Molecular Genetics of Dravet Syndrome

Abstract

Dravet syndrome is a severe epilepsy disorder characterised by infantile onset of fever‐sensitive seizures. Seizures are therapy resistant, and although children develop normal in the first year of life, progressive cognitive decline occurs soon after seizure onset. Dravet syndrome has a genetic etiology and mutations in the sodium channel α1 subunit gene (SCN1A) are found in approximately 70% of patients. Most mutation occur de novo, although some familial SCN1A mutations have been reported. A small percentage of female patients with a phenotype resembling Dravet syndrome have a mutation in the protocadherin 19 gene (PCDH19) on the X‐chromosome. Rare mutations have been found in a few other ion channel genes, but still the genetic cause of approximately 20% of patients with Dravet syndrome remains unknown.

Key Concepts:

  • Dravet syndrome is the most frequent indication for DNA analysis within the group of epileptic encephalopathies.

  • In approximately 70% of patients with Dravet syndrome, a heterozygous dominant de novo mutation in SCN1A can be identified.

  • In patients with a clinical diagnosis of Dravet syndrome who test negative for SCN1A sequence‐based mutations, additional tests that are capable of detecting copy number variations such as MAQ, MLPA or aCGH are required as SCN1A whole gene or exonic deletions/duplications can be missed on Sanger sequencing.

  • SCN1A mutations in Dravet syndrome lead to haploinsufficiency of the gene.

  • Dravet syndrome is at the most severe end of the GEFS+ spectrum.

  • SCN1A germline and somatic mosaicisms are important causes of recurrence of Dravet syndrome within siblings and intrafamilial clinical heterogeneity.

  • In 25% of female patients with Dravet syndrome who test negative for SCN1A mutations a PCDH19 mutation can be found.

  • In 20% of patients with Dravet syndrome the etiology remains unknown after diagnostic testing of all relevant genes.

Keywords: Dravet syndrome; SMEI; SCN1A; PCDH19; copy number variation; haploinsufficiency; mosaicism

Figure 1.

Structure of the Nav1.1 channel coded by the SCN1A gene.

close

References

Baulac S, Huberfeld G, Gourfinkel‐An I et al. (2001) First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2‐subunit gene. Nature Genetics 28(1): 46–48.

Berkovic SF, Harkin L, McMahon JM et al. (2006) De‐novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurology 5(6): 488–492.

Carranza Rojo D, Hamiwka L, McMahon JM et al. (2011) De novo SCN1A mutations in migrating partial seizures of infancy. Neurology 77(4): 380–383.

Carvill SCY Gl, McMahon J, Cook J et al. (2011) Whole Exome Sequencing in SCN1A‐negative Dravet Syndrome Reveals Novel Candidate Genes and Suggests Genetic Heterogeneity. Abstract Presented at the 12th International Congress of Human Genetics/61st Annual Meeting of The American Society of Human Genetics, 12 October 2011, Montreal, Canada.

Claes L, Del‐Favero J, Ceulemans B et al. (2001) De novo mutations in the sodium‐channel gene SCN1A cause severe myoclonic epilepsy of infancy. American Journal of Human Genetics 68(6): 1327–1332.

Claes LR, Deprez L, Suls A et al. (2009) The SCN1A variant database: a novel research and diagnostic tool. Human Mutation 30(10): E904–E920.

Depienne C, Arzimanoglou A, Trouillard O et al. (2006) Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy. Human Mutation 27(4): 389.

Depienne C, Bouteiller D, Keren B et al. (2009a) Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genetics 5(2): e1000381.

Depienne C, Trouillard O, Bouteiller D et al. (2011) Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Human Mutation 32(1): E1959–E1975.

Depienne C, Trouillard O, Gourfinkel‐An I et al. (2010) Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome. Journal of Medical Genetics 47(6): 404–410.

Depienne C, Trouillard O, Saint‐Martin C et al. (2009b) Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. Journal of Medical Genetics 46(3): 183–191.

Dibbens LM, Tarpey PS, Hynes K et al. (2008) X‐linked protocadherin 19 mutations cause female‐limited epilepsy and cognitive impairment. Nature Genetics 40(6): 776–781.

Dravet C (2011) The core Dravet syndrome phenotype. Epilepsia 52(suppl. 2): 3–9.

Escayg A, MacDonald BT, Meisler MH et al. (2000) Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics 24(4): 343–345.

Freilich ER, Jones JM, Gaillard WD et al. (2011) Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Archives of Neurology 68(5): 665–671.

Fujiwara T, Sugawara T, Mazaki‐Miyazaki E et al. (2003) Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures. Brain 126(part 3): 531–546.

