Preparing for a Clinical Trial in Kabuki Syndrome- Characterization of Cognitive and Neuroanatomical Features and Pilot Treatment Trial

项目摘要/摘要 歌舞伎综合症是一种罕见的遗传性疾病，其特征是智力残疾和一种独特的 认知特征。对歌舞伎综合症小鼠模型的研究表明 海马区记忆缺陷和齿状回成年神经发生受阻。 有趣的是，这些缺陷在出生后的生活中被抑制组蛋白的药物正常化。 脱乙酰酶，表明歌舞伎综合症可能是智力障碍的一种可治疗的原因 残疾。初步数据显示，歌舞伎症候群患者在 视觉空间推理和记忆，这些区域在以下情况下明显受损 与智商匹配的对照组相比。这项建议旨在建立在基础科学和 歌舞伎症候群认知功能障碍定位和特征的临床研究 评估潜在的治疗方法。如果成功，这些研究将对 歌舞伎综合征的发病机制和导致的第一个治疗策略。这部作品具有 建立可靠的结果衡量标准和提供一种新的治疗方案的潜力 临床实体(智力残疾)几乎没有治疗选择。 具体目标1：确定符合以下条件的稳健的认知和行为结果衡量标准 在歌舞伎综合症人群中有效、可靠和敏感。这项前瞻性研究将 研究与视觉空间相关的歌舞伎症特异性认知评估方案 功能并建立可靠性，并使用已建立的行为问卷来确定 歌舞伎综合征的神经行为表型。 特定目标2：研究KMT2D突变患者的神经解剖学特征 并为特定损伤的局部化提供进一步的证据。这项研究是在一个 3特斯拉核磁共振扫描仪将调查KMT2D突变患者是否有较小的 齿状回。 具体目标3：测试通过改良的阿特金斯饮食抑制HDAC是否改变 歌舞伎综合征患者的神经认知或神经行为表型。 此前，生酮饮食已被证明可以改善认知和神经组织学。 歌舞伎症候群小鼠模型的缺陷。该提案旨在对10个国家进行试点研究 成年歌舞伎综合征患者接受12周的HDAC抑制，通过饮食和 确定认知评估协议的性能是否发生变化。

Project Summary/Abstract Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and a unique cognitive profile. Studies in a mouse model of Kabuki syndrome have demonstrated hippocampal memory defects and a disruption of adult neurogenesis in the the dentate gyrus. Interestingly, these deficits were normalized in postnatal life with agents that inhibit histone deacetylases, indicating that Kabuki syndrome may be a treatable cause of intellectual disability. Preliminary data shows that patients with Kabuki syndrome have deficits in visuospatial reasoning and memory and that these areas are significantly impaired when compared to IQ-matched controls. This proposal aims to build upon the basic science and clinical work to localize and characterize cognitive impairments in Kabuki syndrome and evaluate a potential treatment. If successful, these studies will yield insights into the pathogenesis of Kabuki syndrome and lead to the first therapeutic strategy. This work has the potential of establishing robust outcome measures and providing a novel treatment option to a clinical entity (intellectual disability) that has few therapeutic options. Specific Aim 1: Determine robust cognitive and behavioral outcome measures that are valid, reliable, and sensitive in a Kabuki syndrome population. This prospective study will investigate a Kabuki syndrome-specific cognitive assessment protocol linked to visuospatial functions and establish reliability and use established behavioral questionnaires to determine the neurobehavioral phenotype of Kabuki syndrome. Specific Aim 2: Characterize neuroanatomical features in patients with KMT2D mutations and provide further evidence of localization of specific impairments. This study done on a 3 Tesla MRI scanner will investigate whether patients with KMT2D mutations have smaller dentate gyri. Specific Aim 3: Test whether HDAC inhibition through modified Atkins diet modifies the neurocognitive or neurobehavioral phenotype in individuals with Kabuki syndrome. Previously, a ketogenic diet has been shown to ameliorate cognitive and neurohistological defects in a mouse model of Kabuki syndrome. This proposal aims to conduct a pilot study of 10 adult patients with Kabuki syndrome given 12 weeks of HDAC inhibition through diet and determine whether performance on the cognitive assessment protocol changes.