Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies. Epilepsia OBJECTIVE:SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. METHODS:We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. RESULTS:DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. SIGNIFICANCE:Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS. 10.1111/epi.17882

Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+). Camfield Peter,Camfield Carol Epileptic disorders : international epilepsy journal with videotape To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Selected literature review. Febrile seizures are the most common convulsive event in humans, occurring in 2-6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long-term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14-16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ∼3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually "come to grips" with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. "Rescue" benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage-gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Febrile seizures may distress parents but rarely have any long-term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling. 10.1684/epd.2015.0737

Genotype-phenotype associations in SCN1A-related epilepsies. Zuberi S M,Brunklaus A,Birch R,Reavey E,Duncan J,Forbes G H Neurology OBJECTIVE:Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype. METHODS:We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. RESULTS:Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031). CONCLUSIONS:These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location. 10.1212/WNL.0b013e31820c309b