Dravet syndrome

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ASESSMENT OF SCN1A, SCN2A, EPM2A GENE MUTATUION IN DRAVET SYNDROME EPILEPSY SEIZURE DISORDER, IN HUMAN, TABRIZ, IRAN

ASESSMENT OF SCN1A, SCN2A, EPM2A GENE MUTATUION IN DRAVET SYNDROME EPILEPSY SEIZURE DISORDER, IN HUMAN, TABRIZ, IRAN

Dravet syndrome spectrum disorders are rare genetic epileptic encephalopathies (dysfunction of the brain) with onset during the first year of life in an otherwise healthy infant. There is a spectrum of severity ranging from no clinical symptoms, to simple febrile seizures, and extending to Dravet syndrome, which is the most severe. Mutations of the SCN1A gene cause 79% of diagnosed cases of Dravet syndrome. Frequently referred to as a sodium channelopathy, this intractable (uncontrollable) epilepsy is characterized by unilateral (one- sided) clonic or tonic clonic (grand mal) seizures that may be prolonged (> 5 minutes) or progress to status epilepticus (>30 minutes). Myoclonic seizures, often called myoclonic jerks, are common but not always present. Over time seizures present without fever, illness or heat triggers. Seizures are frequent and resistant to treatment. The first seizure is often associated with vaccine administration at six months of age. Infants eventually develop other seizure types including atypical absence, eyelid myoclonia and non-convulsive seizures. Multiple drug therapy is necessary for acceptable seizure control. Some anti-epileptic drugs exacerbate seizures and should be avoided. In most cases, surgery is not indicated. The initial EEG is normal but within the second or third year of life, brief generalized spike, polyspike, or polyspike-wave paroxysms appear. MRI and metabolic studies are normal. Developmental delays appear to varying degrees in most patients by age two years and ataxia (abnormal gait) is common. Appropriate and aggressive seizure management, and implementation of global therapies are necessary to improve the outcome of children affected with Dravet syndrome spectrum disorders.
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Impaired intracortical inhibition demonstrated in vivo in people with Dravet syndrome

Impaired intracortical inhibition demonstrated in vivo in people with Dravet syndrome

Results: Short interval intracortical inhibition (SICI), which measures GABAergic inhibitory network behavior, was undetectable in Dravet syndrome, but detectable in all controls.. Other[r]

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Fatal Cerebral Edema With Status Epilepticus in Children With Dravet Syndrome: Report of 5 Cases

Fatal Cerebral Edema With Status Epilepticus in Children With Dravet Syndrome: Report of 5 Cases

Dravet syndrome (DS) is a well-recognized developmental and epileptic encephalopathy associated with SCN1A mutations and 15% mortality by 20 years. Although over half of cases succumb to sudden unexpected death in epilepsy, the cause of death in the remainder is poorly defined. We describe the clinical, radiologic, and pathologic characteristics of a cohort of children with DS and SCN1A mutations who developed fatal cerebral edema causing mass effect after fever-associated status epilepticus. Cases were identified from a review of children with DS enrolled in the Epilepsy Genetics
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Alleged Cases of Vaccine Encephalopathy Rediagnosed Years Later as Dravet Syndrome

Alleged Cases of Vaccine Encephalopathy Rediagnosed Years Later as Dravet Syndrome

Although Dravet syndrome is rare, its recognition is important for pediatri- cians in the campaign for childhood immunizations, because it offers an al- ternative genetic explanation to refute alleged cases of vaccine encephalopa- thy. Of further importance to patients with Dravet syndrome and their fami- lies are the genetic, prognostic, and treatment implications that are gained from correct diagnosis and epilepsy syndrome assignment.

