Folate Metabolism, the Folate Trap, and finding the right therapy for your specific autism

  

Most of the folate and folic acid we eat must be converted into the active form, known as L-methylfolate or 5-MTHF. However, some dietary folate is already in the active form when we eat it and therefore does not rely on MTHFR.

In treating autism, folate metabolism is a key area of therapeutic focus. While folate supplementation seems simple on the surface, the biology behind it is complex — and, if misunderstood, you may even worsen symptoms.

This post explains how folate metabolism works, what the methyl folate trap is, and how different folate and B12 formulations affect outcomes in children and adults with autism, especially those with MTHFR, MTR, or MTRR mutations.

The Normal Folate Cycle 

Folate, a B-vitamin, plays a central role in:

• DNA synthesis 
• Methylation 
• Neurotransmitter production (via SAMe) 

Here is how it works, if you like details:  

• 5,10-methylene-THF helps make thymidine (for DNA).
• Some of this is converted to 5-MTHF by MTHFR.
• 5-MTHF donates a methyl group to homocysteine, converting it to methionine, in a process catalyzed by methionine synthase, which requires vitamin B12.
• This regenerates THF, which goes back into the cycle.

 

The Methyl Folate Trap

 

If there is a vitamin B12 deficiency, or methionine synthase (MTR) dysfunction, the conversion of 5-MTHF → THF is blocked. This causes:

·         5-MTHF to accumulate (it’s “trapped”)

·         THF and 5,10-methylene-THF to fall

·         DNA synthesis to halt

·         Elevated homocysteine, and low SAMe

The result:

·         Anemia

·         Neurological symptoms

·         Behavioral worsening in autism

This is known as the methyl folate trap — and it explains why giving high-dose folate without enough B12 can backfire.

In summary, the methyl folate trap occurs when B12 deficiency or methionine synthase dysfunction prevents 5-MTHF from recycling to THF, stalling DNA synthesis and methylation, even if folate levels are high.

  

Could the Folate Trap Cause Aggressive or Behavioral Regression?

Yes. In autism, worsening behaviors (irritability, aggression etc) after high-dose folinic acid may reflect a relative B12 deficiency or impaired methionine synthase, leading to:

·    Folate trapping

·   Disrupted neurotransmitter synthesis (especially dopamine/serotonin)

·    Low SAMe

In these cases, adding B12 (methylcobalamin or hydroxycobalamin) often improves tolerance to folate therapy and reduces side effects.

 

Other reasons for a possible negative reaction to calcium folinate

Folate metabolism is tightly connected to glutamate and GABA balance.

High folate dosing in some sensitive individuals may cause excess glutamate activity (excitatory), triggering aggression or anxiety-like behaviors.

Children with fragile neurochemical balance may not tolerate sudden shifts in methylation or neurotransmitter levels. A rapid increase in serotonin, dopamine, or norepinephrine can destabilize mood or cause agitation/aggression. This is why you start low and gradually increase your folate supplement.

In such children 5-MTHF may work better, but you still B12.

Apparently, some doctors prescribe antipsychotics to treat agitation caused by calcium folinate; I am not sure that is a good idea.

 

 Choosing the Right Folate: Folinic Acid vs 5-MTHF

	Calcium Folinate / Leucovorin	5-MTHF
Form	Precursor to 5-MTHF	Final active form
Requires MTHFR?	Yes	No
Can enter CSF?	Indirectly	Directly
Behavioral reactions?	More common in some	Usually better tolerated

For whom is 5-MTHF better?

1.      Those with MTHFR mutations (esp. C677T)

2.      Those who react negatively to folinic acid

3.      Those needing direct CNS access

Folinic acid /Leucovorin is converted to 5-MTHF (active folate) through a series of enzymatic steps. First, it is converted into 5,10-methylenetetrahydrofolate, and then the enzyme MTHFR  converts it to 5-MTHF.

In people with MTHFR mutations, this final step may be slower or impaired, meaning folinic acid may not fully convert to active folate. Direct supplementation with 5-MTHF is often preferred in those with these genetic variants.

