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Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1–18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks. [ABSTRACT FROM AUTHOR]

Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19‐ or CHD2‐related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1. The SCN1A gene–Dravet syndrome association is in our opinion highly specific. However, because the syndrome spectrum is wide, fragments of it can at times also be manifested in other genetic epilepsy syndromes, thereby leading to overdiagnosis of Dravet syndrome beyond SCN1A. Dravet syndrome is in turn a severe SCN1A phenotype within a continuum of SCN1A‐related clinical phenomenology. [ABSTRACT FROM AUTHOR]

Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19‐ or CHD2‐related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1. The SCN1A gene–Dravet syndrome association is in our opinion highly specific. However, because the syndrome spectrum is wide, fragments of it can at times also be manifested in other genetic epilepsy syndromes, thereby leading to overdiagnosis of Dravet syndrome beyond SCN1A. Dravet syndrome is in turn a severe SCN1A phenotype within a continuum of SCN1A‐related clinical phenomenology. [ABSTRACT FROM AUTHOR]

Background & Objective: SCN1A gene which encodes for sodium channel alpha 1 subunit has been found to be the most common mutated gene in patients with epilepsy. This study aims to characterize the SCN1A mutations as well as to describe genotype and phenotype association in children with SCN1A-related infantile-onset epileptic encephalopathies in Malaysia. Methods: Children with infantile-onset epileptic encephalopathy mostly suspected to have Dravet syndrome who had mutational analysis for SCN1A gene from hospitals all over Malaysia were included in the study. Their epilepsy syndrome diagnosis was classified into severe myoclonic epilepsy in infancy and its variants. Polymerase chain reaction and bidirectional sequencing were used to identify SCN1A mutations. Results: A total of 38 children with heterozygous mutations were analysed, 22 (57.9%) of which were novel mutations. Truncated mutations were the most common mutation type (19, 50%). Other mutation types were missense mutations (14, 36.8%), splice site mutations (4, 10.5%) and in-frame deletion (1, 2.6%). The mean age of seizure onset was 4.7 months. Seizure following vaccination was observed in 26.3% of the children. All of them had drug resistant epilepsy. There was no significant association between the type of mutation with the syndromic diagnosis, age of seizure onset, tendency of the seizures to cluster or having status epilepticus, mean age when developmental delay was observed and response to various antiepileptic drugs. Conclusion: This study expands the spectrum of SCN1A mutations and proves the importance of SCN1A gene testing in diagnosing infantile-onset epileptic encephalopathies patients. Although, our study does not support any clinically meaningful genotype-phenotype association for SCN1A-related infantile-onset epileptic encephalopathies, the clinical characteristics of our cohort are similar to those that have been described in previous studies. [ABSTRACT FROM AUTHOR]

Purpose we characterized multifocal myoclonus in Dravet syndrome (DS) that was never systematically typified before. Methods we studied EEG-EMG recordings of 19 consecutive patients, aged 2–29 years, with DS associated with SCN1A gene mutations to detect and evaluate myoclonus based on the spectrum of EMG activity on antagonist muscle pairs and cortico-muscular coherence (CMC). Results multifocal action myoclonus was detected in all patients corresponding to brief EMG bursts, which occurred synchronously on antagonist muscles at a frequency peaking in beta band. There was significant CMC in beta band, and a cortico-muscular transfer time consistent with a cortical origin of the jerks. The somatosensory evoked potentials (SSEPs) were giant in only one patient who also showed exaggerated long-loop reflexes (LLRs). The nine patients who had experienced myoclonic seizures showed greater CMC. Conclusions The cortical myoclonus consistently observed in patients with DS shows features that are similar to those characterizing progressive myoclonus epilepsy, but differs because it does not have a severely worsening course and is not commonly associated with increased SSEPs or enhanced LLRs. This kind of myoclonus is an intrinsic feature of DS associated with SCN1A mutations, and may be a cause of disability. Significance We hypothesize that myoclonus is generated in cortical motor areas by hyper-synchronous oscillations, which are possibly due to sodium channel dysfunction. [ABSTRACT FROM AUTHOR]

