Dravet Syndrome: A Genetic Disorder Guide

What is Dravet Syndrome?

Dravet syndrome is a rare and catastrophic form of epilepsy that begins during a child’s first year of life, often beginning around six months of age.

It is characterized by frequent and prolonged seizures that last throughout a sufferer’s life. Those seizures are often triggered by hot temperatures or a fever.

Initially, it was known as Severe Myoclonic Epilepsy of Infancy (SMEI) when it was first described by Charlotte Dravet in France in 1978. But the name was changed to Dravet syndrome in 1989.

In addition to frequent and prolonged seizures, there are a number of other issues associated with Dravet syndrome. They include:

• Behavioral and developmental delays
• Movement and balance issues
• Orthopedic conditions
• Delayed language and speech issues
• Abnormal EEGs
• Growth and nutrition issues
• Lowered immunity and greater incidence of infections
• Hyperactivity
• Sleeping difficulties
• Chronic infections
• Sensory integration disorders
• Dysautonomia which is a disruption of the autonomic nervous system. This can lead to difficulty regulating body temperature, heart rate, blood pressure, and other issues

Patients with Dravet syndrome face a 15-20% mortality rate due to Sudden Unexpected Death in Epilepsy (SUDEP) ¹, as well as prolonged seizures and seizure-related accidents such as drowning.

In terms of overall life expectancy, patients with Dravet syndrome have an overall lower life expectancy than a healthy, normal person. It’s estimated that about 10-15% will pass away when they are children or young adults.

This is due to infections, status epilepticus, and falls and drowning that are all related to epilepsy.

SUDEP is the leading cause of death to those who have Dravet syndrome. That is followed by status epilepticus (defined as a continuous seizure lasting more than 30 minutes, or two or more seizures without full recovery of consciousness between any of them) because they are at risk of brain damage and problems in breathing.

SUDEP of a child with Dravet syndrome tends to be common at a younger age and accounts for nearly half of deaths due to an epileptic syndrome.

The good news is that many children with Dravet syndrome can still lead long and productive lives if seizures are controlled effectively. Early diagnosis is the key in finding the best treatment to control epileptic seizures.

Adult patients suffer multiple impairments in addition to the seizures. These can include cognitive disabilities, behavioral challenges, decreased mobility, sleep and gastrointestinal issues.

Seizure types often change in adults and may decrease in frequency, but the majority of adult patients still experience regular seizures.

Dravet syndrome studies on behavior problems for adults are rare, but anecdotal reports suggest that older patients may experience irritability, aggressiveness, and other behavioral problems that need to be addressed to keep the patient and caregiver safe.

Signs and Symptoms of Dravet Syndrome

Signs and symptoms of Dravet syndrome will usually start to appear in infants under one year old. Children may experience a mild seizure along with a fever at between 4 and 8 months of age.

This will progress to a seizure with or without a fever even if they are dosed with anti-convulsive medications. There is a rapid, jerky movement in both sides or one side of the body.

Dravet syndrome worsens from age one to five years old. During this phase, the seizures that take place are more noticeable because the seizure frequency is increasing.

The type of seizures may change and intensify as well. These can include episodes such as myoclonic seizures, focal seizures, and atypical absences.

These seizures may easily be triggered by environmental factors like bright lights.

Also, between one and two years of age, problems in a child’s development are already visible. For example, difficulty with the language and speech can be seen in one that is impacted.

A child’s behavioral development can also be affected. This may result in a child being moody, irritable, hyperkinetic and stubborn. Impaired coordination and motor skills also change during this phase.

When a child turns five, they begin to stabilize. During this stage, it’s common to see a reduction in the types of seizures that occur and fewer cases of fever. Psychomotor and cognitive development problems of a child no longer progress.

But by this time, intellectual problems are already in the moderate and severe stage. Behavioral development tends to worsen resulting in more aggressive behavior. A child may also experience psychosis and show signs of autism and ADHD.

In general, Dravet syndrome is also associated with sleep disorders including somnolence and insomnia. Chronic infections are also another by-product of the condition as well.

The effects of Dravet syndrome do not diminish over time. Children who are diagnosed require fully committed caretakers with high degrees of patience and the ability to closely monitor them.

