it on to their children. So that's another way of inheritance. 

00:04:13 
Lion: And do you know Lowie, how you got it? In what way? 

00:04:18 
Lowie: Yes, that is quite a complicated story. Last year I was tested myself, and this year my parents, and I was diagnosed with ADOA, and my parents were not. And my parents also had an appointment at the UMC quite recently, so with a colleague of yours, but then at the UMC, and they told me that there is still a 1% chance that my brother has a predisposition. Because my parents don't have it doesn't mean that there is some kind of combination of genes, or... They don't know exactly whether it developed spontaneously with me, or whether it has something to do with my parents' genes. 

00:04:59 
Astrid: Why there is indeed still a small chance for brothers and sisters, the most likely is that it indeed originated in you. But it could still be that it is in a part of the egg cells of your mother or in the sperm cells of your father, that it originated somewhere there in a precursor cell, so to speak. And that is why brothers and sisters then have a slightly increased chance of having it too. But that chance is indeed only about 1%. 

00:05:26 
Lowie: 1%. 

00:05:27 
Astrid: Yes. 

00:05:28 
Lowie: You just mentioned that it is a 50% chance, but that there is also a predisposition. Does having a predisposition for ADOA also mean that you can pass it on? 

00:05:37 
Astrid: Yes, as you do indeed have a predisposition, but it does not manifest itself in you, you can still pass on that predisposition. Only if you really do not have the predisposition - so the error in the gene - then you cannot pass it on. 

00:05:49 
Lowie: Yeah okay, clear. So then that 50% applies, it can go down again. 

00:05:53 
Astrid: To pass on. Yes, definitely. 

00:05:55 
Lion: And what about ADOA-Plus? 

00:05:58 
Astrid: ADOA-Plus, these are errors in the same gene. ADOA is usually caused by the OPA1 gene, and most people who have an error in that gene have optic atrophy without additional abnormalities. But with ADOA-Plus, people also have other problems because of that mutation, because of that error in the gene, and that can be hearing loss, for example, that can be added, or muscle complaints - reduced muscle strength -, or difficulty with coordination. Those are actually the most important problems that you can have with that. And if you look in the medical literature, you see slightly different numbers, but that seems to occur in about 10% of people with ADOA, including those other problems. For some, it is only hearing loss, and for others also problems with walking, with muscle strength. 

00:06:54 
Lion: And could it be, suppose I have ADOA and I have children, could that eventually also become ADOA-Plus? 

00:07:05 
Astrid: Yes, that is possible. There is variation, also within families, but there are certain variants in the gene that give a greater chance of ADOA-Plus than other variables. So you do see within families more often that more people than that have ADOA-Plus, and in other families you don't see that at all. It is not the case that it is always the same for everyone within a family. 

00:07:33 
Lowie: Because does that have anything to do with it, in my case the classical form was there, does that still have any influence on it? Or does the classical form refer to something else? That it means something else. 

00:07:43 
Astrid: I don't know what they mean by that exactly. I can imagine that they mean that you do indeed have a mistake in that OPA1 gene, because that is the most common.  

00:07:53 
Lowie: Yes that's right. 

00:07:55 
Astrid: I think that's what is meant by that, but I don't know exactly what the classic… 

00:08:00 
Lowie: Because I have also heard of the OPA3 gene mutation somewhere. 

00:08:03 
Astrid: Yes, that is very rare. I have never come across that in the 25 years that I have been doing this, but it does indeed exist. But there are more genes that can cause optic atrophy, and OPA3 is one of them, but you usually see other complaints with that. 

00:08:20 
Lowie: That was also ADOA-Plus, that was indeed included in this specific case. Correct. 

00:08:24 
Astrid: Yes exactly, that is more ADOA-Plus than just ADOA. But that is rare. 

00:08:31 
Lion: Of course we already know that, but suppose I have a suspicion, how does it work if I want to have it investigated? 

00:08:40 
Astrid: If you suspect that you have it yourself, for example? 

00:08:42 
Lion: Yes. 

