WHAT IS DRAVET SYNDROME?
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Dravet syndrome is a clinical diagnosis that was recently determined to affect 1:15,700 infants born in the U.S. . Approximately 80% of those diagnosed with Dravet syndrome have an SCN1A mutation (1:20,900), but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude the diagnosis. Dravet syndrome lies at the severe end of the spectrum of SCN1A-related disorders but can be associated with other mutations as well [4,5].
In the 2015 study, clinical diagnostic criteria included at least 4 of the following:
- Normal or near-normal cognitive and motor development before seizure onset
- Two or more seizures with or without fever before 1 year of age
- Seizure history consisting of myoclonic, hemiclonic, or generalized tonic-clonic seizures
- 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
Other earmarks of the syndrome include seizures associated with vaccinations, hot baths, or warm temperatures; developmental slowing, stagnation, or regression after the first year of life; behavioral issues; and speech delay.
Because many of these criteria are not apparent in the first year of life and infants with Dravet syndrome initially experience typical development, the study determined genetic testing via an epilepsy panel should be considered in patients exhibiting any of the following:
- 2 or more prolonged seizures by 1 year of age
- 1 prolonged seizure and any hemi-clonic (sustained, rhythmic jerking of one side of the body) seizure by 1 year of age
- 2 seizures of any length that seem to affect alternating sides of the body
- History of seizures prior to 18 months of age and later emergence of myoclonic and/or absence seizures
If you suspect your loved one might have Dravet syndrome, ask your neurologist about testing, which is available through your doctor or commercially. An epilepsy panel will test for SCN1A as well as many other genes commonly associated with epilepsy. Following testing, consultation with a genetic counselor is recommended.
- Wu, E., et. al. (2015). Incidence of Dravet Syndrome in a US Population. Pediatrics 136(5): 1310-e1315. doi: 10.1542/peds.2015-1807. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621800/
- Cooper, M.S., et. al. (2016). Mortality in Dravet Syndrome. Epilepsy Research Oct 26;128:42-47. doi: 10.1016/j.eplepsyres.2016.10.006.
- Skluzacek, et. al. (2011). Dravet syndrome and parent associations: The IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia Apr;52 Suppl 2:95-101. doi: 10.1111/j.1528-1167.2011.03012.x.
- Ian O Miller, MD, Marcio A Sotero de Menezes, MD. SCN1A-Related Seizure Disorders. Gene Reviews. Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA):University of Washington, Seattle; 1993-2016.
- Silberstein, S.D., Dodick, D.W. (2013). Migraine genetics: Part II.2013 Sep;53(8):1218-29. doi: 10.1111/head.12169. Epub 2013 Aug 6.
Dravet syndrome is a spectrum disorder, meaning patients present with a wide range of severity and seizure types, and no two patients respond to treatment the same way. What helps one may not help another, and vice versa. Still, several medications have proven beneficial in many patients (sometimes called “first line treatments”) and some medications have been known to exacerbate seizures in many patients (called “contraindicated” medications) due to their effects on the sodium ion channel. In 2018, two medications were granted US FDA approval for the treatment of Dravet syndrome due to positive results in clinical trials: Epidiolex, which is a cannabidiol (CBD) extract, and Diacomit (stiripentol).
Many patients with Dravet syndrome experience prolonged seizures (status epilepticus) that require emergency intervention. For this reason, your neurologist may prescribe a rescue medication, typically a benzodiazepine, that is given during the seizure to help stop it.
Rescue medications include:
- Clonazepam (Klonopin)
- Diazepam (Diastat)
- Lorazepam (Ativan)
- Midazolam (Versed)
Other treatments and therapies have shown positive results in the overall care and management of Dravet syndrome in some patients, even though they have not been fully studied. These include IVIG (Intravenous Immunoglobulin) Therapy, dietary interventions such as the Ketogenic Diet, and VNS (Vagus Nerve Stimulation) Therapy. Epidiolex, an oral solution of cannabidiol (CBD), received indication and FDA approval for the treatment of Dravet syndrome in 2018 and is available by prescription. Fintepla, a low-dose oral solution of fenfluramine, received indication and FDA approval for the treatment of Dravet syndrome in 2020 and is available by prescription with enrollment in a REMS program to monitor heart health while taking this medication.
