Febrile seizures (FS) affect 5–12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in ≈7% ...of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23–24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Na v 1.1 channel α-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy. channelopathy FEB3 locus convulsions epilepsy neuronal excitability
Febrile seizures (FS) affect 5-12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures ...in$\approx 7\%$of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomaldominant locus has been identified on chromosome 2q23-24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Nav1.1 channel$\alpha-subunit$cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy.
Purpose: To report in detail the electroclinical features of a large family in which we recently identified a missense mutation (M145T) of a well‐conserved amino acid in the first transmembrane ...segment of domain I of the human SCN1A. We showed that the mutation is associated with a loss of SCN1A function.
Methods: The family originates from southern Italy and contains 35 members spread over four generations. Of the 14 affected individuals, the 13 still living members (7 males, mean age 36.6 ± 20.4) underwent a complete electroclinical evaluation.
Results: All 13 affected family members had febrile seizures (FS) up to the age of 6 years. Age at onset of FS ranged from 5 to 45 months with a mean age of 12.8 ± 12.9 months. One of the 13 was affected by post‐traumatic epilepsy. Three of the 13 later developed temporal lobe epilepsy (TLE) with both simple focal seizures, and also very rare focal complex or nocturnal secondary generalized tonic–clonic seizures. In two of the three patients who later developed TLE, the MRI studies revealed mesial temporal sclerosis.
Conclusions: Our findings illustrate that SCN1A mutations can cause simple FS associated with TLE, which differ from the characteristic clinical spectrum of GEFS+. It is open to conjecture if this unusual phenotype might at least in part be related to the fact that M145T is the first missense mutation found in DIS1 of SCN1A.
Abstract In this study we analysed the DJ-1 gene in 40 sporadic patients with early onset Parkinson's disease and 100 appropriate controls, originated from southern Italy. We identified a single ...patient with age at onset of 38 years carrying two previously undescribed heterozygous mutations, both located in non-coding regions. The first mutation was a nucleotide change in the promoter region of the gene (g.159 C>G) and the second one was an insertion in the intron 4 splice site (IVS4+3insA). In the same patient, genomic rearrangements were excluded. No DJ-1 mutations were found in the remaining parkinsonian patients. Our results support the growing importance of mutations in non-coding portion of human genome, and confirm that alterations in DJ-1 are a cause, even if rare, of early-onset Parkinson's disease.
The results of clinical and genetic analysis of three Serbian families (pedigrees) with autosomal dominant inheritance, incomplete penetrance and phenotypic features of GEFS+ are presented in this ...study. Mutation analysis of the SCN1A, SCN1B and GABRG2 genes was performed in all affected and some unaffected members of these three families. Twenty-six exons of SCN1A, five exons of SCN1B and nine exons of GABRG2 were individually amplified using primers based on intronic sequence. PCR products were sequenced in both forward and reverse directions. Subsequently, the samples were run and analyzed using 377 DNA automated sequencer. No consanguinity was noticed. The MM and OM family members live in Republic of Srpska while KS family originates from the central Serbia. No mutations of the exons of SCN1A, SCN1B and GABRG2 genes were found in tested subjects. Obligate carriers in MM family (III-1, III-2, and III-4) exhibit variable expressivity or incomplete penetrance rather than proof of polygenetic inheritance. OM pedigree follows autosomal dominant pattern despite reduced penetrance. Bilinear transmission may assume the possibility of multigenetic mode of inheritance in KS family. The fact that all affected members in three Serbian families were negative for mutations in SCN1A, SCN1B and GABRG2 genes strongly supports the hypothesis of significant genetic heterogeneity of GEFS+. Recognizing GEFS+ on clinical grounds contributes to more precise integration of this syndrome into already existing classification of epileptic syndromes.
Abstract Purpose Mutations in the genes encoding the alfa2 , alfa4 and beta2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR) play a causative role in autosomal dominant nocturnal ...frontal lobe epilepsy (ADNFLE). Moreover, variations in the promoter of the corticotropic-releasing hormone gene ( CRH ) were also associated with ADNFLE. Here, we investigated whether nine brain-expressed genes ( CHRNA2 , CHRNA3 , CHRNA4 , CHRNA5 , CHRNA6 , CHRNA7 , CHRNB2 , CHRNB3 , CHRNB4 ), encoding distinct nAChR subunits, and CRH are associated with the disease in three distinct ADNFLE families from Southern Italy. Methods There were 14 living affected individuals (9 women), ranging in age from 14 to 57 years, pertaining to three unrelated families. Age at onset of seizures clustered around 9 years of age (range from 7 and 16 years, mean: 9.1 years ± 3.8). All affected individuals manifested nocturnal partial seizures of frontal lobe origin, which were well controlled by medications. Exon 5 of CHRNA4 and CHRNB2 genes, harboring all the known mutations, was sequenced in the probands. Then, we performed a linkage study on 13 affected and 26 non-affected individuals belonging to the three families with microsatellite markers and an intragenic polymorphisms encompassing the chromosome localization of the nAChR subunit genes and of the CRH gene. Results Mutational and linkage analyses allowed us to exclude the involvement of all known nAChR subunit genes and of the CRH gene in ADNFLE in our families. Conclusion Our results further illustrate the considerable genetic heterogeneity for such a syndrome, despite the quite homogeneous clinical picture. It is therefore reasonable to hypothesize that at least another gene not belonging to the nAChR gene family, in addition to CRH , is involved in the pathogenesis of ADNFLE.
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