Atsushi Ishii1,2, Joseph C Watkins3, Debbie Chen1, Shinichi Hirose2, Michael F Hammer1,4. 1. ARL Division of Biotechnology, University of Arizona, Tucson, Arizona, U.S.A. 2. Department of Pediatrics, School of Medicine and Central Research Institute for the Molecular Pathogeneses of Epilepsy, Fukuoka University, Fukuoka, Japan. 3. Department of Mathematics, University of Arizona, Tucson, Arizona, U.S.A. 4. Department of Neurology, University of Arizona, Tucson, Arizona, U.S.A.
Abstract
OBJECTIVE: Two major classes of SCN1A variants are associated with Dravet syndrome (DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment. METHODS: We sequenced all exons and intron-exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals. RESULTS: Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I-II and II-III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants. SIGNIFICANCE: We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency. Wiley Periodicals, Inc.
OBJECTIVE: Two major classes of SCN1A variants are associated with Dravet syndrome (DS): those that result in haploinsufficiency (truncating) and those that result in an amino acid substitution (missense). The aim of this retrospective study was to describe the first large cohort of Japanese patients with SCN1A mutation-positive DS (n = 285), and investigate the relationship between variant (type and position) and clinical expression and response to treatment. METHODS: We sequenced all exons and intron-exon boundaries of SCN1A in our cohort, investigated differences in the distribution of truncating and missense variants, tested for associations between variant type and phenotype, and compared these patterns with those of cohorts with milder epilepsy and healthy individuals. RESULTS: Unlike truncation variants, missense variants are found at higher density in the S4 voltage sensor and pore loops and at lower density in the domain I-II and II-III linkers and the first three segments of domain II. Relative to healthy individuals, there is an increased frequency of truncating (but not missense) variants in the noncoding C-terminus. The rate of cognitive decline is more rapid for patients with truncation variants regardless of age at seizure onset, whereas age at onset is a predictor of the rate of cognitive decline for patients with missense variants. SIGNIFICANCE: We found significant differences in the distribution of truncating and missense variants across the SCN1A sequence among healthy individuals, patients with DS, and those with milder forms of SCN1A-variant positive epilepsy. Testing for associations with phenotype revealed that variant type can be predictive of rate of cognitive decline. Analysis of descriptive medication data suggests that in addition to conventional drug therapy in DS, bromide, clonazepam and topiramate may reduce seizure frequency. Wiley Periodicals, Inc.
Authors: Katri Silvennoinen; Kinga Gawel; Despina Tsortouktzidis; Albert J Becker; Camila V Esguerra; Sanjay M Sisodiya; Julika Pitsch; Saud Alhusaini; Karen M J van Loo; Richard Picardo; Zuzanna Michalak; Susanna Pagni; Helena Martins Custodio; James Mills; Christopher D Whelan; Greig I de Zubicaray; Katie L McMahon; Wietske van der Ent; Karolina J Kirstein-Smardzewska; Ettore Tiraboschi; Jonathan M Mudge; Adam Frankish; Maria Thom; Margaret J Wright; Paul M Thompson; Susanne Schoch Journal: Acta Neuropathol Date: 2022-05-12 Impact factor: 15.887
Authors: Michael F Hammer; Atsushi Ishii; Laurel Johnstone; Alexander Tchourbanov; Branden Lau; Ryan Sprissler; Brian Hallmark; Miao Zhang; Jin Zhou; Joseph Watkins; Shinichi Hirose Journal: PLoS One Date: 2017-07-07 Impact factor: 3.240
Authors: Elena Cardenal-Muñoz; Stéphane Auvin; Vicente Villanueva; J Helen Cross; Sameer M Zuberi; Lieven Lagae; José Ángel Aibar Journal: Epilepsia Open Date: 2021-12-19