Clinical and EEG profile in Dravet and Doose syndromes

Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy

Genetics of the epilepsies: Genetic twists in the channels and other tales

Clinical and molecular genetics of myoclonic–astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome)

Severe myoclonic epilepsy in infancy (SMEI), severe idiopathic generalized epilepsy of infancy (SIGEI) with generalized tonic clonic seizures (GTCS), and myoclonic astatic epilepsy (MAE) may show semiological overlaps. In GEFS+ families, all three phenotypes were found associated with mutations in the SCN1A gene. We analyzed the SCN1A gene in 20 patients with non-familial myoclonic astatic epilepsy -- including 12 probands of the original cohort used by Doose et al. in 1970 to delineate MAE. In addition, 18 patients with sporadic SIGEI -- mostly without myoclonic-astatic seizures -- were analyzed. Novel SCN1A mutations were found in 3 individuals. A frame shift resulting in an early premature stop codon in a now 35-year-old woman with a borderline phenotype of MAE and SIGEI (L433fsX449) was identified. A splice site variant (IVS18 + 5 G --> C) and a missense mutation in the conserved pore region (40736 C --> A; R946 S) were detected each in a child with SIGEI. We conclude that, independent of precise syndromic delineation, myoclonic-astatic seizures are not predictive of SCN1A mutations in sporadic myoclonic epilepsies of infancy and early childhood.

Generalized Epilepsy With Febrile Seizures plus: Novel SCN1A Mutation

EPILEPSY

Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI. Probands with SMEI were identified, and systematic family studies were performed. Epilepsy syndromes were characterized in affected family members. Twelve probands with SMEI were identified. Eleven of the 12 probands with SMEI had a family history of seizures, and the twelfth was the result of a consanguineous marriage. We found that 16.7% of full siblings and 8.3% of parents had definite seizures. A total of 39 affected family members was identified. The most common phenotype was febrile seizures in 14, febrile seizures plus in seven, partial epilepsy in two, and there were single individuals with SMEI, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, and 13 cases with unclassified or unconfirmed seizures. The family history of seizures in SMEI is in keeping with the spectrum of seizure phenotypes seen in generalized epilepsy with febrile seizures plus (GEFS+). Our findings suggest that SMEI is the most severe phenotype in the GEFS+ spectrum.

Severe myoclonic epilepsy in infancy (SMEI) is an epileptic syndrome recognised by the ICE of 1985 and 1989 and in the proposal put forward by the ILAE Task Force on Classification and Terminology in 2001. In this paper, its historical development, nosological characteristics and treatment are described. Although identified by Dravet in 1978, it has been called severe myoclonic epilepsy in infancy since 1981. As an alternative the name polymorphic epilepsy has also been put forward and in 2001 the ILAE recognised the eponym Dravet's syndrome. We describe how it may be mistaken for febrile convulsions in the early stages and later for Lennox Gastaut syndrome, Doose's myoclonic astatic epilepsy and certain progressive myoclonic epilepsies. We outline the risk factors, recognised in 1992, that facilitate an early diagnosis and the defining clinical criteria established in 1984. We point out the existence of atypical forms due to the absence of some of the defining criteria, which will never be above one, to formulate a diagnosis of SMEI. The frequency with which a family background of febrile convulsions and epilepsy appears seems to point to a genetic origin. Recently, de novo mutations have been found in the alpha subunit of the voltage dependent sodium channel as well as mutations in the gamma subunit of the GABAA receptor. Nosologically, it is located in group 3 of the 1989 ICE, which corresponds to epileptic syndromes without a focal determination, or which are generalised, and on the list of epilepsy/syndromes that was presented in 2001. SMEI is an epilepsy syndrome which is, in most cases, resistant to classical and new AED, and other more unusual treatment. The drugs that have proved to be more effective, although only relatively so, are topiramate, valproate and the benzodiazepines. At present another alternative that has appeared is stiripentol. Intravenous use of immunoglobulins can be useful. Dravet's syndrome, admitted as such by the ILAE in 2001 and probably caused by de novo mutations in the sodium channels or in the GABAA receptors, is one of the severest forms of epilepsy in infancy with very little or no response to current antiepileptic drugs. Those that have been seen to be most effective are topiramate, the benzodiazepines, valproate and, more recently, stiripentol.

