Dravet Syndrome: a Genetic Epileptic Disorder

Review http ://escholarship.lib.okayama-u.ac.jp/amo/

Dravet Syndrome: A Genetic Epileptic Disorder

Mari Akiyama＊, Katsuhiro Kobayashi, and Yoko Ohtsuka

Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, and Okayama University Hospital, Okayama 700-8558, Japan

Dravet syndrome (DS), or severe myoclonic epilepsy in infancy, is one of the most severe types of genetic epilepsy. It is characterized by the initial occurrence of febrile or afebrile seizures that often evolve into status epilepticus in infants with normal development, and by the subsequent appearance of myoclonic and/or atypical absence seizures as well as complex partial seizures. The key feature that characterizes DS is fever sensitivity, although photosensitivity and pattern-sensitivity are also often seen. The prognosis is unfavorable in most cases. Seizures become drug-resistant and persist, with many patients suffering from motor and cognitive impairment. Mutations of SCN1A, which encodes the voltage-gated sodium channel NaV1.1, are the most frequent genetic cause of this syndrome. SCN1A mutations and/or microchromosomal rearrangements involving SCN1A are detected in about 85ｵ of patients. Mutations of PCDH19 have also been reported in female patients with clinical findings compatible with DS. PCDH19 mutations might account for 5ｵ of overall DS cases. Thirty years after its first description, DS is considered as a model of channelopathy. This survey reviews recent developments in the research literature on DS, focusing on the clinical course, as well as its genetic causes.

Key words: Dravet syndrome, long-term outcome, SCN1A, PCDH19

ravet syndrome (DS) is a rare form of child- to promote greater understanding of the clinical D hood-onset epilepsy with a genetic etiology. DS course and pathogenesis of DS. was originally named “severe myoclonic epilepsy in infancy” [1, 2], and is characterized by a variety of Clinical and Electroencephalographic treatment-resistant seizures and a poor cognitive Aspects of DS prognosis. DS is considered to be a form of epileptic encephalopathy, in which the epileptic activity itself Onset of epilepsy. The onset of seizures in DS may contribute to severe cognitive and behavioral occurs during the first year of life, with a mean age of impairments [3]. 5-8 months. DS patients usually have no pathological DS is a representative type of channelopathy which history or developmental delay before the onset of is, in most cases, caused by mutation of genes encod- seizures [5]. ing ion channels [4]. In this survey of the recent lit- The first seizure is typically a clonic, generalized erature, the most significant findings are summarized or unilateral, convulsive seizure. Seizures are often triggered by fever. Afebrile seizures, focal seizures, and complex partial seizures can also occur. These Received March 30, 2012 ; accepted May 14, 2012. ＊Corresponding author. Phone : ＋81ﾝ86ﾝ482ﾝ1121; Fax : ＋81ﾝ86ﾝ482ﾝ3883 seizures, with or without fever, tend to last for more E-mail : [email protected] (M. Akiyama) than 20min, and evolve into status epilepticus. 370 Akiyama et al. Acta Med. Okayama Vol. 66, No. 5

