SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis

Background:SCN1A is one of the most common epilepsy genes. About 80% of SCN1A gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in SCN1A. Although it is known that SCN1A is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of SCN1A.Objective: The aim of this study is to systematically review the literature associated with SCN1A and other non-DS-related disorders.Methods: We searched PubMed and SCOPUS for all the published cases related to gene mutations of SCN1A until October 20, 2021. The results reported by each study were summarized narratively.Results: The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox–Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic SCN1A-related sudden deaths, and two on the arthrogryposis multiplex congenital were included.Conclusion: Aside from DS, SCN1A also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of SCN1A.

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SCN1B Gene: A Close Relative to SCN1A

Journal of Pediatric Neurology ◽

10.1055/s-0041-1727268 ◽

2021 ◽

Author(s):

Elisa Pasquetti ◽

Manuela Lo Bianco ◽

Federica Sullo ◽

Francesca Patanè ◽

Laura Sciuto ◽

...

Keyword(s):

Gene Mutations ◽

Febrile Seizures ◽

Dravet Syndrome ◽

Close Relative ◽

Epilepsy Syndrome ◽

Neuronal Function ◽

Excitable Cells ◽

Epileptic Encephalopathies ◽

Generalized Epilepsy ◽

Febrile Seizures Plus

AbstractOne of the first reported genes associated with epilepsy was SCN1B, which encodes for β-subunit of voltage-gated sodium channel of excitable cells and it is critical for neuronal function in both central and peripheral nervous system. β-subunits modulate the expression levels and functional properties of sodium channels and though their immunoglobulin domains may mediate interactions between channels and other proteins. Traditionally, SCN1B mutations were associated with generalized epilepsy with febrile seizures plus, a familial epilepsy syndrome characterized by heterogeneous phenotypes including febrile seizures (FS), febrile seizures plus (FS + ), mild generalized epilepsies, and severe epileptic encephalopathies. Throughout the years, SCN1B mutations have been also associated with Dravet syndrome and, more recently, with developmental and epileptic encephalopathies, expanding the spectrum associated with this gene mutations to more severe phenotypes.

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Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01936-9 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Tommaso Lo Barco ◽

Mathieu Kuchenbuch ◽

Nicolas Garcelon ◽

Antoine Neuraz ◽

Rima Nabbout

Keyword(s):

Natural Language Processing ◽

Early Diagnosis ◽

Natural Language ◽

Language Processing ◽

Rare Diseases ◽

Febrile Seizures ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Written Information ◽

Medical Reports

Abstract Background The growing use of Electronic Health Records (EHRs) is promoting the application of data mining in health-care. A promising use of big data in this field is to develop models to support early diagnosis and to establish natural history. Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy that commonly initiates in the first year of life with febrile seizures (FS). Age at diagnosis is often delayed after 2 years, as it is difficult to differentiate DS at onset from FS. We aimed to explore if some clinical terms (concepts) are significantly more used in the electronic narrative medical reports of individuals with DS before the age of 2 years compared to those of individuals with FS. These concepts would allow an earlier detection of patients with DS resulting in an earlier orientation toward expert centers that can provide early diagnosis and care. Methods Data were collected from the Necker Enfants Malades Hospital using a document-based data warehouse, Dr Warehouse, which employs Natural Language Processing, a computer technology consisting in processing written information. Using Unified Medical Language System Meta-thesaurus, phenotype concepts can be recognized in medical reports. We selected individuals with DS (DS Cohort) and individuals with FS (FS Cohort) with confirmed diagnosis after the age of 4 years. A phenome-wide analysis was performed evaluating the statistical associations between the phenotypes of DS and FS, based on concepts found in the reports produced before 2 years and using a series of logistic regressions. Results We found significative higher representation of concepts related to seizures’ phenotypes distinguishing DS from FS in the first phases, namely the major recurrence of complex febrile convulsions (long-lasting and/or with focal signs) and other seizure-types. Some typical early onset non-seizure concepts also emerged, in relation to neurodevelopment and gait disorders. Conclusions Narrative medical reports of individuals younger than 2 years with FS contain specific concepts linked to DS diagnosis, which can be automatically detected by software exploiting NLP. This approach could represent an innovative and sustainable methodology to decrease time of diagnosis of DS and could be transposed to other rare diseases.

