A de novo mutation in an Italian sporadic patient affected by nocturnal frontal lobe epilepsy

Abstract

Nocturnal frontal lobe epilepsy (NFLE) is a focal epilepsystarting in childhood and persisting into young adulthood.Affected individuals are typically of normal intelligence, butrare cases with intellectual disability and⁄or psychiatricdisorders have been reported (Derry et al., 2008).Sporadic and familial forms of NFLE do not show clinicaldifferences (Combi et al., 2004). Mutations in genes encod-ing three subunits of the neuronal nicotinic acetylcholinereceptor and variations affecting the promoter of the geneencoding the corticotropin releasing hormone have beenassociated with autosomal dominant NFLE (ADNFLE)(Combi et al., 2004, 2005). These mutations are absent inthe majority of ADNFLE families and in nearly all sporadiccases. The proportion of cases caused by de novo mutationsis unknown (Hirose and Kurahashi, 2010).A mutation screening of CHRNA2, CHRNA4, CHRNB2and CRH genes has been performed in an Italian cohort of 28NFLE sporadic patients by sequencing the whole codingregion of each gene. All patients underwent a video-polysomnographic analysis and neurological examinationallowing the correct diagnosis of NFLE. All patients signedan informed consent and the study was approved by theinstitution ethical committee.The study allowed the identification of a c.851C>T muta-tion (numbering referred to ENS0370263 sequence),resulting in a p.Ser284Leu substitution in the CHRNA4 gene.The mutation (dbSNP:rs28931591) was found as a missenseheterozygous in a single patient and absent in both parents.This is a 25-year-old woman of Italian origin with a negativefamily history for epilepsy and parasomnias. Segregation of30 highly polymorphic microsatellite markers spread acrossthe genome was in concordance with paternity and confirmedthat the mutation was originated de novo. From age 7 thepatient had nocturnal episodes while asleep, characterizedby a sudden elevation of the trunk generally associated withdystonic posturing of both arms. She had no memory of theepisodes, but was fully conscious at the end of the seizures.Seizures occurred almost every night and could last from10 to more than 60 s. She never complained of subjectivemanifestations either during sleep or during wakefulness.Seizures did not respond to different drugs in monotherapy orin association.Neurological examination and magnetic resonance imag-ing (MRI) were normal. Video-electroencephalographic(EEG) analysis showed the occurrence of ictal frontalrhythmic slow waves, more evident on the right side.The identified mutation was reported previously in threeADNFLE families (Cho et al., 2003; Hirose et al., 1999;Rozycka et al., 2003) and in a Lebanese woman diagnosedinitially as a sporadic case who subsequently had an affectedson (Phillips et al., 2000). However, the phenotype of thepresent NFLE case appears slightly different from the onereported previously for the p.Ser284Leu mutation: in fact, allprevious cases showed mental retardation or intellectualdisabilities(Choet al.,2003;Phillipset al.,2000),whilenormalintellectandgoodschoolperformanceweredocumentedinthepresent case. Conversely, no pathological variants wereidentified in the CRH, CHRNA2 and CHRNB2 genes.This study describes the first Italian NFLE case with aCHRNA4 mutation and contributes new data suggesting theopportunity of performing both genetic testing and counsel-ling for sporadic cases. Two observations are worthy of note:first, the patient with the CHRNA4 mutation has a typicalform of NFLE without particular distinctive clinical aspects;secondly, the CHRNA4 Ser284 seems to be a hot point formutation. This amino acid was indeed found mutated eitherto Phe or Leu and associated with a cytosine guaninedinucleotide (CpG) hypermutable site (Hwang et al., 2011).In conclusion, the present study highlights that all sporadiccases should be screened for de novo mutations in knownADNFLE genes with special focus at the CHRNA4 Ser284and that clinical data are of no help in evaluating theeffectiveness of a genetic test.DECLARATIONS OF INTERESTThe authors have received no personal compensation, noresearch support, no stocks, stock options and royalties, andhave not been involved in legal proceedings during the last2 years. None of the author has conflicts of interest on thispaper.Veronica Sansoni