Search

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus., (© 2022. The Author(s).)

Objective: To examine the current medical and psychosocial status of patients with epilepsy, aiming to facilitate appropriate application of the Intractable/Rare Diseases Act of Japan., Methods: By analysing the cross-sectional data of patients registered in the tertiary hospital-based Epilepsy Syndrome Registry of Japan, we investigated the proportion of patients who met the severity criteria as defined by the Act (seizure frequency of at least once a month, or presence of intellectual/neurological/psychiatric symptoms, or both) and whether there are candidate syndrome/diseases to be added to the existing list in the Act., Results: In total, 2,209 patients were registered. After excluding self-limited/idiopathic epilepsies, 1,851 of 2,110 patients (87.7%) met the severity criteria. The patients were classified into eight main epilepsy syndromes (594 patients), 20 groups based on aetiology (1,078 patients), and three groups without known aetiology (427 patients). Most of the groups classified by syndrome or aetiology had high proportions of patients satisfying the severity criteria (>90%), but some groups had relatively low proportions (<80%) resulting from favourable outcome of surgical therapy. Several small groups with known syndrome/aetiology await detailed analysis based on a sufficiently large enough number of patients registered, some of whom may potentially be added to the list of the Act., Significance: The registry provides data to examine the usefulness of the severity criteria and list of diseases that are operationally defined by the Act. Most epilepsy patients with various syndromes/diseases and aetiology groups are covered by the Act but some are not, and the list of designated syndromes/diseases should be complemented by further amendments, as suggested by future research.

Missense and truncating variants in protocadherin 19 (PCDH19) cause PCDH19-related epilepsy. In this study, we aimed to investigate variations in distributional characteristics and the clinical implications of variant type in PCDH19-related epilepsy. We comprehensively collected PCDH19 missense and truncating variants from the literature and by sequencing six exons and intron-exon boundaries of PCDH19 in our cohort. We investigated the distribution of each type of variant using the cumulative distribution function and tested for associations between variant types and phenotypes. The distribution of missense variants in patients was clearly different from that of healthy individuals and was uniform throughout the extracellular cadherin (EC) domain, which consisted of six highly conserved domains. Truncating variants showed two types of distributions: (1) located from EC domain 1 to EC domain 4, and (2) located from EC domain 5 to the cytoplasmic domain. Furthermore, we also found that later onset seizures and milder intellectual disability occurred in patients with truncating variants located from EC domain 5 to the cytoplasmic domain compared with those of patients with other variants. Our findings provide the first evidence of two types of truncating variants in the PCDH19 gene with regard to distribution and the resulting clinical phenotype.

Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Importantly, epilepsy is genetically and etiologically heterogenous, but several epilepsy types exhibit similar clinical presentations. Epilepsy-associated genes are being identified. However, the molecular pathomechanisms remain largely unknown. Approximately one-third of epilepsy is refractory to multiple conventional anti-epileptic drugs (AEDs). Induced pluripotent stem cells (iPSCs) provide an excellent tool to study the pathomechanisms underlying epilepsy and to develop novel treatments. Indeed, disease-specific iPSCs have been established for several genetic epilepsies. In particular, the molecular mechanisms underlying certain developmental and epileptic encephalopathies, such as Dravet syndrome, have been revealed. Modeling epilepsy with iPSCs enables new drug development based on the elucidated pathomechanisms. This can also be used to evaluate conventional AEDs and drug repurposing. Furthermore, transplanting neuronal cells derived from iPSCs into the brain has great potential to treat refractory epilepsies. Recent advances in iPSC technology have enabled the generation of neuronal organoids, or "mini brains." These organoids demonstrate electrophysiological activities similar to those of the brain and have the potential for extensive epilepsy research opportunities. Thus, the application of iPSCs in epilepsy provides insight into novel treatments based on the molecular pathomechanisms of epilepsy. In this review, we comprehensively discuss the studies conducted on iPSCs established for genetic epilepsy or epilepsies without major structural dysmorphic features., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by prolonged febrile seizures at onset and subsequent damage to the cerebral cortex of infants and children. The pathogenesis is suspected to be excitotoxicity leading to neuronal death. SCN1A and KCNQ2 are causative genes of genetic epilepsy including Dravet syndrome and Ohtahara syndrome. Here we conducted a case-control rare-variant association study of the two genes in AESD., Methods: The coding regions of SCN1A and KCNQ2 were sequenced by the Sanger method for 175 and 111 patients, respectively, with AESD. As control subjects, we used genetic data from 3554 subjects provided by the Integrative Japanese Genome Variation Database (iJGVD). Then we performed a case-control association study of rare missense and splice region variants (minor allele frequency < 0.005) of each gene with AESD using Weighted Sum Statistics (WSS) and Sequence Kernel Association Test (SKAT)., Results: SCN1A rare variants had a significant association with AESD after correction for multiple tests (WSS, permutated p value 4.00 × 10 -3 : SKAT, p value 2.51 × 10 -4 ). The association was more significant when we focused on deleterious variants (WSS, permutated p = 9.00 × 10 -4 ; SKAT, p = 4.99 × 10 -5 ). Although KCNQ2 rare nonsynonymous variants tended to be more frequent in patients than in controls, there was no significant difference., Conclusion: Our study provided statistical evidence of an association between SCN1A and AESD for the first time, and established SCN1A as one of the susceptibility genes for AESD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.

Benign familial infantile epilepsy (BFIE) is characterized by non-febrile focal seizures, which sometimes evolve to secondarily generalized seizures and are usually resolved in the second year. Proline-rich transmembrane protein 2 (PRRT2) is confirmed as the major cause of BFIE, familial paroxysmal kinesigeneic dystonia (PKD) and infantile convulsions and choreoathetosis (ICCA) syndrome. We examined a female patient with a hot spot mutation of PRRT2 gene. She had recurrent tonic seizures when she was three months old. The seizures were controlled by several kinds of anticonvulsants. Then, she had several times of focal seizures daily at nine months old. However, the seizures were stopped by small amounts of carbamazepine. Later, when she was two years old, she experienced frequent motor seizures characterized by truncal flexion and swaying the body with partially disturbed consciousness. Her father also had the same PRRT2 gene mutation and non-febrile seizures in infancy. The patient had mild to moderate mental retardation, whereas her father was mentally normal. Therefore, the patient revealed a quiet different phenotype from that of her father as a carrier of the same PRRT2 gene mutation. We speculate that the PRRT2 mutation had caused the BFIE-like seizures both in the patient and her father, whereas other unknown genetic factors specific for the patient might be associated with the atypical seizures observed only in her.

On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Despite its frequency in central nervous disease, epilepsy's molecular pathogenesis has been unclear. Still, the association of genes causing epilepsy--and particular familial epilepsy--have ben ascertained, as having abnormalities identified in gene encoding ion channels and receptors. Knowledge of sporadic epilepsy, for its part, has been much improved by a next generation sequencer, but epilepsy's molecular mechanisms remain uncertain even now, when some 400 genes have been identified. The identification of genetic abnormalities is, nonetheless, helpful in diagnosis, treatment, and counseling for the disease. Here, we describe epilepsies in which genetic analyses are useful, the contributions made by new technologies, and future prospects in the understanding and treatment of epilepsy.

