Mutations in the SCN1A gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to generalized epilepsy with febrile seizures plus, type 2, which represents a more severe phenotype. Patients with isolated febrile seizures usually ... Mutations in the SCN1A gene cause a spectrum of seizure disorders, ranging from early-onset isolated febrile seizures to generalized epilepsy with febrile seizures plus, type 2, which represents a more severe phenotype. Patients with isolated febrile seizures usually have onset between ages 6 months and 4 years and show spontaneous remission by age 6 years (summary by Mantegazza et al., 2005), whereas patients with GEFS+ continue to have various types of febrile and afebrile seizures later in life (summary by Singh et al., 2009). Dravet syndrome (607208), or severe myoclonic epilepsy of infancy, is the most severe phenotype associated with SCN1A mutations. Mutations in certain genes can cause a phenotypic spectrum of overlap between the isolated febrile phenotype and the GEFS+ phenotype. For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233. For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see 121210.
Baulac et al. (1999) studied a family in which affected individuals in 3 successive generations presented clinical similarities with families with GEFS+. Patients expressed a variable phenotype combining febrile seizures, generalized seizures ... - GEFS+ Type 2 Baulac et al. (1999) studied a family in which affected individuals in 3 successive generations presented clinical similarities with families with GEFS+. Patients expressed a variable phenotype combining febrile seizures, generalized seizures often precipitated by fever at age greater than 6 years, myoclonic seizures, absence seizures, hemiclonic seizures, and partial seizures, with a variable degree of severity. Moulard et al. (1999) reported a family in which 6 individuals had isolated typical febrile seizures, and 5 had typical febrile seizures associated with generalized epilepsy. Afebrile seizures occurred in childhood until the teenage years. - Familial Febrile Seizures 3A Mantegazza et al. (2005) reported a large Italian family in which at least 12 members spanning 4 generations had simple febrile seizures. The age at onset ranged from 5 months to 4 years, and none had seizures beyond age 6 years. Most seizures were brief, lasting 1 to 5 minutes, although 1 patient had seizures lasting up to 15 minutes. Three affected individuals developed afebrile partial seizures of mesial temporal lobe origin with vegetative or experiential phenomena at the ages of 10, 13, and 11 years. Very rare partial complex seizures or nocturnal secondary generalized tonic-clonic seizures also occurred in all 3 of them. Two of these patients had MRI evidence of unilateral mesial temporal sclerosis. Mantegazza et al. (2005) noted that febrile convulsions had been identified as a risk factor for temporal lobe epilepsy with hippocampal sclerosis (Briellmann et al., 2001). Mantegazza et al. (2005) concluded that the phenotype was distinct from GEFS+ and was most consistent with simple febrile seizures.
Escayg et al. (2000) demonstrated that the 2 GEFS+ families reported by Baulac et al. (1999) and Moulard et al. (1999) each carried a different heterozygous mutation in the SCN1A gene (R1648H, 182389.0001 and T875M, 182389.0002, respectively). ... Escayg et al. (2000) demonstrated that the 2 GEFS+ families reported by Baulac et al. (1999) and Moulard et al. (1999) each carried a different heterozygous mutation in the SCN1A gene (R1648H, 182389.0001 and T875M, 182389.0002, respectively). In 2 unrelated Japanese families with GEFS+2 associated with development of partial epilepsy, Sugawara et al. (2001) identified 2 novel mutations in the SCN1A gene. One of these mutations, val1428-to-ala (182389.0011), was a missense mutation in the pore-forming region of the sodium channel, which the authors hypothesized may affect ion selectivity. 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+ and in 75% of patients with Dravet syndrome (607208) from the overall patient cohort. - Familial Febrile Seizures 3A In 12 affected members of an Italian family with simple febrile seizures mapping to 2q24, Mantegazza et al. (2005) identified a heterozygous mutation in the SCN1A gene (182389.0015). This disorder is designated FEB3A. In a 2-stage case-control study including a total of 234 patients with febrile seizures, Schlachter et al. (2009) found a significant association between the major A allele of SNP dbSNP rs3812718 in the SCN1A gene (182389.0016) and febrile seizures (first stage p value of 0.000017; replication p value of 0.00069). The data suggested that homozygosity for the A allele confers a 3-fold increased relative risk of febrile seizures and may account for a population attributable risk factor of up to 50%. The data were consistent with the hypothesis that low-risk variants with a high population frequency contribute to the risk of common and genetically complex diseases such as epilepsy.