 

  

The Problem with Synthetic Folic Acid

 Status of mandatory folic acid fortification in 2019

 

In countries like the US folic acid is added to many foods such as flour, bread, pasta and rice in addition to products like breakfast cereals. This is to reduce the incidence of neural tube defects like spina bifida that occur when a fetus lacks sufficient folate in the first 28 days of life.

In Europe there is much less mandatory supplementation of folic acid due to the negative effects. In older people folic acid supplementation can mask vitamin B12 deficiency. High intake of synthetic folic acid can correct the anemia caused by B12 deficiency without correcting the neurological damage. This can lead to delayed diagnosis of B12 deficiency, increasing the risk of irreversible nerve damage, cognitive decline, and dementia in the elderly.

Folic acid is synthetic and must be converted by DHFR (slow, limited in humans).

It competes with both folinic acid and 5-MTHF for cellular entry.

High levels of unmetabolized folic acid can block folate receptors and worsen autism symptoms in some.

Some people with autism should avoid folic acid supplements and fortified foods.

 

The Dilemma: One Size Does not Fit All

While folic acid fortification benefits the general population, especially women of childbearing age, it may pose risks for other groups:

·    Elderly: Risk of masking B12 deficiency

·    Children with autism or FRAA: Risk of blocked folate receptors and behavioral regression

·    Those with MTHFR variants. They have reduced ability to activate folic acid because their ability to convert folic acid into the active form, 5-MTHF, is reduced. This can lead to unmetabolized folic acid (UMFA) in the blood, which may interfere with normal folate metabolism. It can lead to blocking the transport of natural folates into the brain.

 

Here is a study showing that folic acid impairs the transport of active folate (5-MTHF) across the blood brain barrier.

 

Folic acid inhibits 5-methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier:Clinical biochemical data from two cases

Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio.

Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

  

B12 - Forms and why it matters

To prevent the folate trap, adequate B12 is critical.

                          

Methylcobalamin        Active, supports methylation directly

Hydroxycobalamin      Longer-lasting, converted to methyl- or adeno-B12

Adenosylcobalamin     Active in mitochondria

Cyanocobalamin         Synthetic, less ideal, may not work in autism

 

Methylcobalamin or hydroxycobalamin are best for autism and CFD.

 

Can it be oral?

Yes, but high doses needed (1–5 mg daily)

Subcutaneous injections may be better absorbed in some

 

What About Betaine / TMG?

Betaine (trimethylglycine) provides methyl groups to convert homocysteine to methionine via the BHMT pathway (mostly in the liver, not brain).

Useful if:

·         Homocysteine is high

·         B12 metabolism is impaired

·         Need extra methylation support

 But, it does not bypass the folate trap in the brain — you still need functional methionine synthase and B12.

 

When Do You Need More SAMe?

SAMe (S-adenosylmethionine) is the body’s master methyl donor, essential for: 

·         Neurotransmitter synthesis

·         Myelination

·         Detox pathways

 

You may need extra SAMe if:

·         You have low methionine/SAMe

·         There is fatigue, depression, or tics

·         Homocysteine is high despite folate + B12

Oral SAMe is poorly absorbed unless enteric-coated.

Do not assume “more folate = better” without addressing B12

 

Conclusion

Whether a person with autism stands to benefit from tuning up their folate metabolism will depend on their unique situation. Many people need no intervention at all.

For others it is highly beneficial to customise an intervention plan. It would include some, or all, of the following. 

·   Reduce expose to synthetic folic acid used to fortify flour, pasta, bread, rice, breakfast cereals etc.

·   Supplement with 5-MTHF or calcium folinate / Leucovorin

·   Supplement vitamin B12, in the form of methylcobalamin or hydroxycobalamin

·    Supplement Betaine/TMG

·    Supplement SAM

     ·  Consider supplementing PQQ if positive for FRAA 

 

The only substance that is prescription-only is calcium folinate / Leucovorin. It looks like 5-MTHF is actually the better choice for most people and it is much more accessible.

