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.
Phenotypes Overview
Dr. Elena Gardella, Senior Physician at the Danish Epilepsy Center, offers an in-depth exploration of the five SCN8A phenotypes and discusses the differences between Gain-of-Function (GOF) and Loss-of-Function (LOF) variants.
Listen as Dr. Gardella navigates through the consensus findings, highlighting the crucial clinical features associated with SCN8A. From neurological manifestations to developmental challenges.
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.
Gene Variant
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.
Function Type
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:
- Autism without epilepsy (Clinicians & Caregivers: Strong)
- Developmental delays or movement disorders without epilepsy (Clinicians & Caregivers: Strong)
- 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.
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)
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.
Disclaimer for Consensus and Individual Variation
This consensus process was carried out by a panel of expert clinicians who actively treat patients with SCN8A-related disorders. Guidelines determined from a consensus differ from those determined from a population-based study*. The extent of consensus reached is restricted by the number of patients seen by each clinician and the portion of the disease spectrum these patients represent.
Consensus guidelines serve as a recommended starting point for clinicians to treat patients based on the best evidence available. If an affected individual does not fit the expected profile, it is important to reassess your treatment plan and revise accordingly. Reassessment of the consensus guidelines will occur as new data become available and the number of patients seen by clinicians increases.
Guidelines based on future consensus processes will therefore reflect advancements in clinical care.
*Population-based studies reveal general trends for large subsets of the population. It is important to remember that each individual is unique and may not necessarily follow these trends regarding developmental progression, seizure remission, or effective treatment.