Objective To report on six patients with SCN1A mutations and malformations of cortical development ( MCDs) and describe their clinical course, genetic findings, and electrographic, imaging, and neuropathologic features. Methods Through our database of epileptic encephalopathies, we identified 120 patients with SCN1A mutations, of which 4 had magnetic resonance imaging ( MRI) evidence of MCDs. We collected two further similar observations through the European Task-force for Epilepsy Surgery in Children. Results The study group consisted of five males and one female (mean age 7.4 ± 5.3 years). All patients exhibited electroclinical features consistent with the Dravet syndrome spectrum, cognitive impairment, and autistic features. Sequencing analysis of the SCN1A gene detected two missense, two truncating, and two splice-site mutations. Brain MRI revealed bilateral periventricular nodular heterotopia ( PNH) in two patients and focal cortical dysplasia ( FCD) in three, and disclosed no macroscopic abnormality in one. In the MRI-negative patient, neuropathologic study of the whole brain performed after sudden unexpected death in epilepsy ( SUDEP), revealed multifocal micronodular dysplasia in the left temporal lobe. Two patients with FCD underwent epilepsy surgery. Neuropathology revealed FCD type IA and type IIA. Their seizure outcome was unfavorable. All four patients with FCD exhibited multiple seizure types, which always included complex partial seizures, the area of onset of which co-localized with the region of structural abnormality. Significance MCDs and SCN1A gene mutations can co-occur. Although epidemiology does not support a causative role for SCN1A mutations, loss or impaired protein function combined with the effect of susceptibility factors and genetic modifiers of the phenotypic expression of SCN1A mutations might play a role. MCDs, particularly FCD, can influence the electroclinical phenotype in patients with SCN1A-related epilepsy. In patients with MCDs and a history of polymorphic seizures precipitated by fever, SCN1A gene testing should be performed before discussing any epilepsy surgery option, due to the possible implications for outcome. [ABSTRACT FROM AUTHOR]

Highlights: [•] NaV1.1 is the major sodium current in specific inhibitory interneurons. [•] Interneuronal dysfunction is linked to epilepsies, schizophrenia, and AD. [•] NaV1.1 plays a modest role in excitatory neurons. [•] Selective NaV1.1 activators may hold great potential as a novel treatment paradigm. [ABSTRACT FROM AUTHOR]

Objective: Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI) is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+) includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome. Materials & Methods: From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+. Results: 35 patients (15 girls and 20 boys) underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years). Three criteria that were best evident in SCN1A mutation positive patients are as follows: "Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3%) patients with clinical Dravet syndrome and 3 of 20 (15%) patients that diagnosed as GEFS+, had SCN1A mutation. Conclusion: In this study, normal development before seizure onset, seizures beginning before age of one year and psychomotor retardation after age of two years are the most significant criteria in SCN1A mutation positive patients. [ABSTRACT FROM AUTHOR]

Summary: We studied clinical and EEG manifestations of absence seizures (AS) in children with Dravet syndrome (DS) to clarify their characteristic features and differences from those of typical AS (TAS). The subjects were 12 children with DS. We retrospectively analyzed electroclinical characteristics of AS. We analyzed a total of 102 ictal EEGs characterized by generalized spike-and-wave (GSW) and semiology of 78 video-taped AS. The mean age at the onset of AS and at the time of the study was 16.2±7.1 months and 40.3±22.1 months, respectively. Ictal EEG showed the focality of initial discharge in 49/102 (48%), a duration ranging from 2 to 180s (mean: 10.2±22.6s; median: 4.0s), frequency ranging from 2 to 4Hz (median=3.0Hz), and irregular and disorganized GSW morphology in 66/102 (65%). AS manifested with eyelid-myoclonus and generalized myoclonus in 9/54 (17%) and 34/78 (44%), respectively. In conclusion, AS in DS were characterized by an early-onset age, a high incidence of irregular and disorganized 3Hz GSW morphology, and the frequent association of generalized myoclonic movement as well as the absence of automatism as compared to TAS. The results should be appreciated in the differential diagnosis of early-onset AS, the treatment of AS in DS and also a further clinical and genetic study for DS. [Copyright &y& Elsevier]

Summary: Background: SCN1A is the most clinically relevant epilepsy gene, most mutations causing Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI). We evaluated clinical differences, if any, between young patients with and without a SCN1A mutations and a definite clinical diagnosis of Dravet syndrome. Methods: Twenty-five patients with a diagnosis of Dravet Syndrome (7 males, 18 females; mean age at inclusion: 10.3; median: 9±7; range: 18 months–30 years) were retrospectively studied. A clinical and genetic study focusing on SCN1A was performed, using DHPLC, gene sequencing and MLPA to detect genomic deletions/duplications. A formal cognitive and behavioral assessment was available for all patients. Results: Analysis revealed SCN1A mutations comprising missense, truncating mutations and genomic deletions/duplications in eighteen patients and no mutation in seven. The phenotype of mutation positive patients was characterized by a higher number of seizures/month in the first year of life, an earlier seizure onset and a higher frequency of episodes of status epilepticus. The cognitive and behavioral profile was slightly worst in mutation positive patients. Conclusions: These findings confirm that SCN1A gene mutations are strongly associated to a more severe phenotype in patients with Dravet syndrome. [ABSTRACT FROM AUTHOR]

Researchers at the Cincinnati Children’s Medical Center, OH investigated the predictive value of features of Dravet syndrome, as defined by the International League Against Epilepsy, as criteria for a positive SCN1A gene mutation in a cohort of consecutively tested children.

