Discovery of endocannabinoid gene mutation leads to identification of new rare pediatric neurological disease

In a study published in the October 2022 issue of Brainresearchers from the Rady Children’s Institute for Genomic Medicine (RCIGM) and the University of California San Diego School of Medicine describe their discovery of a new clinical syndrome, DAGLA-related neuro-ocular syndrome (NODRS), in children with terminating variants in the diacylglycerol lipase alpha (DAGLA) gene which encodes an enzyme in the brain involved in the endocannabinoid system (eCB) signaling pathway.

In the study, the authors evaluated nine children from around the world who exhibited unique neuro-ocular traits, including developmental delays, difficulty with balance and walking, abnormal eye movements and head shaking. In each child, truncating variants in the last exon of DAGLA were found to be the cause of their unique pediatric syndrome. Since the enzymatic activity was preserved, the observed mislocalization of the truncated protein may explain the observed phenotype.

“The phenotype and genotype are extremely well related, which is unusual,” said study principal investigator Jennifer Friedman, MD, clinical professor of neuroscience and pediatrics at UC San Diego and clinical researcher at RCIGM. “The clustering of pathogenic DAGLA variants in these children may provide insight into the mechanism of disease.”

DAGLA is an essential component of the eCB pathway, involved in a wide range of physiological functions. In the developing brain, the eCB signaling pathway has important influences on neuronal development, signaling, and brain repair. In the mature nervous system, eCBs regulate the short- and long-term suppression of neurotransmitter release. The ubiquitous nature of this pathway and evolutionary conservation imply a central role in human health and disease. Despite this, no defined human disorder has so far been conclusively linked to mutations in genes encoding components of this pathway.

“This is the first report linking a component of the endocannabinoid system, DAGLA, to a human genetic disease, NODRS, and allows us to better understand the role of endocannabinoids in health and disease,” said Dr. Friedmann. “The mutation in DAGLA was originally identified by researchers at the Scripps Research Translational Institute.”

“This work is more than a description of a rare pediatric disease; it is the first step towards a better understanding of the impact of cannabinoids on human health; the results of this study could open the door to new drugs. cannabis derivatives for a wide range of because we know that cannabinoid receptors in the eCB system exist throughout a person’s body, not just in the brain,” said Matthew Bainbridge, Ph.D., Deputy Director of Research translational research at RCIGM and lead author.

“It’s an idea that we hadn’t considered before because we didn’t know the gene involved and the exact role of these receptors. Knowing the gene means knowing the pathway and what kinds of therapeutics might be beneficial.”

Dr. Bainbridge also believes that with a diagnosis, parents of a child living with NODRS now have the opportunity to come together as a community to share experiences, knowledge and hope with those who understand. Children with these types of symptoms should be more easily diagnosed now that the gene for this extremely rare condition has been identified. “It is high time that a genetic mutation linked the endocannabinoid system to human disease,” Dr. Bainbridge concluded.

Provided by Rady Children’s Institute for Genomic Medicine