We have seen that the potency of generic calcium folinate / Leucovorin is highly variable, possibly due to different excipients that are added. How reliable the OTC 5-MTHF supplements are is an open question.

If you find this subject confusing, use ChatGPT to help you. You can even upload a screenshot of your MTHFR/MTR/MTRR mutations and then get tailored advice. It is free !!  (for now)

 

If you are someone who likes lab tests, the options include: 

• Folate receptor antibodies (FRAA) – to check for blocking autoantibodies www.fratnow.com
• Serum and CSF 5-MTHF – to detect cerebral folate deficiency
• Homocysteine – elevated if methylation is impaired
• MMA (methylmalonic acid) – elevated in B12 deficiency
• Vitamin B12 – ideally with active B12
• Genetic testing – particularly MTHFR, MTR, and MTRR variants to assess methylation capacity

High MMA = likely B12 deficiency, even if serum B12 is "normal".

This is especially important in people with neurological symptoms or MTHFR-related metabolism issues.

 

Measuring serum (blood) 5-MTHF provides insight into how much active folate is circulating in the body. This helps detect:

• Folate trap from B12 deficiency (high folate, low methylation)
• Impaired folate metabolism in MTHFR or MTR/MTRR variants
• Folate absorption or transport problems, especially if CSF 5-MTHF is also tested
  It’s particularly useful when deciding whether folinic acid, 5-MTHF, or B12 supplementation is effective or needed.

CSF 5-MTHF (cerebrospinal fluid via lumbar puncture) gives a direct measure of active folate availability inside the brain. This is important because:

• Some children with autism or FRAA (folate receptor autoantibodies) have low CSF 5-MTHF even with normal blood folate. Some have FRAA and normal CSF 5-MTHF
• High serum folic acid can block transport of 5-MTHF into the brain, lowering CSF levels.
• It can help diagnose Cerebral Folate Deficiency (CFD), especially if symptoms improve with folinic acid.

Low CSF 5-MTHF with normal serum levels suggests a transport problem, not a folate intake issue.

PQQ as a Folate Transport Enhancer

A supplement called Pyrroloquinoline quinone (PQQ) may help bypass folate receptor autoantibody (FRAA) blockage by upregulating alternative folate transporters (RFC and PCFT) in the brain. This could improve delivery of both calcium folinate (leucovorin) and 5-MTHF into the brain when folate receptor alpha (FRα) is blocked.

Human data is lacking; all evidence from animal/cell studies. Some people report adverse effects (e.g. fatigue, overactivation)

For individuals with FRAA, PQQ might enhance the effectiveness of folinic acid or 5-MTHF by improving alternative transport into the brain.

“Epigenopathies” in Autism and Epigenetic Therapy in Current Use - Part 1

Today’s post is about epigenetics, a complex area of science, that has been touched upon in previous posts.

Since none of us are experts in genetics we will focus on the application of epigenetics rather than going into the excruciating details.  Skip over any parts that get too technical. Some of the interesting studies, that are of more academic interest, I will put in a later post.

Epigenetics is just one way in which gene expression (whether genes are turned on or off) can be altered.  There are other ways, which may be equally important. It is evident that epigenetics plays a role in many conditions including autism, schizophrenia, inflammation, asthma, COPD and cancer.

Even based on today’s highly superficial review, there is an immediate, practical, therapeutic prospect, worthy of investigation.  Thanks to Professor Peter Barnes in London and again those irrepressible researchers in Tehran, who were actually trialing theophylline for entirely different reasons.

You do need some basic definitions to understand what is going on in epigenetics, but in essence epigenetic changes are just like bookmarks.

DNA

DNA is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms.

The problem with DNA is that there is a lot of it.  It has to be very tightly packed since it has to fit inside every cell in your body.  In order to tightly fold up all that DNA you need Chromatin.

