Genetic Epilepsies: The Same Variant But Different Symptoms! - Nazanin Azarinejad Mohammadi, H.C. Andersen Children’s Hospital, Denmark
Neuroscientist Nazanin Azarinejad Mohammadi discusses her research on epilepsy genetics, the clinical and functional characterisation of GABAA-receptor related disorders, and how mutations in the GABAA-receptor subunits can lead to epilepsy and morbidities. Nazanin also highlights the variability in symptoms among individuals with the same mutation and the need for further research to understand the factors that contribute to this variability. Plus, emphasised is the importance of genetic testing and personalised treatment for patients with these mutations.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Nazanin Azarinejad Mohammadi
“Epilepsy was thought to be only going one way (where the receptors were inactivated so there was no inhibition and then, well, then you would have seizures). But that's what we were doing in this study; that actually not only losing the functionality of these receptors that are binding to GABAA will lead to epilepsy, actually, the opposite is possible as well.”
00:24 Torie Robinson
Fellow homo sapiens! Welcome to, or welcome back to: Epilepsy Sparks Insights.
Did you know that people with the same genetic mutation can have different outcomes? I mean, who knew that a slight variation in an amino acid of our Central Nervous System (or a GABAA receptor) could send our brains’ massively out of whack causing some people to have horrifically uncontrollable seizures, intellectual disability, movement disorders and increased mortality…but that that same mutation could also cause a person to have treatable epilepsy and regular intelligence?!
This week, neuroscientist Nazanin tells us all about her research into the clinical and functional characterisation of GABAA-receptors and how symptoms can vary so, so much!
Please don’t forget to share your thoughts on this episode with us in the comments below, I really enjoy the comments and responding to them - they’re fabulous.
And make sure that you do subscribe so that we can educate and empower both more people affected by the epilepsies and indeed more clinicians with patients who have an epilepsy, so that they can provide the best care possible.
01:28 Nazanin Azarinejad Mohammadi
My name is Nazanin and I have a few months ago defended my PhD. So… I have been working on epilepsy genetics and some laboratory work and clinical correlation analyses. So, that's what I have been doing the last 3 ½ years actually. But now, I have just time to relax a bit after the PhD so it's really nice.
01:54 Torie Robinson
So, what was the title of your PhD? Or, maybe if it's simpler, what were you actually studying?
02:00 Nazanin Azarinejad Mohammadi
Yeah, actually the title is very long…but I can read it from my thesis, hahaha! It's not really easy…
02:06 Torie Robinson
Okay, go on then!
02:07 Nazanin Azarinejad Mohammadi
…to remember! Are you ready for the long title?!
20:12 Torie Robinson
Go for it.
02:13 Nazanin Azarinejad Mohammadi
“Clinical and functional characterisation of GABAA receptor related disorders, translating genetic diagnostics into personalized treatment”. So basically, I was working with the genetic mutations in the GABAA receptor subunits and how it was causing epilepsy and other comorbidities in different patients. So…
02:37 Torie Robinson
And just for people who aren't familiar with GABAA receptors, could you just give us a little breakdown of what they are and what they do, please?
02:44 Nazanin Azarinejad Mohammadi
They are receptors in our CNS [(Central Nervous System)] of course (in our brain) and they are responsible for inhibitory signals. So, they are activated by the neurotransmitter GABA; which is inhibitory. So actually, understanding how mutations in this receptor can lead to epilepsy was thought to be only going one way (where the receptors were inactivated so there was no inhibition, and then, well, then you would have seizures). But that's what we were doing in this study; that actually not only losing the functionality of these receptors that are binding to GABA will lead to epilepsy, actually, the opposite is possible as well. So, that's the main result of my thesis, actually.
03:35 Torie Robinson
You can go one way or the other: you can have too much or too little and each of those things can lead to seizures?
03:40 Nazanin Azarinejad Mohammadi
Exactly. And that was amazing to understand - that it doesn't have just one function (these variants), so…
03:50 Torie Robinson
These mutations:, are they inherited from parents or are they mutations in the child themselves?
03:57 Nazanin Azarinejad Mohammadi
The majority I worked with in this cohort, in my own study, was… many of them were de novo ones, so it was just happened in the child. But we also had a few cases where it was inherited, but in my study the functional outcome was neutral. It can be both inherited or that it's de novo. But if your parents had it and they also were equally sick, then if you inherited the same mutation, of course, it's pathogenic, but sometimes when it's familial, sometimes it can be less pathogenic, yeah. But usually, de novo ones are the worst ones.
04:35 Torie Robinson
The type of people in your study, they were all children, was that correct?
04:39 Nazanin Azarinejad Mohammadi
Yes, majority of them were children (at least when the mutations were detected in their system, they were children). But now, after so many years (that I went back and looked at the papers that were published some years ago), some of them were not children anymore, but the data that I was looking at were from when they were children.
05:01 Torie Robinson
I only ask that because much of the time, we hear about the mutations in babies and children and often I think because life expectancy isn't necessarily, you know, overly high, but… So, it's interesting to hear that there are some adults, people who have grown up and lived to the later years still with this mutation.
05:21 Nazanin Azarinejad Mohammadi
I think that was a very interesting point because a lot of parents would also ask us in the hospital, like “How's the future for our kids (having this mutation)?”. So, we also didn't have, like, clear picture before, but now after doing the study, at least we have a spectrum of very mild ones and very severe ones. And then you have some survivors as well (in the mild cases). Then you have, like, an overview: if you have “this”, you might live as well, and you might go to school, and have a normal life, but then it depends on which symptoms you have, of course; if it's very mild or in the middle. But now we have, like, an overview of that you don't die of this mutation, necessarily, and you can also have a normal/semi-normal life living with this mutation. So, now we can answer some of the questions.
06:13 Torie Robinson
I think that's an interesting point because lots of people - and some clinicians too - will assume that if 2 people have the same mutation, then their symptoms will be identical. But that's not always the case, is it? There can be a lot of variants within the same mutation.
06:30 Nazanin Azarinejad Mohammadi
Actually, like, you're right about it. We had 1 case that the amino acid residue at the one position - so it was changed to different amino acids at one position (it's the same position, but it was changed from one to another and from the same to whole another amino acid residue). And the results was: one of them were neutral and there was no effect (according to my measurements), so it didn't hyperactive the receptor, neither making it not function at all. But the other one (that changed from the same to a whole another amino acid in the same position), it had another effect! So, you can even have the same mutation “spot” but changing it to different amino acids can also change the symptoms in the patients and the clinical picture actually.
07:25 Torie Robinson
Which I guess shows more and more research is required to further understand “Why do some people experience some symptoms and why do some people not?!”.
07:33 Nazanin Azarinejad Mohammadi
Exactly, exactly. So, it's very individual according to which position and which amino acid is substituted with what. So, it's very dependent on what you have and it really needs to be tested. But of course, we know that it's not always available for the clinicians to test each individual of these variants. But, as we are testing more and other people in different countries are testing more, some more variants are being tested and it will just contribute to developing some prediction tools. So, that can at least be helpful.
08:09 Torie Robinson
And the results of your work, are they going to be, or are they already, useful in different spheres like different types of epilepsies or one particular epilepsy diagnosis?
08:23 Nazanin Azarinejad Mohammadi
The main part of my studies and the results: they are just published actually and I have shared it on my social media. So actually, - that part is going to be very useful for the patients who will be diagnosed or are diagnosed with the GABRB2 gene, which encodes one subunit of this GABAA receptor. So, I was mainly working on this gene and it's going to be helpful for being diagnosed with this specific gene so that maybe I have already done the functional testing on some of the variants so clinicians can directly go and look at the effects (if it's a loss of function if it's a gain of function) and how it will…it will be in the future for the kid or adult or a teenager with this mutation [and] what is the progression and how the disease is going to look like. So, it can actually be translated and used in the clinics, actually, so, I'm happy about that part.
09:27 Torie Robinson
That's cool, and internationally. And how common is this variant?
09:31 Nazanin Azarinejad Mohammadi
I would say it's very rare if we look at the rare diseases. So, in our cohort I had 42 patients, but it wasn't all patients we had available. So, in our database we had around 70-something patients from the whole world. So…
09:51 Torie Robinson
Cool.
09:51 Nazanin Azarinejad Mohammadi
… I would say it's kind of rare situation, but rare diseases also need attention. So…
09:56 Torie Robinson
Oh no, totally! And do you know what, I think sometimes… from talking to lots of amazingly educated people like yourself is, like, I wonder how many people may have these variants, but because they're… for example, because their symptoms may not be obvious, they might be limited, or because they're from a rural area, or whatever it might be…you know,, they might not be on the system. And so, I don't know, what do you think about that? Do you think that there are potentially lots more people than we currently realise (with, for instance, this mutation - amongst others)?
10:30 Nazanin Azarinejad Mohammadi
Yeah, that's a very nice point, Torie. I think, right now there might be way more people with this mutation in this specific gene, but of course, like genetic testing is not available in many countries still, so, a lot of them are not even being tested and diagnosed with this genetic mutation. And also, like, as you said: often it's children who are diagnosed (and this new technology are used to diagnose them), so, a lot of (I feel at least) the adults are missing in the system somehow; so, they are not diagnosed or they are not getting this opportunity because now they are adults they know how to manage life somehow and [so we think/say] “Let's help the children.”. I also understand that part, but this sad reality makes it, like, harder for us to understand exactly how many people in the world are suffering from this mutation in this gene. But I think there's way more and we will discover more patients with this mutation, but right now it's just limited. I think maybe after some few years we will see how many more people are being diagnosed.
11:43 Torie Robinson
It was, you've made me think of this time (it was actually at one of the DICE conferences in Denmark) - by the way, everyone check out the DICE conference, amazing, our next one is in 2 years time. I'll put the link below - and there was one person there who was a patient with the rare one of the (I don't know if was SCN2A or SCN8A) and he was a data scientist and he stood out because the other, well, at least all the other people that I'd met there with one of these mutations: they were cognitively not nearly as functional, shall we say, as himself (like, they were nonverbal) or in…and often in wheelchairs and had other serious morbidities. And so, I just thought that was a pretty wild example of how different mutations can affect different people differently.
12:38 Nazanin Azarinejad Mohammad
With the patients in this cohort, I didn’t have…I had some patients that were very mild and then going to school and continuing life (as, like, we other people do without this disease), but then some that were dying within 4 years of life. So, it was, like, [a] very wide symptom spectrum. But, we had people with other mutations and they were affected differently. Not even only the mutation itself is enough to determine how you're doing with the disease! Other factors such as environment or epigenetics, and all these things could be contributing - because it can be possible that exactly the same mutation in one family can be [both] so mild and so severe. So, also epigenetics part plays a role, so… I think it's very hard: it's like an onion with many rings(!) so you can keep on revealing [more details/information] but yeah, it's very complicated.
13:41 Torie Robinson
Isn't this like a perfect example of the more you learn, the more you realise you don't know, right?!
13:46 Nazanin Azarinejad Mohammadi
Exactly! Then you're like “Maybe I shouldn't say anything because I don't know enough compared to some others!”. But yeah, then you realise how complicated things are. Yeah, that's true.
13:57 Torie Robinson
This is really inspiring. And I hope that somebody gets the opportunity to take… to further this research into this mutation, ‘cause…
14:05 Nazanin Azarinejad Mohammadi
Yeah.
14:05 Torie Robinson
…obviously it's going to benefit the people with the mutation, which will no doubt be more people in the future, with their families as well. And, you know, if anybody from any governments are listening: it benefits you too, because if you can get people, you know, having… who are more “well”, more easily, it's going to be cheaper for you(!), so, you know, invest more in research.
14:28 Nazanin Azarinejad Mohammadi
Exactly, that's our word for today! Actually, yeah, especially rare diseases because families are just suffering in the silence, I feel. And I know of some other diseases like cancer or cardiovascular diseases; they are also very horrible diseases, but all sick people need the same attention and not just because some more people/a bigger portion of people are suffering from one shouldn't be the reason that we are not getting paid enough attention for the others.
14:59 Torie Robinson
Thank you so much to Nazanin for educating us of the complexities of GABAA receptors, and for sharing with us how a genetic mutation can so simply and significantly alter our neurological, psychiatric, and cognitive function.
Do check out Nazanin’s paper and more about her work on the website torierobinson.com (where you can also access the podcast, the video, and transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to the channel, share this episode with your friends/colleagues/family members(!) and see you next week!
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Nazanin is a Danish-Iranian neuroscientist and completed her PhD in epilepsy genetics at the Danish Epilepsy Center under the supervision of Rikke S. Møller. She worked on functionally and clinically characterising GABAA-receptor related disorders including epilepsy, and translating the genetic diagnosis into personalised medicine.
Currently, Nazanin is doing a postdoc focussing on rare diseases such as varying types of genetic congenital hypoglycaemia in children. Based at the research unit of H.C. Andersen Children's Hospital, she also holds the position of Study Coordinator for an ongoing trial focussing on new treatments for hyperinsulinism.
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X/Twitter: NazaninAzarine1
LinkedIn: nazanin-azarinejad
Paper: clinical-and-functional-characterization-of-gabaa-receptor-relate
SDU: fingerprint publications/clinical-and-functional-characterization-of-gabaa-receptor-relate/fingerprints
OUH:ouh.dk
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