Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare, severe form of childhood epilepsy in which multiple types of seizures, which are recurrent and often prolonged, typically manifest within the first year of life. DS, a lifelong neurological condition, is one of the classic epileptic encephalopathies, in which repeated, treatment-resistant seizures contribute to progressive cognitive decline, motor dysfunction, behavioral problems, and neurodevelopmental delay or regression.¹ 

The Role of the SCN1A Gene in DS

More than 75% of patients with DS carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel protein Na_V1.1. As a result, voltage-gated sodium channels are either dysfunctional or absent.² The regulation of electrical currents is disrupted, and the sodium concentrations necessary for neuronal communication and action potential firing, specifically in GABAergic inhibitory interneurons in the brain, are lacking. Without inhibition, the neurons in the brain are hyperexcitable and promote seizure activity.³ 

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Types of SCN1A Mutations in DS

Researchers have identified more than 500 mutations of the SCN1A gene that are associated with DS, most of which are sequencing mutations. Sequencing mutations include truncating mutations (40%), missense mutations (40%), and splice-site changes (20%).⁴ 

Patients who have a diagnosis of DS without sequence-based mutations of the SCN1A gene may have SCN1A exon deletions or chromosomal rearrangements between SCN1A and nearby genes.⁴ Approximately 12.5% of patients with DS who tested negative for sequence-based mutations in SCN1A demonstrated copy number variations in the SCN1A gene, detected on multiplex ligation-dependent probe amplification (MLPA).⁵

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Approximately 1871 pathological SCN1A variants have been identified.⁶ However, not all mutations of the SCN1A gene cause DS exclusively, but rather a spectrum of disorders ranging from relatively mild conditions, such as migraines, to severe febrile seizures or generalized epilepsy with febrile seizures plus (GEFS+). Severity correlates with Na_V1.1 function: Mild impairments are linked to mild phenotypes, and mutations resulting in complete loss of function cause DS.³

However, the type of mutation does not solely predict disease severity. Diverse modifying factors, including environmental and epigenetic factors, play a role in determining disease severity and development of the epileptic phenotype.^3,6

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De Novo Mutations

Approximately 90% of the SCN1A mutations in patients with DS arise de novo after conception, meaning that most patients with DS have no existing family history of the condition and have not inherited the disorder from a parent.^2,4

Autosomal-Dominant Inheritance

Up to approximately 10% of SCN1A mutations are directly inherited from one parent in an autosomal-dominant pattern, with a 50% chance of passing the mutation on to future children.^2,7 Autosomal-recessive forms of DS have been rarely documented.⁶

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Mosaicism

In one study, approximately 7% of families with inherited DS exhibited mosaicism,^4,8 in which a person has 2 or more genetically different sets of cells in his or her body.⁹ Mosaicism was found in blood cells of the transmitting parent in these families.⁸ 

According to one study, SCN1A mutations with a 12% to 25% mosaic load may become pathogenic but have low penetrance, so that the expression of signs and symptoms is variable.¹⁰ Some patients with mosaicism may be asymptomatic carriers of SCN1A mutations.³

Other Genes

Although most patients with DS have SCN1A mutations, several other genes have been associated with the development of DS. These include SCN1B, SCN2A, GABRA1, GABRG2, and PCDH19.⁷

Genetic Testing

Genetic testing, in which a peripheral blood sample is used to detect sequencing mutations in the SCN1A gene, often confirms a diagnosis of DS. Multiplex-ligation dependent probe amplification (MLPA) testing specifically detects deletions and duplications within the SCN1A gene.¹¹ 

If the results of these genetic tests are negative, an evaluation of other genes associated with DS may be helpful; however, a small minority of patients with DS will not test positive for any genetic mutations, and a clinical diagnosis is required.¹¹ 

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References

1. Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet syndrome: an overview. Cureus. 2019;11(6):e5006. doi:10.7759/cureus.5006
2. Genetics of Dravet syndrome. Dravet Syndrome Foundation. Accessed March 20, 2023.
3. Catterall WA. Dravet syndrome: a sodium channel interneuronopathy. Curr Opin Physiol. 2018;2:42-50. doi:10.1016/j.cophys.2017.12.007
4. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52(s2):24-29. doi:10.1111/j.1528-1167.2011.02997.x
5. Marini C, Scheffer IE, Nabbout R, et al. SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia. 2009;50(7):1670-1678. doi:10.1111/j.1528-1167.2009.02013.x
6. Marco Hernández AV, Tomás Vila M, Caro Llopis A, Monfort S, Martinez F. Case report: novel homozygous likely pathogenic SCN1A variant with autosomal recessive inheritance and review of the literature. Front Neurol. 2021;12:784892. doi:10.3389/fneur.2021.784892
7. Dravet syndrome. GARD. Accessed March 20, 2023.
8. Depienne C, Trouillard O, Gourfinkel-An I, et al. Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. J Med Genet. 2010;47(6):404-410. doi:10.1136/jmg.2009.074328
9. Chromosome mosaicism. Yale Medicine. Accessed March 20, 2023.
10. Meng H, Xu HQ, Yu L, et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat. 2015;36(6):573-580. doi:10.1002/humu.22782
11. Stenhouse SAR, Ellis R, Zuberi S. SCN1A genetic test for Dravet syndrome (severe myoclonic epilepsy of infancy and its clinical subtypes) for use in the diagnosis, prognosis, treatment and management of Dravet syndrome. PLoS Curr. 2013;5:ecurrents.eogt.c553b83d745dd79bfb61eaf35e522b0b. doi:10.1371/currents.eogt.c553b83d745dd79bfb61eaf35e522b0b

Reviewed by Kyle Habet, MD, on 3/28/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.