Chromatin

Chromatin is a complex of macromolecules found in cells, consisting of DNA, protein and RNA. The primary functions of chromatin are to:-

1) Package DNA into a smaller volume to fit in the cell

2) Reinforce the DNA macromolecule to allow mitosis

3) Prevent DNA damage

4) Control gene expression and DNA replication.

The primary protein components of chromatin are histones that compact the DNA.

Epigenetics – book marks on your DNA

Rather like you might stick post-it notes on your cookery book, or science text book, your body has various mechanism to highlight specific genes.  In effect these bookmarks turn on, or turn off that gene.

So in the jargon:-

Epigenetic changes involve non genetic changes in chromatin structure resulting in changes in gene expression

The important thing to note is that we are not talking about genetic defects, mutations, CNVs etc. which are usually what you might think about.

We all have these epigenetic markers and they are subject to change. Some of these markers become fixed and can then be inherited.  So if your ancestor lived/worked in a highly polluted place, you might have inherited some of his/her DNA tags/bookmarks, this would affect how your genes are expressed today.

The problem occurs when these markers get stuck, or are in the wrong place.  Imagine having a bookmark to remind you how long to roast your chicken and instead it takes you to the page with the recipe for pancakes.

In some inflammatory diseases, like COPD, the “good” genes are turned off and the “bad” genes have got stuck turned on.

Epigenetic change is reversible

Whereas genetic defects are irreversible, epigenetic changes are potentially reversible.  You just need to figure out how to rub them out.

Epigenetic Mechanisms

Just as you might use a variety of objects to mark pages in a book, so nature employs multiple methods to tag your DNA.

1.     DNA methylation

In this process the tag is a methyl group (CH₃); to silence the bad gene you add more tags (Stimulate methylation).  To reverse a good gene that has been silenced, remove the tags (use a DNA methyltransferase inhibitors e.g. azacytidine)

• Applicable to lung cancer & inflammation

• Problems of specificity and targeting

I could only find a current methylation epigenetic therapy for schizophrenia:-

Histone modifications, DNA methylation, and Schizophrenia

Recently, Satta et al. reported that nicotine decreases DNMT1 expression in GABAergic mouse neurons leading to decreased methylation at the GAD67 promoter and increased GAD67 protein expression. This effect was found to occur as a result of nicotinic receptor agonism. These improve cognitive functioning in schizophrenia, and may suggest in part why 80% of schizophrenia patients use tobacco. The specific nicotinic receptors that mediate this improved cognition have yet to be established. However, an alpha7-nicotine receptor agonist has been shown in small studies to improve cognition in schizophrenia subjects.

2. Histone modification 

Histones are the chief protein components of chromatin, acting as spools around which DNA winds.

There are several types of histone modification, that act as tags on your DNA:-

·        Lysine methylation

·        Arginine methylation

·        Lysine acetylation

·        Serine/Threonine/Tyrosine phosphorylation

The most studied variant is acetylation, this involves the addition or removal of acetyl groups (O=C-CH₃)

INHIBITORS

In medicine a group of drugs already exists, called Histone Deacetylase inhibitors (HDAC inhibitors, HDIs).  HDIs are a class of compounds that interfere with the function of histone deacetylase.

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are being investigated as possible treatments for cancers, parasitic and inflammatory diseases.

The prime example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. In more recent times, HDIs are being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.  Enhancement of memory formation is increased in mice given the HDIs sodium butyrate or SAHA.  While that may have relevance to Alzheimer's disease, it was shown that some cognitive deficits were restored in actual transgenic mice that have a model of Alzheimer's disease (3xTg-AD) by orally administered nicotinamide, a competitive HDI of Class III sirtuins.

Autism and HDIs 

There is research in mouse models showing that HDIs can improve autism.

Readers of this blog who are using the Supersprouts broccoli powder may not realize that the Sulforaphane produced, is a potent HDI (Histone Deacetylase Inhibitor).

In the autism world, the HDI research is still generally on mice, where social cognition is seen to improve.

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder.