At onset, the electroencephalogram (EEG) is usu- Atypical absence seizures can appear either at 1-3 ally normal for infants at this age, with only rare, if years, together with myoclonic seizures, or later on, any, epileptic discharges [2]. at 5-12 years of age. The symptoms can be divided Evolution of epilepsy. Patients with typical into atypical absence seizures characterized by unre- DS have multiple seizure types during the course of sponsiveness, or may include an additional myoclonic the disease [2]. component. This seizure type corresponds to several Convulsive seizures, including generalized tonic- seconds of bursts of generalized, irregular spike and clonic seizures (GTCS), generalized clonic seizures wave complexes in EEG [5]. (GCS), and alternating unilateral clonic seizures, are Obtundation status is a type of nonconvulsive status the main seizure types occurring throughout life in epilepticus that consists of an impairment of con- most patients. These convulsive seizures may be pro- sciousness of variable intensity with fragmentary and longed or repeated, developing into status epilepticus segmental, erratic myoclonia involving the limbs and that lasts longer than 30min and requires intravenous face. Sometimes it is associated with drooling and a antiepileptic drug administration. The frequency of slight increase of muscle tone. Convulsive seizures convulsive status epilepticus in the first year of life is can either occur at the onset, during, or at the end of very high, and then decreases gradually [6, 7]. obtundation status. These periods can be prolonged Myoclonic seizures appear at the ages of 1-5 for several hours, or even days. EEGs usually show years, with an average of around 2 years. The symp- diffusely slow background, intermingled with focal and toms can be either massive or segmental, and are diffuse epileptic discharges [13]. often observed in clusters - particularly before convul- Simple partial seizures or complex partial seizures sive seizures. Myoclonus observed in DS patients can also occur in many patients. They can appear as early be divided into 2 groups, epileptic myoclonic seizures as 4 months up until the age of 4 years. and non-epileptic myoclonia. The former is concomi- DS seizure onset is characterized by very severe tant with paroxysmal discharges (mainly with general- sensitivity to fevers. In addition to high fevers, sei- ized spike and wave complexes) on the EEG, whereas zures can also be induced by subtle elevation of body the latter does not have an EEG correlate. Both types temperature caused by the very beginning stage of can occur during the clinical disease course, and it is infection, hot bath immersion, exercise, and hot often difficult to distinguish the former from the latter weather [14]. without precise analyses using video-EEG-EMG simul- Photosensitivity can be manifested as a pathologi- taneous monitoring [5]. cal response to intermittent photic stimulation, bright There are some patients with clinical characteris- light, or intense contrast between bright light and tics similar to those of “typical” DS but lacking epi- darkness. All kinds of contrasting patterns, such as leptic myoclonic seizures and atypical absence sei- geometrical designs or dotted lines, can provoke seizures, although appearance of these seizure types is zures [15, 16]. a unique feature of DS. These patients have been The EEG background often becomes progressively defined as having “borderline” DS by some research- slower and more poorly organized. The peculiar theta ers [8, 9]. Myoclonic seizures and atypical absence activity in fronto-central areas that is already observed seizures tend to disappear during the course in typical at onset in some patients, appears in most cases, and DS patients, and it becomes difficult to distinguish persists throughout follow-up. Epileptic discharges typical DS from borderline DS from adolescence are represented by spikes, spike and wave complexes, onward. Several long-term studies [2, 7] have shown and poly spike-waves [13, 16]. that patients with typical DS and those with border- Long-term outcomes. DS was originally believed line DS experience fundamentally similar late clinical to be always associated with unfavorable outcomes. courses, including seizure frequencies and mental All patients were reported to have persistent seizures prognoses. In addition, both types have high rates of and to be cognitively impaired, often severely. Several SCN1A mutations [10, 11, 12], which led to the authors have published longitudinal studies following perception that the spectrum of typical and borderline a series of patients through to adolescence, but only a DS cases constitutes a single syndromic entity. few series included patients older than 20 years [7, October 2012 Dravet Syndrome 371

