In a study published in PNAS, researchers looked at mice with a genetic alteration similar to one found in humans who suffer from a congenital disorder causing intellectual disability, known as Kabuki syndrome (KS). In KS and other Mendelian disorders of the epigenetic machinery, genetic mutations lead to errors in epigenetic tags that attach to DNA or histone proteins and modify gene expression.
Researchers discovered that these epigenetic errors in their KS mice led to a decrease in neurogenesis (the formation of neurons) as well as memory defects in the hippocampus, an area of the brain crucial to memory formation. Individuals with KS have a mutation to one of two genes, KMT2D or KDM6A, which encode for epigenetic enzymes that play a crucial role in opening the DNA and histone protein complex known as chromatin.
Histone modifications can occur to histone proteins and impact gene expression. KMT2D produces a lysine methyltransferase (KMT) that adds an epigenetic mark to histones associated with open chromatin, H3K4me3. On the other hand, KDM6A produces a histone demethylase (KDM) that removes an epigenetic mark associated with closed chromatin, H3K27me3.
The researchers wondered, since a deficiency of chromatin opening has been linked to KS, might histone deacetylase (HDAC) inhibitors which promote open chromatin states by inhibiting the removal of KDMs, potentially halt the disease’s progression? Specifically, they assessed beta-hydroxybutyrate (BHB), a ketone naturally found in the body known to exhibit HDAC inhibitor activity.
The lead investigator, Hans Bjornsson, M.D., Ph.D., Assistant Professor of Pediatrics and Genetics in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine, explained, “Mendelian disorders of the 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.”
The team compared mice that were put on a ketogenic diet versus those on a normal diet and injected some with BHB. Both treated groups grew brain cells in an area connected to learning and new memory formation. They also came very close to performing at the same level as healthy mice on a water maze memory test.
Normally, the intellectual disability that comes with Kabuki syndrome is considered irreversible. “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,” Bjornsson said.
This particular diet, a similar yet stricter version of the popular Atkins diet, has yet to be tested in people afflicted with Kabuki syndrome. The BHB supplements still need additional research to verify their effectiveness. Even if they do work, they would not cure the disorder but, at most boost some individuals’ memory and learning.
“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,” Bjornsson said. “We hope to begin a clinical trial in a few years.”
Source: Benjamin, J.S., Pilarowski, G.O., Carosso, G.A., Zhang, L., Huso, D.L., Goff, L.A., Vernon, H.J., Hansen, K.D., and Bjornsson, H.T. (2016). A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. PNAS, 114(1).
Reference: Johns Hopkins Medicine. Low-Carb Diet Alleviates Inherited Form of Intellectual Disability in Mice. Johns Hopkins Medicine News and Publications. 19 Dec 2016. Web.