Idiopathic Epilepsies with Seizures Precipitated by Fever and SCN1A Abnormalities

Abstract

Summary:Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotypegenotype correlations with SCN1A alterations.Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients.Results: We classified patients as: SMEI/SMEB = 55; GEFS+ = 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations.Conclusion: We obtained a frequency of 71% SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes. Key Words: SMEI-GEFS+-SCN1A-Fever-provoked seizures-MLPA.Mutations in the gene coding for the α1 subunit of the neuronal sodium channel (SCN1A) have been associated with various types of epilepsy. SCN1A abnormalities have been found in about 5-10 % of generalized

Sudden unexpected death in a mouse model of Dravet syndrome

“…At least 80% of cases are associated with heterozygous loss-of-function mutations in the exons of SCN1A, which encodes the brain type-I voltage-gated sodium channel Na V 1.1 (5). DS begins in the first year of life, with fever-or temperature-sensitive seizures that often evolve into refractory generalized tonic-clonic seizures.…”

Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+

“…4,15 In addition, linkage studies have identified 7 genomic regions likely to harbor genes increasing risk for GEFSϩ and 5 regions likely to harbor genes increasing risk for FS (table 1). [16][17][18][19][20][21][22][23][24][25][26] Two loci originally described as FS loci (FEB3 and FEB4) were reported in pedigrees best classified as GEFSϩ due to phenotypes beyond typical FS.…”

Novel SCN1A variants in Dravet syndrome and evaluating a wide approach of patient selection

“…When considering only clinically diagnosed DS cases, combination of sequencing and MLPA testing approach showed a 85.7% sensitivity of causative DNA sequence variant detection, even higher than was reported in previous studies: 82.7% (Ohmori et al 2002), 71% (Marini et al 2007), 73% (Depienne et al 2009). The higher sensitivity observed in present study could be the result of very strict criteria during clinical diagnosis.…”

“…These can be, however, presumed with a relatively high probability as it is generally accepted that haploinsufficiency or gain of toxic function of truncated proteins may play a crucial role in the pathogenesis of the disease. Loss-of-function SCN1A sequence variants, such as nonsense and frameshift causing ones, were reported to be the predominant genetic abnormalities seen in DS patients and are usually associated with the most severe phenotypes and reproductive disadvantage (Sugawara et al 2001;Marini et al 2007). Most of the already described truncating variants, similarly to those identified by us, are found in the 5´ end of the SCN1A gene while the proteins altered in such way likely undergoes a nonsensemediated decay (NMD) pathway (Holbrook et al 2004).…”