In today’s blog post, I answer some frequently asked questions surrounding SCN1A mutations and the diagnosis of Dravet syndrome. Understanding the relationship between a genetic testing result and a clinical diagnosis, not to mention predicting long-term outcomes, can be challenging and the relationships are not always clear cut. The majority of cases of Dravet syndrome are caused by a loss-of-function mutation in SCN1A, which results in half the amount of functional gene product (in this case a sodium channel). However, not every mutation in SCN1A causes Dravet syndrome; mutations in SCN1A actually can lead to a range of seizure and non-seizure related disorders. Two individuals carrying the exact same mutation in SCN1A may still have differences in the presentation of symptoms, response to medications, and can even have different diagnoses- even two individuals in the same family. Even within the patient population with a diagnosis of Dravet syndrome, there is also a lot of variability in the range, presentation, and severity of symptoms patients may present with over their lifetime. Read on to learn more of what we know about these concepts.
If you have a family member with an SCN1A-related epilepsy, consider participating in a DSF-funded project being run by researchers at The Children’s Hospital of Philadelphia to better understand the spectrum of patient presentations and how they relate to the full genetic profile. Visit this webpage to learn more about the Dravet Genome Study including how to sign-up and participate from your own home.
My infant has received genetic test results indicating an SCN1A mutation. What does this mean?
In years past, a mutation in the SCN1A gene has confirmed a diagnosis of Dravet syndrome in patients that were already showing the typical disease progression. When access to genetic testing was more limited, most diagnoses occurred after associated health issues had already started to develop. In more recent years, with greater access to genetic testing, patients are now receiving confirmation of the mutation at very young ages before the typical progression of the disease becomes apparent, leading to confusion in patient families on what to expect for their child’s prognosis.
There is a spectrum of disorders associated with SCN1A mutations, ranging from mild to severe, including Familial Hemiplegic Migraines, Generalized Epilepsy with Febrile Seizures Plus (GEFS+), and Dravet syndrome. Genetic testing can help to guide diagnosis, but it must be considered in the context of clinical symptoms. For example, two patients might carry the exact same mutation and still have different diagnoses, such as Dravet syndrome and GEFS+. Additionally, even within the diagnosis of Dravet syndrome, there can be a lot of variability in when and to what extent symptoms present. Published studies of the patient population can report common trends, but there are outliers and a lot of variability.
When will I know if my child has Dravet syndrome or a different SCN1A disorder?
With earlier genetic diagnoses, we will gain a better understanding of the full spectrum of SCN1A disorders in the coming years. Until then, once seizures occur and a mutation in SCN1A is identified, it is essential to follow a treatment protocol based on the international treatment consensus for Dravet syndrome*. This ensures that contraindicated medications are avoided and that patients receive the highest quality of care. Earlier intervention with the most appropriate treatment plans may also improve the overall picture of long-term outcomes for patients with Dravet syndrome. *In a small proportion of cases, mutations in SCN1A may be Gain-of-Function, rather than the Loss-of-Function mutations that lead to Dravet syndrome. Patients with Gain-of-Function mutations in SCN1A may respond to a different treatment protocol. Some of the key clinical signs that may suggest looking to see if there is a Gain-of-Function mutation including seizures onset before 3 months of age, non-seizure movement disorders, and/or joint contractures.
Some clinicians may decide early on to give an infant the diagnosis of Dravet syndrome based on the seizure types and other symptoms in conjunction with an identified mutation in SCN1A, while other clinicians may wait to see if other developmental areas are impacted before giving an official diagnosis. Regardless of the eventual final diagnosis and long-term outcomes for patients, early intervention and appropriate medication choices based on the expert-consensus recommendations give patients the best chance for positive outcomes regardless of where they land on the spectrum of SCN1A-related disorders.
One of the biological parents of my child has also tested positive with an SCN1A mutation. Does this mean that this parent also has Dravet syndrome?
The diagnosis of Dravet syndrome is based on clinical symptoms. Genetic testing can help to direct or confirm the diagnosis, but a mutation in SCN1A alone is not sufficient to automatically give someone the official diagnosis of Dravet syndrome. As mentioned above, there can be a range of disorders that result from mutations in SCN1A. Keep reading below for more explanation about how the same mutation could result in different outcomes in two individuals.
The International League Against Epilepsy helps to set the criteria for diagnosis of Dravet syndrome. You can read more on this page, but in brief, a diagnosis of Dravet syndrome involves:
- Recurrent, often prolonged seizures (often associated with fever but also unprovoked; focal or generalized)
Onset of seizures between 1-20 months (although diagnosis should be looked at more carefully if on the very early or late range of those ages) - Typical development of infant at onset with a normal EEG outside of seizures (developmental impacts begin in early childhood and slowing of the EEG is common over time)
- Medication-resistant seizures that may evolve over time
- Intellectual disability that becomes apparent generally by school age (commonly moderate to severe; although there are rare reports of individuals who are less impacted in this area). The majority of patients with Dravet syndrome will need supportive care throughout their lifetime.
- Additional symptoms commonly associated with Dravet syndrome include speech delays or impairments, behavior disorders, gait and movements disruptions (such as crouched gait developing during adolescence)
How is it possible for both my child and I to have an SCN1A mutation, yet I don’t have Dravet syndrome?
In a small portion of the population of patients with Dravet syndrome, mutations in SCN1A have been inherited from a parent who carries the same mutation. On the surface this can be confusing, why did the mutation cause Dravet syndrome in a child but did not cause the parent to have the symptoms and diagnosis of Dravet syndrome?
There are actually several factors that can impact how someone’s genotype (the actual ‘code’ of their DNA) impacts their phenotype (the physical symptoms that present from their DNA ‘code’). It is not unique to Dravet syndrome, or the SCN1A gene, to have variability in the presentation of symptoms from the same or similar mutations. Factors that can impact the phenotype resulting from a mutation include:
- Other parts of the person’s genetic code; for example, another small gene change that may compensate for a significant mutation in another gene. Studies of animal models and families with inherited SCN1A mutations have shown that there can be ‘modifier genes,’ or additional mutations that are compensatory which impact the severity of the phenotype from an SCN1A mutation.
- Environmental factors or exposures. In the context of Dravet, this could include things like being on contraindicated medications for long periods of time. In animal models, early-life stressors have been shown to worsen long-term outcomes.
So, a mutation in SCN1A alone is not enough to always say “Dravet.” Which is why phenotype (or clinical symptoms) have to be taken into account with genotype (the mutation in SCN1A) to determine an accurate diagnosis, since there are scenarios where individuals carry a mutation that could be causative but do not develop symptoms (or as severe of symptoms).
For Additional Information:
- Genetics of Dravet Syndrome
- Diagnosis of Dravet Syndrome and Expert Treatment Consensus
- Current Overview of Genetic Therapies in Development