Because the range of severity differs between each person diagnosed and the varying resistance of these seizures to drugs, developing effective universal treatments has been challenging.

How Common is Dravet Syndrome?

It is estimated that Dravet syndrome is found in 1 out of every 15,700 infants ².

About 80-90% of those with Dravet syndrome have a mutation of the SCN1A gene, for a combined frequency of 1 out of every 20,900 births.

This represents about 0.17% of all epilepsies.

The Genetics of Dravet Syndrome

The SCNIA and SCN2A genes produce a protein that is known as the sodium channel, voltage-gated, type I, alpha subunit.

While this is a bit complicated it’s important to know because there is a vertebrate sodium channel that is essential for the generation and propagation of action potentials. You know these better as nerve and muscle actions.

When these genes mutate, they cause a person to develop dysfunctional sodium channels. These sodium channels are crucial for sending chemical signals to the brain and when the channels are disrupted or corrupted, they can cause epilepsy.

A properly functioning sodium channel responds to a voltage difference across the membrane and forms a pore through which only sodium ions can pass.

Introducing sodium causes the generation of action potential by temporarily changing the charge of the cell. But when the gene is mutated, the protein does not properly fold its pore segment in the cell membrane because it has different amino acid chemistry.

That renders the channel inactive.

When the number of channels is reduced in a person, it can lead to the development of Dravet syndrome.

Other genes have been associated with Dravet syndrome. They include SCN2A, SCN8A, GABRA1, GABARG2, PCDH19, STXBP1, and SCN1B, but the clinical presentation in these cases is often somewhat atypical of Dravet syndrome.

Genetic Testing for Dravet Syndrome

SCN1A mutations are found in 80-90% of patients clinically diagnosed with Dravet syndrome. Infants with Dravet syndrome don’t initially present symptoms of atypical development until several months after they are born.

If there is a history of Dravet syndrome or epilepsy in a family, then it may be prudent to have a newborn tested. Otherwise an epilepsy panel should be considered for patients who exhibit any of the following ³:

1. 2 or more prolonged seizures by 1 year of age
2. 1 prolonged seizure and any hemi-clonic (defined as a sustained, rhythmic jerking of one side of the body) seizure by 1 year of age
3. 2 seizures of any length that seem to affect alternating sides of the body
4. A history of seizures prior to 18 months of age and later emergence of myoclonic and/or absence seizures

An epilepsy panel will test for a mutated SCN1A gene as well as many other genes commonly associated with epilepsy.

SCN1A mutations are also found in less severe types of epilepsy, such as generalized epilepsy with febrile seizures plus (GEFS+), and more severe forms of epilepsy such as migrating focal seizures.

That means it is critical to get an accurate diagnosis so that appropriate clinical correlations and treatments can be implemented.

Causes of Dravet Syndrome

About 80% to 90% of Dravet syndrome cases are associated with the mutation of the SCN1A gene. As genetic testing continues to improve and become more widespread, that figure continues to rise.

About 90% of the mutations appear to be new to the child and not inherited from a parent.

In cases where the mutated SCN1A gene was inherited, it has been commonly found that the parent has a milder form of epilepsy or no neurological conditions at all, as opposed to the child who has Dravet syndrome.

Improved genetic testing has uncovered mosaic mutations in parents who previously tested negative for an SCN1A mutation. Mosaicism occurs when some cells within a person differ genetically from other cells within that same person.

This can happen shortly after fertilization when some cells simply undergo a spontaneous mutation.

The risk of the recurrence of Dravet syndrome in families where a mutated SCN1A gene has been inherited is 50%. But due to mosaicism and other types of egg or sperm mutations, the risk of mutations that appear to be new to a child are higher than those of the general public.

Some evidence suggests that vaccines may be a trigger for Dravet syndrome in some children. However, the timing of the first signs and symptoms in Dravet syndrome also take place at about the same time as normal childhood vaccinations.

This has led some people to believe that a vaccine was the cause when it may simply have been symptoms of Dravet syndrome began to manifest themselves.

Some of the patients who tried to make a case for vaccine injury claims from encephalopathy were later found to actually have Dravet syndrome.

