Dravet syndrome, first described by Dravet (1978), is an early-onset epileptic encephalopathy characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Seizures are usually refractory ... Dravet syndrome, first described by Dravet (1978), is an early-onset epileptic encephalopathy characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Seizures are usually refractory to treatment. Later, patients also manifest other seizure types, including absence, myoclonic, and partial seizures. The EEG is often normal at first, but later characteristically shows generalized spike-wave activity. Psychomotor development stagnates around the second year of life, and affected individuals show subsequent mental decline and other neurologic manifestations (summary by Harkin et al., 2007). Since mutation in the SCN1A gene can also cause the less severe disorder autosomal dominant generalized epilepsy with febrile seizures-plus, Dravet syndrome and migrating partial seizures of infancy (MPSI) are considered to be the most severe phenotypes within the spectrum of SCN1A-related epilepsies (Ohmori et al., 2002; Carranza Rojo et al., 2011). Deprez et al. (2009) provided a review of the genetics of epilepsy syndromes starting in the first year of life, and included a diagnostic algorithm. For a general phenotypic description and a discussion of genetic heterogeneity of early infantile epileptic encephalopathy, see EIEE1 (308350).
Dravet syndrome, previously known as 'severe myoclonic epilepsy of infancy' (SMEI), is an epileptic syndrome characterized by normal development before onset, seizures beginning in the first year of life in the form of generalized or unilateral febrile clonic ... Dravet syndrome, previously known as 'severe myoclonic epilepsy of infancy' (SMEI), is an epileptic syndrome characterized by normal development before onset, seizures beginning in the first year of life in the form of generalized or unilateral febrile clonic seizures, secondary appearance of myoclonic seizures, and occasionally partial seizures. It is associated with ataxia, slowed psychomotor development, and mental decline, and is often refractory to medication (Dravet et al., 1992; Sugawara et al., 2002). Renier and Renkawek (1990) reported that an autopsy of a 19-month-old boy with SMEI showed microdysgenesis of the cerebellum and cerebral cortex as well as malformation of the spinal cord. Doose et al. (1998) reported a large group of patients with severe intractable epilepsy of infancy or childhood with frequent generalized tonic-clonic seizures. At onset, the disorder was characterized by prolonged febrile and afebrile seizures as the only seizure type. With advancing age, the symptomatology became increasingly polymorphic due to additional seizure types, such as complex or focal. The most common triggering feature was fever or immersion in a hot bath, and most patients had severe impairment of mental development after seizure onset. Doose et al. (1998) noted the phenotypic overlap with SMEI. Fujiwara et al. (2003) reported 25 Japanese patients with SMEI and 10 Japanese patients with what they termed 'intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC),' which was only distinguished from SMEI by the absence of myoclonus. Twenty-two (62.8%) patients had a family history of seizures, including febrile convulsions and epilepsy consistent with GEFS+. The majority of patients had high voltage 4- to 7-Hz diffuse slow background activity on EEG. A total of 30 heterozygous mutations were identified in the SCN1A gene in this group of patients. Buoni et al. (2006) reported a 13-year-old boy with SMEI in whom the clinical phenotype evolved to GEFS+2 in adolescence. The patient had prolonged febrile seizures at ages 6, 10, and 13 months, afebrile complex partial seizures with secondary generalization beginning at age 18 months, and 2 episodes of status epilepticus at age 2 years. He also had abnormal EEG findings and myoclonic jerks. Antiepileptic medication was unsuccessful. At age 4 years, the seizure frequency decreased in response to medication, and by age 9, he had complex partial seizures with secondary generalization. By age 13, he was treated with valproate and had a febrile seizure. There was no mental retardation. Buoni et al. (2006) emphasized the relatively benign outcome in this patient despite having SMEI. Genetic analysis identified a de novo heterozygous 1-bp deletion in the SCN1A gene (182389.0017). Jansen et al. (2006) reported 14 adults with Dravet syndrome who ranged in age from 18 to 47 years. All had been referred for refractory epilepsy and intellectual disability without an etiologic diagnosis. Medical history revealed seizure onset between 3 to 11 months (mean 6 months), which was associated with fever