Harkin LA, Bowser DN, Dibbens LM et al. (2002) Truncation of the GABA(A)‐receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. American Journal of Human Genetics 70(2): 530–536.

Harkin LA, McMahon JM, Iona X et al. (2007) The spectrum of SCN1A‐related infantile epileptic encephalopathies. Brain 130(part 3): 843–852.

Lossin C (2009) A catalog of SCN1A variants. Brain Development 31(2): 114–130.

Madia F, Striano P, Gennaro E et al. (2006) Cryptic chromosome deletions involving SCN1A in severe myoclonic epilepsy of infancy. Neurology 67(7): 1230–1235.

Marini C, Mei D, Parmeggiani L et al. (2010) Protocadherin 19 mutations in girls with infantile‐onset epilepsy. Neurology 75(7): 646–653.

Marini C, Mei D, Temudo T et al. (2007) Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia 48(9): 1678–1685.

Marini C, Scheffer IE, Nabbout R et al. (2009) SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis. Epilepsia 50(7): 1670–1678.

Meisler MH and Kearney JA (2005) Sodium channel mutations in epilepsy and other neurological disorders. Journal of Clinical Investigation 115(8): 2010–2017.

Mulley JC, Scheffer IE, Petrou S et al. (2005) SCN1A mutations and epilepsy. Human Mutation 25(6): 535–542.

Nabbout R, Gennaro E, Dalla Bernardina B et al. (2003) Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology 60(12): 1961–1967.

Nakayama T, Ogiwara I, Ito K et al. (2010) Deletions of SCN1A 5′ genomic region with promoter activity in Dravet syndrome. Human Mutation 31(7): 820–829.

Ogiwara I, Miyamoto H, Morita N et al. (2007) Nav1.1 localizes to axons of parvalbumin‐positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. Journal of Neuroscience 27(22): 5903–5914.

Patino GA, Claes LR, Lopez‐Santiago LF et al. (2009) A functional null mutation of SCN1B in a patient with Dravet syndrome. Journal of Neuroscience 29(34): 10764–10778.

Ragsdale DS (2008) How do mutant Nav1.1 sodium channels cause epilepsy? Brain Research Reviews 58(1): 149–159.

Scheffer IE and Berkovic SF (1997) Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 120(part 3): 479–490.

Shi X, Yasumoto S, Nakagawa E et al. (2009) Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Development 31(10): 758–762.

Singh NA, Pappas C, Dahle EJ et al. (2009) A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genetics 5(9): e1000649.

Suls A, Claeys KG, Goossens D et al. (2006) Microdeletions involving the SCN1A gene may be common in SCN1A‐mutation‐negative SMEI patients. Human Mutation 27(9): 914–920.

Wallace RH, Hodgson BL, Grinton BE et al. (2003) Sodium channel alpha1‐subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms. Neurology 61(6): 765–769.

Wallace RH, Wang DW, Singh R et al. (1998) Febrile seizures and generalized epilepsy associated with a mutation in the Na+‐channel beta1 subunit gene SCN1B. Nature Genetics 19(4): 366–370.

Yu FH, Mantegazza M, Westenbroek RE et al. (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience 9(9): 1142–1149.

Zuberi SM, Brunklaus A, Birch R et al. (2011) Genotype–phenotype associations in SCN1A‐related epilepsies. Neurology 76(7): 594–600.

Further Reading

Dravet C (2011) Dravet syndrome history. Developmental Medicine & Child Neurology 53(suppl. 2): 1–6.

Dravet C and Guerrinim R (2011) Topics in Epilepsy: Dravet Syndrome. Montrouge, France: John Libbey Eurotext.

Meisler MH, O'Brien JE and Sharkey LM (2010) Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. Journal of Physiology 588(part 11): 1841–1848.

Mullen SA and Scheffer IE (2009) Translational research in epilepsy genetics: sodium channels in man to interneuronopathy in mouse. Archives of Neurology 66(1): 21–26.

Nabbout R and Dulac O (2008) Epileptic syndromes in infancy and childhood. Current Opinion in Neurology 21(2): 161–166.

Roger J, Bureau M, Dravet Ch and Genton P (2006) Chapter 7: Severe Myoclonic Epilepsy of Infancy (Dravet syndrome); Epileptic Syndromes in Infancy, Childhood and Adolescence. Montrouge, France: John Libbey Eurotext, pp. 89–114.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Weckhuysen, Sarah, Suls, Arvid, and de Jonghe, Peter(Mar 2012) Molecular Genetics of Dravet Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023846]