Researchers have long understood that Kabuki syndrome—a genetic disorder causing intellectual disability—stems from mutations in genes that help keep DNA accessible for reading.What has remained elusive is how to fix it.A new study in mice suggests the answer might lie not in a pill, but in a diet.
Kabuki syndrome results from mutations in either of two genes, KMT2D and KDM6A, that play a direct role in "chromatin opening." Chromatin is the tightly packaged form of DNA in a cell nucleus; when it's too tightly wound, genes can't be turned on.Both genes act as epigenetic regulators—one adds a chemical tag associated with open chromatin, while the other removes a repressive tag.The result in both cases is DNA that remains too closed for normal brain development and function.
The logic follows that if the problem is insufficient chromatin opening, drugs that promote open chromatin states might help.Histone deacetylase inhibitors (HDAC inhibitors) do exactly this.In previous work, the same research team showed that a drug called AR-42 could normalize adult neuron production in the hippocampus and rescue memory deficits in a mouse model of Kabuki syndrome.But there's a catch: AR-42 is an antineoplastic agent—a cancer drug.Using a chemotherapy-adjacent drug for a nonlifetime-threatening condition like Kabuki syndrome poses real-world challenges.
This is where the new study pivots.The researchers asked whether a dietary approach could achieve similar effects without the pharmacological baggage.They focused on beta-hydroxybutyrate (BHB), a ketone body produced by the liver during periods of fasting or very low carbohydrate intake.BHB has been shown to function as a natural HDAC inhibitor.Critically, it crosses the blood-brain barrier and can reach the hippocampus—the brain region central to memory and new neuron production.
The investigators placed Kabuki-model mice on a ketogenic diet with a 4:1 fat-to-protein ratio—the same standard used in human clinical ketogenic diets.After two weeks, they measured BHB levels in urine, blood, and brain tissue.The results were striking: BHB increased significantly across all three compartments.Notably, the Kabuki-model mice showed a disproportionately high increase in BHB relative to another ketone body called acetoacetate, compared to healthy mice on the same diet.This elevated BHB-to-acetoacetate ratio was specific to the Kabuki model—it did not appear in mice with Rubinstein-Taybi syndrome, another genetic disorder involving chromatin-opening deficits.
The researchers then examined what the diet actually did in the brain.They found that two weeks of ketogenic diet normalized the global histone modification state in the dentate gyrus granule cell layer of the hippocampus—specifically increasing levels of H3K4me3 (an open-chromatin mark) and normalizing histone acetylation.These are precisely the epigenetic signatures that the mutated KMT2D gene would normally help maintain.
The functional readouts followed.Kabuki-model mice on the ketogenic diet showed increased adult neurogenesis—the production of new neurons in adulthood—as measured by both EdU-positive and DCX-positive cells in the dentate gyrus.This measure rose to the point where it was statistically indistinguishable from healthy mice.Perhaps most importantly, the mice showed actual behavioral rescue: improved performance on the Morris water maze probe trial, a hippocampus-dependent memory task.
To confirm that BHB itself was the active driver rather than some other effect of the diet, the team administered BHB directly via injection and via pump to mimic continuous exposure.Both approaches increased neurogenesis in a dose-dependent manner, supporting BHB as a key mediator of the therapeutic effect.
An intriguing finding emerged when comparing the diet to the earlier drug approach.The ketogenic diet improved memory only in Kabuki-model mice—the healthy mice showed no benefit.In contrast, AR-42 improved performance in both groups.The researchers suggest two possible explanations: either AR-42 acts on additional targets beyond HDAC inhibition (including histone demethylases), making it more potent but less specific, or the healthy mice simply don't achieve high enough BHB levels on the diet to produce dramatic chromatin changes.Either way, the genotype-dependent effect of the diet suggests it corrects a disease-specific deficit rather than acting as a general cognitive enhancer.
The study also uncovered a metabolic phenotype in the Kabuki-model mice that may explain their exaggerated BHB response.During ketosis, these mice showed an increased ratio of both BHB to acetoacetate and lactate to pyruvate—two biochemical markers that both reflect an elevated NADH-to-NAD+ ratio.This suggests their cells are primed toward metabolic pathways that produce NADH, which in turn drives BHB production.This metabolic wiring may be part of why the diet works so specifically in this model.
What does this mean for families affected by Kabuki syndrome? The researchers are careful to note that while the study provides strong preclinical proof of concept, it remains to be seen whether the same exaggerated BHB elevation occurs in human patients with Kabuki syndrome.If it does, the ketogenic diet might represent a particularly effective treatment strategy for this population.The BHB levels achieved in the mice correspond to those reached in humans following standard clinical ketogenic diet protocols, suggesting the translation path, while still unproven, is biologically plausible.
The broader implications extend beyond Kabuki syndrome.The study provides a mechanistic basis for how ketogenic diets affect the brain—a question that has puzzled clinicians since the diet was first used for epilepsy decades ago.By linking BHB to HDAC inhibition and subsequent epigenetic modifications, the work offers one plausible biological explanation for a therapy already used for hard-to-treat seizure disorders.
Other findings from the study:
• The gene Glp1r, which normalizes on the ketogenic diet and is linked to hippocampal memory function, represents one concrete example of how gene expression shifts may connect to behavioral outcomes.
• Changes in the NADH/NAD+ ratio could also affect chromatin through sirtuins, a class of NAD+-dependent HDACs—offering another mechanistic pathway beyond direct BHB-HDAC inhibition.
• While some genes normalize on the ketogenic diet, Kabuki syndrome likely reflects combined effects of many dysregulated genes rather than a single pathway, consistent with how other epigenetic disorders present.
• BHB may also act through mechanisms beyond HDAC inhibition, including direct histone butyrylation or effects on mitochondrial respiration, synaptic physiology, or cellular oxidative stress.
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