Vitamin B6-Dependent Epilepsy & Other Metabolic Epilepsies! - Dr. Phillip Pearl, Boston Children’s Hospital, MA, USA
Can a vitamin stop seizures?! Vitamin B6-dependent epilepsy is a rare but powerful example of how identifying a cause has the potential to make an epilepsy treatable! Dr Phillip Pearl explains this condition and explores wider advances in metabolic epilepsies, from genetics to diets to gene therapy! Transcription and links are below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Phillip Pearl
“...your metabolism is affected, so it's going to cause more than just seizures. It's going to cause problems, say, in so many respects: motor coordination, language, cognition…”
00:11 Torie Robinson
When most people think of epilepsy, they think of seizures alone. But what about the causes and if they run deep; tied to our metabolism, genetics, or even the way our bodies process vitamins? Well today we’re joined by the brilliant Dr Phillip Pearl - Chief of Epilepsy and Clinical Neurophysiology at Boston Children’s Hospital and Professor at Harvard Medical School. He’s taking us on a journey through inherited metabolic epilepsies, from stories of vitamin B6-responsive epilepsy to the exciting world of genetics, diets, and even gene therapy!
If you haven’t done so already, please press the thumbs-up in this episode, comment below, and subscribe to our channel, so that we can get way more people around the world - clinicians, patients, and the general public - learning facts about the epilepsies!
00:54 Phillip Pearl
I'm Dr. Phillip Pearl. I'm the chief of epilepsy and clinical neurophysiology at Boston Children's Hospital, and my official position is the William G. Lennox chair. By the way, William Lennox is said to have been- including by Dr. Simon Shorvon, right there at University College London - is said to have been the most important epileptologist of at least the middle part of the 20th century, when, during the wars (especially World War II), he kept epilepsy alive and the International League Against Epilepsy alive. He was the first president of American Epilepsy Society, he was president of the International League Against Epilepsy for 15 years, and he was here at Boston Children's Hospital. It has some historical valence…
01:43 Torie Robinson
Mmm–hmm.
01:43 Phillip Pearl
…when I say that I'm the William G. Lennox Chair - in the Department of Neurology at Boston Children's Hospital and Professor of Neurology at Harvard Medical School. I'm also involved in the Music and Health Institute of the Berklee College of Medicine [sic] here in Boston, which is actually known for its contemporary jazz education! And it's right next to the New England Conservatory of Music, which, as you can imagine, is known for its classical interpretation and teaching. So, we have some very fine institutions of higher education here in Boston, and I'm proud to be affiliated with Harvard Medical School and the Berklee College of Music. My primary appointment is Boston Children's Hospital, and I run the Division of Epilepsy, which is composed of nearly 30 (depending on who you count), paediatric epileptologists. So, it's a very large program and we have specialty programs in epilepsy surgery, intensive care epilepsy and ICU EEG, quantitative EEG, neuromodulation (which is a big thing right now, especially in the surgical options), ketogenic diet and alternative forms (like diet treatments), epilepsy genetics, and other area; autoimmune epilepsies, which is another hot topic, inflammatory epilepsies. My particular area is the inherited metabolic epilepsies; which you could say come under epilepsy genetics because they are inherited.
03:15 Torie Robinson
Are they ever de novo, or do they… are they always inherited?
03:18 Phillip Pearl
Like genetic diseases, a lot of genetic diseases are de novo, so they're not really transmitted.
03:24 Torie Robinson
Mm-hmm.
03:25 Phillip Pearl
Most of the metabolic ones are transmitted; typically in an autosomal recessive manner, where both parents would be carriers of a pathogenic variant. We used to call it a mutation. Now, mutation is said to be the act of the change in the gene, and the variant is what exists in the gene. But some of us will use those terms kind of interchangeably. So, either parent would be a carrier of the mutation that would be passed down to the child; that'd be autosomal recessive. But some of these can be autosomal dominant; some are X-linke, some are mitochondrial. And they can be de novo. There's also the issue of somatic mosaicism where the change in the gene is just in certain tissues and not everywhere, so it can be very hard to spot it. Sometimes, we actually have to do genetic analysis of the brain tissue itself, like from a surgical specimen, to find that somatic mutation. So, the most transformational change I've seen in my practice now - 35 years of being in epilepsy - is in this area of epilepsy genetics, and my particular area of investigation is very closely linked to that.
04:29 Torie Robinson
When people think of the epilepsies, they think of seizures alone (generally speaking); with the metabolic epilepsies, do people tend to have symptoms other than seizures?
04:38 Phillip Pearl
Yes, absolutely. Like everything else in neurology, everything is based on the company that it keeps. In fact, I was telling my teenage daughter the other day that she's judged based on the company that it keeps. Now, of course, I was being critical of her gang…
04:52 Torie Robinson
Friend group, hehe.