Establish an Emergency Protocol
It is important to design and implement an emergency protocol with your neurologist, including a fast onset benzodiazepine such as Diastat, nasal versed, or lorazepam, for any convulsive seizure lasting longer than five minutes. It is helpful to have a written copy of this protocol with the child at all times, in case of emergency. This protocol should include instructions on seizure treatment and when to call for emergency services, as well as parent and physican contact information.
Monitor & Treat Secondary Health Conditions
Be aware of secondary health conditions common to the syndrome to make sure they are properly managed. These conditions vary from patient to patient and may include:
- Cardiovascular conditions
- Dental health concerns
- Orthopedic & scoliosis issues
- Sleep disturbances
- Weakened immunity
Growth and weight should also be followed closely and parents should be aware of treatment options such as gastrostomy tubes (g-tubes) when appropriate.
Learn & Avoid Seizure Triggers
Avoid seizure triggers whenever possible. Common triggers for patients with Dravet syndrome include rapid changes in environmental and/or body temperature, illness, stress, over-excitement, patterns, and flickering lights. Fevers should always be treated aggressively with a plan established with your pediatrician and/or neurologist.
Children with Dravet syndrome often also face developmental challenges such as autism or autistic-like characteristics, cognitive and/or communication delays, social skills, and behavioral issues. Regular developmental assessments and early and aggressive therapies (speech, OT, PT, developmental, etc.) may help with the overall outcome for the child.
Children with Dravet syndrome typically need constant care and supervision, as well as help in avoiding seizure triggers. Equipment that has been found by families to be useful in the day-to-day management of Dravet syndrome includes video monitoring, protective helmets, cooling vests, pulse oximeters, seizure alarms, and glasses with colored lenses (for photosensitivity).
Coping as a Family
A child’s chronic illness will have both direct and indirect effects on family members and their relationships. It is not uncommon for family members to feel denial, anger, fear, shock, confusion, self-blame, and helplessness. Family and grief counseling can help families deal with having a child with a chronic illness.
GENETICS OF DRAVET SYNDROME
More than 75% of patients diagnosed with Dravet syndrome have an SCN1A mutation . The SCN1A gene codes for the production of sodium ion channels, which are pore-like proteins embedded in the cell membrane that allow sodium ions into and out of the cell, propagating electrical signals. Some patients have other mutations including SCN2A and PCDH19.
- 90% of SCN1A mutations are de novo, meaning they are not found in the patient’s parents
- 4-10% of SCN1A mutations are inherited from the parent. In this case, there is a 50% chance of passing the mutation on to future children
- There are over 6,000 places for a mutation to occur on the SCN1A gene. Therefore, most patients’ mutations have not been reported in other people
- Any type of SCN1A mutation can be seen in Dravet syndrome, and mutation type does not predict the severity of the disease
- SCN1A mutations are also associated with migraines, febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+)
After a positive genetic test result, consultation with a genetic counselor is recommended.
While a mutation is not necessary for diagnosis, it can support a clinical diagnosis and it is helpful to understand what DNA, genes, and mutations are. Each person has two copies of the SCN1A gene: one from each parent. Many mutations found in Dravet syndrome render one copy dysfunctional, leaving only one functional copy. This results in a condition called haploinsufficiency, which means that one functioning copy is not sufficient to prevent symptoms. Approximately 90% of Dravet mutations are de novo, meaning they are not inherited from a parent, but rather are new mutations in the child [1,4].
What is DNA?
DNA is the set of instructions contained within each of our body’s cells. The instructions tell the cell how to build the proteins it needs to function. A strand of DNA is a long chain of 4 different nucleotides (abbreviated A, T, C, and G) strung together in a particular order, billions of nucleotides long. Because there is so much DNA in our cells, it is organized into 23 pairs of chromosomes, much like two sets of encyclopedias would be organized into 23 volumes each. When a sperm and an egg, each containing 23 chromosomes, combine, the result is 46 total chromosomes, organized into 23 matching pairs.
What is a gene?