Follow up study by Foley:-

Pentyl-4-yn-VPA,a histone deacetylase inhibitor, ameliorates deficits in social behavior andcognition in a rodent model of autism spectrum disorders

In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes.

ACTIVATORS

Histone modification is also implicated in inflammation.  We know that Autism is an inflammatory condition and of course we know which are the much better studied inflammatory conditions.

In terms of the brain, schizophrenia and even sometimes ADHD are better studied.

In the rest of the body arthritis, asthma and COPD are interesting.  Thanks to Peter Barnes at Imperial College, the COPD research is again leading the way.

COPD is like a severe drug resistant form of asthma.  Barnes has almost completely figured out the mechanism and how to best treat it.  One of the findings is to use a common drug called Theophylline in low doses as a HDAC activator.

The usual modes of action of Theophylline are:-

1.     competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha  and inhibits leukotriene  synthesis, and reduces inflammation and innate immunity

2.     nonselective adenosine receptor antagonist

The usual dosage involves concentration of 10-20 micrograms/mL blood.  At this level there can be some side effects.

Barnes found that at sub-therapeutic doses (<8 micrograms/mL) , Theophylline actually has a different mode of action; it behaves as a HDAC activator; because the other modes of action were no longer present, no longer were their side effects.  He also showed that as the dose increases, the HDAC activation actually fades.  Another case of less being more.

Once deacetylated, DNA is repackaged so that the promoter regions of inflammatory genes are unavailable for binding of transcription factors such as NF-κB that act to turn on inflammatory activity. It has recently been shown that the oxidative stress associated with cigarette smoke can inhibit the activity of HDAC2, thereby blocking the anti-inflammatory effects of corticosteroids.)

Theophylline is a novel form of adjunct therapy in improving the clinical response to steroids in smoking asthmatics and people with COPD (some of whom do never smoked).

By using a low dose of Theophylline, steroid medication became much more effective allowing lower doses of steroids to be used.

Below is a presentation and one of Barnes’ many papers on this subject:-

EPIGENETIC MODIFICATION FOR THE FUTURE TREATMENT OF INFLAMMATORY DISEASE

Targeting the epigenome in the treatment of asthma and chronicobstructive pulmonary disease.

Abstract

Epigenetic modification of gene expression by methylation of DNA and various post-translational modifications of histones may affect the expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases activates inflammatory genes, whereas histone deacetylation results in inflammatory gene repression. Corticosteroids exert their anti-inflammatory effects partly by inducing acetylation of anti-inflammatory genes, but mainly by recruiting histone deacetylase-2 (HDAC2) to activated inflammatory genes. HDAC2 deacetylates acetylated glucocorticoid receptors so that they can suppress activated inflammatory genes in asthma. In chronic obstructive pulmonary disease (COPD), there is resistance to the anti-inflammatory actions of corticosteroids, which is explained by reduced activity and expression of HDAC2. This can be reversed by a plasmid vector, which restores HDAC2 levels, but may also be achieved by low concentrations of theophylline. Oxidative stress causes corticosteroid resistance by reducing HDAC2 activity and expression by activation of phosphoinositide-3-kinase-delta, resulting in HDAC2 phosphorylation via a cascade of kinases. Theophylline reverses corticosteroid resistance by directly inhibiting oxidant-activated PI3Kdelta and is mimicked by PI3Kdelta knockout or by selective inhibitors. Other treatments may also interact in this pathway, making it possible to reverse corticosteroid resistance in patients with COPD, as well as in smokers with asthma and some patients with severe asthma in whom similar mechanisms operate. Other histone modifications, including methylation, tyrosine nitration, and ubiquitination may also affect histone function and inflammatory gene expression, and better understanding of these epigenetic pathways could led to novel anti-inflammatory therapies, particularly in corticosteroid-resistant inflammation.

COPD and Autism

COPD is not autism, but there are some similarities.  Both conditions are associated with chronic oxidative stress and inflammation.

The antioxidant NAC is effective in both conditions.

The Nrf2 activator Sulforaphane (from broccoli) is being trialed for both conditions and is shown effective in much autism.