04:52 Phillip Pearl
…I'll call “pseudofriends”. But actually, I was trying to make a point, because she's working here this summer in a laboratory with some other students. I was trying to make a point to all of them that when we localise in neurology, which is the heart, which is the foundation of clinical neurology, is localisation, is to find the lesion or find the problem, the location of the problem in the nervous system, whether it's a single location, bilateral, multiple, whether it's CNS or PNS, meaning central versus peripheral nervous system, or combined. It's all based on the company that it keeps. And that's true not only of the neurological sign or symptom, but all the associated. So, in general, as you're asking; children or adults with inherited metabolic epilepsies tend to have other issues as well, and not just isolated seizures. That would be very unexpected for one of the metabolic disorders. Because, hey, your metabolism is affected, so it's going to cause more than just seizures. It's going to cause problems, say, in so many respects: motor coordination, language, cognition, coordination, and sometimes other organ systems: the heart, kidneys, lungs, liver, dermatologic manifestations, so it does get into a kind of a multi-symptomatic phenotype.
06:05 Torie Robinson
With many other epilepsies where we have a higher-than-average incidence of people having intellectual disability, is that the case in the metabolic epilepsies?
06:14 Phillip Pearl
You know the classic presentation of a child with an inherited metabolic epilepsy is neonatal or at least infantile or early childhood onset (but not exclusively. Some are adult onset believe it or not!), but the classic is the newborn who has a presentation that is non-specific; like lethargy, poor alertness, poor feeding, failure to thrive, acidosis sometimes (where acid is building up in the body because the metabolism is off), and seizures. I would say the most classic presentation we think of, or a great one to think of is pyridoxine dependent epilepsy. Pyridoxine is our term for vitamin B6, and, there is a group of children that are born with seizures that sometimes are attributed to other causes, like, hypoxic ischemic injury, low oxygen, low blood flow, that turn out to be metabolic. Sometimes the scenario is pyridoxine dependency, which actually means they respond to vitamin B6! I was blown away when I learned this as a resident. This was first reported in 1954, so, it's not thaaaat long ago, I guess, but it's, you know, it's a while ago, right, it's the middle of the last century.
07:27 Torie Robinson
Yeah!
07:27 Phillip Pearl
But in 1954, a single case report was published. Don't let anyone say single case reports aren't informative because a woman's case was published in the journal of Pediatrics by the group at the Children's Hospital Philadelphia back then, by Dr. Hunt et al., of whom a woman who was on her third pregnancy… now, her first pregnancy was healthy, but her second pregnancy she had vomiting all the time. It's called hyperemesis gravidarum (or, a lot of vomiting during pregnancy). And yet she felt better when she took vitamins. Although when the baby was born, the baby had terrible seizures and by a year of age was profoundly impaired. This is the third pregnancy. In the third pregnancy, she also felt sick, had terrible vomiting, and she felt a little better with vitamins. When the baby was born, she reported feeling better with vitamins. So, they started giving the baby vitamins, and they gave all the vitamins they could think of. And in fact, the last one they gave (and this is after days), was vitamin B6. Why? I spoke to the late great Dr. Peter Berman, who was Chair Emeritus at Children's Hospital, Philadelphia, because as a young trainee, he knew these doctors in the 50s who reported this case. So, this is a very personal story (and I'm getting it firsthand from a trainee at the time!). And he said they gave the vitamin B6 last because it came in a milky white solution and no one wanted to put something like that in a little baby's veins. They only put the clear stuff in. But finally, they gave vitamin B6, and guess what? The seizure stopped. On a dime.
08:54 Torie Robinson
Completely?!
08:54 Phillip Pearl
Completely. And then they ran an experiment (which is published in the paper). You can see it. I have slides of this where they would withdraw the B6 and the EEG would get worse again and show spikes again, the baby would start seizing again, then they would replace the B6, and it got better, and they did it again and again. And for years, when I was in training, it was customary to treat these children until they were five or six years of age, and sometimes even stop the medicine because it didn't seem like they needed it anymore. Well, we've learned a whole lot since then. In fact, it was 50 years later (from 1954 to 2004) when Dr. Peter Clayton at the Great Ormond Street Hospital in London, exactly where you're sitting…
09:30 Torie Robinson
Hehe.
09:30 Phillip Pearl
…discovered the cause of vitamin B6-dependent epilepsy. And he discovered it because it was known that these children were accumulating a compound called pipicolic acid. So, they took pipecolic acid, and they went… sort of looked upstream and looked at what could be causing an uptake or an accumulation of this pipecolic acid, and how is this involved? And they figured out that that was the intermediate in the breakdown of the amino acid lysine. Now, up until then, no one had suspected lysine, which is just another amino acid like alanine, valine, GABA, glutamate, these are all important amino acids that we've all heard of a lot, but lysine? They figured out that these patients were not breaking down lysine properly and therefore they were accumulating something that wasn't being broken down called alpha-amino-typical semi-aldehyde and then alpha-amino-typical adipate, actually. But anyway, don't worry about the biochemistry, the point is that this thing was sequestering vitamin B6 out of the system because they were missing an enzyme called alpha-amino-typical semi-aldehyde dehydrogenase and it's called antiquatin for short. Why antiquatin? Antique because it's so preserved,...
