The Problem
- Poor metabolism of vitamin A leads to high retinal levels
- Retinal can comlex with ethanolamine making A2E
- microglia cells are aggravated by A2E
- this increase inflammation in the brain
- low ethanolamine due to binding to retinal decreases the ethanolamine needed for ether lipid synthesis
- neurological function declines as retinal levels increase
The Solution (in this order)
- avoid vitamin A supplementation and intake above the RDA including carotenoids as these enter at retinal level. (Carrots aren’t safe in large amounts, and having orange skin is not benign.)
- increase choline to support acetycholine production, and to help with bile production needed for clearance of metabolized vitamin A
- maximize CYP26 enzyme function and glucuronidation pathways through proper supplementation
- improve NAD production through proper supplementation
- maximize retinal/retinol metabolism by avoiding NAD disruption
This is not written to diagnose or treat a condition, but only for informative purposes. Please consult your doctor before stopping or starting medications or supplements, and before making dietary or lifestyle changes based on the information provided. – Meredith Arthur, MS, RD, LD
This is a hypothesis on nervous system manifestations of poor vitamin A metabolism There are many ways by which we can impair our ability to metabolize vitamin A through disruption of cellular ratio of NAD:NADH. Low NAD levels impair the conversion of retinol and retinal to retinoic acid. Excess retinal levels in the body may be contributing to neurological decline. I believe that this is a contributor to Autism and neurological diseases.
(For 2q23.1/MBD5 deletion group — I know that our kids have neurodevelopmental disorders, but that doesn’t mean that they can’t have other health conditions that cause brain injury. I’m checking with the Elsea lab to see if MBD5 may be modulating some of the genes that involve these pathways.)
High levels of retinal can form a complex with ethanolamine to form A2E. This may decrease levels of ethanolamine containing ether lipids which may lead to neurological decline in and of itself. Low ethanolamine levels have been found in individuals with Autism and Alzheimer’s disease.
In addition, there is evidence that A2E stimulates microglia cells of the immune system to dysfunction in the eye resulting in macular degeneration. In Alzheimer’s disease, microglia cells have been implicated in neurodegeneration. Perhaps this is by an A2E mechanism as well. Individuals with Alzheimer’s disease typically do have higher levels of retinol binding protein 4 (some retinal is converted back into retinol and can be bound to retinol binding protein).
Another intersting connection between retinal and Autism is that it has been shown that individuals with Autism have impaired aldehyde metabolism. This could be genetic in origin due to polymorphisms in genes related to alcohol and aldehyde metabolism. What if it is related to diet and drug choices. Alcohol dehydrogenase and aldehyde dehydrogenase require NAD to work properly. If individuals with Autism are consuming a high oxalate diet, they are likely impairing LDH and causing low NAD levels. This slows aldehyde metabolism.
Over the past 11 years, my daughter, Zoey, has had periods throughout the day that she walked as if she were drunk. She also suffered from what doctors wanted to diagnose as “cyclic vomiting syndrome”. Looking back, the more oxalate that she was consuming, the more ataxia I would see, and the worse gastrointestinal symptoms she would have (reflux, constipatin, nuasea, vomiting). She would also have extreme mood swings and behaviors that over the past two years that were so extreme that her neurologist recommended she be put on a “mood stabilizer”. These were only symptoms of underlying impaired ability to metabolize aldehydes and the A2E ethanolamine steal altering her autonomic nervous system function.
Oxalate was indirectly impairing her ability to metabolize alcohol and aldehydes. We actually do make these consistently during metabolism, and so any disruption in NAD will impair clearance of these by products of metabolism. There are many ways to alter NAD beyond just oxalates.
My poor girl has been drunk on her own metabolites! I wasn’t giving her sips of beer! Hahahah! And….now that I am no longer accidentally poisoning her with oxalate, she is not running into walls as much or falling as much. It must feel good to not be drunk. She also has no more nausea or vomiting, and no significant reflux.