00:08:43 
Astrid: People are often referred to us by their ophthalmologist because the ophthalmologist thinks so. He sees an optic atrophy, diagnoses an optic atrophy in someone, and it is unclear what the cause is. People are often referred to us by their ophthalmologist with the request to do genetic testing, and we can then have a gene panel tested these days – in the past you really had to do gene-by-gene testing, but for a number of years now we have been doing a gene panel – so we can then test a whole package of genes at once, all of which can cause optic atrophy, with or without other abnormalities. So we do that package and that takes a few months. Blood will then be taken from you if you actually want this test. Then it takes a few months and then there is a result, and then there are different possible results. We may not find anything at all. We do not find a genetic cause in everyone with optic atrophy. It's not always genetic either. We may find a very clear cause, for example an error in the OPA1 gene, which is what occurs most often. Sometimes we also find something unclear. That also happens. Then we find a variant in a gene, but we don't know whether that is actually the cause or not. We then often do further research with family members if possible, for example with the parents, because if as a son such an error occurs more often in the family, but those other family members have no complaints at all, then it becomes somewhat less likely that that is the cause, while if it has newly arisen in someone, and someone is also the first in the family to have a condition, then the chance is much greater that it is. Sometimes we can look further with other additional research, for example RNA research. The DNA is first translated into RNA, so to speak, and then a protein is made. You can then look at the RNA to see: “Is there perhaps something wrong with it?” because of that change in that DNA. If you can demonstrate that, then you also know: “Well, there is indeed something going on here, so this is indeed the cause”. And sometimes we can't figure it out at that moment and then we say: "Well, come back in a few years, maybe we'll know then." So those are kind of the possible outcomes. And if a clear cause is found, then as a patient you at least know what you have, then you know a little more about what to expect, although that also varies a lot because the course also varies a lot between different people. In some people it deteriorates very slowly, in others it remains stable for a long time, in some people it suddenly deteriorates more rapidly. So we can never fully predict how things will go next. But of course if you know what the cause is, then you know at least a little more than you knew before, and family members can also be tested if they want to, if they want to know whether they have that predisposition. And you know how it is with heredity. For example, if you want to have children, or you already have children, and you want to know what the chances are for those children, we can also provide information about that if we have found a cause. 

00:12:04 
Lion: And how does that work? Suppose a couple comes to you and says: "I want to see if I can have children and if I can pass it on." 

00:12:17 
Astrid: When we talk about dominant optic atrophy, then you know as someone who has that predisposition, that the chance for the children is 50%. And yes, then it is up to people themselves to see: "What do we want with that?", but then we at least discuss the possibilities. You can of course just accept the risk, just have children and wait. You can - if you wanted to - do research during a pregnancy if people say "I don't want to pass this on to my children, but I do want biological children of my own", then you can just get pregnant, and then during the pregnancy with research to see if that predisposition has been passed on with a chorionic villus sampling or an amniocentesis, with the aim of then terminating the pregnancy if a child has it, which is of course not an easy choice, and the chance is 50%, so that is a pretty high chance that you will have to terminate the pregnancy, and maybe next time again, and the next time again. So that is of course not so easy. And another option if people say: “Well, I want a biological child of our own, but we don’t want to pass this on, but we also don’t want to interrupt a pregnancy”, then you can do pre-implantation genetic testing, it’s called PGT, and that is an in vitro fertilization in which the fetuses that actually develop in the lab – with the mother’s eggs and the father’s sperm – those fetuses are then genetically examined. One or two cells are removed from those. They are examined in the laboratory, and then only a healthy fetus is placed in the uterus. And in that way you prevent a pregnancy with an affected child. It’s just not a very easy way to get pregnant, because it is an in vitro fertilization, and the woman, she receives hormone treatments to mature multiple eggs at the same time, and those are then removed directly from the ovary with a needle and fertilized in the laboratory with the man’s sperm. And you have to do DNA research on one or two cells of those fetuses, and that’s not very easy. So there is a lot of preparation time before that, because almost all patients have a different error in their DNA, and then that test has to be developed for that specific error that you have, and that takes about half a year, and then there is also a 20-25% chance per treatment that someone will become pregnant. And the health insurers, they pay for three treatments, so you can do that three times in a row. Then about 50% of the couples with such a treatment will be pregnant after those three times, or after one, two or three times. Yes, but 50% also not, then it just won't work, and then you will be a long time further. 

