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Dravet syndrome ( DS), previously known as severe myoclonic epilepsy of infancy ( SMEI), 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. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, characterized by prolonged convulsions and triggered by fever, usually begin.
Prolonged seizures in the first year of life are the most indicative physical manifestation of DS. DS is diagnosed clinically and genetic testing is recommended if there is any doubt. Due to drug-refractory epilepsy in DS, many other therapies are being explored to prolong the life expectancy of patients.
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 hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals. However, any seizure uninterrupted after 5 minutes, without a resumption of postictal (more normal; recovery-type; after-seizure) consciousness can lead to potentially fatal status epilepticus.
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. However, this is likely a non-specific response to fever, as vaccination often induces fever, and fever is known to be associated with seizures in persons with Dravet syndrome. Some of the patients who put forth vaccine injury claims from encephalopathy were later found, upon testing, to actually have Dravet syndrome.
Currently, the SCN1A gene is the most clinically relevant; the largest number of DS-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.
Dravet syndrome is generally associated with mutations in the SCN1A gene, but it can also be found in patients with other mutations. Likewise, the presence of a mutation in the SCN1A gene does not necessarily mean that the patient has Dravet syndrome.
- SCN2A: This gene encodes the alpha-2 subunit of the sodium ion channel (Nav1.2). The expression of this gene increases throughout childhood (unlike SCN1A, which peaks at 7–9 months) and is primarily produced in hippocampal neurons. Mutations in the SCN2A gene have been found in patients with various syndromes, and unlike SCN1A mutations, patients often respond to sodium channel blockers.
- SCN8A: This gene encodes the alpha-8 subunit (Nav1.6) and is primarily expressed in excitatory neurons (unlike SCN1A, which is inhibitory). The clinical presentation is distinct from Dravet syndrome, and patients sometimes experience epileptic spasms (not typically observed in Dravet syndrome), are less susceptible to fever-related seizures, generally do not have myoclonic seizures, and often respond to sodium channel blockers.
- SCN9A: This gene encodes the alpha-9 subunit (Nav1.7), expressed in cells of the dorsal root ganglia, neuroendocrine cells, and smooth muscle. Mutations in this gene cause sensory disorders, including an abnormal response to pain. Some Dravet syndrome patients have been found to have mutations in the SCN9A gene, but there is likely a more polygenic cause of Dravet syndrome in these cases.
- SCN1B: This gene encodes the beta-1 subunit of the sodium ion channel, which regulates sodium channel entry on the outer side of the cell membrane. Mutations in the SCN1B gene have been found in several patients with Generalized Epilepsy with Febrile Seizures Plus (GEFS+), but very few with Dravet syndrome.
- PCDH19: This gene, located on the X chromosome, encodes protocadherin 19, a protein that helps neurons adhere to each other as they migrate to form networks and recognize other cells. Because males only possess one copy of the X chromosome, even if this mutation occurs in males, it creates a type of cells containing functional protocadherin 19, so no problems occur. However, it is believed that females (who have two X chromosomes) are affected when one copy is mutated and the other is normal. Therefore, two different populations of cells containing protocadherin 19 are generated, and their abnormal interactions are believed to cause the disease's symptoms. Epilepsy with Mental Retardation limited to Females (EFMR) is its own syndrome, primarily affecting females, although it mimics and resembles Dravet syndrome in several aspects. Seizure onset is later in this epilepsy (an average of about 11 months versus the average of 6 months in Dravet syndrome), photosensitivity is less common, seizure clusters are more frequent and respond to steroids, an approach not used in Dravet syndrome.
- GABRA1: GABA is the primary neurotransmitter. The receptors on neurons that accept this neurotransmitter are called "GABR" (R for receptor) and are divided into two groups: A and B. GABRA1 encodes the alpha-1 receptor, and mutations are found in several epilepsies, including Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy, and Genetic Generalized Epilepsy. Some cases of Dravet syndrome are associated with mutations in the GABRA1 gene.
- GABRG2: This gene encodes the GABA gamma-2 receptor, and mutations have been found in patients with Generalized Epilepsy with Febrile Seizures Plus (GEFS+), as well as in some Dravet syndrome patients.
- STXBP1: This gene encodes the syntaxin-binding protein 1, which is involved in the vesicle fusion process (sacs containing substances like neurotransmitters) of the cell with the membrane. Therefore, mutations in this gene can affect the cell's ability to release neurotransmitters. Mutations have been found in patients with Ohtahara syndrome, West syndrome, and non-specific epilepsies with variable components of intellectual disability and movement disorders.
- HCN1: This gene encodes a non-selective positive ion channel (allowing the passage of calcium, potassium, and other positive ions), and mutations generally result in a gain of function. In some Dravet patients with HCN1 mutation, the presentation is similar to classic Dravet syndrome.