Mutations in GABRG2, which encodes the γ2 subunit of GABAA receptors, can cause both genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. Most GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects. This study involved search for mutations in candidate genes for Dravet syndrome, namely SCN1A, 2A, 1B, 2B, GABRA1, B2, and G2. A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. Electrophysiological studies with the reconstituted GABAA receptors in HEK cells showed reduced GABA-induced currents when mutated γ2 DNA was cotransfected with wild-type α1 and β2 subunits. In this case, immunohistochemistry using antibodies to the α1 and γ2 subunits of GABAA receptor showed granular staining in the soma. In addition, microinjection of mutated γ2 subunit cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits α1 and β2, and retention of these proteins in the endoplasmic reticulum. The mutated γ2 subunit-expressing neurons also showed impaired axonal transport of the α1 and β2 subunits. Our findings suggested that different phenotypes of epilepsy, e.g., GEFS+ and Dravet syndrome (which share similar abnormalities in causative genes) are likely due to impaired axonal transport associated with the dominant-negative effects of GABRG2., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mutations of the gene encoding the α1 subunit of neuronal sodium channel, SCN1A, are reported to cause Dravet syndrome (DS). The prevalence of mutations reported in such studies (mainly in clinically confirmed DS) seems high enough to make genetic diagnosis feasible. In fact, commercially operating genetic diagnostic laboratories offering genetic analyses of SCN1A are available. Still, the exact prevalence of mutations of SCN1A remains elusive. Fukuoka University has been serving as a genetic diagnostic laboratory for DS for the last 10 years. In this study, we determined the prevalence of SCN1A mutations (SCN1A, SCN2A, SCN1B and SCN2B) in 448 patients with suspected DS and intractable childhood epilepsy. A total of 192 SCN1A mutations were identified in 188 of 448 patients (42.0%). The frequencies of SCN1A mutations in suspected severe myoclonic epilepsy of infancy (SMEI), its borderline phenotype (SMEB) and intractable epilepsy were 56.2%, 41.9% and 28.9% respectively. In addition, four SCN2A mutations were identified in 4 of 325 patients. No mutations of SCN1B and SCN2B were identified. These results are potentially helpful for the diagnosis of DS at early stage., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Syntaxin-binding protein1 (STXBP1) is a member of the Sec1/Munc18-1 protein family, which comprises important regulators of the secretory and synaptic vesicle fusion machinery underlying hormonal and neuronal transmission, respectively. STXBP1 pathogenic variants are associated with multiple neurological disorders. Herein, we present the case of a Japanese girl with a mutation in the STXBP1 gene, who was born at 40 weeks without neonatal asphyxia. At 15 days old, she developed epilepsy and generalized seizures. Around 88 days old, she presented with a series of nodding spasms, with the seizure frequency gradually increasing. Interictal EEG indicated hypsarrhythmia and she presented with developmental regression. At 1.5 years old, genetic testing was performed and mutational analysis revealed an STXBP1 gene mutation (c.875G > A: p.Arg292His). Accordingly, she was diagnosed with developmental and epileptic encephalopathy, presenting West syndrome's clinical characteristics caused by the STXBP1 gene mutation. Although drug treatment has reduced the frequency of epileptic seizures, her development has remained regressive. The relationship between the location and type of genetic abnormality and the phenotype remains unclear. Future studies should investigate the genotype–phenotype correlation and the underlying pathophysiology to elucidate the causal relationships among the multiple phenotype-determining factors. [ABSTRACT FROM AUTHOR]

