The genetics and molecular biology of fever-associated seizures or epilepsy

2018 ◽  
Vol 20 ◽  
Author(s):  
Hao Deng ◽  
Wen Zheng ◽  
Zhi Song
Keyword(s):  
Synaptic Transmission ◽  
Genetic Factors ◽  
Wide Spectrum ◽  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Comprehensive Understanding ◽  
Associated Proteins ◽  
Febrile Seizures Plus ◽  
In Infants And Children ◽  
Underlying Pathogenesis

AbstractFever-associated seizures or epilepsy (FASE) is primarily characterised by the occurrence of a seizure or epilepsy usually accompanied by a fever. It is common in infants and children, and generally includes febrile seizures (FS), febrile seizures plus (FS+), Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFSP). The aetiology of FASE is unclear. Genetic factors may play crucial roles in FASE. Mutations in certain genes may cause a wide spectrum of phenotypical overlap ranging from isolated FS, FS+ and GEFSP to DS. Synapse-associated proteins, postsynaptic GABAAreceptor, and sodium channels play important roles in synaptic transmission. Mutations in these genes may involve in the pathogenesis of FASE. Elevated temperature promotes synaptic vesicle (SV) recycling and enlarges SV size, which may enhance synaptic transmission and contribute to FASE occurring. This review provides an overview of the loci, genes, underlying pathogenesis and the fever-inducing effect of FASE. It may provide a more comprehensive understanding of pathogenesis and contribute to the clinical diagnosis of FASE.

Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families

2015 ◽  
Vol 19 (4) ◽  
pp. 484-488 ◽  
Author(s):  
Andreas Brunklaus ◽  
Rachael Ellis ◽  
Helen Stewart ◽  
Sarah Aylett ◽  
Eleanor Reavey ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Genetic Epilepsy ◽  
Homozygous Mutations ◽  
Febrile Seizures Plus ◽  
Scn1a Gene

scholarly journals Nav1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome

2011 ◽  
Vol 34 (8) ◽  
pp. 1268-1275 ◽  
Author(s):  
Linda Volkers ◽  
Kristopher M. Kahlig ◽  
Nienke E. Verbeek ◽  
Joost H. G. Das ◽  
Marjan J. A. van Kempen ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Genetic Epilepsy ◽  
Febrile Seizures Plus

scholarly journals Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Victoria Marco Hernández ◽  
Miguel Tomás Vila ◽  
Alfonso Caro Llopis ◽  
Sandra Monfort ◽  
Francisco Martinez
Keyword(s):  
Developmental Disorders ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Autosomal Recessive Inheritance ◽  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Compound Heterozygous ◽  
Recessive Inheritance ◽  
Clinical Criteria ◽  
Febrile Seizures Plus

Dominant pathogenic variations in the SCN1A gene are associated with several neuro developmental disorders with or without epilepsy, including Dravet syndrome (DS). Conversely, there are few published cases with homozygous or compound heterozygous variations in the SCN1A gene. Here, we describe two siblings from a consanguineous pedigree with epilepsy phenotype compatible with genetic epilepsy with febrile seizures plus (GEFS+) associated with the homozygous likely pathogenic variant (NM_001165963.1): c.4513A > C (p.Lys1505Gln). Clinical and genetic data were compared to those of other 10 previously published patients with epilepsy and variants in compound heterozygosity or homozygosity in the SCN1A gene. Most patients (11/12) had missense variants. Patients in whom the variants were located at the cytoplasmic or the extracellular domains frequently presented a less severe phenotype than those in whom they are located at the pore-forming domains. Five of the patients (41.7%) meet clinical criteria for Dravet syndrome (DS), one of them associated acute encephalopathy. Other five patients (41.7%) had a phenotype of epilepsy with febrile seizures plus familial origin, while the two remaining (17%) presented focal epileptic seizures. SCN1A-related epilepsies present in most cases an autosomal dominant inheritance; however, there is growing evidence that some genetic variants only manifest clinical symptoms when they are present in both alleles, following an autosomal recessive inheritance.

Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus?

