Tuesday, December 8, 2015

SCN8A epilepsy

In my last post I explained the genetic testing process that led to my daughter Esmé receiving results of two mutations of unknown significance. One, on the gene PCDH19, was discovered in 2012 with the GeneDx infantile epilepsy panel. The other, on SCN8A, was found with whole exome sequencing, also through GeneDx, in 2014.

When we received the SCN8A result, I was fascinated by the notion that it would have been included in our original epilepsy panel had we only waited a handful of months. In fact, in the time since Esmé’s original test in 2012, almost 20 new genes have been added to the GeneDx Infantile Epilepsy panel.

This realization blew open the model I’d had in my head of the stability of genetic diagnosis—a list of disorders to check off—and replaced it with an image of a quickly expanding set of genetic knowns paired with more rapidly expanding unknowns: undiscovered mutations, multiple gene interaction, epigenetics and so on.

Standing in the middle of this new medical reality are patients and parents like myself who struggle to find answers. And when we do find answers, such as they are, we struggle to know what to do with them. The rapidly expanding list of rare genetic epilepsies means that clinicians may have little or no knowledge of our child’s disorder. It means that little or no research may have been published or conducted on the disorder that matters most to our lives.

The discovery of the SCN8A gene in humans was made by a parent of a child with SCN8A Epilepsy, Dr. Michael Hammer, a geneticist at the University of Arizona. Sadly, it came just weeks after the death of his daughter, Shay, due to Sudden Unexplained Death in Epilepsy (SUDEP). (For more on Dr. Hammer’s discovery watch The Gene Detective’s Journey.) In honor of Shay, Dr. Hammer worked with a team to publish their findings and help others with SCN8A mutations find answers.

It wasn’t long before Juliann Bradish, whose 9-month-old daughter, Adeline, had recently been diagnosed with SCN8A Epilepsy, reached out to Dr. Hammer. Juliann was a pharmacist by training, and she quickly got to work creating an SCN8A family Facebook group, adding families as they were referred to her and gathering information about genetic mutations, symptoms and responses to drug treatments. With this information, Juliann is helping families submit skin biopsies to the University of Michigan, where Dr. Jack Parent is doing SCN8A research with induced pluripotent stem cells made from cells donated by SCN8A patients—and helping researchers find patients with a particular mutation of interest. Juliann has recently joined us at The Cute Syndrome Foundation as the SCN8A Advisor, helping drive our SCN8A Epilepsy research and education agenda...

It isn’t only parents with scientific backgrounds and foundations that are advancing the understanding and treatment of rare disorders. Since there are currently around 100 documented cases of SCN8A Epilepsy worldwide, it is safe to say that most are being treated by clinicians who have limited or no experience with SCN8A or access to SCN8A data. Therefore, the parents who follow the successes and failures of various treatments and observe the phenotypes of other children are often the experts in the room.

Yet their ability to share their collective knowledge with medical practitioners can be limited, because there exists no clearly established avenues to do so. In the SCN8A community, for example, we often see one frustratingly consistent problem.

Many children with SCN8A Epilepsy are prescribed Keppra, a common first-line-of defense anticonvulsant. This drug works well for SCN1A epilepsy, sometimes diagnosed as Dravet Syndrome, a more commonly known genetic epilepsy that can have a similar presentation to SCN8A epilepsy. Both SCN1A and SCN8A encode voltage-gated sodium channels (which help neurons build up the membrane potential that enables them to fire), so clinicians may assume that they should be treated similarly. However, SCN1A epilepsy is caused by a loss of function in channels on inhibitory neurons, whereas SCN8A epilepsy is usually caused by a gain of function in channels on excitatory neurons.

Within the SCN8A community, we time and time again see children with SCN8A experience dramatically worsening symptoms on Keppra. Time and time again, we tell new parents to explain to their doctors that Keppra should not be prescribed for children with SCN8A. And, all too often, parents are afraid to speak up or their information is not heeded.

And, all too often, the children bear the brunt of that lack of communication.

Understandably, practitioners are in a bind when it comes to information provided by their patients’ caregivers. They have few ways of validating it. Clinicians are rarely active within parent communities, due to restrictions of the groups themselves or their institutions, or their own time constraints. And certainly, there is the potential within parent groups to jump to conclusions based on limited group information.

At the same time, parents are often unbelievably knowledgeable about their children, and the value of their observations cannot be underestimated. There are emerging mechanisms to take advantage this knowledge—including databases built or populated by parent information. However, these mechanisms do not yet go far enough to bring basic disorder information to the people who most need it. Science and medical practices must continue to evolve to meet the changing relationships among clinicians, researchers, institutions and the citizen scientists who hold so many answers that are needed to better understand and treat rare disorders.