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.

Myoclonic attacks are not characteristic of a specific syndrome. In infancy and early childhood, they are often observed in the context of syndromes that are associated with other types of seizures and with cognitive impairment but no obvious brain lesion. Characterization of the associated seizures and age of expression allows inclusion of a number of cases in two main subgroups: severe myoclonic epilepsy (SME, or Dravet syndrome) and myoclonic-astatic epilepsy (MAE). Severe myoclonic epilepsy is an epileptic encephalopathy with invariably poor outcome in which myoclonic seizures, though frequently observed, may be absent altogether in some children. Prolonged and repeated febrile and afebrile convulsive seizures starting in infancy are the main feature and are probably causally related to cognitive decline. One third of children harbor mutation of the SCN1A gene, but the genetics of SME is probably more complex than expected with simple monogenic disorders. Treatment is usually disappointing. Myoclonic-astatic epilepsy is perhaps more a conceptual category of idiopathic myoclonic epilepsy than a discrete syndrome. Childhood-onset myoclonic-astatic attacks are the characteristic seizures associated in most with episodes of nonconvulsive status and generalized tonic-clonic seizures. Outcome is unpredictable. Either remission within a few years with normal cognition or long-lasting intractability with cognitive impairment is possible. Likewise, the effectiveness of antiepileptic drugs is variable. A number of cases of myoclonic epilepsies in infancy and early childhood, however, remain unclassified, and intermediate forms between the different syndromes exist. They must be distinguished from other syndromes with frequent brief attacks and repeated falls, especially the Lennox-Gastaut syndrome. This differentiation is often difficult and may require extensive neurophysiologic studies.

Background: The myoclonic epilepsies of infancy include myoclonic astatic epilepsy (MAE), severe myoclonic epilepsy of infancy (SMEI) and intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC). In families with GEFS+ mutations in two different sodium channel genes (SCN1A, SCN1B) and one GABA channel gene (GABRG2) were reported. In GEFS+ families patients frequently present with myoclonic epilepsies. Also, children with sporadic SMEI were studied repeatedly. An overall frequency of SCN1A mutation of 60% was observed. In a Japanese study mutations were identified in 8 out of 10 patients with ICEGTC. In sporadic MAE no mutations are reported up to now.

Herman Doose first described the generalized childhood epilepsy syndrome of myoclonic astatic epilepsy (MAE) in 1970, attributing a genetic cause from this first description. However, although the International League Against Epilepsy (ILAE) defined criteria for MAE in 1989, the diagnostic boundaries of the syndrome continue to be debated. Moreover, 40 years since Doose's first description of MAE, although a genetic predisposition is acknowledged and many studies have demonstrated familial aggregation of seizures within MAE families, the actual genetic determinants of MAE still remain unknown. Although initially thought to be within the same spectrum as severe myoclonic epilepsy of infancy, the exclusion of SCN1A mutations in non-generalized epilepsy with febrile seizures plus (GEFS+) MAE cases has confirmed the genetic distinction of MAE. In this critical review, we shall trace the historical evolution of concepts around MAE and its distinction from Lennox-Gastaut syndrome, review the described phenotypic features of MAE from updated studies that will allow its distinction from other overlap epilepsy syndromes, review the evidence of genetic influences and clues for genetic heterogeneity, and discuss strategies that may be helpful in elucidating the etiology of MAE in light of current genetic techniques.

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.

Clinical spectrum of mutations in SCN1A gene: Severe myoclonic epilepsy in infancy and related epilepsies

SMEI, the severest form of the phenotypic spectrum of febrile seizures plus, is a channelopathy that is produced de novo, that is, during meiosis. Its prognosis may be conditioned by the kinds of mutations it is due to, and which are very different to those that induce other, more benign epileptic syndromes from the same phenotypic spectrum.