Therapeutics
Ketogenic Diet Reverses Memory Loss in Kabuki Mice
High-fat diet boosts brain cell growth via a natural epigenetic molecule, offering a potential safe, dietary strategy for cognitive symptoms.
What if a change in diet could partly offset the cognitive effects of Kabuki syndrome? That's the striking implication of a study from the lab of Hans Bjornsson, published in Proceedings of the National Academy of Sciences.
The researchers showed that a high-fat, low-carbohydrate ketogenic diet reversed both memory deficits and a shortfall in new brain cell production in a mouse model of Kabuki syndrome. The key player appears to be beta-hydroxybutyrate (BHB)—a natural molecule the body produces when burning fat for fuel—which acts as an epigenetic drug the body makes itself.
The backstory
Kabuki syndrome results from mutations in one of two genes—KMT2D or KDM6A—both involved in chromatin accessibility, the process of opening up tightly packed DNA so genes can be read. In earlier work, the same group had shown that a lab-made drug called AR-42, a histone deacetylase inhibitor (HDACi), could reopen chromatin and rescue memory deficits in Kabuki mice. HDACis work by preventing the chemical "closing" of histones—the protein spools that DNA wraps around—keeping genes more accessible. But AR-42 is a cancer drug, not something you'd casually prescribe to a child.
Enter the ketogenic diet
BHB, it turns out, is a naturally occurring HDACi. The team confirmed this in cell culture, showing that BHB dose-dependently increased the activity of histone-opening machinery.
They placed Kabuki mice (called Kmt2d+/βGeo mice—animals carrying one disrupted copy of Kmt2d, mimicking the human condition) on a ketogenic diet with a 4:1 fat-to-protein ratio, a regimen commonly used in human medicine. These mice already showed reduced production of new neurons in the hippocampus—a brain region critical for learning and memory—along with clear memory problems.
What happened
After just two weeks on the diet, urine levels of BHB rose significantly, with an even larger spike in Kabuki mice compared to their wild-type littermates. The disproportionate rise in BHB relative to another ketone, acetoacetate, pointed to an underlying shift in the NADH/NAD+ ratio—a fundamental metabolic toggle—that may make Kabuki mice especially responsive to this dietary strategy.
At the level of chromatin, the diet worked. In the granule cell layer of the dentate gyrus (GCL of the DG)—a region of the hippocampus where new neurons are born throughout life—Kabuki mice on the ketogenic diet showed increased levels of two histone marks associated with open, active chromatin: H3K4me3 and H3ac. These are precisely the marks you'd expect an HDACi to boost, and indeed, the concordance with earlier AR-42 results provides strong evidence that BHB acts, at least in part, through the same histone-modifying pathway.
The downstream effects were dramatic. New neuron production in the GCL rebounded to near-normal levels, measured by two independent markers of dividing and maturing brain cells. And in a Morris water maze—a classic test of hippocampal memory in which mice must remember where a hidden platform is located—Kabuki mice on the diet performed significantly better than untreated Kabuki mice.
Is it really the BHB?
To nail down whether BHB itself was doing the work, the team administered BHB directly by injection and osmotic pump, bypassing the diet entirely. Mice receiving enough exogenous BHB to match ketogenic-diet levels showed a comparable rescue of neurogenesis. This strongly suggests that BHB is a major active ingredient in whatever benefit the ketogenic diet provides, not merely a bystander.
Gene expression shifts
Why do Kabuki mice have these problems in the first place? Gene expression profiling of the hippocampus revealed that the majority of genes significantly altered in Kabuki mice were turned down, not up—consistent with the loss of a chromatin-opening enzyme. When the team checked the five most down-regulated genes after two weeks of the ketogenic diet, three of four (excluding Kmt2d itself, which is structurally disrupted) showed significant increases in expression, with two fully normalizing. One of these, Glp1r (encoding a receptor found at neuronal synapses), is itself linked to reversible hippocampal memory deficits when knocked out in mice—a tantalizing convergence.
Why this matters
Unlike a cancer drug, a dietary intervention could move quickly into the clinic and is unlikely to carry major adverse effects. The ketogenic diet is already widely used in human medicine for intractable epilepsy, so its safety profile is well understood.
This study doesn't prove that a ketogenic diet will improve cognition in children with Kabuki syndrome. It's a mouse study, and the leap from rodent hippocampus to human learning is a long one. But it establishes a clear mechanistic chain: dietary fat → BHB → histone modification → gene reactivation → new neuron growth → memory rescue. And it suggests that the cognitive effects of Kabuki syndrome, at least in part, may reflect an ongoing, reversible deficit rather than a fixed developmental injury.
For Kabuki families, that distinction matters enormously.
generated by Claude