Episode #13: Dr. Mirian Janssen on ADOA-plus

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.

00:00:26
Maud: We are here today with Dr. Mirian Janssen, internist at Radboud Hospital, and specialized in metabolic diseases. Welcome Dr. Janssen! Can you tell us something about what you do as an internist?

00:00:41
Mirian: Yes, thank you for the invitation. I am an internist at the Radboud UMC, and I specialize in hereditary metabolic disorders, and that is actually a very broad picture of patients with all kinds of metabolic disorders, but our center is particularly an expert in energy metabolism disorders. So the largest group of patients that we see are patients with energy metabolism disorders. And what I do then is a lot of clinic, so a lot of consultations, at the moment four per week. I work partly in the pediatric department, where I see the adolescents and parents, and then I take them to the adult outpatient clinic when they are eighteen, then I already know them. We have a department where we have patients and see them. And in addition, I teach. And in addition, I also do research with the aim of actually improving the quality of life of the patients.

00:01:44
Lion: But how do you see patients with ADOA-Plus?

00:01:47
Mirian: Patients are referred to me based on the following questions: one: “Is this ADOA-Plus?” or two: “Is this ADOA-Plus, and what can you do for the patient?” These are actually the two reasons for referrals.

00:02:05
Maud: Yes, because ADOA is of course a mitochondrial disorder, which is an energy metabolism. That's how I have to see it, right?

00:02:13
Mirian: Yes, with ADOA there is actually an inadequate energy metabolism that is mainly expressed in the eye. So the optic nerve and the ganglion cells of the retina - of the retina -, so that is the cause of the blindness. And ADOA-Plus is a disease picture in which other organs can participate. So ADOA does not mean ADOA-Plus, 'Plus' is 'Plus', so to speak.

00:02:48
Maud: Yes, okay. And you see mainly from the ADOA patients the 'Plus' category.

00:02:55
Mirian: Yes, because I am not an ophthalmologist, so people with ADOA are mainly under the care of the ophthalmologist I think. And then I see the patients with the question whether there are 'Plus complaints'. And if there are 'Plus complaints', then we look at what we can do for the patients.

00:03:15
Lion: What can you do specifically for a patient, say they have ADOA-Plus?

00:03:22
Mirian: Yes, then maybe a little bit about what ADOA-Plus is: that is to say that there are actually more organs involved than the eye, and about 20% of patients get 'Plus complaints'. And what are they? Mainly neurological, so ataxia, so problems with movement, neuropathy, problems with the nerves, muscle problems, muscle weakness, muscle pain, epilepsy can occur, hearing loss, but also heart problems for example, cardiac conduction disorder, if the heart does not participate, and in addition of course also fatigue, because patients with an energy metabolism disorder are always more tired than the normal person.

00:04:16
Maud: Yeah, okay.

00:04:21
Mirian: Yes, so what can I do? Well, look at the patient, and check the patient, and see which organ systems are involved. And then depending on which problems are at play, especially see if there are ways to better support the patient, because there is no medicine yet to improve energy metabolism.

00:04:43
Maud: No, okay. And can normal ADOA also become ADOA-Plus? Or do you have one or the other?

00:05:00
Mirian: That could also be the case. We do not yet know for all ADOA patients why they get 'Plus'. There are various reasons for this, but of course we do not know some of them. And the first reason is that the type of mutation... so the disease is caused by a gene change, that is called a mutation in the OPA1 gene, and a gene is a very long cable that is formed, changes can occur in it, and certain changes lead to ADOA-Plus sooner. So that is one. In addition, there will certainly be other genes that play a role in this that we do not yet know about. Then there are always environmental factors that play a role, and lifestyle. So for example stress, poor nutrition, smoking, can cause fatigue or less energy sooner. That actually. But we do not yet know exactly why one person gets ADOA-Plus, you cannot always predict it.

00:06:09
Maud: No, exactly. Because the people I know now with ADOA-Plus, I have the idea that they have been given ADOA-Plus since the diagnosis, I'll say, but it could also be that I, for example – I have ADOA – that it will eventually become 'Plus'.

00:06:33
Mirian: Yes, yes. So it doesn't have to be that you have epilepsy or neurological complaints from a young age - sometimes yes - but it can also be that these complaints develop in the course of life, and that is why it is also important to follow people well. So not to say: "Well, you have this, go home and come back when you really have problems".

00:06:59
Maud: Yeah, yeah. We’re all getting older too, that you see the difference, when are those old age symptoms? That you get more tired and things like that, or…

00:07:14
Mirian: That is also really difficult back

00:07:14
Maud: …that it can be traced back to ADOA

00:07:17
Mirian: That's why it's also good to check the patient carefully. Because only tired... well, who isn't tired these days?

00:07:25
Maud: Exactly

00:07:26
Mirian: So that is quite difficult to say: "Well, that is ADOA-Plus". So then a neurologist comes to look for a good neurological examination, because you can determine all those things that I just mentioned quite well with physical examination or additional examination. And an alternative is, for example, a rehabilitation physician or a physiotherapist, who can also examine you well to see: "Well, are the complaints that I have ADOA-Plus, or is it something else?"