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Genotype-Phenotype correlation in Dravet Syndrome with SCN1A mutation increase efficiency of molecular diagnosis

Journal of Epilepsy and Clinical Neurophysiology ◽

10.1590/s1676-26492012000200009 ◽

2012 ◽

Vol 18 (2) ◽

pp. 60-62

Author(s):

MC Gonsales ◽

P Preto ◽

MA Montenegro ◽

MM Guerreiro ◽

I Lopes-Cendes

Keyword(s):

Protein Function ◽

Copy Number ◽

Mutation Screening ◽

Copy Number Variants ◽

Febrile Seizures ◽

Copy Number Variations ◽

Dravet Syndrome ◽

Missense Mutations ◽

The Impact ◽

Doose Syndrome

OBJECTIVES: The purpose of this study was to advance the knowledge on the clinical use of SCN1A testing for severe epilepsies within the spectrum of generalized epilepsy with febrile seizures plus by performing genetic screening in patients with Dravet and Doose syndromes and establishing genotype-phenotype correlations. METHODS: Mutation screening in SCN1A was performed in 15 patients with Dravet syndrome and 13 with Doose syndrome. Eight prediction algorithms were used to analyze the impact of the mutations in putative protein function. Furthermore, all SCN1A mutations previously published were compiled and analyzed. In addition, Multiplex Ligation-Dependent Probe Amplification (MLPA) technique was used to detect possible copy number variations within SCN1A. RESULTS: Twelve mutations were identified in patients with Dravet syndrome, while patients with Doose syndrome showed no mutations. Our results show that the most common type of mutation found is missense, and that they are mostly located in the pore region and the N- and C-terminal of the protein. No copy number variants in SCN1A were identified in our cohort. CONCLUSIONS: SCN1A testing is clinically useful for patients with Dravet syndrome, but not for those with Doose syndrome, since both syndromes do not seem to share the same genetic basis. Our results indicate that indeed missense mutations can cause severe phenotypes depending on its location and the type of amino-acid substitution. Moreover, our strategy for predicting deleterious effect of mutations using multiple computation algorithms was efficient for most of the mutations identified.

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A Case of Neonatal Epileptic Encephalopathy due to SCN2A Mutation Responsive to a Ketogenic Diet

Journal of Pediatric Epilepsy ◽

10.1055/s-0039-1691826 ◽

2018 ◽

Vol 07 (04) ◽

pp. 148-151 ◽

Cited By ~ 1

Author(s):

Fahad A. Bashiri ◽

Abrar Hudairi ◽

Malak Al Ghamdi ◽

Adel A. Mahmoud

Keyword(s):

Ketogenic Diet ◽

Treatment Modality ◽

Genetic Diagnosis ◽

Febrile Seizures ◽

Epileptic Encephalopathy ◽

Intractable Seizures ◽

Ohtahara Syndrome ◽

Newborn Girl ◽

Generalized Epilepsy ◽

Febrile Seizures Plus

AbstractNeonatal seizures may have multiple causes including metabolic and genetic etiologies. If a genetic diagnosis is known, it can guide the physician to choose the most appropriate treatment modality. SCN2A mutation is a rare cause of epileptic encephalopathy in the neonatal age group. It has a wide phenotypic variation, ranging from benign familial epilepsy to a malignant form of epilepsy. This mutation has been associated with Ohtahara syndrome, migrating focal seizures of infancy, West syndrome, Lennox–Gastaut syndrome, and generalized epilepsy with febrile seizures plus. We present the case of a newborn girl who presented with multiple types of seizures, starting at the age of 3 days. Our initial investigations were not able to identify the etiology of her intractable seizures. Whole exome sequencing confirmed an SCN2A mutation. Various antiepileptic drugs (AEDs), including phenobarbitone, phenytoin, levetiracetam, topiramate, vigabatrin, carbamazepine, clonazepam, and mexiletine, were tried. However, none provided an optimal response. She ultimately showed a dramatic response to the ketogenic diet (KD). This report highlights the effectiveness of the KD as a treatment modality for SCN2A mutation-related epileptic encephalopathy, particularly when seizures are intractable and unresponsive to conventional AEDs.

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Severe Epilepsy Syndromes of Early Childhood: The Link Between Genetics and Pathophysiology With a Focus on SCN1A Mutations

Journal of Child Neurology ◽

10.1177/0883073809338152 ◽

2009 ◽

Vol 24 (8_suppl) ◽

pp. 15S-23S ◽

Cited By ~ 25

Author(s):

Carl E. Stafstrom

Keyword(s):

Early Childhood ◽

Sodium Channel ◽

Gene Mutations ◽

Febrile Seizures ◽

Dravet Syndrome ◽

Epilepsy Syndrome ◽

Accessory Subunits ◽

Epilepsy Gene ◽

Generalized Epilepsy ◽

Severe Epilepsy

Advances in genetics have increased our understanding of the underlying pathophysiologic mechanisms that cause severe epilepsy syndromes of early childhood. Many of the mutations associated with these syndromes are located in genes coding for ion channels or their accessory subunits, giving rise to the concept of epilepsy ``channelopathies.'' In particular, the SCN1A gene coding for the pore-forming a-subunit of the voltage-gated sodium channel NaV1.1 appears to be a common target for epilepsy syndrome-specific mutations. An SCN1A mutation can potentially result in either a gain or loss of sodium channel function. Epilepsies linked to SCN1A mutations range from a relatively benign syndrome called generalized epilepsy with febrile seizures plus to severe childhood epilepsies such as severe myoclonic epilepsy of infancy (Dravet syndrome). The availability of genetic tests for SCN1A mutations is expanding awareness of the spectrum of diseases mediated by this gene and is beginning to permit genotype— phenotype correlations. Eventually, such information might enable clinicians to select an appropriate therapeutic regimen for patients with specific epilepsy gene mutations.

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Dravet Syndrome: Early Diagnosis and Emerging Therapies

Journal of Pediatric Epilepsy ◽

10.1055/s-0039-1692171 ◽

2019 ◽

Vol 08 (02) ◽

pp. 031-037

Author(s):

Tyler J. Burr ◽

Karen L. Skjei

Keyword(s):

Status Epilepticus ◽

Early Diagnosis ◽

Seizure Control ◽

Febrile Seizures ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Long Term Outcomes ◽

Treatment Algorithms ◽

Emerging Therapies

AbstractDravet's syndrome (DS) or severe myoclonic epilepsy of infancy is a rare, genetic, and infantile-onset epileptic encephalopathy. DS presents with recurrent febrile seizures and/or febrile status epilepticus in developmentally normal infants, and subsequently evolves into a drug-resistant mixed-seizure disorder with developmental arrest or regression. As many defining clinical features of DS do not become evident until 3 to 4 years of age, diagnosis is often delayed. Early seizure control, particularly the prevention of status epilepticus in infancy, has been shown to correlate with better long-term outcomes. Thus, early diagnosis and seizure control is crucial. Several treatment algorithms have been published in recent years to guide antiepileptic drug selection and escalation. Last year, two agents, stiripentol and cannabidiol, were approved by the U.S. Food and Drug Administration specifically for use in DS, and a third has been submitted (fenfluramine). Additional therapies, including serotonin modulators lorcaserin and trazodone, verapamil, and several first-in-class medications, are currently in various phases of investigation.

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Sodium channels of SCNIA gene mutations in generalized epilepsy with febrile seizure plus (GEFS+) spectrum related to autism

Paediatrica Indonesiana ◽

10.14238/pi50.3.2010.125-32 ◽

2010 ◽

Vol 50 (3) ◽

pp. 125

Author(s):

Elisabeth Herini ◽

Yudha Patria ◽

Gunadi Gunadi ◽

Surini Yusoff ◽

Indra SAri Kusuma Harahap ◽

...

Keyword(s):

Gene Mutations ◽

Febrile Seizures ◽

Chromatography Analysis ◽

Indonesian Population ◽

A Subunit ◽

Dsm Iv ◽

Generalized Epilepsy ◽

Febrile Seizures Plus ◽

Intron 4 ◽

Intron 2

Background Mutations in the a-subunit of the first neuronalsodium channel gene SCNIA have been demonstrated forgeneralized epilepsy \\lith febrile seizures plus (GEFS+), severemyoclonic epilepsy in infancy (SMEI), and borderline SMEI(SMEB). SCNIA mutations are also described in patients 'Withpsychiatric disorders such as autism.Objective To identify the mutations of SCNIA gene in patientswith GEFS+ spectrum which may be related to autism.Methods We examined four patients v.ith autism and GEFS+spectrum who were admitted to the Department of Child Health,Sardjito Hospital, Yogyakarta, Indonesia. Diagnosis of autism wasbased on DSM􀁟IV;ICD X criteria. Mutations in SCNIA wereidentified by PCRamplification and denaturing high􀁟performanceliquid chromatography analysis, Mth subsequent sequencing.Results There were four patients, all boys, aged 1.8 year to 7 years.The phenotypes of epilepsy were GEFS+ in one patient, SMEBin one patient and SMEI in two patients. Sequencing analysisrevealed a G􀁟to􀁟A heterozygous transition which was detectedat nucleotide c.4834G>A (p.V1612I ) in exon 25. Other singlenucleotid polymorphisms (SNPs) were c.383 +66T>C in intron 2,c.603-91G>A and c.603-1060> T in intron 4, c.965-21C> T inintron 6, c.1028+21T>Cin intron 7, c.2173G>A in exon 12 andc. 2177-38C>A, c.2177-12delT, c.2176+44C> T in intron 12.Conclusion In this study, we reported the first cases Mth mutationin SCNIA gene in GEFS+ spectrum related to autistic patientsin Indonesian population, which showed a missense mutationp.V16121. [Paediatr lndones. 2010;50:125-32].

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