SCN1A dysfunction and neuropsychiatric comorbidities

SCN1A 功能障碍和神经精神合并症

• 批准号: 8702781
• 负责人: Andrew P Escayg
• 金额: $ 23.3万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702781
• 关键词: Acute; Address; Adult; Age; Age-Months; Agreement; Ataxia; Behavioral; Behavioral Paradigm; Brain; Clinical; Clinical Management; Cognitive; Comorbidity; Complex; Data; Development; Disease; Drug Controls; Encephalopathies; Epilepsy; Etiology; Event; Exhibits; Exons; Family; Febrile Convulsions; Foundations; Frequencies; Functional disorder; Generations; Genes; Genetic; Human; Hyperactive behavior; Hyperthermia; Inborn Genetic Diseases; Induced Hyperthermia; Infant; Intellectual functioning disability; Intervention; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Life; LoxP-flanked allele; Modeling; Mus; Mutant Strains Mice; Mutation; Neurons; Outcome; Patients; Play; Quality of life; Recurrence; Research; Resistance; Risk; Role; SCN1A protein; Seizures; Severities; Site; Sleep Architecture; Social Interaction; Sodium Channel; Syndrome; TNFRSF5 gene; Tamoxifen; Testing; Time; Transgenic Organisms; Translational Research; Valproic Acid; base; clinically relevant; experience; genetic variant; innovation; insight; loss of function mutation; mouse model; mutant; neuropsychiatry; novel; patient population; postnatal; prevent; public health relevance; recombinase; research study; therapy development; trait; voltage

DESCRIPTION (provided by applicant): Mutations in the SCN1A voltage-gated sodium channel (VGSC) are responsible for a growing number of disorders, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). DS is a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, ataxia, and intellectual disability. GEFS+ is an inherited disorder characterized by FSs that persist beyond the age of six and the development of a wide range of adult epilepsy subtypes. To date, research has focused mainly on the seizure component of these disorders; however, we now recognize that seizure onset is often followed by cognitive stagnation/decline, hyperactivity, and the development of a number of behavioral comorbidities, including autistic and psychotic traits. Although seizure frequency does tend to decline during adulthood, these comorbidities persist and are a major challenge in the clinical management of this patient population. Currently, the cognitive and behavioral outcomes associated with SCN1A dysfunction are poorly characterized, and the factors that influence the severity of these deficits unknown. Mitigating the impact of these comorbidities on quality-of-life outcomes will require broader research efforts to better characterize these cognitive and behavioral deficits, as well as identify factors that influence their severity. Towards this end, te proposed experiments in this R21 application will use Scn1a mouse models developed in our laboratory to address several fundamental gaps in our knowledge. Specifically, we will 1) better define the cognitive and behavioral deficits that result from altered SCN1A function, 2) determine whether prolonged early-life FSs, which are a common clinical feature of SCN1A-derived epilepsies, are likely to contribute to the worsening of cognitive and behavioral outcomes, and 3) determine whether the emergence of cognitive and behavioral abnormalities requires altered SCN1A function during the early period of postnatal brain development or is an invariant (age-independent) outcome of altered SCN1A function. These experiments are both innovative and clinically relevant, and will stimulate much-needed translational research.

描述（由申请人提供）：SCN1A 电压门控钠通道 (VGSC) 突变导致越来越多的疾病，包括 Dravet 综合征 (DS) 和伴有热性惊厥的遗传性癫痫 (GEFS+)。 DS 是一种灾难性的早期脑病，与长期和反复出现的早期热性惊厥 (FS)、难治性非热性癫痫、共济失调和智力障碍有关。 GEFS+ 是一种遗传性疾病，其特征是 FS 持续到六岁以上，并发展为多种成人癫痫亚型。迄今为止，研究主要集中在这些疾病的癫痫发作方面。然而，我们现在认识到，癫痫发作后往往会出现认知停滞/下降、多动以及一系列行为合并症的发展，包括自闭症和精神病特征。尽管成年期癫痫发作频率确实会下降，但这些合并症仍然存在，并且是该患者群体临床管理的主要挑战。目前，与 SCN1A 功能障碍相关的认知和行为结果尚不清楚，影响这些缺陷严重程度的因素尚不清楚。减轻这些合并症对生活质量的影响 结果将需要更广泛的研究努力，以更好地描述这些认知和行为缺陷，并确定影响其严重程度的因素。为此，R21 应用中提出的实验将使用我们实验室开发的 Scn1a 小鼠模型来解决我们知识中的几个基本空白。具体来说，我们将1）更好地定义SCN1A功能改变导致的认知和行为缺陷，2）确定早期生命周期延长（SCN1A衍生性癫痫的常见临床特征）是否可能导致认知和行为结果恶化，以及3）确定认知和行为异常的出现是否需要在治疗期间改变SCN1A功能。 出生后大脑发育的早期阶段，或者是 SCN1A 功能改变的不变（与年龄无关）的结果。这些实验既具有创新性又具有临床相关性，并将刺激急需的转化研究。