In continuing the series on the use of MB12 in autism, I am going to discuss the role of MTHFR and Glutathione. The last article showed that the MTHFR mutation is more common in people with ASD than in the regular population. The study listed below makes a correlation between MTHFR and low levels of Glutathione in the blood.
Experimental Biology 2005. April 2. San Diego . Abstract
Low plasma methionine, cysteine, and glutathione levels are associated with increased frequency of common polymorphisms affecting methylation and glutathione pathways in children with autism
S. Jill James, Stepan Melnyk, Stefanie Jernigan. Pediatrics, University of Arkansas for Medical Sciences, 1120 Marshall St. , Slot 512.40B, Little Rock , AR , 72202
Autism is a complex neurodevelopmental disorder that is thought to involve both genetic and environmental factors. The 10-fold increase in the prevalence of autism in the last 15 years is a major public health concern. Although abnormal thiol metabolism has been associated with other neurologic diseases, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 90 autistic and 45 control children using HPLC with electrochemical detection. Polymorphic variants in transcobalamin II (TCII), methylene- tetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), catecholamine-O-methyltransferase (COMT), and glutathione-S-transferase (GST) M1/T1 were evaluated in 233 autistic children and 183 controls. The results indicated that mean levels of methionine, cysteine, total glutathione, and the ratio of oxidized to reduced glutathione were significantly decreased among the autistic children. The frequency of MTHFR 677CT/1298AG heterozygosity, TCII 776GG, COMT 1947GG, and the GST M1/T1 double null genotype was increased in the autistic children relative to controls. We hypothesize that an increased vulnerability to oxidative stress (environmental and/or intracellular) may contribute to the development and clinical manifestations of autism.
So what does this mean for a patient? Glutathione is the body’s natural detoxification mechanism. Its job is to move ‘bad stuff’ out of the body. If you do not have enough, then harmful substances can accumulate and thus affect health; or if the toxins get too high, they can affect brain function. So how does glutathione affect the brain and what does this have to do with MB12? The following is a comment that Dr. Neubrander gives to his patients that (while a bit technical) may explain some of the processes involved.
According to the work of Dr. Richard Deth, methyl-B12 seems to work better in the brain, especially the cortex, than it does in the liver. This is probably because glutathione is very abundant in the liver but limited in the brain and methionine synthase in the brain is configured differently than in the liver. The methyl-B12-requiring form of the methionine synthase enzyme will only be active when there is enough glutathione around to synthesize methyl-B12. Of course the first step is the conversion of hydroxy-B12 to glutathionyl-B12. This occurs spontaneously when hyroxy-B12 and glutathione are simply mixed together. It’s limited only by the glutathione level, which is how nature designed it. So in tissues like the brain (neurons) where glutathione is scarce, methionine synthase activity will only be turned on when glutathione is adequate. Otherwise homocysteine will be continuously diverted toward glutathione synthesis. Thus methylation (i.e. D4 receptor activity) in the brain is only allowed to occur when there is enough glutathione. Things that lower glutathione (e.g. mercury) will therefore particularly lower methylation activity in the brain. SAM is also required for methyl-B12 synthesis, but does not seem to be as critical a limiting factor as glutathione.
At least theoretically, there could indeed be people for whom hydroxy-B12 might be better than methyl-B12. Making methyl-B12 available all the time removes the glutathione contingency for methionine synthase activity. It does guarantee that the D4 receptor phospholipid methylation mechanism will always be operating at better efficiency, despite lower glutathione levels, which is probably the main cognitive benefit of methyl-B12. However, allowing hydroxy-B12 to be converted to glutathionyl-B12 by glutathione may be important for other aspects of methylation. For example, consider DNA methylation. When methionine synthase stays turned off, homocysteine and SAH accumulate. The SAH will inhibit DNA methylation and “turn on” some genes that used to be silenced by methylation. Some of these genes may serve a useful role in combating oxidative stress. When methyl-B12 is given it will tend to lower homocysteine and SAH, which will tend to increase DNA methylation. Of course at this time we can only speculate about what genes might be involved, so this is just a theoretical perspective.
In general there is the possibility that too much methyl-B12 could be a problem, so finding the right dose and right duration of therapy for a given individual remains an important consideration. Hopefully in the near future there will be laboratory tests allowing us to discriminate between who needs methyl-B12 or hydroxy-B12 and who doesn’t.