17-20]. patients had only moderate to minimum mental dis- All seizure types are extremely resistant to any ability in adulthood. Among these patients, only a kind of treatment during the first several years. Later small number could live independent lives. In our on, partial seizures, myoclonic seizures and atypical series, a lack of occipital alpha rhythms on follow-up absences tend to disappear but convulsive seizures EEGs was significantly correlated with severe mental persist. However, in 2 very long-term studies, seven handicaps in adulthood, and it is thought that a slow patients were reported to have become seizure-free EEG background must represent brain dysfunction. for at least 1 year and up to 5 years [7, 18]. In our To improve the mental prognosis of DS, suppression series, 5 out of 31 patients (16.1ｵ) were seizure- of seizures might have a positive effect, especially free in adulthood. The seizure-free patients had when seizure control is achieved at a young age, experienced significantly fewer episodes of convulsive although this may not be enough to exert a significant status epilepticus. Prevention of the occurrence of effect [7]. convulsive status epilepticus might improve seizure prognosis in DS [7, 21]. Review of the Genetic Aspects of DS (Table 1) In the remaining patients, the frequency of convulsive seizures gradually decreased, despite recurrent Sodium channel α1 subunit gene (SCN1A) periods of worsening during adolescence and early and Dravet syndrome. Mutations of SCN1A are adulthood in some patients. At the end of the follow- the most frequent genetic cause of DS. At present, up, the frequency of seizures was reported to range more than 700 mutations have been associated with DS from 1-12 per year [18]. and are randomly distributed along the gene [23-25]. The convulsive seizures in adult DS have not been SCN1A (on chromosome 2q24.3) encodes the voltage- fully clarified. Some researchers describe them as gated sodium channel NaV1.1. Voltage-gated sodium tonic-clonic seizures without providing detailed infor- channels (VGSCs) play an essential role in neuronal mation, whereas others report focal features [2, 6, excitability. 22]. In our study, 35 (87.5ｵ) of the 40 apparently Mutations of SCN1A were first discovered in the generalized convulsive seizures were demonstrated to syndrome of generalized epilepsy with febrile seizures actually be partial seizures, mostly having a frontal plus (GEFS＋) [26], which has been renamed “genetic origin, with or without secondary generalization in the epilepsy with febrile seizures plus” [27]. A family ictal EEG records [7]. history of epilepsy or febrile seizures is sometimes Convulsive status epilepticus was no longer found in patients with DS and most affected relatives observed in most adult patients, although it still have GEFS＋ phenotypes [28]. In view of the predis- occurred in adulthood in only a few patients. position to seizures with fever that typically occurs in Obtundation status remained in most severely affected Dravet syndrome, Claes et al. performed a mutation patients [19]. Fever and infections were triggering analysis on SCN1A in 7 children and found that all had factors for only one-third to half of the cases in adult- de novo mutations [4]. hood. Photosensitivity and pattern sensitivity disap- Functional effects of voltage-gated sodium peared in most patients [7, 18]. channel α1 mutations. Most mutations respon- Interictal epileptic EEG abnormalities can disap- sible for DS are either missense or truncation muta- pear completely or become sporadic. They are char- tions, both of which would give rise to nonfunctional acterized by focal and multifocal spikes, spike-waves channels. and sharp waves, and are only rarely associated with Epilepsy is a disorder characterized by brain generalized spike-waves. Photosensitivity becomes hyperexcitability and it initially seemed puzzling that progressively less apparent. Nevertheless it persists mutations in a VGSC lead to loss of function and in some cases and was observed in 12ｵ of patients reduced Na＋ current. However, data from Scn1a older than 18 years in one series [13]. knock-out mice [29] and knock-in mice with a nonsense It is generally believed that almost all patients with mutation in the Scn1a gene [30] have shown that the DS show severe mental deficits [12, 16], although α1 subunit is fundamental for the excitability of at recently published long-term studies showed that some least some types of γ-aminobutyric acid (GABA)-ergic 372 Akiyama et al. Acta Med. Okayama Vol. 66, No. 5

Table 1 Genetic background of Dravet syndrome

Proportion of Gene (location) Product cases in Dravet Contribution References syndrome

SCN1A (2q24) Voltage-gated Around 85% Typical and Claes et al. [4] sodium channel α1 borderline Depienne et al. [25] subunit Dravet syndrome

PCDH19 (Xq22) Protocadherin 19 Around 5% Mild type of Depienne et al. [51] Dravet syndrome

GABRG2 (5q34) GABAA receptor γ2 Rare Not yet Harkin et al. [53] subunit established

SCN1B (19q13) Voltage-gated Rare Not yet Patino et al. [54] sodium channel β1 established subunit

SCN2A (2q24) Voltage-gated Rare Not yet Shi et al. [55] sodium channel α2 established subunit

SCN9A (2q24) Voltage-gated Unknown Modiﬁer Singh et al. [47] sodium channel α9 subunit

CACNB4 (2q22-q23) Voltage-dependent Unknown Modiﬁer Ohmori et al. [48] calcium channel β4 subunit

