Epilepsy genes. It has admittedly been quiet around the gene pages on our blog and many pages require an update. When we initially launched the Epilepsiome pages, we wanted to create a small resource for gene-based information according to the “what you need to know” principle, a condensed digest regarding epilepsy genes written by clinicians and researchers with deep expertise in the field. We chose CACNA1A as the first gene to get an update. The reason for this is the following: Laina has taken on the role of modernizing this blog and CACNA1A is the main condition that she is working on. Here are five things to know in 2022 about CACNA1A.
Figure 1. An overview of various disease-causing variants in CACNA1A, including several of the most common recurrent variants.
1 – Zeroing in on pediatric phenotypes
As pediatric neurologists, we are frequently confronted with questions regarding spinocerebellar ataxia (SCA6) or episodic ataxia (EA2), conditions that CACNA1A was linked to when it was first discovered as a disease gene. However, in 2022, the pediatric presentations that dominate among the wide range of genetic testing that is currently performed typically do not include either of these conditions. In contrast, developmental delay and mild ataxia, developmental and epileptic encephalopathy and severe hemiplegic migraine are the main clinical presentations that we encounter in 2022. The historical link to milder presentations in adults may unfortunately distract from the overall severity of these conditions. In 2022, we have become aware of the range of pediatric presentations.
2 – LoF versus GoF
As with many channelopathies, CACNA1A-related disorders may present with gain-of-function (GoF) and loss-of-function (LoF) phenotypes. We are in the process of understanding the clinical range of both presentations, which is critical as only the GoF variants carry the risk of hemiplegic migraine. Outlining both domains further in the next few years will give us an even more complete picture of the LoF versus GoF presentations.
3 – Hemiplegic migraine, the big unknown
Severe hemiplegic migraine attacks are life-threatening neurological emergencies that need to be treated promptly. Unfortunately, the historical nomenclature and perceived proximity to common headache disorders betrays the severity of these episodes. In 2022, we are appreciating the severity and burden of severe hemiplegic migraine and in the next few years, we hope to understand if and how severity and frequency can be predicted in order to treat these episodes as efficiently as possible, including dedicated hemiplegic migraine action plans.
4 – The CACNA1A Foundation
I was extremely happy when I learned that the CACNA1A Foundation was formed – the CACNA1A field didn’t have a unified voice previously and advocacy was really important. Even though the Foundation only emerged in 2020, the CACNA1A families have accomplished a lot, including the first virtual meeting in 2021 and the first in person meeting in San Antonio in July 2022, with attendees traveling from all around the US, Canada, Australia, Europe and South America. More than 175 people attended, with 100 in person and 75 online, and the speakers included physicians, genetic counselors, and scientists across a range of disciplines. The Foundation has also supported several research initiatives and brought together experts in a variety of fields related to CACNA1A, bringing some much-needed energy to research on this long-neglected gene.
5 – Variant testing
In contrast to sodium and potassium channels, variant testing for CACNA1A-related disorders has traditionally not been performed on a similar scale. Within our Center Without Walls for Channelopathy-associated epilepsies, we have taken on CACNA1A as one of our tasks and we hope to soon perform variant testing at a level that is comparable to other channelopathies. In turn, this functional data can help to inform families and clinicians as to the phenotypes they may expect (i.e. the likelihood of hemiplegic migraine or epilepsy).
Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.