  1. Frasier CR, Wagnon JL, Bao YO, McVeigh LG, Lopez-Santiago LF, Meisler MH, Isom LL. Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy. Proc Natl Acad Sci U S A. 2016 Oct 26. pii: 201612746. [Epub ahead of print]


    Patients with epileptic encephalopathy have a high risk of sudden unexpected death in epilepsy (SUDEP), an event described as arrhythmia of brain and heart. We investigated the cardiac phenotype of a model of an epileptic encephalopathy caused by mutation of sodium channel SCN8A. We observed that mutant heart cells were hyperexcitable, exhibiting abnormal contraction and action potential wave forms. Mutant mice also had reduced heart rates compared with controls. This difference in heart rate was not observed in isolated hearts, implicating changes in cardiac regulation by the parasympathetic nervous system. When challenged with norepinephrine and caffeine, mutant mice had ventricular arrhythmias. These cardiac and parasympathetic abnormalities are predicted to contribute to the mechanism of SUDEP in patients with SCN8A mutations.

    Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Nav1.6-N1768D). We tested Scn8aN1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8aN1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8aN1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8aN1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8aN1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8aN1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a.

  2. Ammar Hussain, Syndi Seinfeld, Lawrence Morton. Genetic Association with Ictal Cardiorespiratory Phenomena: SCN8A Case Series. J Pediatr Neurol 2016; 14(04): 151-155.

    Increased availability of genetic testing has led to identification of expanding SCN8A phenotypic spectrum ranging from early-infantile epileptic encephalopathy (EIEE) to developmental and cognitive disabilities, movement disorders, and a possible high incidence of sudden unexplained death in epilepsy patients (SUDEP). Children with SCN8A mutations may also have dysfunction of cardiac voltage gated sodium channels, resulting in ictal cardiac symptoms with associated respiratory distress. We report a case series of two patients with de novo SCN8A mutation. These patients presented with recurrent tonic seizures at 4 and 6 months of age, along with ictal bradycardia and asystole respectively. Interictally both patients had normal EEG and cardiac evaluation. The antiepileptic drug treatment choice was made prior to known genetic abnormality, with resultant decrease in seizure frequency and severity of cardiorespiratory symptoms in both patients. The association of SCN8A mutation–related rare epilepsy with ictal cardiac symptoms has not been well described in the literature. The association of ictal cardiac phenomena with this mutation is important in patient treatment, family education, and risk of complications such as SUDEP. The role of SCN8A in the mechanism of SUDEP requires future studies.

  3. Three organizations dedicated to promoting research about SCN8A Epilepsy are joining families around the world for the first International SCN8A Awareness Day on February 9. Their goal is to inform affected families about available resources and educate the public about this rare but devastating genetic disorder.

    The organizations leading the charge are Ajude o Rafa, The Cute Syndrome Foundation, and Wishes for Elliott, which are members of the Rare Epilepsy Network (REN).

    Honoring Shay

    February 9, 2017, would have been Shay Hammer’s 21st birthday. Shay passed away suddenly in 2011 and is the first documented case of sudden unexpected death in epilepsy (SUDEP) in a child with an SCN8A mutation. A geneticist, Shay’s father Michael was the first to isolate the SCN8A gene as the cause of his daughter’s struggle with epilepsy. Sadly, that discovery came weeks after her death. Formerly a population geneticist, he now dedicates his life and professional work to advancing the scientific understanding of SCN8A. One of his efforts is the development of an online registry for children with SCN8A.

    About SCN8A Epilepsy

    SCN8A mutations are associated with some of the most severe forms of epilepsy. There currently is no known treatment. Children with SCN8A mutations struggle with debilitating and severe effects, including:

    70% suffer from intractable seizures, double the rate among the overall epilepsy population.
    Half are unable to walk.
    More than half are nonverbal.
    30% cannot control their head.
    They are at very high risk of SUDEP.

    About REN

    Rare Epilepsies Network (REN) logo
    To expedite research into the rare epilepsies, more than 25 rare epilepsy organizations have joined forces with the Epilepsy Foundation, Research Triangle Institute, and Columbia University to create REN.

    “The Rare Epilepsy Network is a consortium of partners dedicated to conducting research to improve outcomes of rare conditions associated with epilepsy and seizures. REN is committed to addressing the urgent health challenges of our rare epilepsy community,” said Brandy Fureman, vice president of research and new therapies at the Epilepsy Foundation. “We do this by engaging people living with a rare epilepsy and caregivers, making data available to researchers, and investigating causes and consequences of rare epilepsies in order to improve diagnosis, treatment, and find cures.”

    REN is building a registry to collect information about people with rare epilepsies to:

    Support and encourage research
    Better understand these conditions
    Develop treatments
    Improve the lives and quality of care of people affected