Novel locus on chromosome 12q22-q23.3 responsible for familial temporal lobe epilepsy associated with febrile seizures.

I diopathic epilepsies have a genetic basis and are characterised by the absence of an overt underlying neurological abnormality. Most idiopathic epilepsies are complex diseases with considerable clinical and genetic heterogeneity and an unclear inheritance pattern because of genetic and environmental factors. Families in which the disease segregates as an autosomal dominant trait with reduced disease penetrance have been identified occasionally. In some of these families, a single gene defect was identified as the cause of epilepsy. To date, mutations in 13 genes have been identified for distinct epilepsy types. Most genes encode subunits of ion channels. 2 In addition, the gene remains to be identified for 21 mapped loci for epilepsy, which highlights the genetic heterogeneity of the idiopathic epilepsy syndromes. 4 Familial temporal lobe epilepsy (MIM 608096) was first described by Berkovic et al. and was recognised as a distinct epileptic syndrome by the International League Against Epilepsy. It is defined by familial occurrence of simple partial seizures, complex partial seizures, and secondarily generalised seizures of temporal lobe origin. Two genetically distinct autosomal dominant familial temporal lobe epilepsy syndromes have been reported. Autosomal dominant lateral temporal lobe epilepsy (MIM 600512), or autosomal dominant partial epilepsy with auditory features, was described first by Ottman et al., and recently, mutations in the leucine rich glioma inactivated 1 (LGI1) gene on chromosome 10q24 were identified. 9 Auras that present as auditory and visual hallucinations are a clinical hallmark of this syndrome. The other variant of familial temporal lobe epilepsy is characterised clinically by onset in teenage years or early adulthood, absence of antecedent factors, low frequency of deja vu, and a usually good prognosis. This variant, which still can be heterogeneous genetically, is not mapped yet. In a large family with febrile seizures (MIM 121210) and familial temporal lobe epilepsy without hippocampal sclerosis, digenic inheritance with loci on chromosomes 1q25–q31 and 18qter was suggested. Finally, in a large pedigree with a mutation in SCN1A, a few affected mutation carriers had temporal lobe epilepsy, while others had febrile seizures. Febrile seizures occur between six months and five years of age and affect 2–5% of all children. They are characterised by clonic, tonic–clonic, or atonic seizures that are provoked by fever but are without evidence of intracranial pathology. Sometimes febrile seizures extend beyond the age of five years, when they are designated febrile seizures plus. Association of febrile seizures and febrile seizures plus with a wide variety of afebrile seizures often is observed in patients with epilepsy. This syndrome was named generalised epilepsy with febrile seizures plus (MIM 604233). Although afebrile seizures in these families mostly are generalised, partial seizures, including temporal lobe epilepsy, also have been reported, which renders the designation of generalised epilepsy with febrile seizures plus less appropriate in these families. Several loci for febrile seizures and generalised epilepsy with febrile seizures plus have been identified: FEB1 on chromosome 8q13–q21 (MIM 602476), FEB2 on chromosome 19p13.3 (MIM 602477), FEB3 on chromosome 2q24 (MIM 604403), FEB4 on chromosome 5q14–q15 (MIM 604352), FEB5 on chromosome 6q22–q24, GEFS+1 on chromosome 19q13.1 with mutations in SCN1B (MIM 600235), GEFS+2 on chromosome 2q24 with mutations in SCN1A (MIM 182389), and GEFS+3 on chromosome 5q31– q33 with mutations in GABRG2 (MIM 137164). We performed a 10 cM density genomewide scan in a five generation family affected by familial temporal lobe epilepsy and febrile seizures.