Dravet Syndrome

What Causes Dravet Syndrome?

Most children with DS have an abnormal change (mutation) in a gene called SCN1A. The SCN1A gene is involved in developing a cell’s sodium channel, a chemical pathway that is a crucial part of nerve cell function.

Although SCN1A mutations are present in at least 80 percent of DS cases, they don’t appear to be the only cause of the disorder. Some children with DS don’t have SCN1A mutations, and some children with mutations don’t develop DS. It is also likely that mutations in other genes can cause the disorder.

Is Dravet Syndrome Hereditary?

In most DS cases, the SCN1A mutation appears to occur spontaneously at some point during fetal development. In these cases, the mutation is not inherited by the child from either of their parents.

In a small percentage of cases, the SCN1A mutation is passed from parent to child. In many cases, the parent who carries the mutation has either a milder form of epilepsy or no symptoms at all. When a child has an inherited SCN1A mutation, there is a 50 percent chance that another child from the same parents will have the mutation.

Sometimes the mutation is passed from parent to child in a process called mosaicism. In these cases, a parent carries the mutation in some of their cells but not others. Because of this, a child can inherit the mutation from a parent who appears to have normal SCN1A genes.

How Is Dravet Syndrome Detected?

Early diagnosis of DS is sometimes difficult because doctors must have a detailed history of a child’s seizures and other symptoms to spot the disorder’s distinctive pattern. The fact that the condition emerges in an otherwise healthy child can also complicate diagnosis, as the exams commonly used to detect other types of epilepsy may appear normal at first. In children whose DS seizures are triggered by increased body temperature, the symptoms may be misdiagnosed as febrile seizures, which are also triggered by fevers.

Experts recommend that doctors conduct genetic testing to look for possible DS-causing mutations if a child exhibits any of the disorder’s warning signs, including:

• At least two prolonged seizures before 12 months
• A prolonged seizure and a seizure that affects one side of the body by 12 months
• Two seizures that affect different sides of the body
• Seizures that begin before 18 months, followed by recurrent seizures, including myoclonic seizures (jerking of isolated muscles) and/or absence seizures (brief periods of staring into space)

How Is Dravet Syndrome Diagnosed?

To diagnose DS and rule out other seizure disorders, doctors will look for a distinctive pattern of seizures and other symptoms. The pattern includes:

• Seizure onset between 1 and 18 months, usually before 12 months.
• Recurrent seizures that affect the whole body or half of the body.
• Myoclonic seizures that begin by two years. Other seizure types may start later as well.
• Seizures triggered by increases in body temperature. Triggers may also include light or visual stimuli, eating, or bowel movements.
• Normal neurological exams and development at the onset of symptoms.

In older children and adults, DS may be suspected if other symptoms are present, such as:

• Continuing seizures
• Decline of temperature-triggered seizures
• Worsening seizures when certain medications are administered
• Intellectual or motor impairments

Genetic testing can identify mutations in the SCN1A gene and other mutations that have been associated with DS.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Dravet Syndrome Treated?

DS has no cure. Standard treatments are used to control seizures in the hope that seizure reduction may reduce the impact of potential complications. DS seizures may not respond well to traditional treatments. Doctors may have to try multiple medications or combinations of drugs to find a treatment that works.

Commonly used anti-seizure medications include:

• Clobazam
• Valproic acid
• Stiripentol
• Topiramate
• Clonazepam
• Levetiracetam
• Zonisamide
• Ethosuximide
• Fenfluramine
• Epidolex

Some non-medication treatments, such as vagal nerve stimulation and a ketogenic diet, may also be effective at controlling DS seizures.

Some anti-seizure medications affect the sodium channel and may make DS seizures worse. Medicines that should not be used by children or adults with DS include:

• Carbamazepine
• Oxcarbazepine
• Lamotrigine
• Vigabatrin
• Rufinamide
• Phenytoin
• Fosphenytoin

How Does Dravet Syndrome Progress?

Up to 20 percent of children with DS don’t reach adulthood. The most common causes of death are sudden unexpected death in epilepsy patients (SUDEP) and status epilepticus, a significantly prolonged seizure event.

Seizure activity usually decreases as a child gets older, and adults with DS don’t typically have a shorter than average life span.

Developmental problems associated with DS often cause life-long impairments. Most adults with DS require at least some assistance from caregivers and are unlikely to live independently on their own.

Long-term complications and conditions often associated with DS include:

• Coordination and balance difficulties
• Recurrent infections
• Nutrition problems
• Sleep disruptions
• Autism
• Attention-deficit/hyperactivity disorder (ADHD)

How Is Dravet Syndrome Prevented?

There is no known way to prevent DS. Parents with a family history of epilepsy or have had another child with DS may consult a genetic counselor to assess their risk if they plan to have another child.