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Dravet Syndrome in Lebanon: First Report on Cases with SCN1A Mutations

Dravet Syndrome in Lebanon: First Report on Cases with SCN1A Mutations

with Dravet syndrome and immunoglobulin G subclasses deficiency treated with valproic acid, intravenous immuno- globulin, and vagal nerve stimulator,” Journal of Middle East and North Africa Sciences, vol. 2, no. 6, pp. 27–29, 2016. [15] M. J. Cho, S. S. Kwon, A. Ko et al., “Efficacy of stiripentol in

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Determination of SCN1A genetic variants in Mexican patients with refractory epilepsy and Dravet syndrome.

Determination of SCN1A genetic variants in Mexican patients with refractory epilepsy and Dravet syndrome.

The SCN1A (MIM#182389) gene encodes for type 1 subunit of the neuronal voltage- gated sodium channel, and is one of the four voltage-gated sodium channel genes that play an important role in controlling neuronal excitability (Plummer and Meisler, 1999). Mutations in this gene have been associated with a variety of neurological diseases including epilepsy, autism, and migraine. Other syndromes associated with SCN1A mutations include the Dravet syndrome (DS), also named severe myoclonic epilepsy of infancy (SMEI), as well as epileptic encephalopathy, partial epilepsy, generalized epilepsy, and febrile seizures (Meng et al., 2015). A total of 1727 mutations and genomic rearrangements have been reported in the SCN1A mutation database, with higher predominance in DS patients (58.6%). In addition, most of the reported SCN1A mutations (20.76%) occur in exon 26, which encodes for the pore region. This region contains the voltage sensor, whose mutations have been associated with severe disease phenotypes (Meng et al., 2015). Based on this information, our objective was to carry out a mutational screening on exon 26 in a group of Mexican patients with refractory epilepsy (RE) and/or DS in order to determine the frequency of SCN1A mutations in these diseases.
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Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

Data on the efficacy and safety of cannabidiol (CBD) in various epilepsies are emerging. Randomized controlled trials have suggested that an orally administered pharmaceutical formulation of purified CBD as an add-on to existing anti- epileptic drugs (AEDs) has efficacy in treating convulsive seizures associated with Dravet syndrome (DS) and drop seizures associated with Lennox-Gastaut syndrome. 1,2 Open- label trials support these findings and suggest there is efficacy in other generalized and focal epilepsies, including tuberous sclerosis complex and febrile infection-related epilepsy syndrome. 3–5 Adverse effects of CBD in patients with treatment-resistant epilepsy are well-documented in ran- domized controlled and open-label trials, and most com- monly include somnolence, diarrhea, and decreased appetite. 1–5
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Few individuals with Lennox-Gastaut syndrome have autism spectrum disorder: a comparison with Dravet syndrome

Few individuals with Lennox-Gastaut syndrome have autism spectrum disorder: a comparison with Dravet syndrome

Background: Autism spectrum disorder (ASD) in epilepsy has been a topic of increasing interest, which in general occurs in 15 – 35% of the patients with epilepsy, more frequently in those with intellectual disability (ID). Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are two typical forms of intractable epileptic encephalopathy associated with ID. We previously reported that ASD was diagnosed in 24.3% of patients with DS, higher in those with profound ID. Given the severe epilepsy and high frequency of ID in LGS, it is necessary to know whether ASD is a common psychomotor co-morbidity of LGS. This study evaluated the autistic behaviors and intelligence in patients with LGS and further compared that between LGS and DS, aiming to understand the complex pathogenesis of epilepsy-ASD-ID triad. Methods: A total of 50 patients with LGS and 45 patients with DS were enrolled and followed up for at least 3 years. The clinical characteristics were analyzed, and evaluations of ASD and ID were performed.
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Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy

Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy

Dravet syndrome (DS) is a severe epilepsy presenting in the first year of life with clonic seizures triggered by fever, often unilateral and long lasting in a child with previously normal development. Other seizure types may develop between one and four years of age, includ- ing myoclonic jerks, focal seizures and atypical absences. Electroencephalogram (EEG) is usually normal at onset, and then shows slowing of basal activity with asymmet- rical spikes or polyspikes-waves [1,2]. In addition to pharmacoresistant seizures and frequent episodes of sta- tus epilepticus (SE) often triggered by fever, severity of the condition results from the frequent occurrence of progressive worsening of psychomotor delay and sudden death. Mutations in SCN1A have been identified in 75% of DS patients [3], and mutations in PCDH19 were found in 10% of the SCN1A -negative population [4].
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Double somatic mosaicism in a child with Dravet syndrome