The 23 pairs of chromosomes are further divided into smaller segments called genes. A gene is much like a chapter in an encyclopedia and contains the instructions for producing a specific protein. Each gene is a small segment of DNA and is thus also a long chain of 4 different nucleotides strung together in a particular order. Because our cells have one copy of each gene from each parent, every cell has two copies of each gene unless the gene is carried on the sex-determining X or Y chromosome. SCN1A is not on the X or Y chromosome.
Genes are read in groups of 3 nucleotides called codons. Each codon is translated into one of twenty amino acids, which are then strung together like beads on a necklace. The amino acids interact with each other based on their chemical properties similar to how magnetic beads attract and repel each other when folded up in one’s hand. As the amino acids interact, the long chain folds on itself to form a very specific 3-D shape. In the case of SCN1A, this 3-D shape is an ion channel that functions as a gated channel in the cell membrane, letting sodium ions into and out of the cell. The influx and efflux of ions allows electrical signals to propagate along neurons.
What is a mutation?
A mutation is a change in the expected sequence of nucleotides within a gene. This change in the original sequence of DNA may alter the sequence of amino acids, which may cause the chain to terminate prematurely, fold improperly, or otherwise alter the functionality of the sodium ion channel. Dysfunctional sodium ion channels can result in improper electrical activity and seizures.
Although SCN1A has 160,000 nucleotides, the body edits this sequence of 160,000 down to about 6,000 in the final SCN1A transcript that serves as the instructions for the sodium ion channel . Still, with over 6,000 nucleotide positions, it is no wonder that most mutations reported in the literature have not yet been seen in another patient.
Remember that every cell actually contains two copies of SCN1A; one from each parent. Usually, only one copy is mutated, a condition termed heterozygosity . Approximately 4% of the mutations seen in Dravet syndrome are inherited directly from parents, with the parent often experiencing fewer and less severe symptoms than the child in a phenomenon known as reduced penetrance .
There are three main types of mutations: missense, nonsense, and insertions/deletions.
A missense mutation is a simple substitution of one nucleotide for another at a single location in a gene. This slight change in the sequence of nucleotides may or may not result in one changed amino acid in the long chain.
If a missense mutation occurs near a pore-forming region of the sodium ion channel, it is likely to significantly alter the ion channel’s function and cause a more severe case of SCN1A-related epilepsy such as Dravet syndrome . If a missense mutation occurs at a less critical location on the gene, it may produce milder clinical symptoms or no symptoms at all. Approximately 47% of the mutations seen in Dravet patients are missense mutations .
A missense mutation reported by a testing company may look like this:
- Variant 1: Transversion G>T
- Nucleotide Position: 4073
- Codon Position: 1358
- Amino Acid Change: Tryptophan>Leusine
- Variant of Unknown Significance (heterozygous)
This says that the mutation was a substitution of T for G at the 4073rd nucleotide position (of 6000 in the final gene that is read) . Remember that nucleotides are read in groups of 3, called codons, so 4073 divided by 3 gives you the amino acid or codon position of 1358. The amino acid Leucine was substituted for the amino acid Tryptophan. The lab is unable to determine the significance because missense mutations can be associated with both mild and severe clinical presentations. The patient has only one copy of this mutation and is thus heterozygous. This real-life mutation is indeed in a pore region of the sodium ion channel, and this patient does have Dravet syndrome.
Nonsense mutations are similar to missense mutations in that one nucleotide is substituted for another. However, in the case of a nonsense mutation, that substitution causes the codon to be read as a “STOP” signal. The cell stops reading the gene prematurely, and the protein is significantly shortened, or truncated. Nonsense mutations are often associated with more severe SCN1A-related epilepsies such as Dravet syndrome . Approximately 20-40% of mutations in Dravet syndrome are nonsense (truncation) mutations [1,10]. A nonsense mutation may be reported like this:
“The mutation c.3985C>T (heterozygous) resulting in a termination or stop codon at Arg 1329 was detected in exon 20 of the patient sample and is associated with Dravet syndrome.”
This says that the nucleotide C was replaced with a T at position 3985, which resulted in the amino acid Arginine being replaced with a stop codon at position 1329. (3985 nucleotides, read in groups of 3, correspond to 1329 amino acids.) Only one of the two copies of SCN1A in the patient is mutated (heterozygous), as is usually the case. “Amber,” “Opal,” and “Ochre” may appear on the lab report and are some of the names for stop codons. The lab can be fairly confident this mutation is disease-producing because of the high correlation between truncation mutations and Dravet syndrome.