So, there is a huge connection here between retinal metabolism and the existence of impaired aldehyde metabolism in Autism, but not just Autism….
Perhaps Alzheimer’s disease is at least in part due to impaired Vitamin A metabolism and altered aldehyde metabolism. Anger and emotional dysregulation can be a serious issue in individuals with Alzheimer’s disease.
Perhaps individuals with underlying neurodevelopmental disorders caused by genetic aberrations, are more sensitive to alterations in vitamin A metabolism which leads them down a worsening pathway of neurological decline. People with genetic syndromes should be closely monitored for impaired vitamin A metabolism.
Perhaps other psychiatric disorders such as schizophrenia, bipoloar disorder, and major depressive disorder are symptoms of impaired Vitamin A metabolism. There is literature that shows interactions between Vitamin A and these psychiatric disorders. (See studies below)
The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910734/
Ethanolamine low in Autism and Alzheimer’s
https://europepmc.org/article/med/28796901
Brain ethanolamine https://pubmed.ncbi.nlm.nih.gov/33319663/
Retinal and Ethanolamine complexes to make A2E
In skin https://www.sciencedirect.com/science/article/pii/S1873506118300205
In eye https://pubmed.ncbi.nlm.nih.gov/10887199/
In eye https://pubmed.ncbi.nlm.nih.gov/11006290/
Macular Degeneration (A2E schiff base from retinal-ethanolamine complex ) is associated with Alzheimer’s disease and here it is reported that amyloid beta is involved in this process.
https://www.nature.com/articles/eye2015100
Microglia Cells Implicated in Alzheimer’s disease
https://pubmed.ncbi.nlm.nih.gov/29196460/
https://www.nature.com/articles/s41582-020-00435-y
A2E accumulation influences retinal microglial activation and complement regulation (in eyes)
https://pubmed.ncbi.nlm.nih.gov/22819137/
Brain levels of retinol binding protein 4 higher in Alzheimer’s disease
(mouse study) https://pubmed.ncbi.nlm.nih.gov/21538175/
(human study) https://pubmed.ncbi.nlm.nih.gov/3119778/
Vitamin A in Major depressive disorder, Bipolar Disorder, and Schizophrenia
https://pubmed.ncbi.nlm.nih.gov/28755877/
https://pubmed.ncbi.nlm.nih.gov/31708400/
https://pubmed.ncbi.nlm.nih.gov/32827610/
https://www.sciencedirect.com/science/article/abs/pii/S0149763420300014
https://pubmed.ncbi.nlm.nih.gov/32381369/
https://www.nature.com/articles/s41380-019-0566-2
SOLUTIONS:
At first I thought about liquid sunflower lecithin which is a good source of choline and also ethanolamine to help with low levels. Now I caution doing this, it will increase ethanolamine levels. This may cause more damage by increasing A2E complexes while retinal is still high in the body and cause a huge flair in microglia cells
However, increasing overall choline intake is important because ethanolamine can be a precursor for choline synthesis. Low levels of choline will impair acetylcholine production. When acetylcholine is low, there will be impaired autonomic nervous system function leading to slow gut motility, GERD, constipation. The best dietary source of choline is egg yolks. Do NOT use liver without considering your total body vitamin A status. Liver is extremely high in vitamin A.
Definitely address impaired vitamin A metabolism and fix areas that you are able such as low oxalate diet, B6, thiamine, and stopping melatonin or miralax (see other blog posts). This should be AFTER increasing choline intake.
If carotenoid levels are high or your child is obsessed with high carotenoid foods like carrots, possibly go on a low carotenoid diet.
Also you may have to go on a low animal source of vitamin A diet if there is evidence of retinol toxicity. This is because retinol is converted to retinal to some degree during impairment, but also it is highly likely that as this metabolic pathway is restored, then retinal levels will increase.
Avoid supplementing above the RDA for vitamin A.