Última actualización:
July 24, 2020
Años publicados: 2009, 2012, 2015, 2018
NORD gratefully acknowledges Joseph Sullivan, MD, University of California, San Francisco; Kelly Knupp, MD, Children’s Hospital Colorado; Elaine Wirrell, MD, Mayo Clinic; and the Dravet Syndrome Foundation for assistance in the preparation of this report.
Dravet syndrome (DS) is a severe form of epilepsy characterized by frequent, prolonged seizures often triggered by high body temperature (hyperthermia), developmental delay, speech impairment, ataxia, hypotonia, sleep disturbances, and other health problems. DS is thought to be at the severe end of a spectrum of disorders associated with changes (mutations) in genes for the sodium ion channel. The sodium ion channel is a gated pore-like structure in the cell membrane that regulates the movement of sodium ions into and out of the cell, helping to propagate electrical signals along neurons. Sodium ion channels are critical components of any tissue requiring electrical signals including the brain and heart. More than 80% of patients with Dravet syndrome have a mutation in the SCN1A gene (Rosander 2015), but not all SCN1A mutations lead to Dravet syndrome. DS is considered an epileptic encephalopathy, or disorder of the brain due to seizures. In addition, it is considered a “channelopathy” because the effects of the mutation on the sodium channel appear to contribute to the disorder independently of the seizures.
DS appears during the first year of life in an otherwise healthy infant, usually with a generalized tonic clonic or hemiclonic seizure which is often prolonged (>5 minutes). Status epilepticus, or a seizure lasting longer than 5 minutes and sometimes 30 minutes or more, is common, especially in the early years, and requires emergency medical intervention. Additional seizure types including myoclonic, atypical absence, and complex partial seizures appear before age 5 years (Wirrell 2017).
The EEG, imaging, and development are usually normal at first, but abnormal EEGs and developmental delays often appear in the 2nd and 3rd years of life (Wirrell 2017). Delay can range from mild (rare) to moderate/severe (common), and most adult patients are dependent on caregivers (Catarino 2011).
Incoordination (ataxia) and low muscle tone (hypotonia) are often apparent in the early years and remain a characteristic of the syndrome throughout life (Villas 2017). Gait may worsen over time leading to decreased mobility in adolescence. Speech delay is frequently seen before age 2 years. Physical, occupational, and speech therapy are recommended (Wirrell 2017). Other common characteristics and health problems include behavioral issues, growth and nutrition issues, and disruptions of the autonomic nervous system, which regulates things such as body temperature and sweating (Lagae 2018).
Mortality is elevated in Dravet syndrome above that found in the general population of epilepsy patients. Estimates of mortality range from 15% to 20% by adulthood. Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death and usually occurs during sleep. The second most common cause of death is status epilepticus (SE) and complications from SE (Cooper 2016).
Other conditions believed to be on the spectrum of SCN1A-associated disorders include (in order of increasing severity):
The average age at seizure onset is 5.2 months, with a range of 1-18 months, but most often under 12 months (Cetica 2017, Wirrell 2017). The first seizure is often prolonged, either of the generalized tonic clonic or hemiclonic variation, and may or may not be associated with fever. Shorter seizures may also occur. Hyperthermia, or overheating, is a common seizure trigger in DS, and patients display heightened sensitivity to warm baths, fevers, exertion, and other forms of temperature elevation (Wirrell 2017).
Myoclonic seizures, when they occur, are typically seen by age 2 years but are not required for diagnosis. Non-convulsive status (obtundation status) focal seizures with impaired awareness and atypical absence seizures generally occur after 2 years. Typical absence seizures and epileptic spasms are unusual. The initial EEG, CT, MRI, and spinal tap are often normal, although background slowing may be evident if performed after a seizure. Subsequent EEGs may show diffuse slowing and/or generalized discharges while other imaging remains normal. MRI may show mild generalized atrophy or hippocampal sclerosis later in life. Development is usually on track during the first year but delay often appears in the 2nd and 3rd years of life and is usually evident by age 18-60 months (Wirrell 2017).
In older children and adults, seizures persist, though status epilepticus becomes less frequent with time. Developmental delay, speech impairment, crouched gait, hypotonia, lack of coordination, and impaired dexterity are evident.
Any patient with a clinical history suggestive of DS should undergo genetic testing for SCN1A and/or other epilepsy-related genes. The presence of an SCN1A mutation can help confirm diagnosis, but the presence of a mutation alone is not sufficient for diagnosis, nor does the absence of a mutation exclude diagnosis. Most experts believe an infant with two or more prolonged generalized tonic clonic or hemiclonic seizures with or without fever before age 12 months should undergo genetic testing (Wirrell 2017).
