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

点击翻译按钮获取中文摘要

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.