Dravet Syndrome Diagnosis

According to the Dravet Syndrome Foundation and other medical bodies, the diagnostic criteria for this condition should include several of the following symptoms:

• Onset of seizures in the first year of life in an otherwise healthy infant. The average age of onset is 5.2 months.
• Initial seizures that are typically prolonged and are generalized or unilateral
• Presence of other seizure types (i.e. myoclonic seizures, tonic-clonic or hemiconvulsive seizures)
• Seizures associated with fever due to illness or vaccinations
• Seizures induced by prolonged exposure to warm temperatures
• Seizures in response to strong lighting, photosensitivity or certain visual patterns
• Initially normal EEGs and later EEGs with slowing and severe generalized polyspikes
• Normal initial development followed by slow development during the first few years of life
• Some degree of hypotonia
• Unstable and crouched gait and balance issues
• An MRI may be normal or show mild generalized atrophy and/or hippocampal sclerosis
• Ankle pronation and flat feet and/or development of a crouched gait with age
• In older children and adults, persisting seizures, which may or may not be prolonged. Status epilepticus becomes less frequent with time and may not be apparent by young adulthood
• MRI may be normal or show mild generalized atrophy and/or hippocampal sclerosis
• Two or more seizures with or without fever before 1 year of age
• Two or more seizures lasting longer than 10 minutes
• Failure to respond to first-line antiepileptic drug therapy with continued seizures after 2 years of age

Although about 80% of those diagnosed with Dravet syndrome have an SCN1A mutation, the presence of a mutation alone is not sufficient for diagnosis. The absence of a mutation does not exclude the diagnosis.

Dravet syndrome is considered the most severe of all SCN1A mutation disorders, but other disorders are also associated with the mutation of the SCN1A gene as well.

Some people with Dravet syndrome are misdiagnosed with other seizure disorders such as Lennox-Gastaut syndrome.

They may also be diagnosed with intractable epilepsy because infants with Dravet syndrome are developmentally on track until the second year of life.

How Dravet Syndrome is Treated

There is no cure for Dravet syndrome, so treatments center around trying to reduce the frequency and severity of seizures. Because Dravet syndrome varies from patient to patient, the treatment protocols will vary as well.

Patients may be given anticonvulsant medications such as:

1. Clobazam (branded as Onfi or Frisium
2. Valproic acid (branded as Depakote, Depakene)
3. Stiripentol (branded as Dicomit, approved for seizure treatments in patients two or older who are also taking clobazam)
4. Topiramate (branded as Topamax)

Dravet syndrome may also be treated by putting a patient on a ketogenic diet (a diet high in fats and low in carbohydrates) or a modified ketogenic diet such as the Modified Atkins Diet. A modified diet will help, but it will not eliminate all of the symptoms.

Less frequently used treatments may include clonazepam (Klonopin), levetiracetam (Keppra), zonisamide (Zonegran), ethosuximide (Zarontin), and vagal nerve stimulator (VNS).

Valproate is often given to prevent recurrence of febrile seizures and benzodiazapine is used for long lasting seizures, but these treatments are usually not sufficient.

Medications that should not be used in DS include sodium channel blockers such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), lamotrigine (Lamictal), vigabatrin (Sabril), rufinamide (Banzel), phenytoin (Dilantin), fosphenytoin (Cerebyx, Prodilantin).

In addition, when taking stiripentol to treat Dravet syndrome, there needs to be heightened clinical monitoring and also after taking it has stopped.

The same prudence needs to be exercised when taking medications in the following therapeutic classes:

1.  Anti-histamines
2.  Nsaids
3.  Benzodiazepines
4.  Beta-blockers
5.  Biguanides
6.  Hormonal contraceptives
7.  Hypnotics
8.  Hypoglycemia inducing sulphamides
9.  Divers

Status epilepticus is frequent with Dravet syndrome and caregivers should know how to administer at-home medications to stop prolonged seizures. Rectal diazepam and buccal (by mouth) or intranasal midazolam are frequently used.

In 2018, cannabidiol was approved in the US to treat Dravet syndrome ⁴. This came after a study the year before showed the frequency of seizures per month decreased from 12 to 6 with the use of cannabidiol, compared with a decrease from 15 to 14 with placebo.

