Akihisa Mitsudome

A missense mutation of the Na+ channel αII subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction

Generalized epilepsy with febrile seizures plus (GEFS+), a clinical subset of febrile seizures (FS), is characterized by frequent episodes beyond 6 years of age (FS+) and various types of subsequent epilepsy. Mutations in β1 and αI-subunit genes of voltage-gated Na+ channels have been associated with GEFS+1 and 2, respectively. Here, we report a mutation resulting in an amino acid exchange (R187W) in the gene encoding the α-subunit of neuronal voltage-gated Na+ channel type II (Nav1.2) in a patient with FS associated with afebrile seizures. The mutation R187W occurring on Arg187, a highly conserved residue among voltage-gated Na+ channels, was not found in 224 alleles of unaffected individuals. Whole-cell patch clamp recordings on human embryonic kidney (HEK) cells expressing a rat wild-type (rNav1.2) and the corresponding mutant channels showed that the mutant channel inactivated more slowly than wild-type whereas the Na+ channel conductance was not affected. Prolonged residence in the open state of the R187W mutant channel may augment Na+ influx and thereby underlie the neuronal hyperexcitability that induces seizure activity. Even though a small pedigree could not show clear cosegregation with the disease phenotype, these findings strongly suggest the involvement of Nav1.2 in a human disease and propose the R187W mutation as the genetic defect responsible for febrile seizures associated with afebrile seizures.

Mutations of Neuronal Voltage-gated Na+ Channel α1 Subunit Gene SCN1A in Core Severe Myoclonic Epilepsy in Infancy (SMEI) and in Borderline SMEI (SMEB)

Summary:  Purpose: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes.

A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.

Objective: To identify the mutation responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a nonwhite family. Background: ADNFLE is newly recognized as an entity of idiopathic partial epilepsy. Recently, two different mutations of the neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) gene were identified in a white family as a cause of ADNFLE. Methods: Four affected and three unaffected individuals in three generations of a Japanese family with ADNFLE, and 100 unrelated healthy Japanese volunteers were studied. Clinical features and EEG findings in affected individuals were consistent with those of ADNFLE reported in white families with ADNFLE. Mutations within the CHRNA4 gene were screened for using single-strand conformation polymorphism analysis (SSCA) and were determined by direct sequencing. The mutation identified was sought in volunteers by the amplification refractory mutation system. Results: A C-to-T exchange (C755T) was found in exon 5 of the CHRNA4 gene on one allele of affected individuals. C755T segregated in affected individuals and was not found in 200 alleles obtained from the volunteers. C755T replaced serine 252 (Ser252) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine. Ser252 is conserved characteristically in the α-subunit of acetylcholine receptor and is considered to play an important role in channel function. Conclusion: C755T is a novel missense mutation of the CHRNA4 gene causing autosomal dominant nocturnal frontal lobe epilepsy in this Japanese family.

Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures

Recent evidence has suggested that the neuronal voltage-gated sodium channel α1-subunit gene (Nav1.1: SCN1A) is responsible for generalized epilepsy with febrile seizures plus (GEFS+2). Here the authors report two novel disease mutations of Nav1.1 in patients with febrile seizures associated with afebrile partial seizures. One is a Val1428Ala substitution in the pore-forming region, and the other is Ala1685Val in the transmembrane helix. These results support the previous findings and contribute to the reliable diagnosis of epilepsy.

Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity

Background and Methods: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships. Results: Mutations in SMEI occurred more frequently in the “pore” regions of SCN1A than did those in GEFS+. These SMEI mutations in the “pore” regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient. Conclusions: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.