2009 ◽  
Vol 31 (5) ◽  
pp. 394-400 ◽  
Author(s):  
Ingrid E. Scheffer ◽  
Yue-Hua Zhang ◽  
Floor E. Jansen ◽  
Leanne Dibbens
Keyword(s):  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

scholarly journals Model systems for studying cellular mechanisms of SCN1A-related epilepsy

2016 ◽  
Vol 115 (4) ◽  
pp. 1755-1766 ◽  
Author(s):  
Soleil S. Schutte ◽  
Ryan J. Schutte ◽  
Eden V. Barragan ◽  
Diane K. O'Dowd
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Febrile Seizures ◽  
Model Systems ◽  
Dravet Syndrome ◽  
Response To Treatment ◽  
Patient Specific ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Induced Pluripotent ◽  
Febrile Seizures Plus

Mutations in SCN1A, the gene encoding voltage-gated sodium channel NaV1.1, cause a spectrum of epilepsy disorders that range from genetic epilepsy with febrile seizures plus to catastrophic disorders such as Dravet syndrome. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. Distinct effects of individual SCN1A mutations on neuronal function are likely to contribute to variation in disease severity and response to treatment in patients. Several model systems have been used to explore seizure genesis in SCN1A epilepsies. In this article we review what has been learned about cellular mechanisms and potential new therapies from these model systems, with a particular emphasis on the novel model system of knockin Drosophila and a look toward the future with expanded use of patient-specific induced pluripotent stem cell-derived neurons.

scholarly journals Genetic epilepsy with febrile seizures plus (GEFS+)

2020 ◽  
Vol 12 (1S) ◽  
pp. 50-56
Author(s):  
A. A. Sharkov
Keyword(s):  
Genetic Factors ◽  
Febrile Seizures ◽  
Final Diagnosis ◽  
Copy Number Variations ◽  
Genetic Causes ◽  
Genetic Epilepsy ◽  
Diagnosis And Prognosis ◽  
The Family ◽  
Febrile Seizures Plus ◽  
Atonic Seizures

Febrile seizures (FS) occur in about 2–3% of children aged 3 months to 5 years. Atypical febrile seizures are those with a focal component. Each subsequent febrile attack increases the risk of transformation into epilepsy. After the third febrile seizure, the risk of additional episodes of febrile seizures is already approaching 50%, and the risk of formation of epilepsy is 15.8%. Recent studies show the great contribution of genetic causes to the development of genetic epilepsy with febrile seizures plus (GEFS+). GEFS+ includes a combination of some febrile seizures with subsequent afebrile attack, or recurring febrile seizures after 6 years. The genetic causes of GEFS+ are both monogenic (in particular, disorders in the SCN1B, SCN1A, GABRG2, GABRD, SCN9A, STX1B, HCN1 genes, etc.) and copy number variations. Twin methods suggest that different genetic factors play a role in the case of FS, FS+ and FS with subsequent epilepsy. Genetic cause can be found in about 30% of cases, that affects not only the final diagnosis and prognosis for the patient, but also the prevention of disease in the family. In GEFS+ seizures are usually generalized tonic-clonic, less often myoclonic, myoclonic-atonic seizures, absences and status epilepticus, but sometimes they also describe focal seizures. The clinical picture of patients with GEFS+ varies from family febrile seizures (the least severe cases) to Drave-like syndrome (the most severe cases), although all of them have a predominantly normal level of intellect.

Role of the sodium channelSCN9Ain genetic epilepsy with febrile seizures plus and Dravet syndrome

Epilepsia ◽  
2013 ◽  
Vol 54 (9) ◽  
pp. e122-e126 ◽  
Author(s):  
John C. Mulley ◽  
Bree Hodgson ◽  
Jacinta M. McMahon ◽  
Xenia Iona ◽  
Susannah Bellows ◽  
...  
Keyword(s):  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Genetic Epilepsy ◽  
Febrile Seizures Plus

scholarly journals Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations

Neurology ◽  
2017 ◽  
Vol 88 (11) ◽  
pp. 1037-1044 ◽  
Author(s):  
Valentina Cetica ◽  
Sara Chiari ◽  
Davide Mei ◽  
Elena Parrini ◽  
Laura Grisotto ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Focal Epilepsy ◽  
Early Recognition ◽  
Roc Curves ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Seizure Onset ◽  
Predictive Values ◽  
Mutation Type