- CHD2: This gene encodes the chromodomain helicase DNA-binding protein 2, which modifies gene expression. All patients diagnosed as Dravet syndrome with CHD2 mutations began their epilepsy later than usual (ages 1, 2, and 3 years), which generally seems to be a common feature of CHD2 mutations. It has also been described in patients with Jeavons syndrome, Lennox-Gastaut syndrome, and other epilepsies.
- KCNA2: This gene encodes a delayed potassium channel that helps a neuron repolarize after activation. Patients believed to have Dravet syndrome with this mutation managed to remain seizure-free in adulthood, a result that is often not achieved in classic Dravet syndrome.
Certain anticonvulsant medications that are classed as sodium channel blockers are now known to make seizures worse in most Dravet patients. These medications include carbamazepine, gabapentin, lamotrigine, and phenytoin.
As there are still very few randomized controlled trials (RCTs) available, evidence-based therapy remains difficult: RCTs are now only available for the drugs fenfluramine (FFA), cannabidiol (CBD), and stiripentol (STP). A North American consensus panel and, more subsequently, a European expert committee both established treatment guidelines.
As a first-line medication, valproic acid (VPA) is recommended in both published recommendations. The American recommendations provide clobazam (CLB) monotherapy as an alternative; however, very few European facilities would use it. It is a prevalent misconception that since the first seizures are typically hemiclonic (focal), antiseizure medicine (ASM) can be a good choice for focal seizures. However, using sodium channel blockers is not recommended as it is can lead to fatal results over an extended period.
Children may experience fewer seizures and less severe, shorter seizures as a result of first-line therapy with VPA; however, it is uncommon for them to live a life free of seizures. According to the recommendations, second-line options include the ketogenic diet (KD), topiramate (TPM), and STP combined with VPA and CLB. The more current European recommendations now mention CBD and FFA as potential second-line treatments (in Europe, CLB and CBD are combined).
Treatments include cognitive rehabilitation through psychomotor and speech therapy. In addition, valproate is often administered to prevent recurrence of febrile seizures and a benzodiazepine is used for long lasting seizures, but these treatments are usually insufficient.
Stiripentol was the only medication for which a double-blind placebo-controlled randomized controlled trial was performed and this medication showed efficacy in trials. It acts as a GABAergic agent and as a positive allosteric modulator of GABAA receptor. Stiripentol, which can improve focal refractory epilepsy, as well as Dravet's syndrome, 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. A Cochrane review first published in 2014 and updated 2022 called for larger, randomized, well controlled trials to be able to draw conclusions.
Cannabidiol (CBD) was approved in United States for treatment of Dravet syndrome in 2018. A 2017 study showed that 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.
In 2020, fenfluramine was approved for the medical treatment in the European Union and the USA. Fintepla, on ema.europa.eu Fintepla (fenfluramine). An overview of Fintepla and why it is authorised in the EU, on ema.europa.eu
target="_blank" rel="nofollow"> FDA Approves New Therapy for Dravet Syndrome, on fda.gov
Prior to the age of 20, photosensitivity and pattern sensitivity each have a tendency to vanish; nevertheless, some individuals still displayed light sensitivity. Consequently, for those who are older, triggering variables ought to be minimized.
Stoke Therapeutics developed STK-001 is an antisense oligonucleotide (ASOs) that can modify gene expression in the nervous system. The FDA approved ASOs for treatment of ten genetic disorders. The technique consists of targeted augmentation of nuclear gene output which allows to selectively boost expression only in tissues where the protein is normally expressed. STK-001 can increase the level of productive SCN1A mRNA by preventing inclusion of a poison exon and consequently increase the expression of sodium channel gene SCN1A.
Stoke Therapeutics is currently evaluating the long-term safety and tolerability of repeated doses of STK-001 in patients with Dravet syndrome. Change in seizure frequency, overall clinical status and quality of life will be measured as secondary endpoints in this open-label study. Recently, the company announced positive results of MONARCH and ADMIRAL in which patients received 3 doses of STK-001 and were observed for 6 months.
In parallel, Encoded Therapeutics is developing an adeno-associated virus serotype 9 (AAV9) SCN1A gene regulation therapy. It has been designed to target transgene expression to GABAergic inhibitory neurons and reduce off-target expression within excitatory cells. In this case, the treatment would be administered as a single dose intracerebroventricularly. This company has started a clinical trial in phase 1 and 2 to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome aged 6 to 36 months.
Charlotte Figi, who was diagnosed as having Dravet syndrome, was the focus of a cause célèbre to provide a means for use of cannabidiol for persons with intractable seizures. She died from pneumonia, possibly caused by COVID-19, in April, 2020.
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