Objective: Pathogenic variants of KCNQ2, which encode a potassium channel subunit, cause either benign (familial) neonatal epilepsy—B(F)NE)—or KCNQ2 encephalopathy (KCNQ2 DEE). We examined the characteristics of KCNQ2 variants. Methods: KCNQ2 pathogenic variants were collected from in‐house data and two large disease databases with their clinical phenotypes. Nonpathogenic KCNQ2 variants were collected from the Genome Aggregation Database (gnomAD). Pathogenicity of all variants was reevaluated with clinical information to exclude irrelevant variants. The cumulative distribution plots of B(F)NE,KCNQ2 DEE, and gnomAD KCNQ2 variants were compared. Several algorithms predicting genetic variant pathogenicity were evaluated. Results: A total of 259 individuals or pedigrees with 216 different pathogenic KCNQ2 variants and 2967 individuals with 247 different nonpathogenic variants were deemed eligible for the study. Compared to the distribution of nonpathogenic variants, B(F)NE and KCNQ2 DEE missense variants occurred in five and three specific KCNQ2 regions, respectively. Comparison between B(F)NE and KCNQ2 DEE sets showed that B(F)NE missense variants frequently localized to the intracellular domain between S2 and S3, whereas those of KCNQ2 DEE were more frequent in S6, and its adjacent pore domain, as well as in the intracellular domain between S6 and helix A. The scores of Protein Variation Effect Analyzer (PROVEAN) and Percent Accepted Mutation (PAM) 30 prediction algorithms were associated with phenotypes of the variant loci. Significance: Missense variants in the intracellular domain between S2 and S3 are likely to cause B(F)NE, whereas those in S6 and its adjacent regions are more likely to cause KCNQ2 DEE. With such regional specificities of variants, PAM30 is a helpful tool to examine the possibility that a novel KCNQ2 variant is a B(F)NE or KCNQ2 DEE variant in genetic analysis. [ABSTRACT FROM AUTHOR]

Objective Two major classes of SCN1A variants are associated with Dravet syndrome ( DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment. Methods We sequenced all exons and intron-exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals. Results Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I- II and II- III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants. Significance We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency. [ABSTRACT FROM AUTHOR]

Background: Alternating hemiplegia of childhood is an intractable neurological disorder characterized by recurrent episodes of alternating hemiplegia accompanied by other paroxysmal symptoms. Recent research has identified mutations in the ATP1A3 gene as the underlying cause. Adenosine-5'-triphosphate has a vasodilatory effect, can enhance muscle strength and physical performance, and was hypothesized to improve the symptoms of paroxysmal hemiplegia.Methods: A 7-year-old boy with alternating hemiplegia of childhood who was positive for a de novo ATP1A3 mutation was treated with adenosine- 5'- triphosphate supplementation orally as an innovative therapy for 2 years. Outcome was evaluated through the follow-up of improvement of hemiplegic episodes and psychomotor development. Side effects and safety were monitored in regularity.Results: With the dosage of adenosine-5'-triphosphate administration increased, the patient showed significantly less frequency and shorter duration of hemiplegic episodes. Treatment with adenosine-5'-triphosphate was correlated with a marked amelioration of alternating hemiplegia of childhood episodes, and psychomotor development has improved. The maximum dose of oral administration of adenosine-5'-triphosphate reached 25 mg/kg per day. Adenosine-5'-triphosphate therapy was well tolerated without complaint of discomfort and side effects.Conclusions: The 2-year follow-up outcome of adenosine-5'-triphosphate therapy for alternating hemiplegia of childhood was successful. [ABSTRACT FROM AUTHOR]

The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63–100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine’s scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations. [ABSTRACT FROM AUTHOR]

Abstract: We performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most antiepileptic drugs but responded to vagus nerve stimulation in one and clorazepate in the other. Bidirectional sequencing for KCNT1 was analyzed by standard Sanger sequencing method. A de novo c.862G>A (p.Gly288Ser) missense mutation was identified at the pore region of KCNT1 channel in both patients, whereas all KCNT1 mutations in the previous reports were identified mostly in the intracellular C-terminal region. Computational analysis suggested possible changes in the molecular structure and the ion channel property induced by the Gly288Ser mutation. Because the G-to-A transition was located at CG dinucleotide sequences as previously reported for KCNT1 mutations, the recurrent occurrence of de novo KCNT1 mutations indicated the hot spots of these locations. [Copyright &y& Elsevier]

