Our knowledge of human disease and its connection to the Endocannabinoid System has grown over three decades as science connects the dots. Adding to this, a genetic failure within the production of 2-AG causes a deficient endocannabinoid system in children. Now known as NORDS, the clinical syndrome includes several unique symptoms. (1)
An endocannabinoid explained
From birth, various messengers and receptors comprise a biological system that works in an orchestrated tandem to keep every human alive on the planet. Within the endocannabinoidiome, as the large matrix is known, exists 2-arachidonic glycerol, or 2-AG.
Discovered in canines in 1995, (2) 2-AG is one endocannabinoid and biological messenger not to be undermined. The messenger is a unique fatty acid that maintains balance and drives many functions throughout the body. In the brain, 2-AG serves a critical role in cognition and regulating inflammation. As an agonist of CB1 and CB2 receptors, a failure in the production of 2-AG can cause numerous deficits in adults as well as developmental issues in children.
Genetic reasons behind ECS failures
Genetic mutations in children shorten a biological machine that produces 2-AG according to a study published by Oxford University Press. That machine is an enzyme known as DAG-l (diacylglycerol lipase). And mutations cause what is technically known as truncated enzymes.
A failure in 2-AG production occurs when genetic predispositions produce shortened DAG-l enzymes. And the symptoms identified in the new disease include trouble with head and eye (ocular) movement in nine children. Genetic mutations to Type A DAG-l enzymes also cause ataxia and delay neurological development, likely by depleting 2-AG. For this reason, researchers named the condition NORDs — Neuro Ocular DAG-l Related Syndrome.
Other diseases cause eye and head movement disorders that loosely resemble NORDS. Yet the DAG-related condition identified in children is unique.
Endocannabinoids in the morning
Fasting increases 2-AG levels. (3) Moreover, burning up fat knocks down another cannabinoid, anandamide. (3) Endocannabinoid tone is, therefore, most acute in the morning. Interestingly, however, the most severe symptoms of NORDs occur in the morning. But symptoms also develop after a nap which suggests fasting does not aggravate symptoms in children with deficient production of any endocannabinoid. (1)
The origin of 2-AG in the brain and eye
Lipids — a type of fat — surround cells. When the cells activate, their associated lipids metabolize. A phospholipid can transform into 2-AG, but the process depends on enzymes, including DAG-l. Otherwise, enzymes metabolize Omega-3 fats into endocannabinoids.
The study did not mention phytocannabinoids, (1) likely due to the funding barriers they unfortunately create. With that said, CBD protects anandamide by inhibiting FAAH. But FAAH inhibitors, like CBD, increase ocular inflammation due to the enzyme’s position in the eye’s center. CBG is ideal for ocular conditions, and it also protects 2-AG from degradation. But again, phytocannabinoids produce research barriers due to the lingering prohibition era. Cannabis, therefore, cannot yet be recommended for children with a deficient endocannabinoid system.
Let us know in the comments if you know of a child with an upward eye posture or any delays in development.
Funding and limitations
With a study size of only nine children from eight families, the discovery is a solid footing to establish the clinical genetic 2-AG failure further.
The Rady Children’s Institute for Genomic Medicine (RCIGM) and the National Institute of Health (NIH) independently funded esearchers involved in the project. The international team included two scientists from McGill University with financial support from the Canadian Institutes of Health Research (CIHR). Furthermore, the Fondation du Grand défi Pierre Lavoie and Healthy Brains for Healthy Lives (HBHL) funded one of the two Canadians.
Three members of Scripps Research Institute coauthored the research with funding from Shaffer Family Foundation and the Anne and Henry Zarrow Foundation. Finally, the Assistant Director of Medical Genomics at Children’s Mercy in Kansas City received gifts from the hospital to support her collaboration.
Bainbridge MN, Mazumder A, Ogasawara D, et al. Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome (NODRS) [published online ahead of print, 2022 Jun 23]. Brain. 2022;awac223. doi:10.1093/brain/awac223
Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83-90. doi:10.1016/0006-2952(95)00109-d
DiPatrizio NV, Igarashi M, Narayanaswami V, et al. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. Am J Physiol Regul Integr Comp Physiol. 2015;309(8):R805-R813. doi:10.1152/ajpregu.00239.2015