What is New in Dravet Syndrome?

Epilepsia, 2017

is a pediatric neurology trainee in London teaching hospitals.

Epilepsy Research

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.

Journal of Medical Genetics, 2010

Background. Mutations in SCN1A can cause Genetic Epilepsy with Febrile Seizures Plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. Objectives and patients. We studied 19 selected families with at least one DS patients to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele-specific assays. Results. Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04% to 85%. In the 6 remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. Our results indicate that mosaicism is found in at least 7% of families with at least one DS patient and that it accounts for 68 % (13/19) of inherited mutations associated with DS. On the contrary, in the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.

The Journal of …, 2009

Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na v 1.1 α subunits. Sodium channels ...

Epilepsy Research, 2013

A homozygous SCN1B mutation was previously identified in a patient with early onset epileptic encephalopathy (EOEE) described as Dravet syndrome (DS) despite a more severe phenotype than DS. We investigated whether SCN1B mutations are a common cause of DS. Patients with DS who did not have a SCN1A sequencing mutation or copy number variation were studied. Genomic DNA was Sanger sequenced for mutations in the 6 exons of SCN1B. In 54 patients with DS recruited from four centres, no SCN1B mutations were identified. SCN1B mutation is not a common cause of DS.

Epilepsia, 2009

1670 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2-3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.

Neurology, 2017

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...

Developmental Medicine & Child Neurology, 2011

Before the advent of molecular genetics, the nature of Dravet syndrome remained largely obscure, and arguments in favour of either an acquired origin, such as the occurrence of Dravet syndrome after vaccination, or an inherited origin, such as the occurrence of epilepsy in relatives, were formulated. In 2001 we demonstrated that the majority of Dravet patients have a genetic cause due to loss-of-function mutations in the SCN1A gene. Understandably, since this syndrome severely affects reproductive fitness, these mutations almost exclusively arise de novo, with the rare exceptions of mosaic mutations in a non-affected transmitting parent. Besides classical Sanger sequencing, mutation analysis of the SCN1A gene also requires a method that allows the detection of genomic rearrangements (MAQ, MLPA), since microdeletions or whole gene deletions also result in Dravet syndromes. Depending on the series reported and their recruitment strategies, the yield of SCN1A mutations detected varied from 50 to 80%, implying that other genes or factors must be involved in these 'SCN1A-negative Dravet patients'. Recently mutations in some other genes have been described in these genuine Dravet patients who do not carry an SCN1A mutation. The second most important Dravet-associated gene is PCDH19.These patients initially may have all characteristics of Dravet syndrome but may later run a somewhat different course.

Case Reports in Medicine

Dravet syndrome, also known as severe myoclonic epilepsy in infancy, is a rare disease characterized by the appearance of different types of seizures in a healthy baby, triggered by various factors and stressful events. We report 8 Lebanese cases referred for molecular analysis of the SCN1A gene. Results were positive in 7 cases and revealed de novo variants at the heterozygous state in different exons of the gene for all except one, where the variant was intronic. Four variants were novel. Confirmation of Dravet syndrome is important for a better follow-up and treatment, preventing the occurrence of status epilepticus and severe neurological deterioration.

Schweizer Archiv für Neurologie und Psychiatrie, 2013

Dravet syndrome is a severe epilepsy syndrome of infancy characterised by seizures of multiple types, often prolonged and particularly fever-sensitive, with onset in the first year of life, and subsequent developmental delay. This article aims to present updated data on this syndrome, for which complete and extensive clinical descriptions led to the discovery of a link with a major gene, SCN1A, on which abnormalities are found in at least 70% of the patients tested. Our review article follows and summarises the data published in a 2011 supplement issue of Epilepsia, entitled Severe Myoclonic Epilepsy-Dravet Syndrome: Thirty years Later.