Dravet syndrome is associated with a mutation in the SCN1A gene in 80-90% of cases (Rosander 2015). Improved genetic testing including duplication, deletion, and mosaicism identification continues to increase this percentage (Djemie 2016). Missense (40%), nonsense (20%), frameshift (20%), duplications/deletions (7%), and splice site mutations (10%) have all been associated with Dravet syndrome. (A description of different types of gene mutations is available here: https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations )
Milder presentations (phenotypes) of conditions associated with SCN1A are more often associated with missense mutations, but neither the type of mutation nor the location on the gene corresponds to clinical severity of DS. (gzneurosci.com/scn1adatabase/by_im_phenotype.php)
90% of mutations appear to be de novo, or new to the child and not inherited from a parent. In the documented cases of inherited SCN1A mutations, the parent has a milder form of epilepsy or no neurological symptoms, whereas the child presents with DS. Improved testing has discovered mosaic mutations in parents who previously tested negative for an SCN1A mutation. Mosaicism is a condition in which some cells within a person differ genetically from other cells within that same person. This can happen shortly after fertilization, when a single cell within a cluster of cells undergoes a spontaneous mutation. Only the cells descending from that mutated cell will carry the mutation: The non-mutated cells will give rise to healthy cells, and thus the developed individual may have slightly different makeup of his/her cells.
Risk of recurrence is 50% in families with inherited SCN1A mutations. Because of the identification of mosaicism and the possibility of mutations in egg or sperm cells (germ-line mutations), the risk of recurrence for even apparently de novo mutations is elevated above that of the general public, and thus genetic counseling is recommended.
Other genes have been associated with DS including SCN2A, SCN8A, GABRA1, GABARG2, PCDH19, STXBP1, and SCN1B, but the clinical presentation in these cases is often somewhat atypical of DS (Wirrell 2017).
Dravet syndrome affects an estimated 1:15,700 individuals in the U.S., or 0.0064% of the population (Wu 2015). Approximately 80-90% of those, or 1:20,900 individuals, have both an SCN1A mutation and a clinical diagnosis of DS. This represents an estimated 0.17% of all epilepsies.
Dravet syndrome is a clinical diagnosis. Presentation is uniquely characteristic and, according to the 2017 consensus of North American neurologists with expertise in DS, includes:
In older children and adults:
Treatment
Although there is no cure for Dravet syndrome, most treatments aim to reduce seizures. First line anti-seizure medications include clobazam (Onfi, Frisium) and valproic acid (Depakote, Depakene). Second line treatments include stiripentol (Diacomit), topiramate (Topamax), and the ketogenic diet. Variations of the ketogenic diet including the Modified Atkins Diet may also be beneficial in DS. Third line treatments include clonazepam (Klonopin), levetiracetam (Keppra), zonisamide (Zonegran), ethosuximide (Zarontin), and vagal nerve stimulator (VNS) (Wirrell 2017).
In 2018, Epidiolex (cannabidiol or CBD) was approved by the U.S. Food and Drug Administration (FDA) to treat seizures associated with Dravet syndrome in patients two years of age and older. Epidiolex was the first FDA-approved product to treat Dravet syndrome. Also in 2018, Dicomit (stiripentol) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older who are also taking clobazam.
Most recently, in 2020, Fintepla (fenfluramine) was approved for the treatment of seizures associated with Dravet syndrome in patients two years of age and older.
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). Note that phenytoin and fosphenytoin should be avoided as a daily medication but their efficacy in emergency treatment of status epilepticus is unclear.
Status epilepticus is frequent in DS and caregivers should be trained to administer at-home medications to stop prolonged seizures. Rectal diazepam and buccal (by mouth) or intranasal (via the nose) midazolam are frequently used.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
JOURNAL ARTICLES
de Lange IM, Koudijs MJ, van ‘t Slot R, Gunning B, Sonsma ACM, van Gemert LJJM, Mulder F, Carbo EC, van Kempen MJA, Verbeek NE, Nijman IJ, Ernst RF, Savelberg SMC, Knoers NVAM, Brilstra EH, Koeleman BPC. Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. Epilepsia. 2018 Mar;59(3):690-703. doi: 10.1111/epi.14021. Epub 2018 Feb 20. PubMed PMID: 29460957.
