CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Low-carb diet relieves a form of intellectual disability
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.
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.
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.
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.
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.
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.
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).
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).