Outcomes and comorbidities of SCN1A-related seizure disorders

Lange, Iris; Gunning, Boudewijn; Sonsma, Anja C. M.; Gemert, Lisette van; Kempen, Marjan van; Verbeek, Nienke E.; Sinoo, Claudia; Nicolai, Joost; Knoers, Nine V A M; Koeleman, Bobby P. C.; Brilstra, Eva H.

doi:10.1016/j.yebeh.2018.09.041

Cited by 36 publications

(51 citation statements)

References 48 publications

(83 reference statements)

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“…In our two cohorts, in line with previous reports, in the large majority of patients, language is impaired (84% of adults) and ID is moderate or severe (70.5% of adolescents and 80% of adults); normal cognitive functioning, as exceptionally reported was observed in 1 of 24 adolescents and 3 of 50 adults. Also in keeping with previous reports is the relevance of motor disturbances that are present in 65% of adolescents and in 88% of adults, with crouch gait in one‐third of cases . The most severe cognitive and motor impairment was observed in patients with persisting seizures .…”

Section: Discussionsupporting

confidence: 89%

“…The severity of cognition, language, and neurologic impairment, as well as the impairment of adaptive functioning, statistically correlate, both in adolescence and in adulthood, with the complete/myoclonic phenotype as reported previously . Moreover, among the variables considered in the analysis of the adult cohort, a statistically significant correlation was found between the early onset of seizures, the presence of RS, and the severity of cognitive/language and neurologic impairment.…”

Section: Discussionsupporting

confidence: 82%

“…Also in keeping with previous reports is the relevance of motor disturbances that are present in 65% of adolescents and in 88% of adults, with crouch gait in one‐third of cases . The most severe cognitive and motor impairment was observed in patients with persisting seizures . Whether the severity of these comorbidities is related to the severity of epilepsy or to an intrinsically severe phenotype is still unclear.…”

Section: Discussionsupporting

confidence: 81%

“…The neuropsychological decline usually appears evident in the second/third year of life, and becomes more pronounced in adolescence. Cognitive disabilities and behavioral disturbances are among the most important negative prognostic factors of quality of life in adults . Disabling motor disorders are also frequently reported both in adolescents and adults, and the presence of a parkinsonian component has been recently outlined …”

Section: Introductionmentioning

confidence: 99%

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Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

et al. 2019

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To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course.At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age.Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy. K E Y W O R D Sadolescents and adults, complete Dravet syndrome, developmental and epileptic encephalopathy, longterm outcome, myoclonic phenotype, reflex seizures S50 | DARRA et Al.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

et al. 2019

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“…Dravet syndrome is a severe, infant-onset epileptic encephalopathy with at least 80% of cases resulting from de novo pathogenic variants in SCN1A (1). Individuals with Dravet syndrome display multiple seizure types that are often refractory to standard therapeutics, an elevated SUDEP risk, cognitive and behavioral deficits, and motor system dysfunctions (2,3). Phenotype heterogeneity is common in monogenic epilepsy syndromes, with a spectrum of clinical presentations, ranging from benign seizures to intractable epilepsy and increased SUDEP risk (4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Gabra2is a genetic modifier of Dravet syndrome in mice

Hawkins¹,

Nomura²,

Duarte³

et al. 2020

Preprint

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Pathogenic variants in epilepsy genes result in a spectrum of clinical presentation, ranging from benign phenotypes to intractable epilepsies with significant co-morbidities and increased risk of sudden unexpected death in epilepsy (SUDEP). One source of this phenotypic heterogeneity is modifier genes that affect penetrance, dominance or expressivity of a primary pathogenic variant. Mouse models of epilepsy also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a +/-) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a +/heterozygous mice recapitulate key features of Dravet syndrome, including febrile and afebrile spontaneous seizures, SUDEP, and cognitive and behavioral deficits. The Scn1a +/mouse model also exhibits strain-dependent phenotype severity. Scn1a +/mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no overt seizures. In contrast, admixture with C57BL/6J (B6) results in severe epilepsy and premature lethality in [B6x129]F1.Scn1a +/mice. In previous work, we identified Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for straindependent differences in survival. Gabra2, encoding the GABAA α2 subunit, was nominated as the top candidate modifier at the Dsm1 locus on chromosome 5. Direct measurement of GABAA receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide intronic deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this de novo deletion reestablished normal levels of Gabra2 transcript and protein expression. In the current study, we used B6 mice with the repaired Gabra2 allele to validate it as a modifier of phenotype severity in Scn1a +/mice. Repair of Gabra2 restored transcript and protein expression, increased abundance of α2-containing GABAA receptors in hippocampal synapses, and improved seizure and survival phenotypes of Scn1a +/mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome.

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Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

et al. 2021

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Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug-resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

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Outcomes and comorbidities of SCN1A-related seizure disorders

Cited by 36 publications

References 48 publications

Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

Gabra2is a genetic modifier of Dravet syndrome in mice

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe

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