Double somatic mosaicism in a child with Dravet syndrome

variants with 17.6% and 30.6% mosaic allele frequencies in blood respectively, while their nonmosaic offspring had Dravet syndrome. 2 In contrast to the milder phenotypes in the parents with mosaic variants in these families, our patient reported here had the classical features of Dravet syndrome similar to a reported individual who was heterozygous for the same p.(Phe1808Leu) pathogenic variant. 8 Marked differences in phenotypic severity associated with mosaicism are likely explained by variation in mosaicism levels in disease-relevant tissues. For the brain, perhaps this may even be determined by region-specific and cell-type-specific differences. Comprehen- sive studies of disease-relevant tissue will be required to gain a more accurate picture of somatic mosaicism levels and how this affects disease severity.
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Incidence of Dravet Syndrome in a US Population

Incidence of Dravet Syndrome in a US Population

comprising nearly half of the insured population of Northern California. The study was approved by the institutional review boards at KPNC and the University of California, San Francisco. Patients with Dravet syndrome typically present with seizures by 1 year of age and continue to have refractory epilepsy after age 2. We performed an electronic search for patients who had $2 inpatient or outpatient encounters generating a diagnosis of seizure, ie, epilepsy (International Classification of Diseases, 9th revision [ICD-9], 345), convulsion (ICD-9 780.39), or febrile convulsion (ICD-9 780.31), before 12 months of age and who were also prescribed an
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Dravet syndrome

Dravet syndrome

The SCN1A gene has a dominating role in the pathogene- sis of DS with over 100 different mutations. The majority of these mutations are de novo (88%) but several are recurrent [26]. These mutations are spread throughout the entire protein with some clusters in the C-terminal and N- terminal ends and in segment 5-6 of the first 3 domains. SCN1A is the most clinically relevant epilepsy gene. A few cases of DS children show a SCN1A microdeletion associated with mild dysmorphic traits and increased sei- zure resistance. This pattern has been called Dravet syn- drome plus [27,28].

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A human Dravet syndrome model from patient induced pluripotent stem cells

A human Dravet syndrome model from patient induced pluripotent stem cells

We next examined action potential generation in the current clamp configuration, using 10-ms depolarizing current injections from a holding potential of − 70-mV, and we found no statisti[r]

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Sudden unexpected death in a mouse model of Dravet syndrome

Sudden unexpected death in a mouse model of Dravet syndrome

Severe bradycardia and reduced R-wave amplitude were observed immediately preceding the death of F/+:Dlx-Cre+ mice during thermal seizure-induction experiments, and all F/+:Dlx-Cre+ mice[r]

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Severe peri ictal respiratory dysfunction is common in Dravet syndrome

Severe peri ictal respiratory dysfunction is common in Dravet syndrome

A variety of mechanisms have been proposed for SUDEP (1, 2, 4– 6), including cardiac arrhythmias (7–10), dysfunction of autonomic control (11–15), apnea/hypoventilation (3, 16–21), airway obstruction (22), pulmonary edema (23), brain stem spreading depolarization (BSD) (24), and postictal generalized EEG suppression (PGES) (25). Many investigators have focused on cardiac tachyarrhythmias as the cause of death, in part because of an association between SUDEP and mutations of genes expressed in the heart, such as those that underlie long QT syndrome (10, 26–28). In some cases these muta- tions may cause both arrhythmias and seizures (10, 29, 30), whereas in other cases the mutations may predispose patients to arrhyth- mias if they have seizures due to other reasons. In patients who are monitored in epilepsy monitoring units (EMUs), nonfatal seizures can sometimes induce bradycardia, asystole, O 2 desaturation, or apnea (4, 5, 8, 16, 17). A small number of patients (n = 11) who died of
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Child Neurology: Dravet syndromeWhen to suspect the diagnosis