Lagae L, Brambilla I, Mingorance A, Gibson E, Battersby A. Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey. Dev Med Child Neurol. 2018 Jan;60(1):63-72. doi: 10.1111/dmcn.13591. Epub 2017 Oct 6. PubMed PMID: 28984349.
Cetica V, Chiari S, Mei D, Parrini E, Grisotto L, Marini C, Pucatti D, Ferrari A, Sicca F, Specchio N, Trivisano M, Battaglia D, Contaldo I, Zamponi N, Petrelli C, Granata T, Ragona F, Avanzini G, Guerrini R. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations. Neurology. 2017 Mar 14;88(11):1037-1044. doi: 10.1212/WNL.0000000000003716. Epub 2017 Feb 15. PubMed PMID: 28202706; PubMed Central PMCID: PMC5384833.
Villas N, Meskis MA, Goodliffe S. Dravet syndrome: Characteristics, comorbidities, and caregiver concerns. Epilepsy Behav. 2017 Sep;74:81-86. doi: 10.1016/j.yebeh.2017.06.031. Epub 2017 Jul 18. PubMed PMID: 28732259.
Wirrell EC, Laux L, Donner E, Jette N, Knupp K, Meskis MA, Miller I, Sullivan J, Welborn M, Berg AT. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol. 2017 Mar;68:18-34.e3. doi: 10.1016/j.pediatrneurol.2017.01.025. Epub 2017 Feb 4. PubMed PMID: 28284397.
Djémié T, Weckhuysen S, von Spiczak S, Carvill GL, Jaehn J, Anttonen AK, Brilstra E, Caglayan HS, de Kovel CG, Depienne C, Gaily E, Gennaro E, Giraldez BG, Gormley P, Guerrero-López R, Guerrini R, Hämäläinen E, Hartmann C, Hernandez-Hernandez L, Hjalgrim H, Koeleman BP, Leguern E, Lehesjoki AE, Lemke JR, Leu C, Marini C, McMahon JM, Mei D, Møller RS, Muhle H, Myers CT, Nava C, Serratosa JM, Sisodiya SM, Stephani U, Striano P, van Kempen MJ, Verbeek NE, Usluer S, Zara F, Palotie A, Mefford HC, Scheffer IE, De Jonghe P, Helbig I, Suls A; EuroEPINOMICS‐RES Dravet working group.. Pitfalls in genetic testing: the story of missed SCN1A mutations. Mol Genet Genomic Med. 2016 Apr 14;4(4):457-64. doi: 10.1002/mgg3.217. eCollection 2016 Jul. PubMed PMID: 27465585; PubMed Central PMCID: PMC4947864.
Cooper MS, Mcintosh A, Crompton DE, McMahon JM, Schneider A, Farrell K, Ganesan V, Gill D, Kivity S, Lerman-Sagie T, McLellan A, Pelekanos J, Ramesh V, Sadleir L, Wirrell E, Scheffer IE. Mortality in Dravet syndrome. Epilepsy Res. 2016 Dec;128:43-47. doi: 10.1016/j.eplepsyres.2016.10.006. Epub 2016 Oct 26. PubMed PMID: 27810515.
Rosander C, Hallböök T. Dravet syndrome in Sweden: a population-based study. Dev Med Child Neurol. 2015 Mar 13. doi: 10.1111/dmcn.12709. [Epub ahead of print] PubMed PMID: 25772213.
Wu YW, Sullivan J, McDaniel SS, Meisler MH, Walsh EM, Li SX, Kuzniewicz MW. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015 Nov;136(5):e1310-5. doi: 10.1542/peds.2015-1807. Epub 2015 Oct 5. PubMed PMID: 26438699; PubMed Central PMCID: PMC4621800.
Catarino CB, Liu JY, Liagkouras I, Gibbons VS, Labrum RW, Ellis R, Woodward C, Davis MB, Smith SJ, Cross JH, Appleton RE, Yendle SC, McMahon JM, Bellows ST, Jacques TS, Zuberi SM, Koepp MJ, Martinian L, Scheffer IE, Thom M, Sisodiya SM. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain. 2011 Oct;134(Pt 10):2982-3010. doi: 10.1093/brain/awr129. Epub 2011 Jun 29. PubMed PMID: 21719429; PubMed Central PMCID: PMC3187538.
INTERNET
Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical , Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou 510260, China. 2014 gzneurosci.com/scn1adatabase/by_im_phenotype.php. Accessed June 19, 2018.
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