00:07:54
Maud: Okay. Interesting, because I’ve never really…

00:07:58
Mirian: And for example hearing loss, that is also something that occurs often. But of course you also have hearing loss due to noise, festival, work, you name it, or old age. But those patterns of hearing loss with ADOA-Plus are different. If you make an audiogram, and that looks different than an audiogram with someone who has noise-induced deafness.

00:08:21
Lion: Yes / Yes.

00:08:21
Maud: Okay, yes.

00:08:23
Lion: Now, if someone is listening and they have ADOA, and they think: “Yes, I do hear less, or I am tired”, what advice would you give them?

00:08:37
Mirian: I think the patient with ADOA has always been to an ophthalmologist for the diagnosis, so you could ask that person first – your treating physician, or head of treatment – ​​for advice. I think I would also visit the family doctor first to see – fatigue can have all sorts of causes, so to rule out other things, that you don't have a vitamin deficiency or whatever. And what did you say again? Hearing loss?

00:09:06
Lion: Yes.

00:09:07
Mirian: Then you can have an audiogram, which you can simply do at Beter Horen, or an audiologist, audiological center. And that says something.

00:09:21
Maud: So you wouldn't say you have to go straight to the internist.

00:09:25
Mirian: No, I don't think you have to go to the internist right away. Only after the GP has looked at it, I think. Well, it really depends on the complaints, so I find it quite difficult to say: "Now you have to come to me", or: "Now to the neurologist". In our hospital we also look at a referral from: "Well, what complaints does the patient have?" and: "Who is the patient most at home with? Is that the neurologist or the internist?" And of course the GP can also look: "Who do I refer the patient to? Is that the neurologist, or the internist, or another specialist?"

00:10:05
Maud: Yeah, yeah, okay.

00:10:09
Lion: And if you now come to the hospital for an examination, do you still have to go to multiple doctors? Or is it really just a case-by-case approach of: “Okay, what is needed?”

00:10:24
Mirian: Yes. I always look together with the patient first: "What are the complaints?", and: "What can we do for you?" Suppose the patient has multisystem complaints - so complaints on multiple fronts - then we have a short admission for the patients in which the patients are seen by our rehabilitation team, so the physiotherapist, the ergo, the speech therapist, the rehabilitation physician, the cardiologist for heart examination, the audiologist for hearing, the ophthalmologist if necessary, the neurologist, the dietician for nutritional advice, and we do all that in three days. And then we can look together with the patient what came out of that and give supportive advice. So we have that for the people, also because people often come from far away, and for people with multiple complaints, or people who are new.

00:11:24
Maud: Yes, it's nice that it can all be done at the same time.

00:11:28
Mirian: That yes we have been doing that for years, we have been doing that for about five years I think. And we have now admitted more than 350 people like that, and it is still very busy. We have an admission like that every week.

00:11:42
Maud: Oh yeah.

00:11:43
Mirian: And we like working with it because we can immediately – we call that ‘mapping out’ the patient. Because an hour in the consulting room, or three quarters of an hour, then I never really have a clue what is going on. And the nice thing is that the entire team is specialized in energy metabolism disorders, so then the patients are also understood, and then you can give advice together. So that works really well.

00:12:08
Maud: Yes, that's good.

00:12:10
Lion: And can you give some good practical examples?

00:12:13
Mirian: Yes, well for example, someone who comes, but he has not been admitted, but someone who comes with: "Do I have ADOA-Plus? I am especially very tired", with the most important question of: "Gosh, what can I do myself?", that is what people often want to know, of: "Can I change something in my lifestyle myself", and completely checked, and actually found no neuropathy, balance disorders, that kind of thing. But anyway, more tired, and he went to the rehabilitation department, and that was completely checked by the physiotherapist, and the physiotherapist noticed good strength and good balance, but still entrance for training to improve your condition. The patient received advice about how to train that, and the occupational therapist did find a disturbed balance in load and load capacity - so then you are, as it were, in the red. So quite a lot of complaints of fatigue, and he gave advice about that, about energy management. The speech therapist found no abnormalities at the time, and the dietician looked at it, and she was able to dot the i's and cross the t's in terms of nutrition. And that is different for each person, so it is difficult to explain what advice someone gets. So the dietician measures how active you are, she measures what you eat, looks at how much protein, fat, carbohydrates, vitamins are in it, and then the patient gets a kind of personal dietary advice.

00:13:53
Lion: Yes.

00:13:53
Maud: Yes.

00:13:56
Mirian: And what also came out, is that there were quite a few concerns in the family of that patient of: "Gosh, I have a child, and maybe he will get ADOA too", and he was then advised to go to a psychologist. So actually summarized: dietary advice, physiotherapy, psychological support, and he really benefited a lot from that.

00:14:22
Maud: Well, that's good. Yeah.

00:14:25
Mirian: Yes.

00:14:26
Maud: Yes, that is a good example, yes. That it works when it is looked at multidisciplinarily. Yes, good. And you just said in the intro that you are involved in studies? Or trials? Is ADOA involved in that? Can you tell us a bit more about that?

