Idiopathic epilepsies with seizures precipitated by fever: clinical and genetic study of 132 patients
Marini, C. (C.); Mei, D. (D.); Temudo, T. (T.); et al. "Idiopathic epilepsies with seizures precipitated by fever: clinical and genetic study of 132 patients". Epilepsia. 48 (9), 2007, 1678 - 1685
Purpose: Mutations in the genes coding for subunits of ion channels have been associated with epilepsy. Of these known epilepsy genes SCN1A, coding for the α subunit of the sodium channel, is currently the most clinically relevant gene. The majority of SCN1A mutations lead to severe myoclonic epilepsy of infancy (SMEI) including borderline SMEI (SMEB) and to generalized epilepsy with febrile seizures plus (GEFS+). Both syndromes have febrile seizures (FS) as a common clinical feature. The aim of this study was to achieve a better definition of the spectrum of phenotypes that might be associated with SCN1A mutations. We aimed to performing phenotype-genotype correlations of SCN1A mutations with specific epilepsy syndromes. Methods: We selected 132 patients in whom most seizures occurred during febrile episodes. A clinical and genetic study focussing on SCN1A screening was performed. Results: Patients were classified as follow: SMEI/ SMEB = 55; GEFS+ spectrum= 25; sporadic myoclonic astatic epilepsy= 3; classical FS= 10; other phenotypes= 25. We identified 40 SCN1A mutations. Of the 40 mutations 37 were found in patients with SMEI in whom mutations were missense in 16 probands (2 familial) and truncating in 21 (2 familial). The remaining 3 missense mutations were associated with GEFS+. Missense mutations in the pore forming parts (S5-S6) of the Na+ channel occurred in 10 out of the 16 SMEI (62,5%) and only in one of the three GEFS+ patients. Mutations in the pore forming region seem to correlate in 70% with the classical SMEI type and only with 30% of the SMEB phenotype. Analysis of the age of seizures onset between SMEI patients with: a) SCN1A truncating mutations, b) SCN1A missense mutations and c) no SCN1A mutations showed that the differences of the age of FS onset was extremely significant between the three groups (p=0,0007, ANOVA test). Patients with truncating mutations had the earlier onset of FS, patients with missense mutations had an intermediate onset, and individuals without SCN1A mutations had the latest age of FS onset. Conclusion: We obtained a prevalence of about 70% of SCN1A mutations in SMEI and SMEB patients and of 12% in GEFS+ probands confirming the predominant and important role of SCN1A in patients with SMEI. None of the other patients with fever-provoked seizures carried mutations in SCN1A gene. The high correlation between SMEI and SCN1A mutations suggests a phenotypical specificity of SCN1A rather than a dysfunction of neurons exacerbated by high body temperature
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