A novel mutation of KCNQ3 (c.925T→C) in a Japanese family with benign familial neonatal convulsions

At present, only one mutation of KCNQ3, a KCNQ potassium channel gene, has been identified as a cause of benign familial neonatal convulsions type 2 (BFNC2). We found a T to C substitution (c.925T→C) on one allele of affected individuals in a Japanese family with BFNC but not on 200 alleles from healthy subjects. c.925T→C replaced Trp309, a conserved residue within the P‐loop of the KCNQ potassium channel family that holds the channel pore open, with an Arg (W309R). We report c.925T→C as the second mutation of KCNQ3 responsible for BFNC2. Ann Neurol 2000;47:822–826

Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (Na^+)-channel α1 subunit gene, SCN1A

Evidence that febrile seizures have a strong genetic predisposition has been well documented. In families of probands with multiple febrile convulsions, an autosomal dominant inheritance with reduced penetrance is suspected. Four candidate loci for febrile seizures have been suggested to date; FEB1 on 8q13-q21, FEB2 on 19p, FEB3 on 2q23-q24, and FEB4 on 5q14-15. A missense mutation was identified in the voltage-gated sodium (Na(+))-channel beta 1 subunit gene, SCN1B at chromosome 19p13.1 in generalized epilepsy with the febrile seizures plus type 1 (GEFS+1) family. Several missense mutations of the (Na(+))-channel alpha 1 subunit (Nav1.1) gene, SCN1A were also identified in GEFS+2 families at chromosome 2q23-q24.3. The aim of this report is precisely to describe the phenotypes of Japanese patients with novel SCN1A mutations and to reevaluate the entity of GEFS+. Four family members over three generations and one isolated (phenotypically sporadic) case with SCN1A mutations were clinically investigated. The common seizure type in these patients was febrile and afebrile generalized tonic-clonic seizures (FS+). In addition to FS+, partial epilepsy phenotypes were suspected in all affected family members and electroencephalographically confirmed in three patients of two families. GEFS+ is genetically and clinically heterogeneous, and associated with generalized epilepsy and partial epilepsy as well. The spectrum of GEFS+ should be expanded to include partial epilepsies and better to be termed autosomal dominant epilepsy with febrile seizures plus (ADEFS+).

Are some idiopathic epilepsies disorders of ion channels? a working hypothesis

Epilepsy is a common neurological disease and encompasses a variety of disorders with paroxysms. Although there is a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remains poorly understood. Linkage analysis and positional cloning have not been sufficient tools for determining the pathogenic mechanisms of common idiopathic epilepsies, and hence, novel approaches, based on the etiology of epilepsy, are necessary. Recently, many paroxysmal disorders, including, epilepsy, have been considered to be due to ion channel abnormalities or channelopathies. Results of recent studies employing gene analysis in animal models of epilepsy and human familial epilepsies support the hypothesis that at least some of the so called idiopathic epilepsies, i.e. epilepsies currently, classified as idiopathic could be considered as a channelopathy. This hypothesis is consistent with the putative prerequisites for genes responsible for the majority of idiopathic epilepsies that can adequately explain the following characteristics of epilepsy. Neuronal hyperexcitability, dominant inheritance with various penetrance, pharmacological role of some conventional antiepileptic drugs, age dependency in the onset of epilepsy, and the involvement of genetic factors in the pathogenesis of post-traumatic epilepsy. Search for mutations in ion channels expressed in the central nervous system may help in finding defects underlying some of idiopathic epilepsies, thereby enhancing, our understanding of the molecular pathogenesis of epilepsy. A working hypothesis to view certain idiopathic epilepsies as disorders of ion channels should provide a new insight to our understanding of epilepsy and allow the design of novel therapies.

Genetics of Idiopathic Epilepsies

Summary:  Purpose: To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies.

Electroclinical Picture of Autosomal Dominant Nocturnal Frontal Lobe Epilepsy in a Japanese Family

Summary: Purpose: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first described partial epilepsy syndrome known to be due to a single gene mutation. We found a first Japanese ADNFLE family with a novel mutation of the neuronal nicotinic acetylcholine receptor (nAChR) α4 subunit (CHRNA4) gene. The aim of this report is precisely to describe the electroclinical manifestations of ADNFLE in this family and to compare these findings with those of other families reported previously in the literature.