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Understanding phenotypes is key for several reasons, most critically because it directly influences care strategies and family support plans. Below are essential insights that will guide you through the latest research on SCN8A phenotypes. Here, you can find links to detailed information about each of the 5 phenotypes.

SCN8A Phenotypes

An SCN8A phenotype refers to the unique set of symptoms and characteristics seen in individuals. These are caused by variations in the SCN8A gene, primarily affecting a child’s neurological development and function.

The spectrum of SCN8A-related disorders ranges from intense neurological challenges to milder, even temporary conditions, affecting each individual uniquely.

SCN8A phenotypes are categorized by two important characteristics gene variant and function type.

SCN8A phenotypes are categorized by two important characteristics gene variant and function type.

Variants are errors or changes within the SCN8A gene. These changes can disrupt how parts of brain cells called sodium channels are built and function, potentially leading to a wide range of health and developmental problems.

When talking about the SCN8A gene and how it works, the word “function” refers to either too much or too little sodium entering the sodium channel, disrupting sodium levels within the brain cells.

Gain-of-Function (GOF) Variants lead to too much sodium entering the channel.

Loss-of-Function (LOF) Variants lead to too little sodium entering the channel.

Features more likely to be seen in patients with loss of function (LOF) variants include: 

  1. Autism without epilepsy (Clinicians & Caregivers: Strong) 
  1. Developmental delays or movement disorders without epilepsy (Clinicians & Caregivers: Strong) 
  1. Lack of positive response to sodium-channel blockers except lamotrigine (Clinicians: Strong; Caregivers: Moderate) 

Important: While there is not yet consensus, there is evidence of some individuals who show properties of both gain- and loss-of-function as well as more severe cases of LOF. These are among the emerging forms of SCN8A that we will continue to monitor and document in order to understand the full spectrum of diversity in SCN8A. 


Severe DEE

Severe Developmental
& Epileptic Encephalopathy

Mild/moderate Developmental &  Epileptic Encephalopathy


SeL(F)IE

Self-Limited (Familial) Infantile Epilepsy

 


NDD w/ GE

Neurodevelopmental Delay with Generalized Epilepsy


NDD w/o Epilepsy

Neurodevelopmental Delay without Epilepsy


Additional Information

  • Refinement of Phenotypes: Ongoing research needed to further define and differentiate phenotypes based on large cohorts and genotype-phenotype correlations.
  • Treatment Efficacy and Options: Expanding understanding of first-line and subsequent treatment options for complex cases, including those resistant to current first-line therapies.
  • Personalized Treatment Approaches: Importance of considering individual variant functions and potential mixed gain and loss-of-function scenarios.
  • Age of Onset: Varies significantly across phenotypes, from early months to years.
  • Seizure Types and EEG/MRI Findings: Differ across phenotypes; initial EEGs may be normal, becoming abnormal with the course of the condition. MRIs may show atrophy in severe cases.
  • Treatment Approaches: Tailored based on phenotype, with a strong emphasis on the distinction between gain-of-function and loss-of-function variants.

There are 5 distinct phenotypes of SCN8A-related disorders, varying in severity, age of onset, seizure types, and other clinical features.

  • Gain-of-Function Phenotypes (Early Seizure Onset):
    • Severe DEE
    • Mild/Moderate DEE
    • Self-Limited (Familial) Infantile Epilepsy (SeL(F)IE)
  • Loss-of-Function Phenotypes (Later or No Seizure Onset):
    • Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE)
    • Neurodevelopmental Delay without Epilepsy (NDDwoE)
SCN8A Research

For Clinicians & Researchers

We are excited about collaboration. If you are interested in collaborating around SCN8A patient care and /or research for SCN8A-releated disorders, PLEASE let us know. We want to hear from you. Currently we work with over a dozen labs and leading SCN8A clinicians to advance the science of SCN8A.

Learn about the work of the Invitation only SCN8A Research Consortium meeting quarterly to share updates on ongoing work, share assets, and develop new collaborative projects [not sure if we’d open up an application process??]

Learn about the International SCN8A Registry, highlights of what’s been learned and how to collaborate/get access to registry data for planned research projects

Follow the public Facebook group where updates on our programs, research, and new findings from the SCN8A Registry are shared

Learn more about the Alliance’s Global Research Strategy and efforts to accelerate progress toward better treatments and outcomes – and how I might get involved

Be added to the periodic SCN8A Newsletter


– Keep Exploring –

IMPORTANT: While this consensus data provides new and valuable insights about best practices in the diagnosis and treatment of SCN8A, this is not medical advice. It can inform clinicians and caregivers alike in developing optimal treatment plans for each individual.

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