Rare endocannabinoid gene mutations cause neurological disorders

In a study published in the October 2022 issue of the journal Brain, researchers from the Rady Children's Institute for Genomic Medicine and the University of California San Diego School of Medicine describe a new clinical syndrome they have discovered, Neuro-Ocular DAGLA-related Syndrome (NODRS), in children whose diaacylglycerol lipase α (DAGLA) gene terminates mutations, This gene encodes an enzyme
in the brain involved in the signaling pathway of the endocannabinoid (eCB) system.

In the study, the authors evaluated nine children from around the world who exhibited distinctive neuroocular features, including developmental delays, difficulty balancing and walking, abnormal eye movements, and nodding
.
In each child, truncated variants of the last exons of DAGLA were found to be responsible for
their unique pediatric syndrome.
Since enzyme activity is preserved, the observed mislocalization of the truncated protein may explain the observed phenotype
.

"It's unusual that phenotypes and genotypes are very closely linked," said Jennifer Friedman, M.
D.
, principal investigator of the study, clinical professor of neuroscience and pediatrics at UC San Diego and clinical investigator
at RCIGM.
"The aggregation of pathogenic DAGLA variants in these children may provide insight into
the mechanisms of the disease.
"

DAGLA is a key component of the eCB pathway and involves a wide range of physiological functions
.
In the developing brain, the eCB signaling pathway has important effects
on neurodevelopment, signal transduction, and brain repair.
In the mature nervous system, eCBs regulate short- and long-term inhibition
of neurotransmitter release.
The ubiquitous nature of this pathway and evolutionary protection implies a central role
in human health and disease.
Still, so far, there has been no clear human disease associated
with genetic mutations encoding components of this pathway.

Dr Friedman said: "This is the first report linking DAGLA, a component of the endocannabinoid system, to the human genetic disease NODRS, giving us a better understanding of the role of
endocannabinoids in health and disease.
The DAGLA mutation was originally discovered by researchers at the Scripps Research Translational Institute, and we continue to collaborate
with the institute on this project through a Clinical and Translational Science Award grant.
”

"This work is not just a description of a rare pediatric disease; It is at the forefront of better understanding how cannabinoids affect human health; The findings of this study may open the door to the development of new, cannabis-derived drugs to treat a wide range of diseases, as we know that the cannabinoid receptors in the eCB system are present throughout a person's body, not just in the brain," said Matthew Bainbridge, PhD, assistant director and lead author
of RCIGM Translation Research.
"It's an idea we haven't considered before because we don't know the genes involved and the exact role
of these receptors.
" Understanding genes means understanding their pathways and which therapies might be beneficial
.
”

Dr.
Bainbridge also believes that after being diagnosed, parents of children with NODRS now have the opportunity to come together as a community and share experiences, knowledge and hope
with those who understand NODRS.
Children with these symptoms should be easier to diagnose because the gene for this super rare disease has already been identified
.
"Finally discovered the mutated gene linked to human disease in the endocannabinoid system
.
"

Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome