Seizures Caused By Insufficient Glucose: GLUT1 Deficiency Disorder! - Carla Marini, Child Neurology & Psychiatric Unit Salesi Children's Hospital Ancona, Italy
A mutation of a gene can lead to lack of absorption of glucose (our fuel) and cause epilepsy! Carla Marini, a paediatric neurologist and neuropsychiatrist tells us all about the rare epilepsy and metabolic disorder GLUT1 Deficiency Syndrome, emphasising the importance of early diagnosis, treatment using the ketogenic diet (which can help control seizures, improve cognitive function, and decrease the impacts of movement disorders). She also highlights the value of working closely with patient and family groups to understand the clinical manifestations and natural history of the disease. Carla shares an uplifting success story of a patient who has thrived with early intervention.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Carla Marini
“They have a normal development (so, nothing that really would make you think that they have a metabolic disorder) and all of a sudden, at the age of 1, 2, 3, or even later on, they develop this sort of, you know, age-related epilepsy, which is done by absences.”
00:15 Torie Robinson
Fellow homo sapiens! My name is Torie Robinson, and welcome to, or welcome back to: Epilepsy Sparks Insights.
Now, if I say “GLUT” - what do you think of? Would you think of one’s rear?! Or of gluten? Well, in this case, we are talking about “gluCOSE” - often referred to, casually, as sugar or a form of energy. Actually, the molecule glucose is actually a mix of 6 atoms of carbon, 12 of hydrogen, and 6 of oxygen, and It is crucial for our survival. And if someone happens to have a genetic mutation that restricts the absorption to our brains: we have a severe problem. In fact, we have a rare, genetic type of epilepsy called GLUT1 Deficiency Disorder.
I am delighted to be chatting today with the director of the Child Neurology & Psychiatric Unit at Salesi Children's Hospital, neuropsychiatrist: Carla Marrrrini
Please don’t forget to share your thoughts on this episode with us in the comments below - I enjoy reading your thoughts and responding to them! Do subscribe so that we can educate and empower way more people affected by the epilepsies around the world, and, indeed, more clinicians with patients who have an epilepsy - to provide the best care possible.
01:28 Carla Marini (00:10.849)
I am a child neurologist and neuropsychiatrist. I'm currently working in Ancona, Italy. And in my career, I went through the University in Bologna and then I lived in Melbourne and worked with Sam and Ingrid, Sam Berkovich in English for several years where I did a PhD on clinical genetics - and I actually trained as an adult neurologist to start with(!) because I was so interested in genetics then I decided to train also to become a paediatric epileptologist and neurologist. I came back to Italy and I landed in Pisa with Renzo Guerrini who I worked with for nearly 20 years; first of all in Pisa and then in Florence at the Mayer Hospital where I was until 4 years ago. And here I am directing the Child Neurology and Psychiatric Unit in Ancona, so, I'm starting this new adventure!
02:26 Torie Robinson
Fantastic! And so we're going to talk a little bit, specifically, about the GLUT1 Disorder, a type of epilepsy, which, I don't know , but maybe this is my experience; I say “GLUT1” and people think “gluten” or “protein” or “ketogenic diet”. What is, what is GLUT1?!
02:43 Carla Marini
GLUT1 is actually a metabolic disorder with neurological symptoms; predominantly epilepsy, but not only. It's caused by the lack of glucose in the brain (so, there's nothing to do with gluten, but it has to do with glucose). So, the sugar cannot be transported into the brain so the brain lacking sugar can't work properly because the glucose is the fuel for the brain. And so, the brain is actually really working very slow or inappropriately. And it is a genetic condition: it's actually caused by genetic mutations in this gene that we called the GLUT1 gene - but it's actually called SCLA21 gene, so that's the proper name, but let's call it GLUT1. So, this mutation actually impact on the function of the protein that should really shift, you know, transfer the sugar into the brain, and so, it's not working properly. So, the patients with GLUT1 Deficiency have symptoms very early on, normally from really early infancy, a few months of life, and can be epilepsy to start with, but it also will eventually have some learning disabilities or intellectual disabilities and also eventually movement disorders (because the brain doesn't have enough fuel to, you know, make the body move properly).
04:22 Torie Robinson
Or develop, I presume, as well?
04:23 Carla Marini
Yeah, or develop properly, yes, exactly. And these are the main symptoms: so related to epilepsy, intellectual disability, and seizures and movement disorders, yeah.
04:35 Torie Robinson
This type of epilepsy: how common is it? And is it a de novo mutation or is it one that is passed down from mum and dad?
04:45 Carla Marini
It's actually, fortunately, quite rare. For instance, in Italy we created a national registry for the disease. So, it's a collaborating work with several centres throughout Italy and the familial association of GLUT1 - they've done a great work, and collaborating with them has been fantastic, and we are still collaborating. And in this national registry we have about 70 patients - but I'm sure not all patients are diagnosed properly so there may be more, maybe 100, maybe 150, but that would be more or less the number we have in Italy. So, as you can understand, it's a rare condition and it is inherited in a small proportion of patients (so passed on through families), and normally the parent transmitting the disease is very mild or can be even, even non-symptomatic (so can be a normal, just a “carrier” we say (a healthy “carrier”), but most of the mutations could be actually de novo (so occurring during early phase of after the conception and in the, you know, in the foetus' phase, yeah.
05:55 Torie Robinson
So, what benefits does having a registry for, well, any rare disease (but in this case, of course, GLUT1); what does that bring and what's the value of working with patient groups or family groups and organisations?
06:09 Carla Marini
There are several benefits. I mean, first of all is working very close with the family; you start to get to know them better. You get all the information from the patients and from the parents and they really are very important in understanding how these disorders and diseases work because they observe their children every day 24 hours a day(!) so they can tell you exactly what the symptoms are, what the reactions are, and so it's very important to understand the clinical manifestations of the disease. The registry is very important to understand the natural history of the disease and the disorder because we have patients that just had their symptoms [onset] (so very little [in age]), but we also have patients that are maybe 10, 20, 30 [years of age], and we can see how they are after 10, 20, 30 years of the disorder. So, we have this understanding of the natural history and the evolution of the disorder, which is really important for the prognostic features and for the outcome of the disease, and so that's quite important.
07:22 Torie Robinson
It is amazing really, how… because, I mean… I know that lots of people (especially researchers) do know that if you have, what on paper, looks like the same genetic diagnosis, it can affect people very differently. And to not know that, you know, that you have this rare genetic disease is just pretty, pretty amazing. And it makes me think how many more people would have not just GLUT1, but any type of rare disease.
07:50 Carla Marini
Yeah, you're absolutely right. This is still one of the… partly, one of the mysteries of the genetic conditions because we know that the same mutation in different genes (including GLUT1), can cause a severe phenotype in some patients and others can have a very, very mild phenotype. And so, definitely: I think it might be the influence of the rest of the genetic background, which, you know, really must do something. You know, it's completely… the patient has the same mutation but a completely different genetic background and so the reaction of the body and the rest of the DNA and the genes react differently. And I think for GLUT1, it's important even the type of mutation: some mutations can cause a very, very mild deficit in the transportation of the glucose into the brain. And so that means that the patient has some glucose into the brain; therefore the brain works better [than that of people with less glucose] and the symptoms can be really mild, whereas other patients have mutations that cause a complete lack of transport of glucose to the brain and then the symptoms, as you can understand, are much worse. So, there is a correlation between the genotype, what we say, so the genetics and the phenotype, which is the clinical manifestation. And we can also see it from the lumbar puncture because these patients; we normally do a lumbar puncture and we see that the glucose, the glucoracia is (so the level of glucose in the brain) is affected differently in these patients. So, after the genetic study, we normally, we can do a lumbar puncture and measure the quantity of glucose in the brain.
09:31 Torie Robinson
And I will provide a link also to your paper below so anyone can check this paper out. Have there been any, like, unexpected discoveries that you have made through working with the patient group, family group?
09:45 Carla Marini
What we discovered, actually (that was quite some time ago), is that some patients can have a very, very mild epilepsy, like, for instance, “just” the absence epilepsy that we think is the most common type of epilepsy in children: they have a normal development (so, nothing that really would make you think that they have a metabolic disorder), and all of a sudden, at the age of 1, 2, 3, or even later on, they develop this sort of, you know, age-related epilepsy, which is done by absences, and they can have a metabolic disorder including GLUT1 Deficiency. So, that was quite important to uncover those patients that, as you said, can be hidden away - because these symptoms are so mild that you would never think that they have a metabolic disorder including GLUT1 and you don't treat them with the ketogenic diet (which is the treatment for GLUT1), because you wouldn't think that they will just have absence, absence epilepsy. So, we did this paper and we did a publication - together with Ingrid Scheffer and Sam Berkovic and Renzo and a few others on the early onset absence epilepsy as a phenotype related to GLUT1 Deficiency which was quite interesting. Yeah, so, it's something that everyone should keep in mind that even the so-called absence epilepsies can be related to GLUT1 Deficiency.
11:07 Torie Robinson
And can worsen as the child gets older?
11:11 Carla Marini
They don't particularly worsen. Maybe they're not controlled by the current common anti-epileptic medications we use - because they maybe, maybe they would need the ketogenic diet, as I said...
11:23 Torie Robinson
Why is the ketogenic diet used for this? Is it because, you know, are we talking about mitochondria and, you know, and ketones and things like that?
11:32 Carla Marini
The ketone bodies, actually, are very important because they can be transferred into the brain using a different metabolic way (which is not the common one, not the same as glucose) and so, then they can be used as a fuel for the brain instead of the glucose that is not there. So, that's a reason. It's an alternative metabolic way. So, this hyperglycorrhachia is bypassed by using the ketone bodies.
12:01 Torie Robinson
And does this tend to be, what one might call “effective”, like, does it control seizures generally in people with GLUT1?
12:08 Carla Marini
It does. It controls seizures, it controls the movement disorder problem, and also we have seen patients improving, especially if the treatment is started really, really early on. They can improve the cognition, the movement and the intellectual disability. I think a GLUT1 Deficiency should be considered one of these treatable conditions and treatable metabolic disorders that if it is diagnosed really early on, possibly even really postnatal and the treatment is started really early on; the symptoms can be prevented with this Precision Medicine treatment.
12:50 Torie Robinson
Well, yes, “precision medicine”, gosh, whenever anybody says “precision medicine”, it always makes me think of Rikke Møller.
12:57 Carla Marini
We think about Rikke quite often - and even in this case because we published something on GLUT1 as well. Yes, so this is definitely a preventing, treatable metabolic disorder that should be really thought about very early on; because the treatment which is the ketogenic diet is a “replacement treatment”. It’s not curing the disease but, you know, we can actually bypass the metabolic problem and the metabolic disorder and then can really…
I have got a patient and I really think about her: Greta. We diagnosed Greta when she was 1. She went on the ketogenic diet and she now lives in Germany because she thinks that Germany is a better country for a ketogenic diet!). Anyway, so, the family moved there and now she is fantastic. She studies languages: she speaks English, Italian, German, and she wants to, you know, she's doing great and she’s… absolute success, yeah.
13:57 Torie Robinson
Thank you so much to Carla for educating us on the complexities of GLUT1 Deficiency Disorder and sharing with us the value of working with families to obtain an improved understanding of what they experience and how they can best be helped.
Do check out Carla’s paper sand 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 our channel, share this episode with your friends/colleagues/family members, and see you next week!
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Carla Marini is a child neurologist and neuropsychiatrist and director of the Child Neurology & Psychiatric Unit Salesi Children's Hospital Ancona, Italy.
Through her career Carla went through the University of Bologna and then lived in Melbourne for several years where she completed a PhD in clinical genetics and trained as an adult neurologist - working with Sam Berkovic and Ingrid Sheffer.
Afterwards, due to her interest in genetics, Carla trained as a paediatric epileptologist and neurologist. She went back to Italy and I worked in Pisa - and then Florence - with Renzo Guerrini, for nearly 20 years.
4 years ago Carla moved to Ancona where she is now directing the Child Neurology and Psychiatric Unit.
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LinkedIn: carla-marini
Research Gate: Carla-Marini
Neuroscience & Genetics: carla-marini
Paper mentioned: GLUT1-DS Italian registry: past, present, and future: a useful tool for rare disorders
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