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

项目总结/摘要 歌舞伎综合征是一种罕见的遗传性疾病，其特征是智力残疾， 认知侧写对歌舞伎综合征小鼠模型的研究表明， 海马记忆缺陷和成年齿状回神经发生中断。 有趣的是，这些缺陷在出生后的生活中被抑制组蛋白 脱乙酰酶，这表明歌舞伎综合征可能是一个可治疗的原因， 残疾。初步数据显示，歌舞伎综合征患者在以下方面存在缺陷： 视觉空间推理和记忆，这些领域是显着受损时， 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 临床工作定位和表征歌舞伎综合征的认知障碍， 评估潜在的治疗方法。如果成功的话，这些研究将深入了解 Kabuki综合征的发病机制，并导致第一个治疗策略。这项工作有 建立稳健的结局指标并为患者提供新的治疗选择的潜力 临床实体（智力残疾），几乎没有治疗选择。 具体目标1：确定稳健的认知和行为结果指标， 在歌舞伎综合征人群中有效、可靠和敏感。这项前瞻性研究将 探讨与视觉空间相关歌舞伎综合征特异性认知评估方案 功能和建立可靠性，并使用既定的行为问卷，以确定 歌舞伎综合征的神经行为表型 具体目标2：描述KMT 2D突变患者的神经解剖学特征 并进一步提供特定损伤定位的证据。这项研究是在一个 3特斯拉MRI扫描仪将调查KMT 2D突变患者是否具有较小的 齿状回 具体目标3：测试通过改良的阿特金斯饮食的HDAC抑制是否改变了HDAC。 在患有歌舞伎综合征的个体中的神经认知或神经行为表型。 以前，生酮饮食已被证明可以改善认知和神经组织学 Kabuki综合征小鼠模型的缺陷。这项建议旨在进行一项试验性研究， 通过饮食给予12周HDAC抑制的成年歌舞伎综合征患者， 确定认知评估方案的表现是否改变。

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.