Summary of clinical factors:
- “Methyls” are one-carbon methyl groups which play an important role in the function of the body’s biochemistry. They change the shape and behaviour of organic molecules through methylation processes or “pathways”.
- Expression of genes is regulated individually by epigenetic methylation markers on the DNA or in groups by the methylation of DNA histone bundles. Higher methylation levels at the individual genes or the histone groups reduces the expression of these genes.
- In the context of brain function and mental health, methylation status specifically affects expression of the genes for re-uptake proteins which regulate dopamine and serotonin levels at the neuronal synapse.
- People known as “overmethyators” (OMs) have methylation pathways with excess methyl groups in circulation, which increases epigenetic methylation. These people can have an excess of those neurotransmitters at the synapse.
- People known as “undermethylators” (UMs) can have the opposite predicament, with a lack of those neurotransmitters at the synapse.
- Either an excess or a lack (“imbalance”) of these neurotransmitters can affect brain function and lead to different clusters of mood disorder symptoms. These clusters of symptoms historically tend to be grouped together as either “Depression”, “Anxiety”, or “Schizophrenia” in the DSM diagnostic system.
- Folates reduce epigenetic methylation at the DNA and promote reuptake gene expression. OMs will do better, UMs will do worse. This is despite folates generally adding methyls to the methylation cycle hence the “folate paradox”.
- Methyl donor supplements like SAMe have the opposite effect, similar to SSRIs but in a different way. UMs will do better, OMs will do worse. This seems to be the reason for the severe worsening of symptoms when either is given to OMs.
- These clinical considerations are the reason why testing for methylation status is optimal to enhancing diagnosis and treatment.
Key technical points:
- Histones and genes on DNA have both acetyls (Ac) and methyls (Me) attached which make up the epigenetics that affect gene transcription.
- The balance of Ac and Me at any DNA area will determine gene expression. On DNA itself, more Me than Ac is an epigenetic “off” switch to transcription. The gene will not be expressed into a protein or enzyme, or to a lesser degree.
- The histones also have Ac and Me, and this regulates general chromatin open/closed configuration. Here, more Me than Ac creates a closed configuration. Closed means a bunch of genes together in the affected histones are less likely to be expressed.
- Therefore more Me than Ac generally tends to switch off genes, either individually on DNA or in bunches at the histones. These effects combine to make some genes more or less expressed than others depending on the overall sum of methylation and acetylation at each point.
- Nutrient therapy and nutrition in general can affect histone methylation more easily but slowly, and individual gene methylation is more permanent at the moment. Individual gene epigenetic methylation can be changed during early pregnancy in the fetus or later in life or through oxidative stress effects on DNA , but this latter is apparently a more random effect.
Images below from a powerpoint presentation By Dr Walsh
In the 1950s Dr Hoffer observed initially the success of niacins and folates treatments in people with the then current schizophrenia diagnosis, and deleterious effects of methionine. This was not satisfactorily explained and constituted a stumbling block in adoption of his treatment methods. Later came refinements from further clinical research which distinguished the two depression/psychosis groups of under/overmethylation (UM/OM) or histadelia/histapenia which are opposite in their treatments and contraindications.