Child Neurology: Dravet syndromeWhen to suspect the diagnosis

Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is an epileptic encephalopathy that presents with prolonged seizures in the first year of life. The sei- zures often occur with fever or illness, and are frequently initially categorized as febrile seizures. The correct diagnosis of DS and appropriate follow-up are typically delayed. The EEG is normal at onset, and neuroimaging reveals no structural lesion. Early development is normal, but signs of regression appear in the second year of life and are often accompanied by convulsive status epilepticus, alternating hemiconvulsions, and myoclonic seizures. Diagnosis can be confirmed by genetic testing that is now available, and shows mutations within the SCN1A gene. Early recogni- tion and diagnosis of DS and management with appropriate anticonvulsants and treatment plan may reduce the seizure burden and improve long-term developmental outcome. Neurology ® 2009;
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Not all SCN1A epileptic encephalopathies are Dravet syndromeEarly profound Thr226Met phenotype

Not all SCN1A epileptic encephalopathies are Dravet syndromeEarly profound Thr226Met phenotype

Early infantile SCN1A encephalopathy can be readily distinguished from Dravet syndrome by sev- eral features. It has a younger age at onset, beginning at ,3 months compared with the typical seizure onset age range of 4 to 15 months in Dravet syn- drome. It is associated with profound developmental impairment rather than the severe to mild intellectual disability usually seen in Dravet syndrome. Infantile movement disorders are not part of the Dravet phe- notype, whereas our patients have a distinctive move- ment disorder with choreoathetosis, dystonia, and perioral hyperkinesia. Other features differentiating early infantile SCN1A encephalopathy from Dravet syndrome are epileptic spasms, which are not seen in Dravet syndrome. Tonic seizures are described in adults with Dravet syndrome but are not part of the childhood phenotype. 7
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Hunter Syndrome

Hunter Syndrome

Researchers seeks to address the challenges of treating the neurological complications of Hunter syndrome, with focusing on developing well- tolerated therapies that can cross the blood-brain barrier [30]. Investigational experiments in animal models of LSDs, including Hunter syndrome, have shown that ERT with a different formulation of idursulfase to that used in conventional ERT delivered via the intrathecal route distributes throughout the CNS, penetrates brain tissue, and promotes clearance of lysosomal storage material [45]. In addition, analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II [46]. Finally, induced pluripotent stem cell (iPSC) technology, endows personalized medicine for future therapy without ethical issues and immunological rejection which embryonic stem cell (hES) treatment of many untreatable diseases in which Hunter syndrome is one of them [47].
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Antiphospholipid syndrome

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is characterized by venous or arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL) (namely lupus anticoagulant (LA)), anticardiolipin antibodies (aCL) or antibodies directed to various proteins, mainly beta 2-glycoprotein I ( β 2 GPI), or in the presence of all three [1]. Despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. The aPL have been implicated in reactions that interfere with almost all known hemostatic and endothelial cell reactions [2]. Some evidence regarding the effect of aPL on the complement has been described recently, and related to pregnancy complications and throm- bosis [3]. Given the heterogeneity of clinical manifestations in APS it is likely that more than one pathophysiological process may play a role.
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Turner’s Syndrome

Turner’s Syndrome

ficult to recognize clinically because the charac- teristic facial features can be subtle. Key clinical features of Turner’s syndrome are lack of breast development or amenorrhea, with elevated follicle-stimulating hormone levels by 14 years of age; and infertility in women. Other characteris- tics of Turner’s syndrome include short stature, webbed neck, low posterior hairline, mis- shapen or rotated ears, a narrow palate with crowded teeth, a broad chest with widely spaced nipples, cubitus valgus, hyperconvex nails, multipigmented nevi, pubertal delay, and cardiac malformation. 5
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