00:14:46
Mirian: Yes, the trials for the eyes, we don't do that at Radboud UMC, you know that too, for that you have to go to professor Boon who is most involved. We know each other because he was trained at Radboud UMC. So if there are patients who have questions, I can always easily ask him those questions. So we don't do the trials that happen at ADOA. Complaints everywhere, energy management problems, at the moment I think there are three trails, and then you have different trials for people with mitochondrial DNA mutations. Well, that's not ADOA, ADOA is a nuclear mutation. And for those patients with nuclear mutations, ADOA-Plus patients can participate in that as well.

00:15:42
Maud: Okay, interesting. And is there anything interesting going on there at the moment?

00:15:51
Mirian: The study with the core mutation has just been completed. So what is still running now are two studies for patients with mitochondrial DNA changes. But those are all strict selections, that is quite complicated. Manufacturers often want a kind of rarely homogeneous group, as homogeneous as possible with the same genetic change, in order to be able to measure properly whether a patient benefits from a drug at all. And measuring whether a patient benefits from a drug - and then a patient who has multisystem complaints is already very complicated. So we also do a lot of research into: "What is now the right outcome measure to measure whether someone has more energy, or whether their muscle strength is improving?" Strength is easy to measure, but just well-being everywhere is quite difficult. Studies for the eyes with, for example, gene therapy, and then measuring the vision - the sense of sight - that is easier than a study in which you measure the general feeling of fatigue or well-being.

00:17:07
Maud: Yeah, yeah, I get that.

00:17:09
Lion: And you just said: “In Nijmegen that happens multidisciplinary, those three days…”

00:17:12
Mirian: That recording, yes.

00:17:16
Lion: Do you know if this happens in other houses too?

00:17:18
Mirian: No, no. So people are referred to us for that. What we do is if we find things during that admission, we look for doctors or for example a rehabilitation team in the region of the patients. They only come to us once, and then you continue to see them annually, but you don't have to come to Radboud every time. So for example the Rotterdam region, then we refer many people to Rijndam Revalidatie. And in every academic center we also have contact with cardiologists, heart specialists, neurologists.

00:17:52
Maud: Okay, great. Then I think we're there. Did we forget to ask something important that you'd like to tell us?

00:18:04
Mirian: Yeah, not necessarily. Maybe… I get asked a lot whether patients are allowed to use certain medications or not, and I made a kind of list for today’s presentation, and that presentation can be shared later. So I can always be called, and people often call me, but okay, I have a kind of list – I’m not going to list it all now – but what I can share with you…

00:18:30
Maud: Oh, that's nice!

00:18:31
Mirian: …so that you can see if you can also share this with general practitioners or other doctors.

00:18:39
Maud: We already have a list on the website, but then we can check whether it is the same or whether it needs to be updated again.

00:18:47
Mirian: Yes, and I've divided it a bit into cholesterol problems, sugar, blood pressure, a bit practical, let's say, antibiotics, painkillers. So that's a bit practical where you can look specifically: "Am I allowed to do this or not?"

00:19:03
Maud: Yes. And is that: “You are not allowed to do it because it could cause additional damage”?

00:19:07
Mirian: Yes, so medication can affect mitochondria. And a number of medications have been proven, for example at the cellular level, or at the animal level, but there was recently a kind of meeting of all kinds of specialists who know about this, and the literature was listed, and it turns out that more medication is allowed than was previously thought. So that is important. So one of the things is painkillers, drugs such as diclofenac, naproxen, people still have on their list that that is not allowed, but that is actually quite allowed. Certainly for a short period, but not for weeks, but well, that is not good for anyone.

00:19:47
Maud: No, exactly, no. Well, nice, fine.

00:19:50
Lion: And where do you hope to be in five years?

00:19:55
Mirian: Yes, I hope that in five years when I have a new patient I will have something to offer in terms of medication. Look, I have a lot to offer in terms of support now, but it would be really nice if you could prescribe a drug. So that is something we are all working very hard for.

00:20:17
Maud: Yes, that is a very nice aspiration.

00:20:20
Lion: And what else is needed to achieve this within five years?

00:20:24
Mirian: Well, one: the good one compound, and two: the proof that it works. There are some resources that seem to work, but drug research is done in phases, right? Phase zero is healthy volunteers, and phase three is the ultimate proof. The phase three studies – a number of them are running, or they still have to run, and – they have to prove it.

00:20:48
Maud: Yes.

00:20:48
Lion: Yes.

00:20:50
Mirian: But okay, we're not there yet, right? So then that's proven, then it still has to be approved by the EMA - the European Medicines Agency - and then it has to be approved again in the Netherlands in terms of reimbursement.

00:21:05
Maud: Exactly, yes.

00:21:06
Mirian: There is still a long way to go, but yes, well, I personally get energy from that trials do, because then you have the idea that progress is being made.

00:21:18
Maud: Yes, I understand yes. Well, very nice. Then we want to thank you for this nice contribution.

00:21:27
Mirian: You're welcome!

00:21:28
Lion: Thank you. Thank you for listening to this podcast.

00:21:32
Maud: Should you have any further questions or wish to discuss this further? Please contact us via our website adoa.eu.