Dravet Syndrome Caregiver Tips

Parents of children with DS can best help their children if they understand as much as they can about the disorder and are prepared for its challenges.

• Plan ahead. It’s helpful to put together an emergency kit to keep with you so that you’re prepared to deal with a seizure at any time. The kit can include medications, clean clothes, water, contact information for medical providers, and a medical alert bracelet.
• Keep a diary of your child’s symptoms. A careful record of your child’s seizures and the circumstances surrounding them can help your doctor adjust your child’s treatment strategy.
• Find support when you need it. The Dravet Syndrome Foundation can connect you with online and local support groups and other families living with DS.

Many people with DS also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with DS:

• Many people with DS also suffer from attention-deficit/hyperactivity disorder (ADHD) or learning disabilities.
• About a third of people with some form of epilepsy, including DS, suffer from depression, and about a quarter suffer from anxiety.
• Autism spectrum disorder is more common in people with DS.
• Several mental health-related issues, including interictal dysphoric disorder, interictal behavior syndrome, and psychosis of epilepsy, are only experienced by people with epilepsy.

Dravet Syndrome Brain Science

Scientists believe that convulsive seizures such as those of the early stages of DS are caused by abnormal functioning in brain cells called neurons. When neurons work correctly, some neurons (called excitatory neurons) signal other neurons to take action. Different neurons (called inhibitory neurons) calm the cells and keep them from taking on too much activity. In some people, the excitatory neurons sometimes are too active, and/or the inhibitory neurons are not active enough. The result is neurons that are too excited, and a seizure occurs.

Studies have suggested that some inhibitory neurons are especially inactive in DS patients. Other studies have indicated that inhibitory neurons in a part of the brain called the thalamus are overactive in DS patients. This overactivity might explain the prevalence of non-convulsive seizures in older DS patients. Non-convulsive DS seizures are particularly resistant to standard anti-seizure medications, but ongoing research is focused on finding alternative treatments, such as light-based therapies, that may be effective.

Dravet Syndrome Research

Title:  Transcranial Magnetic Stimulation to Measure Cortical Excitability in Dravet Syndrome

Stage: Recruiting

Principal Investigator: Alexander Rotenberg, MD, PhD

Boston Children’s Hospital

Boston, MA

Dravet syndrome (DS) is an epileptic encephalopathy caused by pathogenic variants in the SCN1A gene resulting in medically refractory epilepsy and psychomotor delays.

As a pilot study assessing feasibility, the investigators aim to test whether alterations in cortical excitatory : inhibitory ratio can be reliably recorded. The investigators will utilize transcranial magnetic stimulation (TMS) metrics of cortical excitatory and inhibitory tone as an initial step towards translating findings from rodent genetic models of DS into disease-specific biomarkers and offer future measures of therapeutic target engagement in this patient population.

Participants will complete two visits, each consisting of a TMS session and an EEG session. Visits will be scheduled 4-8 weeks apart.

Title: An Open-Label Study to Investigate the Safety of Single and Multiple Ascending Doses in Children and Adolescents With Dravet Syndrome

Stage: Recruiting

Study Director:  Javier Avendaño, MD

Stoke Therapeutics

Bedford, MA

STK-001 is an investigational new medicine for the treatment of Dravet syndrome. STK-001 is an antisense oligonucleotide (ASO) intended to increase the level of productive SCN1A messenger RNA (mRNA) and consequently increase the expression of the sodium channel Nav1.1 protein. This RNA-based approach is not gene therapy, but rather RNA modulation, as it does not manipulate nor insert genetic deoxyribonucleic acid (DNA).

STK-001 is designed to upregulate Nav1.1 protein expression from the nonmutant (wild-type) copy of the SCN1A gene to restore physiological Nav1.1 levels. Nav1.1 levels are reduced in people with Dravet syndrome. Stoke has generated preclinical data demonstrating proof-of-mechanism for STK-001.

Title: Genetics of Severe Early Onset Epilepsies

Stage: Recruiting

Principal Investigator: Annapurna Poduri, MD, MPH

Boston Children’s Hospital

Boston, MA

Many children with epilepsy experience seizures which respond well to treatment. A few types of epilepsy, however, are characterized by seizures that begin very early in childhood and are associated with severe intellectual and/or developmental disabilities. These conditions, known as progressive epileptic encephalopathies, are particularly severe and are often difficult to treat. These syndromes include infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, early myoclonic epileptic encephalopathy, and severe myoclonic epilepsy of infancy (Dravet syndrome).

The investigators’ current research effort is focused on children with epileptic encephalopathies, in particular Ohtahara syndrome. The investigators’ goal is to identify genetic alterations (known as “mutations”) that cause Ohtahara syndrome. By doing so, the investigators hope to improve the diagnosis and treatment for this condition. It is also possible that understanding the genetic basis of Ohtahara syndrome may, in some instances, make it possible to prevent it from occurring in the future.