Objective:To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations.Methods:Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients.Results:Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%).Conclusions:In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.

scholarly journals Febrile temperatures unmask biophysical defects in Nav1.1 epilepsy mutations supportive of seizure initiation

2013 ◽  
Vol 142 (6) ◽  
pp. 641-653 ◽  
Author(s):  
Linda Volkers ◽  
Kristopher M. Kahlig ◽  
Joost H.G. Das ◽  
Marjan J.A. van Kempen ◽  
Dick Lindhout ◽  
...  
Keyword(s):  
Voltage Dependence ◽  
Febrile Seizures ◽  
Dravet Syndrome ◽  
Slow Inactivation ◽  
Loss Of Function ◽  
Peak Current Density ◽  
Delayed Recovery ◽  
Generalized Epilepsy ◽  
Use Dependency ◽  
Febrile Seizures Plus

Generalized epilepsy with febrile seizures plus (GEFS+) is an early onset febrile epileptic syndrome with therapeutic responsive (a)febrile seizures continuing later in life. Dravet syndrome (DS) or severe myoclonic epilepsy of infancy has a complex phenotype including febrile generalized or hemiclonic convulsions before the age of 1, followed by intractable myoclonic, complex partial, or absence seizures. Both diseases can result from mutations in the Nav1.1 sodium channel, and initially, seizures are typically triggered by fever. We previously characterized two Nav1.1 mutants—R859H (GEFS+) and R865G (DS)—at room temperature and reported a mixture of biophysical gating defects that could not easily predict the phenotype presentation as either GEFS+ or DS. In this study, we extend the characterization of Nav1.1 wild-type, R859H, and R865G channels to physiological (37°C) and febrile (40°C) temperatures. At physiological temperature, a variety of biophysical defects were detected in both mutants, including a hyperpolarized shift in the voltage dependence of activation and a delayed recovery from fast and slow inactivation. Interestingly, at 40°C we also detected additional gating defects for both R859H and R865G mutants. The GEFS+ mutant R859H showed a loss of function in the voltage dependence of inactivation and an increased channel use-dependency at 40°C with no reduction in peak current density. The DS mutant R865G exhibited reduced peak sodium currents, enhanced entry into slow inactivation, and increased use-dependency at 40°C. Our results suggest that fever-induced temperatures exacerbate the gating defects of R859H or R865G mutants and may predispose mutation carriers to febrile seizures.

SCN1A and Its Related Epileptic Phenotypes

2021 ◽  
Author(s):  
Federica Sullo ◽  
Elisa Pasquetti ◽  
Francesca Patanè ◽  
Manuela Lo Bianco ◽  
Simona D. Marino ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Neurological Disorders ◽  
Wide Spectrum ◽  
Febrile Seizures ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Behavioral Alterations ◽  
Α Subunit ◽  
Hyperactivity Disorder ◽  
Whole Exome

AbstractEpilepsy is one of the most common neurological disorders, with a lifetime incidence of 1 in 26. Approximately two-thirds of epilepsy has a substantial genetic component in its etiology. As a result, simultaneous screening for mutations in multiple genes and performing whole exome sequencing (WES) are becoming very frequent in the clinical evaluation of children with epilepsy. In this setting, mutations in voltage-gated sodium channel (SCN) α-subunit genes are the most commonly identified cause of epilepsy, with sodium channel genes (i.e., SCN1A, SCN2A, SCN8A) being the most frequently identified causative genes. SCN1A mutations result in a wide spectrum of epilepsy phenotypes ranging from simple febrile seizures to Dravet syndrome, a severe epileptic encephalopathy. In case of mutation of SCN1A, it is also possible to observe behavioral alterations, such as impulsivity, inattentiveness, and distractibility, which can be framed in an attention deficit hyperactivity disorder (ADHD) like phenotype. Despite more than 1,200 SCN1A mutations being reported, it is not possible to assess a clear phenotype–genotype correlations. Treatment remains a challenge and seizure control is often partial and transitory.

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