Children with deficient endocannabinoid production have NORDs

Our knowledge of human diseases and their connection to the endocannabinoid system has grown over three decades as science bridges the dots. Additionally, a genetic failure to produce 2-AG in children results in a deficient endocannabinoid system. The clinical syndrome now known as NORDS includes several unique symptoms. (1)

An endocannabinoid explained

From birth, various messengers and receptors form a biological system that works in orchestrated tandem to keep every human being alive on the planet. Within the endocannabinoidome, known as the large matrix, exists 2-arachidone glycerol or 2-AG.

Discovered in dogs in 1995, (2) 2-AG is an endocannabinoid and biological messenger that must not be undermined. The messenger is a unique fatty acid that maintains balance and powers many functions throughout the body. In the brain, 2-AG plays a crucial role in the perception and regulation of inflammation. As an agonist of CB1 and CB2 receptors, failure to produce 2-AG can cause numerous deficiencies in adults and developmental problems in children.

Genetic reasons for ECS failures

According to a study published by Oxford University Press, genetic mutations in children shorten a biological machine that produces 2-AG. This machine is an enzyme known as DAG-1 (diacylglycerol lipase). And mutations cause what are technically known as truncated enzymes.

Failure of 2-AG production occurs when genetic predispositions produce truncated DAG-1 enzymes. Symptoms identified in the new disease include problems with head and eye (eye) movement in nine children. Genetic mutations to type A DAG-1 enzymes also cause ataxia and delay neurodevelopment, likely through depletion of 2-AG. For this reason, the researchers named the condition NORDs – Neuro Ocular DAG-1 Related Syndrome.

Other diseases cause eye and head movement disorders similar to NORDS. However, the DAG-related condition identified in children is unique.

Endocannabinoids in the morning

Fasting increases 2-AG levels. (3) In addition, fat burning knocks down another cannabinoid, anandamide. (3) Endocannabinoid tone is therefore strongest in the morning. Interestingly, however, the most severe symptoms of NORDs occur in the mornings. But symptoms also develop after a nap, suggesting that fasting does not worsen symptoms in children with deficient endocannabinoid production. (1)

2-AG is produced by an enzyme that is absent in children with NORDs.

The origin of 2-AG in the brain and eye

Lipids – a type of fat – surround cells. When cells become activated, their associated lipids are metabolized. A phospholipid can convert to 2-AG, but the process depends on enzymes including DAG-1. Otherwise, enzymes convert omega-3 fats into endocannabinoids.

The study did not mention phytocannabinoids, (1) probably due to the funding barriers they unfortunately create. With this in mind, CBD protects anandamide by inhibiting FAAH. But FAAH inhibitors, like CBD, increase eye inflammation due to the enzyme’s location in the center of the eye. CBG is great for eye conditions and also protects 2-AG from breakdown. But again, phytocannabinoids create research barriers due to the ongoing prohibition era. Therefore, cannabis cannot yet be recommended for children with a deficient endocannabinoid system.

Let us know in the comments if you know of a child with upward eye posture or developmental delayst.

Funding and Restrictions

With a study size of only nine children from eight families, the discovery provides a solid foundation to further establish 2-AG clinical genetic failure.

The Rady Children’s Institute for Genomic Medicine (RCIGM) and the National Institutes of Health (NIH) independently funded researchers involved in the project. The international team included two scientists from McGill University with funding from the Canadian Institutes of Health Research (CIHR). In addition, the Fondation du Grand défi Pierre Lavoie and Healthy Brains for Healthy Lives (HBHL) sponsored one of the two Canadians.

Three members of the Scripps Research Institute co-authored the research with funding from the Shaffer Family Foundation and the Anne and Henry Zarrow Foundation. Finally, the Associate Director of Medical Genomics at Children’s Mercy in Kansas City received gifts from the hospital to support their collaboration.

Sources

1. Bainbridge MN, Mazumder A, Ogasawara D, et al. Endocannabinoid Dysfunction in Neurological Disorders: Neuroocular DAGLA-Related Syndrome (NODRS) [published online ahead of print, 2022 Jun 23]. Brain. 2022;awac223. doi:10.1093/brain/awac223
2. Mechoulam, R., Ben-Shabat, S., Hanus, L., et al. Identification of an endogenous 2-monoglyceride present in the canine gut that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83-90. doi:10.1016/0006-2952(95)00109-d
3. DiPatrizio NV, Igarashi M, Narayanaswami V, et al. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic signaling. Am J Physiol Reg Integr Comp Physiol. 2015;309(8):R805-R813. doi:10.1152/ajpregu.00239.2015