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Dravet Syndrome

Dravet's Syndrome, Severe myoclonic epilepsy of infancy, SMEI, Myoclonic epilepsy, severe, of infancy, SME

Overview

Dravet syndrome is a severe form of epilepsy with seizures that are often triggered by hot temperatures or fever. The condition appears during the first year of life as frequent fever-related (febrile) seizures. As the condition progresses, other types of seizures typically occur, including myoclonus and status epilepticus. A family history of either epilepsy or febrile seizures exists in 15 percent to 25 percent of cases. Intellectual development begins to deteriorate around age 2, and affected individuals often have a lack of coordination, poor development of language, hyperactivity, and difficulty relating to others. In 30 to 80 percent of cases, Dravet syndrome is caused by changes in the SCN1A gene, which is required for the proper function of brain cells.

Symptoms - Dravet Syndrome

Dravet syndrome has been characterized by prolonged febrile and non-febrile seizures within the first year of a child’s life. This disease progress to other seizure types like myoclonic and partial seizures, psychomotor delay, and ataxia. it is characterized by cognitive impairment, behavioral disorders, and motor deficits. Behavioral deficits often include hyperactivity and impulsiveness, and in more rare cases, autistic-like behaviors. Dravet syndrome is also associated with sleep disorders including somnolence and insomnia. The seizures experienced by people with Dravet syndrome become worse as the patient ages since the disease is not very predictable when first diagnosed. This coupled with the range of severity differing between each individual diagnosed and the resistance of these seizures to drugs has made it challenging to develop treatments.

Dravet syndrome appears during the first year of life, often beginning around six months of age with frequent febrile seizures (fever-related seizures). Children with Dravet syndrome typically experience a lagged development of language and motor skills, hyperactivity and sleep difficulties, chronic infection, growth and balance issues, and difficulty relating to others. 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 categories known as simple and complex. A febrile seizure would be categorized as complex if it has occurred within 24 hours of another seizure or if it lasts longer than 15 minutes. A febrile seizure lasting less than 15 minutes would be considered simple. Sometimes modest hypothermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals. However, it goes without saying that any seizure at all- whether generalized or partial, absence or tonic/clonic- that goes on uninterrupted for much longer than 2 to 5 minutes, without a resumption of postictal (more normal; recovery-type; after-seizure) consciousness, should be treated as a medical emergency, since uninterrupted seizures can lead to status epilepticus (SE) - a state of unremitting seizures that can be difficult to stop, and eventually potentially fatal, if not soon treated.

Causes - Dravet Syndrome

In most cases the mutations in Dravet syndrome are not hereditary and the mutated gene is found for the first time in a single family member. In 70-90% of patients, Dravet syndrome is caused by nonsense mutations in the SCN1A gene resulting 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. In mouse models, these loss-of-function mutations have been observed to result in a decrease in sodium currents and impaired excitability of GABAergic interneurons of the hippocampus. The researchers found that loss of NA(V)1.1 channels was sufficient to cause the epilepsy and premature death seen in Dravet syndrome.

Genetics:

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. A mutation in either of these two genes will cause an individual to develop dysfunctional sodium channels, which are crucial in the pathway for sending chemical signals in the brain, causing the phenotypic display of myoclonic epilepsy from the individual. A properly functioning channel would respond to a voltage difference across the membrane and form a pore through which only sodium ions can pass. The influx of sodium induces the generation of action potential by temporarily changing the charge of the cell. When the gene is mutated, the eventually translated protein improperly folds its pore segment within the cell membrane because it has different amino acid chemistry, which renders the channel inactive. It is also possible for a mutation to reduce the number of channels produced by an individual, which leads to the development of Dravet syndrome.

Currently, the SCN1A gene is the most clinically relevant; the largest number of epilepsy related mutations characterized thus far occur in this gene. Typically, a missense mutation in either the S5 or S6 segment of the sodium channel pore results in a loss of channel function and the development of Dravet syndrome. A heterozygous inheritance of an SCN1A mutation is all that is necessary to develop a defective sodium channel; patients with Dravet syndrome will still have one normal copy of the gene.

Prevention - Dravet Syndrome

Not supplied.

Diagnosis - Dravet Syndrome

According to the Dravet Syndrome Foundation, the diagnostic criteria for DS requires patient to present with multiple 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 (i.e. myoclonic seizures)
  • 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

Prognosis - Dravet Syndrome

  • Little information is available on the long-term prognosis and life expectancy for children with Dravet syndrome. The degree of intellectual impairment appears to correlate with the frequency of seizures. The decline in cognitive function tends to stabilize after age 4. An individual with Dravet syndrome has an 85 percent chance of surviving into adulthood.
  • Seizures are refractory to medications. This means that medical treatment is very complicated. Currently available medications are not able to achieve complete seizure control.
  • Other health problems need to be identified and treated early. These also affect a child’s development and outlook for the future.
  • People with epilepsy that is difficult to treat, who have tonic clonic seizures, who are on multiple seizure medicines, and who have developmental delays have a higher risk of Sudden Unexplained Death in Epilepsy (SUDEP).  Other causes of mortality associated with Dravet syndrome include consequences of status epilepticus and accidental death from injury or drowning.
  • While the diagnosis and consequences of Dravet Syndrome can be catastrophic, the cause is known. Ideally, more research can be targeted to improve treatment and find a cure.

Treatment - Dravet Syndrome

Seizures in Dravet syndrome are difficult to manage, but they can be somewhat reduced by anticonvulsant drugs like phenytoin or carbamazepine. Because the course of the disorder varies from individual to individual, a standard treatment protocol is difficult to establish. A diet high in fats and low in carbohydrates also may be beneficial, known as a ketogenic diet. Although diet adjustment can help, it does not eliminate the symptoms. Until a better form of treatment or cure is discovered, those with this disease will have myoclonic epilepsy for the rest of their lives.

Current therapeutic treatments include cognitive rehabilitation through psychomotor and speech therapy. In addition, valproate is often administered to prevent recurrence of febrile seizures and benzodiazapine is used for long lasting seizures, but these treatments are usually insufficient. Stiripentol was the only drug for which a double-blind placebo trial was performed and this drug showed efficacy in trials for treatment of Dravet syndrome. This compound acts as a GABAergic agent and as a positive allosteric modulator of GABAA receptor. Stiripentol, which can improve, quote: "focal refractory epilepsy", as detailed in a 2014 Cochrane Library article (by Francesco Brigo and Monica Storti), as well as Dravet's syndrome (which is, by its very definition, usually, though not always, very refractory- resistant to treatment and with a tendency to recur), supplemented with clobazam and valproate was approved in Europe in 2007 as a therapy for Dravet syndrome and has been found to reduce overall seizure rate by 70%. In cases with more drug resistant seizures, topiramate and the ketogenic diet are used as alternative treatments.

Cannabidiol (CBD) has received orphan drug status in the United States, for treatment of Dravet syndrome which will allow it to be studied.

Resources - Dravet Syndrome

  • NIH
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by Harish Ravi
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