in 9 patients. During childhood, all had generalized or unilateral tonic-clonic seizures, 12 had myoclonic seizures, 11 had absence seizures, 8 had complex partial seizures, and 6 had atonic seizures. Psychomotor development slowed in all after initial normal development. Eight patients had a family history of seizures. As adults, generalized tonic-clonic seizures were the dominant type, but all other types of seizures still occurred. Ten patients had motor abnormalities, including cerebellar signs in 4, pyramidal signs in 6, and extrapyramidal signs in 4. One patient had low-average intellect, 2 had mild intellectual disability, 5 were moderately retarded, and 6 had severe impairment. Two patients lived independently but were unemployed. Genetic analysis showed that 10 patients had mutations in the SCN1A gene and 1 had a mutation in the GABRG2 gene. Jansen et al. (2006) noted that the findings indicated a poor outcome for affected individuals and emphasized that correct diagnosis in adult patients requires a knowledge of early medical history. Riva et al. (2009) found that 2 unrelated children with genetically confirmed Dravet syndrome had progressive neurocognitive decline when longitudinally assessed from ages 11 and 23 months to 7 and 8 years, respectively. Importantly, delayed motor, intellectual, and rational development was already apparent at the time of seizure onset in both patients. One patient had a more severe seizure phenotype consistent with an epileptic encephalopathy, with numerous myoclonic seizures occurring almost daily and more frequent occurrence of tonic-clonic seizures compared to the second patient. However, both patients showed progressive deterioration in cognitive function over time, although there were differences in specific neuropsychologic functions affected. Riva et al. (2009) concluded that SCN1A mutations may play a role in early and progressive mental impairment in addition to their role in epilepsy. - Clinical Variability Harkin et al. (2007) identified SCN1A mutations in a cohort of patients with a wide spectrum of infantile epileptic encephalopathies. Among a total of 188 patients, SCN1A mutations were found in 52 (79%) of 66 with SMEI (Dravet syndrome) and in 25 (69%) of 36 with 'severe myoclonic epilepsy of infancy-borderline (SMEB),' a phenotype lacking one or more features of SMEI, such as myoclonus or generalized spike-wave discharges on EEG. In addition, SCN1A mutations were less commonly found in patients with other forms of early-onset epilepsy, characterized as cryptogenic generalized or focal epilepsy, myoclonic-astatic epilepsy, and severe infantile multifocal epilepsy (SIMFE). Although the study indicated that a broader range of seizure phenotypes is associated with SCN1A mutations, Harkin et al. (2007) noted that the nosologic boundaries between these phenotypes is blurred. There were no apparent genotype/phenotype correlations. 'Malignant migrating partial seizures of infancy' (MPSI, MMPSI) is a clinical term for a severe form of infantile epileptic encephalopathy with seizure onset between 1 day and 6 months. EEG studies typically show migrating focal onset progressing to multifocal onset, and seizures are refractory to therapeutic intervention. Affected individuals have developmental regression after seizure onset, severe global developmental delay, and progressive microcephaly. Early death often occurs. The phenotype is considered to be more severe than that of typical Dravet syndrome (summary by Freilich et al., 2011 and Carranza Rojo et al., 2011). Freilich et al. (2011) reported a female infant with EIEE6 manifest clinically as MPSI associated with a heterozygous mutation in the SCN1A gene (A1669E; 182389.0023). She had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, status epilepticus, EEG evidence of migrating focal onset progressing to multifocal seizures, progressive microcephaly, and profound psychomotor delay. She died at age 9 months. Carranza Rojo et al. (2011) found that 2 of 15 unrelated infants with a clinical diagnosis of MPSI had defects in the SCN1A gene. One had a de novo missense mutation (R862G; 182389.0024) and the other had a de novo 11.06-Mb deletion of chromosome 2q24.2-q31.1 encompassing more than 40 genes that included SCN1A. The patient with the R862G mutation had onset of multifocal hemiclonic seizures at age 2 weeks with status epilepticus. She had acquired microcephaly, developmental regression, and severe intellectual disability. These reports expanded the severity of the epileptic phenotype associated with SCN1A mutations to include MPSI. Moreover, the lack of SCN1A mutations in 13 patients with a similar diagnosis by Carranza Rojo et al. (2011) indicated genetic heterogeneity for the MPSI entity.
