Using Exogenous βHB as an Epigenetic Modifier to Mitigate the Symptoms of Kabuki Syndrome

Abstract

BackgroundKabuki Syndrome is a rare genetic disorder that leads to many developmental abnormalities, and is caused by a heterozygous mutation in either KMT2D (Type 1) or KDM6A (Type 2) that leads to a loss of function. Both genes play a role in gene regulation via histone modification. KMT2D is a gene that codes for the protein kmt2d, a lysine methyltransferase responsible for methylating H3K4. The KDM6A gene encodes the protein kdm6a, a demethylase responsible for demethylating H3K27. Both gene functions contribute to the opening of the chromatin. When either of these two proteins are deficient, craniofacial, skeletal, mental, and dermatologic development are severely impacted. Other developmental processes are impacted, but to varying degrees across patients. The endogenous ketone metabolite beta‐hydroxybutyrate (βHB) is a known epigenetic modifier, functioning as a class I and IIa histone deacetylase inhibitor. Previous research has shown that the ketogenic diet increases H3K4 acetylation and methylation rates, making βHB a potential therapeutic intervention for Kabuki syndrome. Additionally, H3K4 is a beta‐hydroxybutyrylation site, further underlying the potential for βHB to affect the epigenetic modifications observed in the disease. However, there is no current research on beta‐hydroxybutyrylation in Kabuki, nor on the effects of continuous exogenous βHB supplementation in the disorder.MethodsKmt2d+/βGeo (Type 1 Kabuki syndrome model) mice were fed standard diet with or without 15% BHB‐MCT supplementation for 12–15 weeks. Blood ketones, glucose, and body weight were monitored during the treatment period. Open field, Elevated Plus Maze, Novel Object Recognition, and Grip Strength behavioral tests were performed at the end of treatment. Various tissues were harvested, including the brain, for ongoing ex vivo analysis of markers associated with learning, memory, and development.ConclusionsThe 15% BHB‐MCT supplementation is sufficient to raise blood ketone levels in Kmt2d+/βGeo mice. Behavioral and molecular analysis is ongoing.Support or Funding InformationDisruptive Nutrition, Florida high Tech Corridor