Perspective. This blog post is about a topic that I had planned to write about for a while – the intersection of neurogenetics and self-advocacy. This is a potentially loaded topic in many disease areas, and I had held off on writing this for a while. However, when I put together my prior blog post on the different perspectives on stuttering, it occurred to me that I could use stuttering genetics as a vehicle to get these thoughts across. Stuttering genetics is relatively underdeveloped, and I feel that I can speak to the intersection of self-advocacy and genetic research as pediatric neurologist involved in neurogenetics research and as a person who stutters. However, this post is not only about stuttering, it is about how neurogenetics and self-advocacy may be synergistic, adding nuance to both perspectives.
The I and the Why – stuttering and the infinity of neurogenetics
Dysfluency. I typically reserve my more contemplative blog posts for our summer beach vacation, but there are some thoughts that I had during this Spring Break that I wanted to share. In brief, I read Life on Delay by John Hendrickson and started reading The Beginning of Infinity by David Deutsch. At first glance, these two books couldn’t be any more different – a story about bullying, depression, isolation, and other issues that people who stutter face on a daily basis, and a wide-ranging narrative about the cosmic power of the search for good, scientific explanations. Then something occurred to me: there are two ways to spell dysfluency/disfluency. Hendrickson spells dysfluency with an “I,” while the scientific literature often prefers the “Y”. And this ambivalence may actually tell us something about the nature of neurogenetics more broadly.
Expanding clinical actionability in GLUT1 Deficiency through a blood-based biomarker
GLUT1DS. Disease-causing variants in SLC2A1 are associated with a rare genetic neurometabolic condition known as GLUT1 Deficiency Syndrome (GLUT1DS). While GLUT1DS is typically diagnosed through molecular genetic testing, the diagnostic strategy in some cases includes lumbar puncture to measure cerebrospinal fluid (CSF) glucose to confirm the diagnosis. In a recent study, Mochel and collaborators performed a multicenter validation study of a blood-based biomarker for GLUT1DS. Here is a brief review on their publication and the utility of molecular biomarkers in GLUT1DS and genetic epilepsies more broadly.
FIRES, NORSE, Omics, and Urgency
FIRES. Febrile infection-related epilepsy syndrome (FIRES) is characterized by refractory status epilepticus following a non-specific febrile illness. FIRES is a subtype of New Onset Refractory Status Epilepticus (NORSE) without a clear cause in individuals without active epilepsy. The cause of FIRES and NORSE is unclear, and it is not even clear whether both conditions share a joint mechanism or represent distinct entities. In a recent publication, we contributed to a review of the state-of-the-art in NORSE and FIRES research and suggested a very first step to understand these conditions better – standardized biosamples. This blog post is about the intersection of omics and urgency, long-term strategies and scientific principles.
CACNA1A: the unusual tale of two proteins encoded by a single gene
CACNA1A. CACNA1A is a large gene with a long history. Its first gene-disease association was with spinocerebellar ataxia type 6 (SCA6), an adult-onset progressive neurological disorder. Next, it was found to be associated with episodic ataxia and familial hemiplegic migraine. It took several more years before it was also found to be associated with epilepsy, developmental delay, and a more severe form of hemiplegic migraine. Here is a blog post on the range of neurological disorders associated with CACNA1A and the mechanism driving it.
Ring Chromosome 20 – here is what you need to know in 2023
Ring chromosome 20. If you are a regular reader of this blog, you’ll know that much of our focus is on single genes and their relationships to neurodevelopmental disorder. Admittedly, we may neglect cytogenetic conditions. However, in today’s post, we highlight ring chromosome 20 as a likely underdiagnosed genetic epilepsy with distinct clinical features.
Decoding rare disease through 77,000 genomes
Genome sequencing. Despite continual progress in understanding the genetic etiology of human disease, more than half of rare disorders remain unsolved. Resolving the remaining etiologies in rare disease are a major focus of ongoing efforts in the field, including a shift towards standardized analysis of large-scale genome sequencing data from large patient cohorts. In a recent study, Greene and collaborators aimed to identify associations between genes and rare disease subgroups, leveraging genomes of 77,539 people including 29,741 probands. Here is a brief review on their publication in the context of etiological resolution in rare disease.
CLTC: The neurological backpacker of intracellular transport
Shouldering the Load. The CLTC gene encodes the protein clathrin, which plays a crucial role in the formation of clathrin-coated vesicles, responsible for transporting proteins and other molecules within neurons. Clathrin-mediated endocytosis is also a crucial process for the recycling of synaptic vesicles in neurons, enabling efficient neurotransmitter release and synaptic transmission. The discovery of CLTC-related disorders has revealed a diverse spectrum of neurological conditions, ranging from intellectual disability to epilepsy. Here is a blog post on CLTC-related disorders as the forgotten disease of synaptic vesicle recycling, highlighting the crucial role of clathrin in maintaining proper neurological function.
Revisiting the genetics of cerebral palsy
CP. Over the last few years, a range of high-impact publications have revolutionized our understanding of the genetics of cerebral palsy (CP). While CP is traditionally thought of as an exclusively acquired disorder, massive parallel sequencing studies have suggested causative genetic etiologies in up to 30% of individuals. Here is an overview of the emerging genetics of CP through the lens of neurodevelopmental disorders, questioning some of the assumptions that are typically made when comparing both disease groups. Continue reading
Five things to know about SLC6A1 in 2023
GAT1. The SLC6A1 gene remains one of the most common genetic etiologies to be associated with genetic generalized epilepsy and myoclonic atonic epilepsy. SLC6A1 has not received an update on our blog in a while, perhaps because unlike many other genes we see, this one has remained with a somewhat consistent clinical picture, albeit with much more detail and confidence than available back when the first papers were published in 2015-2018. Here are the five things to know about SLC6A1 in 2023.