This same mutation may be reported by another lab like this:
This report does not specify the nucleotide position, but it identifies the amino acid position as 1329, and the asterisk (*) next to the amino acid position indicates a stop codon. Again, the lab is confident this mutation will result in Dravet syndrome.
Sometimes, one or more nucleotides are deleted from the gene. If one or two nucleotides are inserted or deleted, the reading frame of codons is shifted, and every amino acid is incorrect from that point in the chain on. This usually causes a dysfunctional sodium ion channel. In addition, the shift in reading frame will often cause one of the codons farther down the chain to be interpreted as a stop codon, prematurely terminating an already dysfunctional chain.
If a group of 3 nucleotides is inserted or deleted, only one codon is added or deleted, respectively, and the protein may still be functional depending on the location of that insertion or deletion.
Large segments of DNA may be inserted or deleted including the entire SCN1A gene and/or nearby genes. These mutations have varying phenotypes, and account for roughly 2-5% of Dravet mutations [1,5].
When the mutation occurs in the sperm, egg, or very soon after fertilization, all of the daughter cells derived from the growing embryo will contain the mutation. This is the case for most mutations found in Dravet syndrome .
However, if the mutation occurs later in the development of the embryo, only the cells descended from the mutated cell will carry the mutation. The cells descended from the non-mutated cells of the embryo will remain healthy. This results in an individual who is mosaic for the mutation. The later the mutation took place, the lower the percentage of cells descended from the mutated cell, and the lower the “% mosaicism” or “mosaic load.” (This is a broad generalization: In reality, the degree of specialization of the cells at the time of mutation plays a significant role in where the mutated cells are concentrated in the patient’s body and what the ultimate mosaic load is.) One study reported that SCN1A mutations with 12-25% mosaic load were potentially pathogenic, with reduced penetrance, meaning not all who carried the mutation in mosaic form exhibited signs or symptoms .
Mutations are actually a natural phenomenon that has been occurring in all organisms for thousands of years. Most changes in DNA sequence have little to no effect on the final protein products because they occur in regions that are edited out during gene processing, or their location in the final protein does not alter its function. In fact, many members of the healthy population have variants in their genes that are shared with a significant percentage of the population. Because these variants have no obvious clinical symptoms, they are called single nucleotide polymorphisms (SNP’s) and are not considered mutations. Your lab report may include these SNP’s, but their presence is not considered a positive SCN1A test.
What does this mean for the patient?
Researchers and epileptologists are learning more about the role SCN1A mutations play in Dravet syndrome and related epilepsies every day. At this point, it is clear that SCN1A mutations of any kind can be responsible for Dravet syndrome. However, because some SCN1A mutations are present in individuals with mild symptoms, there are probably many modifying factors that determine the severity of symptoms that result from the mutation. SCN1A mutations are helpful in supporting a clinical diagnosis, but remember that roughly 20% of patients with Dravet syndrome have no detected mutation, and a mutation is not required for diagnosis.
Is it all bad news?
No! There is so much active research on SCN1A and related epilepsies that scientists are uncovering new knowledge and potential therapeutic pathways every day. The fact that an epilepsy syndrome like Dravet can be traced to a root cause, despite many unknown factors and modifiers, makes it an appealing target for research and gives patients hope for a cure.
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- 5. 2015. Meng H, Xu HQ, Yu L, Lin GW, He N, Su T, Shi YW, Li B, Wang J, Liu XR1, Tang B, Long YS, Yi YH, Liao WP . TheSCN1AMutation Database: Updating Information and Analysis of the Relationships among Genotype, Functional Alteration, and Phenotype. Hum Mutat. 2015 Jun;36(6):573-80
- 6. http://www.scn1a.info/Exons
- 7. http://igbiologyy.blogspot.com/2014/03/chromosomes-dna-genes-and-alleles.html
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Updated 2016 by Nicole Villas
Dravet syndrome presents differently in each patient. Individuals with Dravet syndrome are often misdiagnosed with another seizure disorder such as Lennox Gastaut or Myoclonic Astatic Epilepsy, or given a broad diagnosis of intractable epilepsy. Some epilepsy syndromes, like PCDH19, a rare x-linked epilepsy found more often in females than males, share many characteristics with Dravet syndrome. There are subtle differences between these epilepsy syndromes and Dravet, and you should consult with your child’s neurologist if you have any questions about related epilepsies.
