PubMed · 11091869
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P D Williamson, B C Jobst. 2000. Frontal lobe epilepsy.. https://pubmed.ncbi.nlm.nih.gov/11091869/
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Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief. They vary from simple arousals during sleep to dramatic, bizarre, hyperkinetic events with tonic or dystonic features. A minority of patients may experience aura. This disease is caused by various mutations of genes coding for subunits of neuronal acetylcholine receptor comprising the sodium/potassium ion channel. Recent advances in molecular genetics have provided the means for a better understanding of human epileptogenesis at a molecular level, which can facilitate clinical diagnosis and provides a more rational basis of therapy of this form of epilepsy. In this review, we report the recent data in the genetics of ADNFLE.
Mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy have been identified in two members of the neuronal nicotinic acetylcholine receptor gene family: CHRNA4(ENFL1 locus) and CHRNB2 (ENFL3 locus) coding for alpha4 and beta2 subunit, respectively. However, mutations in these genes account for only a minority (less than 10%) of cases. For a third ADNFLE locus (ENFL2) on chromosome 15q24 the gene was not identified. The involvement of the three loci in the pathogenesis of ADNFLE was investigated in 12 unrelated Italian families, selected on the basis of anamnestic and video-polysomnographic data. Compliant family members were typed for polymorphic markers spanning the analyzed chromosome regions. Linkage analyses excluded association of all chromosome regions with ADNFLE in 72% of cases. In two, four and one families it was impossible to ascertain or exclude association with ENFL1, ENFL2, or ENFL3, respectively, however, no mutations have been detected in the nicotinic receptor genes located in these regions. These data strongly suggest that ENFL1, ENFL2 and ENFL3 are minor loci for the disease and point to the existence of at least a fourth locus for ADNFLE.
OBJECTIVES: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by a strong family history of epileptic seizures, which predominantly occur during sleep. ADNFLE has been associated with mutations in two genes coding for the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2). Thus far, three different mutations have been detected in the CHRNA4 gene, and two in the CHRNB2 gene. The aim of this study was to compare the frequency of psychiatric disorders in two ADNFLE families with different CHRNA4 mutations (776ins3 and Ser248Phe). METHODS: Information was gathered from hospital charts and therapists, and the family members were assessed by clinical interviews and structured clinical interviews. RESULTS: Of the 10 individuals diagnosed with epilepsy in the CHRNA4-776ins3 family, at least four had been in contact with psychiatric services. One individual had schizophrenia, while another family member had experienced at least two severe psychotic episodes, and had been taking antipsychotic medications for years. The third family member had been hospitalized at least three times for psychiatric problems. The fourth family member needs help with activities of daily living due to incapacitating apathy, although she does not have a psychiatric diagnosis. Such accumulation of psychiatric problems was not seen in the family with the Ser248Phe mutation. CONCLUSION: These findings suggest that there may be an association between the 776ins3 mutation and the psychiatric symptoms, a hypothesis that needs further testing.