10:44 Torie Robinson
Huh!
10:44 Phillip Pearl
…so preserved phylogenetically across species and ontogenically across the human organism. You need it for life. You need it to sustain life. So, it's one of these life-sustaining enzymes, alpha-minoidic semi-autohydrogynase. It was discovered, and therefore now we treat this disease with extra peridoxin and lysine-restriction (because you can't break down lysine) and arginine (because it competes with lysine to get across the cell membrane). There are all these new things we know now, but this is a classic example of inherited metabolic epilepsy due to a vitamin dependency state. Not actually a deficiency state where you're not getting enough in your diet, but a dependency state where you're born with an inborn error metabolism that causes you not to be able to have enough of this vitamin endogenously in your system. And, it's eminently treatable by giving a vitamin! And now we know there are a bunch of these vitamin-responsive epilepsies and its other encephalopathies. And now we know there are transporter conditions where you can't transport something in through your nervous system, like for example, glucose transporter deficiency, where you can't transport glucose in, and you need glucose as your main metabolic fuel of the brain, and therefore as an alternative to glucose, how do we treat it? We treat that with a ketogenic diet. So here we have a group of disorders that are responsive to a vitamin, and we have another group of disorders responsive to a diet. It's pretty interesting stuff.
12:02 Torie Robinson
And it sounds pretty… a lot better than just popping a load of pills, right? If you have this option…!
12:06 Phillip Pearl
It does sound better than popping pills, although I'm prescribing pills all the time, so I'm not anti-pill! But the point is, we are trying to go from the targeted therapeutics of vitamin or diet to the current era. What's the current era? It's gene therapy. We are trying to move into the era of enzyme replacement therapy, gene therapy, gene editing, correction of gene problems using gene replacement through vectors that are safe, the most common one is AAV, Adeno-Associated Virus, to mRNA or RNA insertion, to working on a natural process called nonsense-mediated decay (which is a normal decay process of DNA, but if you can impair that, maybe you can improve the good DNA) - that's being used right now for Dravet syndrome with the SCN1A gene. So, all of these new directions we're headed now, into targeted therapeutics (to actually correct the problem and not just keep throwing pills at the problem) or to correct the problem and not have to do surgery (which has its own risks and costs - although I'm not saying not to do epilepsy surgery when it's indicated but if we can find something targeted at the underlying problem we've really accomplished something). So that is my bird's eye view of what's happened in this field over the last almost century now because it's again… this vitamin B6 dependency was described in 1954. The whole area of metabolic disease really started around the 1920s when it was recognised that there are these inborn errors of metabolism with the crooning and lectures, which was by Sir Arthur Bald Garrod - also in London…
13:44 Torie Robinson
Hehe.
13:44 Phillip Pearl
…at the British Medical Association. And the whole process of trying to prevent these things really started with newborn screening, which came about in the 1950s. The first disease for newborn screening was PKU, phenylketonuria. So, it was really around the 50s with newborn screening, the discovery of pyridoxine dependent epilepsy, the biochemical elucidation of these things, the decade of the brain, which was back in the 90s, and now genomics and gene therapy, and that's kind of what's been happening! I haven't gotten into the AI and all that other stuff, but that is my description of what's happened in this field that I've been engrossed in for a long time in my own career.
14:24 Torie Robinson
Thank you to Phillip for sharing his incredible knowledge on inherited metabolic epilepsies and helping us understand how treatments have progressed from vitamins to today’s cutting-edge therapies. Check out more about Phillip at the website torierobinson.com where you can access this podcast, the video, and the transcription of the entire episode all in one place. And if you haven’t done so already, please press the thumbs-up for this episode, comment below, and do subscribe to our channel, so that we can get way more people around the world - clinicians, patients, and the general public - learning facts about the epilepsies! See you next week!
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Phillip L. Pearl, M.D. is Director of Epilepsy and Clinical Neurophysiology at Boston Children’s Hospital and William G. Lennox Chair and Professor of Neurology at Harvard Medical School. His major research interest is inherited metabolic epilepsies. Dr. Pearl has published over 275 peer-reviewed manuscripts, over 160 chapters/reviews, and written or edited eight books, one of which is translated into Chinese and one into Japanese. Dr. Pearl a member of the Music and Health Institute at the Berklee College of Music in Boston, and is Past President of the Professors of Child Neurology and the Child Neurology Society. He is currently on the Board of the International Child Neurology Association.
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