A world-first study has shown a low carbohydrate, high fat diet could have a life-changing impact on cognitive function for children living with Kabuki syndrome.

The study, led by Professor Russell Dale’s Clinical Neuroimmunology Group at The Children’s Hospital at Westmead (CHW), in collaboration with The Children’s Medical Research Institute (CMRI), the University of Sydney and Westmead Institute for Medical Research (WIMR), trialled the ketogenic diet over a period of 12-months in a teenage boy with the rare condition.

Fifteen-year-old Hugo was diagnosed with Kabuki syndrome when he was four years old. The multi-system genetic condition is caused by DNA mutations in a single gene (KMT2D) and affects the brain, heart, kidneys, and skeletal system.

Currently, there are no curative treatments, with symptoms only able to be managed in isolation. 

For Hugo, even with symptom management, he had begun experiencing debilitating brain fog episodes where he increasingly struggled to focus on the simplest of tasks like reading. These episodes would occur three or four times a year and could last up to three months, meaning Hugo was effectively living half his life in cognitive decline.

Study lead, Erica Tsang, Senior Ketogenic Dietitian at CHW, said the study proved that diet can change gene regulation and improve clinical outcomes, with life changing results for children like Hugo.

“We have shown that a medically-monitored ketogenic diet presents a promising therapy to improve cognitive function and resolve brain fog episodes in some individuals with Kabuki syndrome,” Ms Tsang said.

"In Kabuki Syndrome, the chromatin structure is changed due to the DNA mutation. What we know is that the ketogenic diet produces ketones which are epigenetic molecules that can ‘reopen’ chromatin and therefore encourage gene expression.”

“This improves the original genetic issue, allowing genes to be read correctly.”

“For Hugo, it has completely changed his life and we are optimistic about the doors our study has now opened for children with the condition.”

Hugo’s mum, Chloe, is amazed at the difference it has made for Hugo.

“The trial has made a massive difference for Hugo. Within three months, he was talking about being able to concentrate better, he could read books again and focus and could follow the instructions for Lego better than before,” Chloe said.

“Hugo is no longer on a path of decline towards ‘acquired intellectual disability’ but keeping up with school and peers and at real risk of being a productive adult in society. The study has truly been transformative for our family.”

By using multi-omic sequencing technologies, researchers were also able to understand how the ketogenic diet changes gene expression and cellular function, heralding a new chapter in research for Kabuki syndrome.

The medically-monitored ketogenic diet has already been shown to be effective in managing other neurological conditions such as epilepsy and with these findings, there are new possibilities for the emerging use of the ketogenic diet and ketones in other epigenetic and neurodevelopmental diseases.

“With these next-generation sequencing technologies, we have an unprecedented ability to understand and explore the mechanisms of action of various therapies, including diet,” Ms Tsang said.

“As a dietitian, the emerging field of ‘nutritional epigenomics’ is particularly exciting as it highlights the capacity for diet to change our gene regulation and metabolic function to improve clinical outcomes in health and disease.”

Ms Tsang said collaboration, both locally and internationally, was vital in the success of the study.

“This study involved significant collaboration, bringing together 17 experts in dietetics, neurology, immunology, basic science, and bioinformatics across Australia, Singapore and the US.”

“Without these valued collaborations, we would not have the depth of understanding of therapeutic mechanisms of action that allow us to conduct translational research that directly benefits our patients.”

“This project also highlights the power of collaborating with our consumers, including the families of children with rare diseases, as these studies would not be possible without their passion and dedication.”

Hugo has now been on the ketogenic diet for three years and has not had a single brain fog episode. He is now in Year 9 at a mainstream high school and taking every day in his stride.

The study, published recently in the eBioMedicine – a Lancet Discovery journal, was generously funded and supported by the Wood family, the Dale NHMRC Investigator Grant, The Sydney Children’s Hospitals Foundation Early and Mid-Career Researcher Grant and the Petre Foundation. 

Ms Tsang is part of the Clinical Neuroimmunology group at the Kids Neuroscience Centre at Kids Research, part of Sydney Children’s Hospitals Network.