Understanding epilepsy through genomic medicine
By Charles Steward1.
The vast majority of people with epilepsy are overwhelmingly treated with no knowledge of their genomic makeup. However, the future of medicine would seem to lie in the ability to more accurately target epilepsy treatment based upon knowledge of a person’s genome. This is commonly referred to as precision medicine, personalised medicine or genomic medicine2 and I explore this using specific examples of genes known to be implicated in epilepsy,
In the first example, I explore a genetic disorder called GLUT1 deficiency syndrome3 that affects brain metabolism and can result in recurrent seizures. This is caused by a malfunction in the gene SLC2A1 which is involved in transporting glucose (a sugar) across the blood-brain barrier2. Research has shown that in some patients who have Glut1 deficiency syndrome, the ketogenic diet2 can help reduce the number of seizures they experience. GLUT1 deficiency syndrome affects only about 500 people worldwide. Usually, the body uses glucose from carbohydrates for its energy source, which means that patients with the faulty SLC2A1 gene are unable to transport the required amount of glucose naturally required to fuel the brain. However, the ketogenic diet forces the body to use fat as a source of energy instead, generating ketones, which are believed to reduce seizures for some people. There is some disagreement as to exactly how the ketogenic diet works, but it is generally considered that the ketones produced have anticonvulsant properties. Sadly, it is now recognised that people who have been diagnosed in later life with Glut1 deficiency syndrome could have had their symptoms prevented, if genomic technology had been in existence when they were young. Other examples of gene-specific disorders that can respond well to the ketogenic diet include Rett syndrome3 (MECP2), Dravet syndrome3 (SCN1A), tuberous sclerosis complex3 (TSC1 and TSC2), and Doose syndrome3 (SLC6A1), although only around 15% of patients with Doose syndrome have a known genomic cause.
A second example is pyridoxine-dependent epilepsy3, a condition characterised by intractable seizures beginning in infancy or in some cases, before birth and is caused by variants in the gene ALDH7A1. Those affected typically experience prolonged seizures lasting several minutes and, if left untreated, patients can develop severe and irreversible brain dysfunction. However, research by Professor Peter Clayton of Great Ormond Street Hospital (GOSH) in 2006, found that it could be successfully treated by administering large doses of pyridoxine, which is a type of vitamin B64.
Even genes that do not directly cause epilepsy may be important in choosing anti-epilepsy drugs (AEDs), such as genes involved in drug metabolism2,5. Differences in these genes are known to result in different responses in patients to the medication they are given, which is referred to as pharmacogenomics2, and a great deal of research is going into this field. Such genomic knowledge will increasingly help clinicians to inform on Adverse Drug Reactions (ADRs)2 and resistance to AEDs2. Therefore, even if the cause of the epilepsy is not genetic, knowing what the best AED medication is, through pharmacogenomics, beneficial.
The importance of a fast genome analysis2 turnaround, particularly for critically ill children cannot be overstated, since early intervention can potentially provide actionable outcomes that could prevent irreversible malfunctioning of the brain. Rapid diagnosis operations already exist for children in the UK and the USA, such as the Rapid Paediatric Sequencing (RaPs)6 project at GOSH in London, UK, the Next Generation Children (NGC) project at Addenbrooke’s Hospital in Cambridge, UK and Rady’s Children’s hospital in San Diego, USA, where it is possible to take the blood of a patient and do a genome analysis in a matter of days or even hours. Crucially, it is thought that up to 40% of rare epilepsy in infants is a result of a new (de novo2) variant7 that is present in the child but not in their biological parents. This is of particular importance considering there are only around 70 de novo variants present in any person’s genome compared to their mum and dad8. In neonatal onset epilepsies, nearly 60% of babies might have a de novo variant, meaning that a genomic investigation has a reasonable chance of finding the cause. These studies are providing results in a matter of weeks or even days. In a significant proportion of children, these results are leading directly to Rapid Paediatric Sequencing (RaPs) and a change in patient management, thus illustrating the power of genomic medicine, but also the importance of getting a genetic diagnosis as quickly as possible.
By understanding how these disorders manifest in daily life, it may help identify possible ways to reduce the progression of their syndrome, and at the very least put into place as much support for patients and families as possible. This empowers parents to join, making the healthcare system more effective and ultimately driving progress in research and diagnostics. New advances in science and social media mean that the future for patients and families with epilepsy grows more promising every year. Patients have a very powerful voice that can bring about change in care pathways. This is illustrated by patient-specific organisations who have a group identity, such as the KCNQ23 and CDKL53 communities, who have actively encouraged genomic and pharmacological research in their respective fields. These advances will help us understand why current technology may fail to identify the pathogenic basis of a patient’s disorder. They will also help us identify why more worryingly current technology can produce an incorrect result where the wrong variant is labelled as causative. This understanding will help medics to explain the advantages and limitations of genomics to families and healthcare professionals when caring for patients with epilepsy. The implication is that it will empower medics to request re-analysis of unsolved cases as newer technology improves our understanding of the human genome. It will also encourage medics to request a referral for disease modification when therapy becomes available for a clinical disease caused by specific genetic changes.
And what of gene therapy? Many epilepsies of childhood are caused by a single faulty gene. As such, replacing the gene (or affected part of the gene) should help. Adeno-associated virus (AAV)9 is a small harmless virus that lives in humans (the way gut bacteria do) and that freely travels around the body, including crossing the blood-brain barrier2 unimpeded. Scientists are removing the virus' DNA2 and replacing it with a ‘normal’ copy of a ’faulty’ gene in the specific genetic nervous system disease. The virus then travels and delivers the ‘normal’ gene to the cells making them functional again. The remaining major hurdle at this juncture is that the viruses do not deliver to the majority of cells yet. Extensive work is in progress to solve this problem. The latter is not as much of an issue in diseases affecting only the spinal cord (versus the much larger brain). The spinal cord has fewer cells and can be extensively targeted by the virus. This has recently led to an approved therapy for a disease called Spinal Muscular Atrophy10. Patients with the most severe form of this disease rapidly become unable to move and die in the first years of life - unable to breathe. Gene therapy can alleviate the weakness greatly, allowing the children to move/breathe better, grow up and develop. It is believed the day is near to achieving the same for diseases of the brain.
Currently, there are only a few therapeutic interventions for epilepsy that are based on the underlying genome, but this will increase greatly over time. However, finding a therapy may be one of several reasons for investigating a person’s genome. For example, it may inform on family planning and whether another child could have the same epilepsy. While genomic medicine has enormous potential to treat these terrible disorders, it is important to remain cautious about how quickly such promises can be turned into reality. However, what is clear is that this emerging field of medicine is already having a great impact on healthcare already but can only reach its potential with continued funding and support from governments and industry.
There is another compelling and ethical consideration for clinical genomics. Such technology can change the way clinicians and patients interact with each other, especially in low and middle-income countries. Economically, the world is extremely unbalanced. Consequently, medical experience in such countries is limited, particularly regarding clinical genomics. Providing clinical decision software platforms via the internet can begin to level up the playing field by allowing these countries access to world-leading clinical genetics interpretation, reducing the need for specialist clinical geneticists, who are limited in number, even in the most advanced clinical settings.
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To read Charles’ other blog “The Complexity of Epilepsy”, click here.
For references to much of the wording used in this blog, check out the main glossary here and rare epilepsy glossary here.
To learn about the new Patient Advocacy and Engagement Advisory Board at Congenica, click here.
Charles Steward
W: congenica.com | T: @charlesasteward | L: charles-steward
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