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
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.