Our brain uses electrical currents to spread communication. These electrical currents are maintained by a balance of positive and negative charges that are carried by small charged molecules like sodium, potassium, calcium, and chloride (also called “ions”). When the cells in our brain are unable to move these ions in the correct way at the correct time, it disrupts communications. Sometimes that means neurons communicate “too much,” spreading too much electrical activity to their neighbors, which can lead to seizure activity. In many individuals with Dravet syndrome, they have a mutation that affects the ability to regulate electrical currents using sodium ions. If you want to know more, the explanation below goes into detail about how this works at the level of individual brain cells.
1. Neurons communicate with electric current.
One of the major cell types in our brains are neurons. Neurons have long extensions that form connections with other neurons so they can communicate with each other. Neurons communicate using electrical currents that travel down their long extensions to the next neuron, similar to the wires that carry electricity to our appliances.
2. Neurons use ions to generate electric current.
How do neurons generate electricity?!? It’s all based on the movement of charged particles, or “ions,” that have positive charges (+) and negative charges (-). Sodium (Na, + charge) and potassium (K, + charge) are two important ions that help neurons do this. When a neuron is “resting,” or not talking to a neighbor neuron, it is more negatively charged inside and is keeping more of the positive charged ions, like sodium (Na+), outside the cell.
When a neuron gets stimulated and needs to send a message, it suddenly lets a bunch of the sodium (Na+) rush into the cell to start an electrical current. All of these changes in the balance of positive and negative ions leads to an electrical current that can move very quickly down the long extensions of the neuron to communicate to the next cell.
When it’s time to stop communicating, the neuron has to reverse the ions so that there are more negative inside again and more positive outside. Balancing ion movement is an important step for the cell to stop the electrical activity. This means moving more positive ions out than it brings in.
3. Neurons use channels to move the ions that generate electric current.
To move ions inside and outside of the cell, the neuron needs special channels. There are specific channels for each type of ion (sodium, potassium, etc).
When these channels do not work properly, the neuron has a hard time making, regulating, and then stopping the electrical currents. When neurons are unable to regulate electrical currents it can lead to seizures.
The most common cause of Dravet syndrome results from a problem with a specific sodium (Na+) channel, called “Nav1.1” (Na for sodium, V for electrical voltage, 1.1 because there are several channels that are similar). Many patients with Dravet syndrome have a mutation in SCN1A, the gene that makes Nav1.1. The mutations in SCN1A in Dravet syndrome usually only affect one copy (we get two copies of every gene in our DNA). That means about half of the Nav1.1 sodium (Na+) channels that the neuron needs either (1) do not work correctly, or (2) do not get made at all. This ultimately means less sodium channels that work correctly. This makes it very hard for neurons to properly make and stop electrical currents for communication, which can lead to seizure activity.
4. Reduction in Nav1.1 affects the electrical activity of inhibitory neurons.
This last section gets into the very specifics of what can go wrong in Dravet syndrome. At this point, you may wonder:
- if you have to bring sodium (Na+) into the neuron to start an electrical current,
- and this channel to bring sodium (Na+) into the neuron does not work as well in Dravet syndrome,
- should the problem be with too little electrical current and not too much?!
To understand how this is working to cause seizures in Dravet syndrome, we have to step back and talk about how there are different TYPES of neurons in the brain.
- When some neurons use electrical currents to talk to their neighbors, they always tell them to “get excited” and keep spreading the message. These are called excitatory neurons.
- A different group of neurons always uses their electrical currents to tell their neighbors to “STOP signaling!”. These are called “inhibitory” neurons.
The sodium channel Nav1.1 is most important to inhibitory neurons. So in Dravet syndrome, these inhibitory neurons have trouble communicating. Normally, they should be telling the excitatory neurons when to STOP, but since they cannot do that properly, the excitatory neurons can get “too excited”, or generate too much electrical current, which leads to seizures.