SCN2A Awareness Day: 2.24

February 24th is international SCN2A awareness day! This week we recognize the individuals and families affected by SCN2A and share some insights into new science coming out of our lab.

What is SCN2A?

The FamiliesSCN2A Foundation website does a fantastic job describing SCN2A and provides a more comprehensive overview of how to advocate for families.  Here we highlight some key elements:

SCN2A is a gene located on the long-arm of  chromosome 2 at position 24.3 (hence, 2/24 as awareness day!). This gene generates code controlling voltage-gated sodium channels (NaV1.2) that work to help regulate neurons in the brain.

Changes to SCN2A: Children with a change to this gene that interferes with its ability to function may have an associated medical condition:

Image from FamiliesSCN2A Foundation

• Autism Spectrum Disorder
• Autonomic Dysfunction
• Cerebral Palsy (spasticity, hypotonia)
• Cortical Vision Impairment
• Epilepsy
• GI Dysfunction (Reflux & constipation)
• Intellectual Disability

• Movement Disorders (chorea, ataxia, dystonia)
• Neuropathic Pain
• Sleep Disorders
• Speech and Language Deficit
• Urology problems (infections & urinary Retention)

Two different presentations of SCN2A: In the past few years, we have learned more about different possible presentations (which scientists often call "phenotypes") of SCN2A.

Gain-of-function mutations leads to improper channel closing, causing more sodium to enter the cells and excess neuronal firing or excitability. 

Loss-of-function mutations leads to improper channel opening, causing less sodium to enter the cells and insufficient neuronal firing.​​

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What is it like to research SCN2A? Perspectives from our trainees

Wes Ganz, University of Washington: My time as a research assistant began at the SCN2A conference in Seattle, and I could not be more thankful for this opportunity. The SCN2A conference significantly influenced my lens as a researcher. Particularly, I want the science I contribute to be beneficial for the population that is being researched. I have carried this philosophy forward in all research that I am involved in. Whenever working with SCN2A participants and their data, I am constantly reminded of the families and carriers that will potentially benefit from this work. I could not be more grateful to be contributing to this fascinating research and contributing to the SCN2A community.

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Nicole Friedman, University of Alabama: For the last few years before starting graduate school at the University of Alabama, I worked as a research assistant at the Fragile X Research and Treatment Center at Cincinnati Children's Hospital. In this role, I had the pleasure of getting to know some of the most amazing FXS kiddos, teens, adults, and many of their extended families. Our team was extremely involved with the National Fragile X Foundation at both the local and national level, so I attended many events hosted by the local family group as well as 2 International Fragile X conferences. I really grew close to so many families and felt honored to be welcomed as a part of their tight knit community. My experience with FXS drew me to the B-RAD Lab at UA, where Dr. Hudac is doing really amazing work in rare genetic populations. I am so excited for the opportunity to work with the SCN2A families and expand my knowledge of genetics in the field of neurodevelopmental disorders. I look forward to supporting SCN2A projects this upcoming summer! 

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What is it like to research SCN2A? Perspectives from our clinicians

Dr. Eva Kurtz-Nelson, University of Washington: It's an honor to research SCN2A--people with SCN2A events are so resilient, and their family members are committed advocates and research partners. We hope our research will help medical and treatment providers give the best care possible to people with SCN2A.

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Tell us about your progress on developing EEG biomarkers.

Two happy participants in the BioGENE study!

The COVID-19 pandemic created in obstacle in seeing more participants for our BioGENE study, but we are excited to debut some preliminary results related to our resting state biomarker. We submitted an abstract to the International Society for Autism Research (INSAR) looking at underlying brain responses from resting state EEG. Here, we were looking to see if there are differences across spectral frequencies that reflect varying brain states -- with a special focus of looking more at the differences between loss-of-function (LOF) and gain-of-function (GOF) mutations.

How do we know if a variant is LOF/GOF?: To know for certain whether a person's genetic mutation is LOF/GOF, it is important to identify each variant's function using molecular neuroscience and cellular electrophysiology to test what happens in a neuron. We use scalp electrophysiology , which measures ALL the neurons instead of one at a time. Although many variants have been tested and are known to be LOF/GOF,  we do not know the status for ALL of our participants. Instead, we work from the assumption that participants with a presentation of infantile epileptic encephalopathy (+IEE or "with IEE") or other disruptive seizures during early development (<12 months of age) may have a GOF mutation. And those that do NOT have IEE (-IEE) may have a LOF mutation. 

Study design: Our participants watched screensaver-like videos while we recorded electrical signals using electroencephalography (EEG) using a wet net with over 120 recording locations. We take the raw signal and extract out information related to overall/broad brain states -- delta (deep sleep, slow rhythms), theta (daydreaming,  moderate rhythms), alpha (reflection after a task, fast rhythms), and beta (engagement, fastest rhythms). 

Study results: We found that:

• Unique pattern for SCN2A group related to slower rhythms (delta and theta)
  • -IEE SCN2A participants (likely LOF) had the most delta and theta rhythms 
  • +IEE SCN2A participants (likely GOF) had greater delta and theta relative to autism and neurotypical control groups
• Alpha rhythms were greater for +IEE SCN2A participants
• Beta rhythms were different for SCN2A groups
  • -IEE SCN2A participants (likely LOF) had more beta than an autism group with average IQ
  • +IEE SCN2A participants (likely GOF) had more beta than autism and neurotypical groups

What does this mean?: Some of these findings relate to other work characterizing brain states in adults with a more broad or "generalized" epilepsy (for instance, see this study from 2000). It is encouraging that the SCN2A participants have distinct profiles relative to our control groups. To feel more confident in our findings, we will continue to add additional participants to our study. 

Next steps:

1. We are hoping to add a few more families to the study, as soon as our university resumes permission for off-campus research. Be on the look out for more details as Dr. Hudac plans a COVID-safe, 1-woman research road trip in Summer and Fall of this year! 
2. We want to keep working to think through how SCN2A biomarkers may help separate between the two different presentations. We are working to learn more about resting state in the context of other populations with epilepsy.
3. This summer, graduate student Nicole Friedman, will be completing our analyses and preparing these data for publication. We will update as these results are finalized!  

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