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Low-carb diet relieves a form of intellectual disability

Experimenting on mice with a genetic change similar to that found in people with the rare inherited disease Kabuki syndrome, Johns Hopkins scientists report a very low-carbohydrate diet can "unwind" histones of DNA and improve mental function.

Along with providing a potential treatment for memory and other intellectual losses seen in people with Kabuki Syndrome, the study's findings also suggest a new way of thinking about a category of genetic diseases known as Mendelian disorders of the epigenetic machinery. In these disorders, a genetic mutation causes errors in chemical tags on DNA which affects the rate at which DNA makes proteins.

In a Kabuki-like condition in mice, researchers found these errors lead to a persistent, treatable decrease in new cell growth in a part of the brain where memory forms. They believe their study adds to growing evidence that some forms of inherited intellectual disability, may be reversible.

The results of their experiments are described the week of Dec. 19 in an early edition of PNAS.

"Mendelian disorders of epigenetic machinery affect how cells 'package' and use DNA, so they tend to have complicated and far-reaching effects.

"Finding a way to ease some of the symptoms in this group of rare disorders suggests that other such inherited disorders of the histone protein machinery may be treated in a similar manner."

Hans Bjornsson MD PhD, Assistant Professor, Pediatrics and Genetics, Johns Hopkins University School of Medicine, McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland, USA, and lead investigator.

Histones are specialized proteins that DNA wraps around to keep itself organized. DNA wound around histones is known as chromatin. Only by forming chromatin can several feet of DNA fit inside the tiny nuclei of each cell. But to read the DNA and put it to use to make new proteins, chromatin must temporarily unwind to allow those genes to express proteins.

Bjornsson heads the McKusick-Nathans Epigenetics and Chromatin Clinic, and has long researched Kabuki syndrome, which is caused by mutations in one of two genes that govern histones. Specialized enzymes act as "writers" and "erasers" to add or subtract chemical groups to histones and induce chromatin to wind or unwind.

Recently, Bjornsson and his collaborators found mutations leading to Kabuki syndrome cause an imbalance between chromatin's wound and unwound states — and believe that correcting that imbalance might alleviate some intellectually disabling symptoms of the condition.

A naturally occurring compound called beta-hydroxybutyrate (BHB) had already been reported to help unwind chromatin. For the new study, the Johns Hopkins researchers tested whether two weeks of a low-carbohydrate ketogenic diet.

A ketogenic diet is a very low-carb, high-fat diet that shares many similarities with the Atkins and other low-carb diets. It involves drastically reducing carbohydrate intake, and replacing it with fat. A reduction in carbs puts your body into a ketosis metabolic state in which the body enters an extremely high fat-burning rate. Even the brain runs on fat, via ketone bodies. These are energy molecules in the blood (like blood sugars) which become fuel for our brains after being extracted from fat by our liver.

A ketogenic diet forces the body to produce high levels of beta-hydroxybutyrate (BHB) on its own - naturally. This ability alleviated symptoms in mice genetically engineered to have a Kabuki-like condition. The diet has long been known to have an impact on brain activity, particularly as a treatment for severe seizure disorders.

In experiments, researchers compared mice given the ketogenic diet to mice fed a normal diet and to those injected with BHB. Compared with their untreated counterparts, both groups of treated mice grew more new brain cells in an area called the granule cell layer of the dentate gyrus — associated with the ability to learn and form new memories. They also performed nearly as well as non-Kabuki mice on a test known as the Morris water maze, which assesses a rodents' ability to remember an underwater resting platform during a maze swimming exercise.

Physicians generally consider the intellectual disability that accompanies disorders like Kabuki syndrome to be irreversible, Bjornsson notes. "But we now know that new brain cells continue to form throughout our lives. If Kabuki syndrome and related disorders cause fewer neurons to be made in adulthood, stimulating neuronal growth may be an effective strategy for treating intellectual disability," he explains.

Bjornsson cautions that the diet and BHB supplements have not yet been tested in people with Kabuki. Those studies need to be done before any conclusions can be drawn about their effectiveness.

He also warns that a ketogenic diet, which is similar but even more stringent than the commercial Atkins diet of the early 2000s, is difficult for most people to maintain.

He also emphasizes that even if the diet or BHB supplements do work, they would at best boost some patients' learning and memory, not cure the disorder. Bjornsson is now working with colleagues to devise effective tests to measure cognitive function and detect potential changes in the brains of patients with Kabuki syndrome.

"We want to make sure we have good metrics in place before we try to test the diet in patients, so that we can see whether it makes a meaningful difference for them," he says. "We hope to begin a clinical trial in a few years."

According to the National Institutes of Health, Kabuki syndrome affects approximately 1 in 32,000 newborns. In addition to intellectual disability, it causes distinctive facial features, and sometimes seizures, an unusually small head size, weak muscles and/or other health problems.

Intellectual disability is a common clinical entity with few therapeutic options. Kabuki syndrome is a genetically determined cause of intellectual disability resulting from mutations in either of two components of the histone machinery, both of which play a role in chromatin opening. Previously, in a mouse model, we showed that agents that favor chromatin opening, such as the histone deacetylase inhibitors (HDACis), can rescue aspects of the phenotype. Here we demonstrate rescue of hippocampal memory defects and deficiency of adult neurogenesis in a mouse model of Kabuki syndrome by imposing a ketogenic diet, a strategy that raises the level of the ketone beta-hydroxybutyrate, an endogenous HDACi. This work suggests that dietary manipulation may be a feasible treatment for Kabuki syndrome.

Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

Keyword search: epigenetics histone machinery adult neurogenesis intellectual disability ketone bodies

Other authors on the paper are Joel S. Benjamin, Genay O. Pilarowski, Giovanni Carosso, Li Zhang, David L. Huso, Loyal A. Goff, Hilary J. Vernon and Kasper D. Hansen, all of Johns Hopkins University.

Conflict of interest statement: J.S.B. and H.T.B. have a pending patent for the use of a ketogenic diet and injection of BHB for treatment of Mendelian disorders of the epigenetic machinery.

This work was supported by the NIH Director's Early Independence Award (grant number DP5OD017877) and a gift from the Benjamin family (no relation to the first author).
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Jan 4, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Newborn neurons (green) in the brain's dentate gyrus of a normal mouse on a regular diet (upper left), a Kabuki-like mouse on a normal diet (lower left), a normal mouse on a ketogenic diet (upper right) and a Kabuki-like mouse on a ketogenic diet (lower right).
Image Credit: Joel S. Benjamin/Johns Hopkins Medicine



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