Dravet syndrome, previously known as severe myoclonic epilepsy of infancy.
It is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever.
Dravet syndrome is a severe form of epilepsy, responsible for roughly 10% of cases in children.
It is a rare genetic disorder that affects an estimated 1 in every 20,000–40,000 births.
It often begins before 1 year of age.
Characterized by prolonged febrile and non-febrile seizures within the first year of a child’s life.
Dravet syndrome progresses to seizure types like myoclonic and partial seizures, and is associated with psychomotor delay, and ataxia, cognitive impairment, behavioral disorders, and motor deficits.
Children typically experience a lag in development of language and motor skills, hyperactivity and sleep difficulties, chronic infection, growth and balance issues, hypotonia, and difficulty relating to others.
Patients may experience ataxia and dysautonomia.
Behavioral disorders include: hyperactivity impulsiveness, and in more rare cases, autistic-like behaviors.
It is also associated with sleep disorders including somnolence and insomnia.
The seizures become worse as the patient ages.
Initially, the disease is not very observable when symptoms first appear.
It appears during the first year of life, usually around six months of age .
It begins with frequent febrile seizures.
The effects of this disorder do not diminish over time, and children diagnosed with Dravet syndrome require fully committed caretakers with tremendous patience and the ability to closely monitor them.
Febrile seizures are divided into two simple and complex.
A febrile seizure is complex if it occurs within 24 hours of another seizure or if it lasts longer than 15 minutes.
A simple febrile seizure lasts less than 15 minutes.
Hyperthermic stressors like physical exertion or a hot bath can precipitate seizures in affected individuals.
Seizures, if uninterrupted after 5 minutes, without a resumption of postictal consciousness can lead to potentially fatal status epilepticus.
In most cases the mutations in Dravet syndrome are not hereditary.
The mutated gene is found for the first time in a single family member with Dravet syndrome: In 70–90% of patients, Dravet syndrome is caused by nonsense mutations in the SCN1A gene.
SCN1 gene normally codes for neuronal voltage-gated sodium channel Nav1.1.
The loss of Nav1.1 channels is sufficient to cause the epilepsy and premature death seen in Dravet syndrome.
The mutation results in a premature stop codon and thus a non-functional protein.
This gene normally codes for neuronal voltage-gated sodium channel Na(V)1.1.
The genotypic explanation of the disorder has been located on the specific voltage-gated sodium channel genes known as SCN1A and SCN2A.
These genes are located on the long (q) arm of chromosome 2 at position 24.3 and code for the alpha subunit of the transmembrane sodium channel protein.
Mutations in either of these two genes will cause dysfunctional sodium channels, sending chemical signals in the brain causing myoclonic epilepsy.
The SCN1A gene is the most clinically relevant; the largest number of epilepsy related mutations characterized thus far occur in this gene.
The loss of NA(V)1.1 channel causes the epilepsy and premature death seen in Dravet syndrome.
The timing of the first signs and symptoms in Dravet syndrome occur about the same time as normal childhood vaccinations, leading some to believe the vaccine was the cause.
The specific voltage-gated sodium channel genes known as SCN1A and SCN2A.
These genes are located on the long (q) arm of chromosome 2.
Mutations in either of these two genes causes a dysfunctional sodium channel, which is crucial sending chemical signals in the brain, causing myoclonic epilepsy.
A properly functioning sodium channel responds to a voltage difference across the membrane and allows sodium ions to pass, inducing the generation of action potential by temporarily changing the charge of the cell.
With a mutated gene, the translated protein improperly folds its pore within the cell membrane rendering the channel inactive.
Such mutations reduce the number of channels produced, which leads to the development of Dravet syndrome.
Criteria for DS requires the patient to present with several of the following symptoms:
Onset of seizures in the first year of life in an otherwise healthy infant
Initial seizures are typically prolonged and are generalized or unilateral
Presence of other seizure types
Seizures associated with fever due to illness or vaccinations
Seizures induced by prolonged exposure to warm temperatures
Seizures in response to strong
lighting 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 gait and balance issues
Ankle pronation and flat feet and/or development of a crouched gait with age
TREATMENT:
Seizures in Dravet syndrome can be difficult to manage.
Seizures may be reduced by anticonvulsant medications.
A ketogenic diet may be beneficial.
No cure exists and those with this disease have myoclonic epilepsy for the rest of their lives.
Carbamazepine, gabapentin, lamotrigine, and phenytoin classified as sodium channel blockers are now known to make seizures worse in these patients.
Cognitive rehabilitation through psychomotor and speech therapy are offered.
Preventative for recurrence of febrile are usually insufficient.
Stiripentol is the only medication for which a double-blind placebo-controlled randomized controlled trial was performed and showed efficacy in trials.
Stiripentol acts as a GABAergic agent and as a positive allosteric modulator of GABAA receptor.
Stiripentol, can improve focal refractory epilepsy, as well as Dravet’s syndrome.
Cannabidiol (CBD) treatment of Dravet syndrome showed that the frequency of seizures per month decreased from 12 to 6 compared with a decrease from 15 to 14 with placebo.
Seizures in Dravet syndrome may be managed by anticonvulsant medications such as clobazam, stiripentol, topiramate and valproate.
A ketogenic diet high in fats and low in carbohydrates may be beneficial, but does not eliminate the symptoms.
Patient with this disease will have myoclonic epilepsy for the rest of their lives.
Sodium channel blockers are now known to make seizures worse in most Dravet patients: carbamazepine, gabapentin, lamotrigine, and phenytoin.
Treatments include cognitive rehabilitation through psychomotor and speech therapy.
Valproate is often used to prevent recurrence of febrile seizures and a benzodiazepine is used for long lasting seizures, but are usually insufficient.
Stiripentol acts as a GABAergic agent and is a positive modulator of GABAA receptor.
Stiripentol, can improve focal refractory epilepsy, as well as Dravet’s syndrome, and has been found to reduce overall seizure rate by 70%.
In patients with drug-resistant seizures, topiramate and the ketogenic diet are used as alternative treatments.
Cannabidiol (CBD) was approved in United States for treatment of Dravet syndrome, as it showed that the frequency of seizures per month decreased from 12 to 6 with its use of cannabidiol.
Fenfluramine is approved for treatment.