Abstract: Purpose: PRRT2 mutations were recently identified in benign familial infantile epilepsy (BFIE) and infantile convulsions with paroxysmal choreoathetosis (ICCA) but no abnormalities have so far been identified in their phenotypically similar seizure disorder of benign convulsions with mild gastroenteritis (CwG), while mutations in KCNQ2 and KCNQ3 have been recognized in benign familial neonatal epilepsy (BFNE). The aim of this study was to identify PRRT2 mutations in infantile convulsions in Asian families with BFIE and ICCA, CwG and BFNE. Methods: We recruited 26 unrelated Japanese affected with either BFIE or non-familial benign infantile seizures and their families, including three families with ICCA. A total of 17 Japanese and Taiwanese with CwG, 50 Japanese with BFNE and 96 healthy volunteers were also recruited. Mutations of PRRT2 were sought using direct sequencing. Results: Heterozygous truncation mutation (c.649dupC) was identified in 15 of 26 individuals with benign infantile epilepsy (52.1%). All three families of ICCA harbored the same mutation (100%). Another novel mutation (c.1012+2dupT) was found in the proband of a family with BFIE. However, no PRRT2 mutation was found in either CwG or BFNE. Conclusions: The results confirm that c.649dupC, a truncating mutation of PRRT2, is a hotspot mutation resulting in BFIE or ICCA regardless of the ethnic background. In contrast, PRRT2 mutations do not seem to be associated with CwG or BFNE. Screening for PRRT2 mutation might be useful in early-stage differentiation of BFIE from CwG. [Copyright &y& Elsevier]

A few mutations in the gene encoding the gamma 2 subunit of the gamma-aminobutyric acid receptor type A (GABRG2) have been reported in various types of epilepsy. The aim of this study is to investigate the role of GABRG2 in the pathogenesis of childhood epilepsy in a large Japanese cohort. Genetic analysis of GABRG2 was performed on 140 Japanese patients with various childhood epilepsies largely including Dravet syndrome and genetic epilepsy with febrile seizures plus. The mutational analysis identified one novel missense mutation of GABRG2 (c.236A>G: p.N40S) in a patient with generalized tonic-clonic seizures (GTCS). The mutation was heterozygous and replacing a highly conserved Asn residue with a Ser. The affected amino acid was located at residue 40 of the mature GABRG2 protein, which was near the first one of two high-affinity benzodiazepine-binding domains of the γ2 subunit (Lys-41-Trp-82). This mutation in such an important position may hamper the function of the channel and contribute to the case’s pathogenesis of GTCS. [ABSTRACT FROM AUTHOR]

Abstract: Background: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K+ channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. Objective: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. Methods: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. Results: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K+ channel. The mutant channels were expressed on the cell surface. Conclusion: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K+ channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy. [Copyright &y& Elsevier]

CDKL5 deficiency is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene and clinically manifests often in females as drug-resistant intractable epilepsy and severe psychomotor retardation. We report the case of a girl with a CDKL5 mutation born at 39 weeks without neonatal asphyxia. She developed epilepsy at age 1 month with myoclonus of the face and limbs, and non-rhythmic and irregular opsoclonus. She developed tonic seizures and epileptic spasms at 6 months of age and was diagnosed with symptomatic West syndrome and underwent adrenocorticotropic hormone therapy but her seizures were refractory. At the age of 4, she was introduced to our hospital and development was at 2 months of age. We diagnosed her with early myoclonic encephalopathy (EME) due to the remaining suppression-burst pattern observed on an electroencephalogram and her symptoms since onset were mainly myoclonus. At 14 years of age, mutational analysis revealed a CDKL5 mutation (c.380A > G:p.His127Arg). She was diagnosed with epileptic encephalopathy exhibiting clinical features of early myoclonic epilepsy caused by CDKL5 deficiency. Early onset epilepsy with severe psychomotor retardation without a known etiology may be caused by a mutation in CDKL5. More research investigating a genotype-phenotype correlation of CDKL5 mutations is necessary because clinical severity may be associated with the location and type of mutations. [ABSTRACT FROM AUTHOR]

Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30 s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis. Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient’s younger years. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A , which encodes the Na + channel Na v 1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2 days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10 months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14 months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings. [ABSTRACT FROM AUTHOR]