interneurons in the neocortex and hippocampus. (MPLA) and further characterized by comparative Therefore, reduced firing of inhibitory neurons and genome hybridization (CGH) to determine the size of compromised network inhibition could be the major the abnormality and identify any additional genes pathophysiologic mechanism causing SCN1A-related involved. Intragenic and whole-gene deletions includ- genetic epilepsies. ing SCN1A and/or contiguous genes account for 2-3ｵ Detection of SCN1A mutations. The overall of Dravet syndrome cases and for about 12.5ｵ of frequency of SCN1A alterations in DS, which includes those who are mutation-negative on classical Sanger sequence-based mutations, single or multiple exon sequencing [35]. deletions, and chromosomal rearrangements, is around Mode of inheritance. Most mutations are de 85ｵ. By classical Sanger sequencing, mutations are novo, comprising both truncating and missense changes. found in about 80ｵ of cases and comprise truncating However, familial mutations also occur in 5-10ｵ of (40ｵ) and missense (40ｵ) mutations, with the remain- cases and are usually missense in nature [4, 10, 36, ing alterations being splice site changes [31]. 37]. In these cases, other family members with the Patients with a clinical diagnosis of DS who test SCN1A mutation have no symptoms or mild pheno- negative for SCN1A mutations after sequencing may types consistent with the GEFS+ spectrum [10, 36]. still have exonic deletions or chromosomal rearrange- An important genetic counseling issue is that sev- ments involving SCN1A [23, 24, 32-34]. The size of eral families with more than one child with DS have these genomic alterations varies from the megabase been recorded. Somatic or germline mosaic mutations range, involving a large number of contiguous genes, might explain the presence of an unaffected or mildly- down to one exon within SCN1A. Duplications and affected transmitting parent [38-41]. A recent study amplifications involving SCN1A can be identified with indicates that mosaicism is found in at least 7ｵ of multiplex ligation-dependent probe amplification families with DS. The proportion of the mutated October 2012 Dravet Syndrome 373 allele in the blood of the 12 patients described varied humans and mice, and is postulated to be involved in from 0.04ｵ to 85ｵ and may be a significant factor establishing neuronal connections and signal transduc- underlying intrafamilial phenotypic variability [39, tion at the synaptic membrane [52]. 42, 43]. Possible causative genes of DS. The etiol- Genotype-phenotype correlations. Some gen- ogy of DS in about 10ｵ to 20ｵ of patients remains eral genotype‒phenotype correlations have been unknown, and additional genes are likely to be impli- suggested: truncating, nonsense, frame shift muta- cated. Among these patients, only a few cases with tions, and partial or whole-gene deletions are corre- mutation of other genes (GABRG2, SCN1B, and lated with a classical DS phenotype and appear to SCN2A genes) have been reported [53-55]. have a significant correlation with an earlier age of seizure onset [24]. SCN1A Mutations Associated with Other The severity of the phenotypes may also be corre- Forms of Epilepsy lated with the location of SCN1A missense mutations: for example, those in the pore-forming region of the The second most common phenotypes among sodium channel may cause DS, whereas missense SCN1A-related epilepsies are febrile seizures and changes associated with the GEFS＋ spectrum may be related syndromes [56]. The remaining associated more frequently located outside the pore-forming epileptic conditions comprise a heterogeneous group of region [44]. However, this genotype-phenotype cor- cryptogenic focal and cryptogenic generalized epilepsy, relation is not consistent. Moreover, the same SCN1A as well as infrequent occurrences of myoclonic astatic mutations and deletions cause DS in some patients and epilepsy [57, 58], severe idiopathic generalized epi- GEFS＋ in others [26, 45, 46], suggesting that lepsy of infancy [58], West syndrome [37], Lennox- modifier genes, the genetic background, and/or envi- Gastaut syndrome [57], and Rasmussen encephalitis ronmental factors may also play a role in some [59]. patients, and thus DS may sometimes follow a complex model of inheritance. SCN9A or CACNB4 muta- Conclusion tions, along with SCN1A mutations, have been reported as candidates for modifier genes in DS It has been more than 30 years since the first patients [47, 48]. description of DS, and the syndrome is now considered a model for channelopathy and is the subject of Dravet Syndrome without SCN1A Alterations wide interest in the scientific and medical community. DS is one of the most severe types of genetic epilepsy, PCDH19. Mutations of PCDH19 (on chromo- and we need further studies to understand its patho- some Xq22), the gene encoding protocadherin 19, genesis and the mechanisms by which it causes cogni- have been found in a disorder called “epilepsy limited tive impairments. Finally, further study is needed to to females with mental retardation” (EFMR) [49, improve the care and treatment of afflicted patients. 50]. 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