It’s also important to note that the normal treatment for the epilepsy must not be interrupted.

Treatment Resources

You can learn more about treatment options for Dravet syndrome by clicking on the links below.

Dravet Foundation

Orphanet Emergency Guidelines

National Library of Medicine Drug Information Portal

Medline Plus Health Information

Cannabidiol & CBD

Ketogenic Diet

Glossary of Terms Brochure

DSF CBD Position Statement

Is Dravet Syndrome Curable?

At the present time, no. The condition and the symptoms can only be managed and monitored to aggressively minimize impacts from Dravet syndrome.

Earlier diagnosis improves long-term outcomes for patients overall, with improved cognition and seizure control.

However, as genetic research continues to grow by leaps and bounds, scientists are unlocking the mysteries of our bodies at a cellular level.

Because a vast majority of Dravet syndrome cases are linked to a mutated SCN1A gene, if and when research can lead to correcting a modified gene or muting its effects on an individual, the medical community may be well on its way to finding a cure.

What is the Prognosis for Dravet Syndrome? Is Dravet syndrome fatal?

People with Dravet syndrome need constant care. It is a lifelong condition that can severely impact an entire family’s quality of life.

According to estimates, about 10-20% of people afflicted by Dravet syndrome will pass away before they become adults. Most of these deaths happen before a sufferer is 10 years old, but deaths can take place at any age.

The most common cause of death from Dravet syndrome is Sudden Unexpected Death in Epilepsy, also known as SUDEP. It is a fatal complication of epilepsy.

Dravet Syndrome and SUDEP

The definition of SUDEP was standardized in 1993 when the US Food and Drug Administration (FDA) and Burroughs-Wellcome developed the following criteria which are still in use today:

The individual has epilepsy, which is defined as recurrent unprovoked seizures.

1. The individual died unexpectedly while in a reasonable state of health.
2. The death occurred suddenly (i.e. within minutes).
3. The death occurred during normal and benign circumstances.
4. An obvious medical cause of death could not be determined at autopsy.
5. The death was not the direct result of a seizure or status epilepticus.

In lay terms, a person with epilepsy that dies unexpectedly, with no other clear cause of death found when a post-mortem examination is done is said to have passed away from SUDEP.

SUDEP is a major concern for families of those people who have Dravet syndrome. Seizures can turn fatal for several reasons. Many SUDEP victims lose their lives due to accidents, illness or status epilepticus.

Needless to say, this can be upsetting, but there are preventative measures families can take to lessen the incidence of SUDEP in someone with Dravet syndrome.

Although the medical community does not know how to prevent SUDEP, it is known that the risk for SUDEP is higher for people of suffer from uncontrolled seizures ⁵.

So a way to lower the risk for SUDEP is to do a better job of controlling seizures. Here are some tips for doing just that:

• Make sure that seizure medications are given consistently and at the correct doses.
• Find the best seizure control, with the fewest side effects. If medications are not working, consider other therapies such as dietary therapy or VNS (vagus nerve stimulator).
• Know what a child’s seizure triggers are and adjust their environment accordingly.
• Make sure that family, friends, teachers and caregivers know what to do if your child has a seizure.
• Keep your child’s emergency seizure protocol up-to-date and make sure those who may need it have a copy.
• Have your child wear some type of identifying information at all times. If he or she won’t tolerate a medical ID bracelet, necklaces, shoe tags and wearable QR codes are available.
• Consider using a GPS enabled tracking device or watch.
• Make sure your neighbors know your child’s special needs and your concerns for your child’s safety.
• Consider using a seizure alert monitor during the night, since SUDEP occurs most often during sleep.
• Place padding around tables and other furniture with sharp edges.
• Remove potential choking hazards from your child’s environment.
• Install gates or fencing around pools. Make sure your child is never left alone in the pool or bathtub
• Children with Dravet syndrome often elope, placing themselves in unsupervised, potentially dangerous situations.

Several websites and patient organizations are available to help answer questions about SUDEP. You may want to check out the following resources:

1. Danny Did
2. Epilepsy Foundation/PAME
3. SUDEP Aware

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