Ketogenic diet and beta-hydroxybutyrate improve gene transcription and reduce intellectual disability in Kabuki syndrome.
Kabuki syndrome is a debilitating inherited disorder caused by mutations in two genes involved in the regulation of chromatin remodeling, one of the first steps in DNA transcription. Ketones such as beta-hydroxybutyrate have been shown to enhance DNA transcription and gene expression. Findings from one group of researchers show that a ketogenic diet can alleviate some of the neurological deficits of Kabuki syndrome and improve memory.
Kabuki syndrome is named for the facial features common to people with the disorder, which looked similar to Kabuki theatre makeup to the Japanese scientists who first researched the disease. In addition to distinctive facial features, the syndrome causes a wide range of health problems such as heart defects, difficulty eating, weak muscle tone, immune deficiency, and intellectual disability. This wide range of severe health issues is explained by the fundamental importance of chromatin remodeling to the body’s functioning, which is impaired in those with Kabuki syndrome.
Chromatin is the name for the coiled structure DNA forms within the cells of plants and animals, which looks a bit like a tangled telephone cord. This coiled structure prevents DNA from being opened and transcribed (the first step in gene expression and DNA replication) randomly. Chromatin is wrapped around histone proteins that open or close the chromatin, based on whether the histone has a chemical tag called an acetyl group attached or not. As DNA accumulates epigenetic changes over the lifespan, histones become resistant to acetylation, chromatin is harder to open, and gene expression slows. Histone deacetylase (HDAC) inhibitors, such as the ketone beta-hydroxybutyrate (BHB), are compounds that help release histones, open chromatin, prevent loss of gene expression with aging, and may even lengthen lifespan.
The researchers used a strain of mice that have the same DNA mutations that cause Kabuki syndrome in humans and fed them either a normal diet or a ketogenic diet for two weeks. The researchers fed a third group of mice a normal diet and gave them three daily injections of BHB for two weeks. To assess memory and cognitive performance, mice completed a water maze, a sensitive measure of hippocampal function, which is closely related to memory. The researchers measured changes in gene expression, HDAC activity, and neurogenesis.
Compared to a normal chow diet, a ketogenic diet increased the concentration of serum BHB, normalized acetylated histone levels, and increased the expression of several genes that are downregulated in Kabuki syndrome. These changes in gene expression enhanced multiple markers of neurogenesis and improved performance during the water maze test. Mice eating a normal diet that received daily BHB injections achieved similar serum BHB levels as mice eating a ketogenic diet and experienced the same gains in neurogenesis.
This comprehensive study provides insight into the potential of ketogenic diets and supplemental BHB to improve deficits in gene expression in mice with a debilitating genetic disorder. Future research is needed in order to translate these insights into clinically useful information for humans.