CNS Biomarkers. In the last two days, our team attended the Workshop for Multimodal Biomarkers in CNS Disorders held at the National Academies of Sciences, Engineering, and Medicine in Washington, DC. This conference provided a needed review of the current state of multimodal biomarker discovery and development. While most of the speakers focused on more common CNS disorders such as Alzheimer’s disease and neuropsychiatric disorders, there stands to be important lessons that can be translated into the rare disease field. Here is what we learned about the clinical utility of biomarkers and their potential as we move towards precision medicine in rare disease.
Tag Archives: precision medicine
The landscape of epilepsy genetics in 2023
Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.
How precise is precision medicine – the difference between theoretical guidelines and real-world practice in pediatric epilepsy
Precision medicine. This post continues the discussion on how we can make sense of clinical data in the absence of outcomes in the context of precision medicine – a concept that drives much of what we do on a research basis. The fundamental idea is that clinical care in pediatric epilepsies can be personalized and tailored to underlying etiologies. With continual progress in gene curation and variant interpretation alongside clinical knowledge, we typically expect that treatment suggestions are immediately implemented after the discovery of the causative genetic etiology. For example, a child with early onset epileptic encephalopathy is found to have a gain-of-function variant in SCN8A and is almost immediately started on a sodium channel blocker such as Trileptal. However, to what extent is this the case? In the context of precision medicine, how precise are we exactly?
Precision medicine in the absence of outcomes
EMR. Genomic data is increasingly available for large patient cohorts. In parallel, healthcare is increasingly digitized and large amounts of data can easily be extracted and analyzed at the click of a button. In principle, this should provide tremendous opportunities to understand how epilepsy care can be personalized based on genetic factors. However, we quickly run into challenges. Obtaining information on seizure frequencies, for example, requires manual chart review. Trying to understand how a person’s genetic makeup affects responses to anti-seizure medications is therefore not possible in large healthcare systems where related questions in other diseases can increasingly be answered. Here is a brief overview of how we can meaningfully engage with clinical data when outcomes are simply not available. Continue reading
DNM1 and when transcripts matter more than genes
What comes next. Earlier this month, Ingo made a bit of a splash at the American Epilepsy Society Annual Course, with his surprising comment that, in some contexts, “genes don’t matter.” This was in reference to transcripts and gene expression, which ultimately determine if and how variants can cause disease. In this post, I wanted to explore this idea, diving into the world of transcripts and their increasing relevance in approaching diagnosis and treatment of genetic epilepsies and neurodevelopmental disorders. And I wanted to share one of the most surprising findings in epilepsy genetics in 2022, namely, how examining transcripts rather than genes helped us understand how an intronic variant can be dominant-negative. Continue reading
Walking in Memphis – TARGETing Epilepsy at St. Jude
Memphis, TN. Prior to this year’s AES meeting, the epilepsy genetics community descended upon St. Jude Children’s Research Hospital in Memphis. I had previously largely associated St. Jude with pediatric cancer treatment, but within the last few years, a large-scale pediatric neuroscience program was launched, putting Memphis on the epilepsy genetics map. And with Heather Mefford’s new lab, the program at St. Jude includes one of the major epilepsy genetics groups. While blogging about scientific meetings is always tricky, one particular quote from the first day struck me as particularly relevant for the current state of therapeutic development: “quick, but not too quick”. Here is where the field of epilepsy genetics and precision medicine finds itself at the end of 2022. Continue reading
Precision medicine is instructive when it fails
KCNT1. This is my third blog post on our precision medicine review by Knowles and collaborators. In this post, I wanted to review the experience with precision medicine in the epilepsy community since the initial precision medicine road map that we published in 2015. Here is a quick summary of why the community’s experience with quinidine was an important lesson for the future. No, it did not fail, it simply revealed a weakness in the way we introduce repurposed medications into clinical practice and how we think about them. Continue reading
Epilepsy genetics is more than just sending gene panels
Genetic testing. I smiled into my camera during our virtual Wednesday teaching session — pausing for effect. One of our junior team members has just made the statement that one of our patients qualified for a sponsored genetic testing program. I politely corrected them: “I think what you wanted to say was that this program qualifies for doing genetic testing on our patient”. The focus of epilepsy genetics is changing, shifting away from genetic testing to what genetic tests mean and how we can use them for better treatment. However, getting to a diagnosis requires the ability to perform genetic testing in the first place. And the framework for how this can be accomplished is vastly different within the US and internationally. In this second blog post on our review on epilepsy precision medicine, I would like to revisit the current state of genetic testing in the epilepsies. And yes, genetic testing should be standard of care and affordable for people with epilepsy. It’s that simple. Period. Continue reading
The Accelerando of epilepsy precision medicine
Half Moon Bay. Earlier this week, our precision medicine paper came online in Epilepsia, summarizing the state of the art in epilepsy precision medicine in 2022. This paper was initially inspired by the 2019 Precision Medicine Workshop in Washington, D.C., which was the sequel to our initial Half Moon Bay Conference in 2014. Yes, this was a publication that was almost three years in the making and I would like to give a shout-out to Juliet Knowles for pushing this herculean effort across the finish line. In this post, I would like to revisit what precision medicine actually is, sharing some of our initial thoughts that did not make it into the final version of our manuscript. But let’s first clarify what the Accelerando is. Continue reading
Areas of uncertainty – an unusual introduction to 2016
Happy 2016. Talking about things we don’t know or are not sure about may be a strange introduction to a new year that is full of promises for the field of epilepsy genetics. However, there were two questions during the holidays that carried over from 2015 into the new year that I didn’t know the answer to and that we repeatedly discussed in our group. Two relatively simple questions: Can we give lamotrigine to a patient with GEFS+ -not Dravet Syndrome– and a mutation in SCN1A? Should we withhold valproic acid from a patient with a single POLG mutation identified through diagnostic gene panel? You feel that you know the answer to these questions, but what is actual data and what is only inference? Follow me through a brief discussion on why we need to be careful when it comes to claiming knowledge that we don’t really have yet. Continue reading