The role of SCN1A gene mutations in the etiology of severe myoclonic epilepsy of infancy (SMEI) was investigated in 93 patients followed at the Hopital Saint Vincent de Paul, Paris, and other centers in France and Italy.

Object: Mutations in the sodium channel alpha 1 subunit gene (SCN1A) have been associated with a wide range of epilepsy phenotypes including Dravet syndrome. There currently exist few histopathological and surgical outcome reports in patients with this disease. In this case series, the authors describe the clinical features, surgical pathology, and outcomes in 6 patients with SCN1A mutations and refractory epilepsy who underwent focal cortical resection prior to uncovering the genetic basis of their epilepsy., Methods: Medical records of SCN1A mutation-positive children with treatment-resistant epilepsy who had undergone resective epilepsy surgery were reviewed retrospectively. Surgical pathology specimens were reviewed., Results: All 6 patients identified carried diagnoses of intractable epilepsy with mixed seizure types. Age at surgery ranged from 18 months to 20 years. Seizures were refractory to surgery in every case. Surgical histopathology showed evidence of subtle cortical dysplasia in 4 of 6 patients, with more neurons in the molecular layer of the cortex and white matter., Conclusions: Cortical resection is unlikely to be beneficial in these children due to the genetic defect and the unexpected neuropathological finding of mild diffuse malformations of cortical development. Together, these findings suggest a diffuse pathophysiological mechanism of the patients' epilepsy which will not respond to focal resective surgery.

Sodium channel inhibitors have been developed and approved as drugs to treat a variety of indications. By contrast, sodium channel activators have not previously been considered relevant in a therapeutic setting owing to their high risk of toxicity and side effects. Here we present an opinion that selective activators of the Na(V)1.1 sodium channel may hold therapeutic potential for diseases such as epilepsy, schizophrenia, and Alzheimer's disease. Central to this novel avenue of sodium channel drug discovery is that fact that Na(V)1.1 comprises the majority of the sodium current in specific inhibitory interneurons. Conversely, it plays only a modest role in excitatory neurons owing to the high redundancy of other types of sodium channels in these cells. We discuss the biological background and rationale and present reflections on how to identify activators of Na(V)1.1., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Dravet syndrome or severe myoclonic epilepsy of infancy (SMEI) is a baleful epileptic encephalopathy that begins in the first year of life. This syndrome specified by febrile seizures followed by intractable epilepsy, disturbed psychomotor development, and ataxia. Clinical similarities between Dravet syndrome and generalized epilepsy with febrile seizure plus (GEFS+) includes occurrence of febrile seizures and joint molecular genetic etiology. Shared features of these two diseases support the idea that these two disorders represent a severity spectrum of the same illness. Nowadays, more than 60 heterozygous pattern SCN1A mutations, which many are de novo mutations, have been detected in Dravet syndrome., Materials & Methods: From May 2008 to August 2012, 35 patients who referred to Pediatric Neurology Clinic of Mofid Children Hospital in Tehran were enrolled in this study. Entrance criterion of this study was having equal or more than four criteria for Dravet syndrome. We compared clinical features and genetic findings of the patients diagnosed as Dravet syndrome or GEFS+., Results: 35 patients (15 girls and 20 boys) underwent genetic testing. Mean age of them was 7.7 years (a range of 13 months to 15 years). Three criteria that were best evident in SCN1A mutation positive patients are as follows: "Normal development before the onset of seizures, onset of seizure before age of one year, and psychomotor retardation after onset of seizures. Our genetic testing showed that 1 of 3 (33.3%) patients with clinical Dravet syndrome and 3 of 20 (15%) patients that diagnosed as GEFS+, had SCN1A mutation., Conclusion: In this study, normal development before seizure onset, seizures beginning before age of one year and psychomotor retardation after age of two years are the most significant criteria in SCN1A mutation positive patients.