00:15:16 
Lion: Because I can also imagine that as a doctor you inform the person about this, that you also think: “Yes, maybe it is better to just get pregnant like this and enjoy it than a very long…” 

00:15:34 
Astrid: Well, that is very personal, so we mainly tell people what the options are, and then people have to make that choice themselves. Because yes, one person says: "Well, I have a great life with this condition, and I don't think it's a big deal if I pass this on to my children". And that is of course also completely fine. And the other says: "Yes, I really don't want to consciously pass this on to my child". They are also afraid that they will then feel guilty about it, or that the children will resent that they consciously passed it on. So yes, there are people who really say: "I don't want to pass this on", and if you also don't want to terminate a pregnancy - which is of course also very intense - then the PGT is a good option, that is actually the best option, but indeed not an easy option. But yes, it is very personal for people. What is most important to them? So we look at that carefully with people, from: "What is the best choice for you now?" And if they don't come to a good agreement there, or they don't agree among themselves, which is of course also possible, that the woman wants one thing and the man wants another, or that they have serious doubts, then we also have medical social work in our department who then have conversations with the people to see: "What is the best choice for you now?" That can indeed be quite difficult. 

00:16:55 
Lowie: Because usually couples come to you via the GP? Or are they mainly people who are already known within your clinic? Or how…? 

00:17:04 
Astrid: Yes, that can be done in different ways. The GP can indeed refer if it has been known for a long time and people come to the GP with that question, then the GP can refer. It is also possible that the ophthalmologist refers, because someone often comes to the ophthalmologist again and again and then that question can also come up with the ophthalmologist, who can also refer.  

00:17:22 
Lowie: So in principle, if someone is listening now with ADOA who does want to have children, then it can actually be done via the GP, the ophthalmologist, but perhaps also via Bartimeus? I don't know exactly, but of course we also have ophthalmologists on staff here. 

00:17:33 
Astrid: Yes, definitely. Bartimeus ophthalmologists also refer to us, yes, definitely. So other specialists, general practitioners, obstetricians, they can all refer to a clinical geneticist. 

00:17:45 
Lion: Yes, and do they have to go to Amsterdam especially, or is that…?  

00:17:50 
Astrid: No, that is possible in all academic hospitals, the university medical centers, they all have a department of clinical genetics, so people can be referred there. And often there are also external clinics. From all university medical centers, external clinics are also held in other hospitals, so there is always a clinical geneticist nearby to whom people can be referred.  

00:18:17 
Lion: And how does that work when you have the results? What does that look like in a consulting room? 

00:18:26 
Astrid: You mean the results of DNA testing in general?  

00:18:29 
Lion: Yes / Yes. 

00:18:30 
Astrid: When people have been for their first consultation, and we are going to use DNA testing, we agree with them: "How do you want to hear the results?", then people can choose, by telephone - "Do you want to hear that by telephone?" - or with a video consultation? Since corona, we also do a lot of video consultations, we didn't do that before. Or do you want to hear that at the clinic? So people have that choice themselves. And then we tell the results, and then of course it depends very much on: "Yes, did people expect this or not? What do they want to do with it?" how you then proceed. We then discuss if people have questions about a desire to have children, then we can discuss that further. Because you can only do these types of tests during pregnancy, or such a PGT, if a clear variant has really been found in a gene. We also discuss family research, whether that is possible. If necessary, we also make a letter for the family that someone can then distribute in the family to inform the family, so that family members can then of course decide for themselves whether they want to have that tested. But we discuss that too. 

00:19:45 
Lion: Yes, and are there ever good examples where you say: “Well, someone came to us and he wanted to have that tested, and he thought he had ADOA, but something completely different came out of it, or the other way around”? 

