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）：SCN 1A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）和遗传性癫痫伴热性惊厥+（GEFS+）。DS是一种灾难性早期脑病，与长期和复发性早期热性惊厥（FS）、难治性无热性癫痫、共济失调和智力残疾相关。GEFS+是一种遗传性疾病，其特征是持续超过6岁的FS和广泛的成人癫痫亚型的发展。迄今为止，研究主要集中在这些疾病的癫痫发作部分;然而，我们现在认识到，癫痫发作通常伴随着认知停滞/下降，多动，以及许多行为共病的发展，包括自闭症和精神病特征。虽然癫痫发作频率在成年期确实趋于下降，但这些合并症持续存在，是该患者人群临床管理的主要挑战。目前，与SCN 1A功能障碍相关的认知和行为结果的特征很差，影响这些缺陷严重程度的因素未知。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，以及确定影响其严重程度的因素。为此，R21应用中的拟议实验将使用我们实验室开发的Scn 1a小鼠模型来解决我们知识中的几个基本空白。具体而言，我们将1）更好地定义由SCN 1A功能改变引起的认知和行为缺陷，2）确定作为SCN 1A源性癫痫的常见临床特征的早期FS延长是否可能导致认知和行为结果的恶化，和3）确定认知和行为异常的出现是否需要出生后大脑发育早期期间SCN 1A功能的改变，或者是不变的（与年龄无关）SCN 1A功能改变的结果。这些实验既具有创新性，又与临床相关，将刺激急需的转化研究。