In 7 patients with Dravet syndrome, Claes et al. (2001) found heterozygous mutations in the SCN1A gene, including 3 deletions and 1 insertion that resulted in premature stop codons, a ... - Mutations in the SCN1A Gene In 7 patients with Dravet syndrome, Claes et al. (2001) found heterozygous mutations in the SCN1A gene, including 3 deletions and 1 insertion that resulted in premature stop codons, a nonsense, a splice donor site, and a missense mutation; see, e.g., 182389.0007-182389.0009. The mutations were absent in all parents, suggesting that de novo mutations are a major cause of SMEI. Claes et al. (2001) noted that most of the mutations resulted in early termination of translation, producing a truncated SCN1A protein. In 14 patients, including a pair of monozygotic twins, with classic symptoms of Dravet syndrome, Sugawara et al. (2002) identified 10 heterozygous mutations in the SCN1A gene. There were 3 frameshift mutations which resulted in intragenic stop codons and truncated channels, and 7 nonsense mutations which also resulted in truncated channels. In 4 patients, no mutations were detected in either the SCN1A or SCN1B (600235) genes. In 24 of 29 patients with Dravet syndrome, Ohmori et al. (2002) found heterozygous de novo mutations in SCN1A, mutations in which have been identified also in GEFS+. That mutations in the SCN1A gene can cause severe myoclonic epilepsy in infancy supports the suggestion of Singh et al. (2001) that Dravet is part of the GEFS+ spectrum. Indeed, Dravet syndrome and GEFS+ have been observed in the same family. Among 93 patients with Dravet syndrome, Nabbout et al. (2003) identified 29 different mutations in the SCN1A gene in 33 patients (35%). All cases were sporadic, but a history of febrile seizures and epilepsy was found in the families of 32% and 12% of the probands, respectively. Three of the mutations were inherited from a parent. The authors concluded that the disorder is genetically heterogeneous and may also exhibit complex inheritance. In 7 of 10 unrelated Japanese patients with intractable childhood epilepsy with generalized tonic-clonic seizures, Fujiwara et al (2003) identified mutations in the SCN1A gene (see, e.g., 182389.0013; 182389.0014). All of the mutations were missense. Two unrelated affected children had mothers with the mutation who had a phenotype consistent with GEFS+. Fujiwara et al. (2003) concluded that myoclonus is not a necessary feature of the disorder. Using multiplex ligation-dependent probe amplification (MLPA), Mulley et al. (2006) identified exon deletions in the SCN1A gene (182389.0018; 182389.0019) in 2 (15%) of 13 unrelated SMEI patients who did not have point or splice site mutations in the SCN1A gene. The findings provided a new molecular mechanism for the disorder. Depienne et al. (2009) identified pathogenic mutations or deletions, including 161 novel point mutations, in the SCN1A gene in 242 (73%) of 333 patients with Dravet syndrome. The most common mutations were missense (42%), and 14 patients had microrearrangements in or deletions of the gene. Thus, the disease mechanism appeared to be haploinsufficiency of the SCN1A gene. Mutations were scattered throughout the gene, and there were no apparent genotype/phenotype correlations. Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ (604233) and in 75% of patients with SMEI from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (600235), and no mutations were found in the GABRG2 gene (137164). Sun et al. (2010) identified pathogenic mutations in the SCN1A gene in 49 (77.8%) of 63 Chinese probands with Dravet syndrome. The majority of mutations were truncating (61.2%). The mutations included 19 missense, 14 frameshift, 6 nonsense, and 8 splice site alterations. MLPA analysis identified deletions or duplications of SCN1A in 2 (12.5%) of 16 patients who were negative by sequencing. Forty mutations were de novo, and 1 was inherited from a mother who was mosaic for the mutation and had a phenotype consistent with GEFS+. Ten of 12 de novo mutations studied were of paternal origin, and 2 were of maternal origin. Sun et al. (2010) emphasized that MLPA analysis is essential for correct diagnosis in sequencing-negative patients with Dravet syndrome. - Potential Modifier Genes Harkin et al. (2002) reported a family with GEFS+ (604233) caused by a heterozygous mutation in the GABRG2 gene (Q351X; 137164.0003); 1 family member had a more severe phenotype, consistent with Dravet syndrome. However, Ohmori et al. (2002) found no mutations of the GABRG2 gene in 29 patients with Dravet syndrome. They also found no mutations in SCN1B (600235), the other gene that had been related to generalized epilepsy with febrile seizures. In 2 patients diagnosed with Dravet syndrome, Singh et al. (2009) identified a heterozygous mutation in the SCN9A gene (K655R; 603415.0019); one of the patients also had a mutation in the SCN1A gene (182389). The K655R mutation was also identified in a patient with GEFSP7 (see 604233). Singh et al. (2009) also presented evidence that the SCN9A gene on chromosome 2q24 may be a modifier of Dravet syndrome; 9 (8%) of 109 patients with Dravet syndrome were found to have an SCN9A mutation, including 6 patients who were double heterozygous for SCN9A and SCN1A mutations and 3 patients with only heterozygous SCN9A mutations, consistent with multifactorial inheritance.