00:20:02 
Astrid: Phew, then I have to think carefully. Yes, more generally you sometimes have that, that one condition is thought of and that something else comes out. I can remember that we once had a family where retinitis pigmentosa occurred, and that a family member also had eye complaints and that we did a more extensive DNA test and that an OPA1 mutation - so that there was ADOA - came out in that person. So that was an unexpected finding indeed. So that is possible, certainly now that we are doing such large packages of genes, then something else can indeed unexpectedly come out. 

00:20:44 
Lion: And is that also your advice to do such a family study if possible and people are open to it? 

00:20:52 
Astrid: People have to decide for themselves whether they want to know. If someone in a family has been diagnosed with it, it can come from the parents, brothers and sisters can have it. So we usually advise informing the family about it, and possibly with a letter, then we make a family letter if people need it. But then family members have to decide for themselves whether they want to be tested. Of course that is not necessary, so it is also very personal whether people want to or not. There are people who say: “Well, I don't want to know any data at all. I don't want to know anything about it”. And others want to be prepared, also for when they have children to know whether they can pass this on. But that is very different how people think about it and how they deal with it. 

00:21:44 
Lion: Yes, so in summary it's basically a blood test and then waiting for the results.  

00:21:51 
Astrid: Ja 

00:21:52 
Lion: And how long does something like that take? Such a trajectory? Suppose you were to enter into that. 

00:21:57 
Astrid: Yes, at the moment such a DNA test takes four months if you have to investigate that whole package. But if a variant is already known in the family, then it takes three weeks, because then you only have to look at that known variant. So it depends on what exactly the question is. 

00:22:20 
Lowie: I have heard that there are people who are afraid to have it tested, because if ADOA is found, it can affect mortgages or things like that. Is that a myth? Or…? 

00:22:30 
Astird: Well, that's not entirely a fairy tale, but in practice it's often not that bad. But that is indeed generally what people think about genetic testing, and especially predictive testing... Because that's actually the only thing that plays a role there, because if you already have the disease, then it doesn't matter whether or not that is demonstrated by DNA testing, because then you have to report that anyway when you take out insurance if asked. So it's mainly about predictive research, if someone does indeed know: "Well, ADOA runs in the family, and I might want to be tested for that predisposition", then that can indeed play a role, and then that will mainly be for disability insurance, because of course you won't die sooner from ADOA, so life insurance, that won't be such a problem there. But disability insurance could be a problem. Insurers are allowed to look at hereditary diseases in the family, or whether you've been tested for them, above a certain limit - so of an amount that you want to insure. And of course you have to answer that honestly, but not below that limit. So you can always insure a certain amount, and that limit varies a bit, or at least, over time it is also adjusted with inflation. And it is also the case that insurance companies deal with that differently. So one insurer sets that limit higher than the other. Some do not ask about that at all, so in practice it is often very limited, but it is worth asking insurers how that works. And on heredity.nl there is a lot of information about heredity, about all kinds of hereditary diseases, also about ADOA. But they also have information about insurance, so people can get more information about that, about genetic research and insurance. 

00:24:35 
Lowie: And you also take these kinds of things into account when you have a preliminary interview with someone who says: “I might have ADOA”, then you also take someone who is ignorant with you who says: “Well, it could mean this or that if it is diagnosed”. 

00:24:46 
Astrid: Yes, definitely. We do indeed discuss all the ins and outs of testing. And: “Why would you test? Why now? Do you really want to? What are the consequences? What do you do with it?” Yes, we discuss all that, definitely. 

00:25:03 
Lion: And where would people… suppose they say: “I don't want to take that step right away, but I do want to read up on it or find information”, where can they find that? 

00:25:12 
Astrid: Yes, that is also possible heredity.nl . There is also information about whether you want to be tested. A question like: "Do I want genetic testing?" is also information about. And it is also true, if people come to us, that does not mean that they have to have DNA testing done. So they can just come to us for a conversation, and if they then decide: "Yes, I don't want this at all", then that is of course completely fine. So that is also possible. People can also come to us if they just want to know more about whether they want to be tested, then they can also be referred to us. Does not mean that anything has to be done. 

00:25:51 
Lion: Yeah, great, thank you. Thank you for listening to this podcast. 

00:25:59 
Maud: If you have any questions or would like to chat, please contact us via our website adoa.eu