Advantages:
- Precision Control: Exogenous βHB enables precise and controlled administration, ensuring consistent and predictable βHB levels for tailored therapies.
- Easy Administration: It simplifies treatment compared to the ketogenic diet, particularly beneficial for pediatric patients and practical clinical use.
- Sustained Impact: Supplementation with 15% βHB and medium chain triglyceride (MCT) leads to prolonged elevation of serum βHB, facilitating lasting epigenetic modifications for sustained symptom alleviation in Kabuki Syndrome patients.
Summary:
Kabuki 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.
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.
Our researchers tested using exogenous βHB as an epigenetic modifier to mitigate the symptoms of Kabuki Syndrome. Studies show that 15% βHB and MCT supplementation allows for a more prolonged rise in serum βHB levels while still being palatable to the mice.
Therefore, using βHB to induce epigenetic modifications is ideal because it increases the availability of BHB to the cells. Using exogenous βHB is also ideal because it is easier to administer in a clinical setting than the ketogenic diet (especially when the disease affects children).
(A) Lung weights were similar between BHB-treated and untreated mice.(B) BHB-treated mice had higher brain weights compared to untreated mice.(C, D) BHB treatment did not affect femur and tibia lengths.(E, F) Treated mice spent less time in closed arms and more time in open arms of the elevated plus maze.(G, H, I) BHB treatment had no significant impact on center and perimeter time in the open field test.
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