Inhaled steroids keep people with COPD alive, and oral steroids are beneficial to many people with autism.  Their use in autism is severely limited by side effects of long term oral steroid use.

Some HDI drugs improve autism and some HDI drugs improve COPD.

It would seem that the Epigenopathies of autism and COPD may well overlap.  Could the COPD epigenetic therapy be effective in some autism?

  

Theophylline for Neurological Disorders?

You might have realized that epigenetic therapy should be highly focused, since some genes need to be switched on while others need to be switch off.

Nonetheless that natural question to ask is what is the effect of Theophylline on neurological disorders like autism.

I cannot answer that question; but we can see the effect on ADHD (autism-lite).

It should be noted that the below trial was nothing related to epigenetics and the dosage was the more typical high dosage.  The histone modifying (epigenetic) effect would have been greater at a slightly lower dosage.

At these doses Theophylline would act as a mild stimulant;  note that Theophylline is very closely related to caffeine.  Somewhat counter-intuitively, psychiatrists treat hyperactive people with stimulants.

Efficacy of theophylline compared to methylphenidate for the treatment of attention-deficit hyperactivity disorder in children and adolescents: a pilot double-blind randomizedtrial

A total of 32 children with ADHD as defined by DSM IV were randomized

to theophylline and methylphenidate dosed on an age and weight-adjusted basis at 4 mg/kg/day (under 12 years) and 3 mg/kg/day theophylline

(over 12 years) (group 1) and 1 mg/kg/day methylphenidate

(group 2) for a 6-week double-blind and randomized clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist, at baseline and at 14, 28 and 42 days after start of the medication.

The results suggest that theophylline may be a useful for the treatment of ADHD. In addition, a tolerable side-effect profile is one of the advantages of theophylline in the treatment of ADHD.

In autism it would be nice if somebody made a trial with 2mg/kg

Let us digress a little and see just what is Theophylline:-

Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.

Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L, which is significantly less than a therapeutic dose.

As a member of the xanthine family, it bears structural and pharmacological similarity to theobromine and caffeine

Derivatives of xanthine (known collectively as xanthines) are a group of alkaloids commonly used for their effects as mild stimulants and as bronchodilators, notably in the treatment of asthma symptoms. In contrast to other, more potent stimulants like sympathomimetic amines, xanthines mainly act to oppose the actions of the sleepiness-inducing adenosine, and increase alertness in the central nervous system. They also stimulate the respiratory centre, and are used for treatment of infantile apnea. Due to widespread effects, the therapeutic range of xanthines is narrow, making them merely a second-line asthma treatment. The therapeutic level is 10-20 micrograms/mL blood; signs of toxicity include tremor, nausea, nervousness, and tachycardia/arrhythmia.

Theophylline degrades to caffeine.

Inhibitor or Activator of HDAC ?

You may be wondering why we would want an HDAC activator for autism, if we know that Sulforaphane (broccoli) does just the opposite; it is an inhibitor.  The reason is that we have made a few simplifications in the science; there are many types of HDAC, and you might need an inhibitor of one type of HDAC and an activator of another.  Worse still, you might need something on one part of your body and something quite different in another part.

The HDACs can be divided into 3 classes based on their structure and sequence homology: class I consists of HDACs 1, 2, 3, 8, and 11; class II includes HDACs 4, 5, 6, 7, 9, and 10; and class III enzymes are HDACs originally found in yeast and include Sir2-related proteins. Increased HDAC activity and expression are common in many cancers and can result in repression of transcription that results in a deregulation of differentiation, cell cycle, and apoptotic mechanisms. Moreover, tumor suppressor genes, such as p21 appear to be targets of HDACs and are “turned off” by deacetylation. Prostate cancer cells also exhibit aberrant acetylation patterns. The use of class I and class II HDAC inhibitors in cancer chemoprevention and therapy has gained substantial interest.

   

Epigenopathies

When the epigenetic bookmarks appear in the wrong place, trouble will follow.  Genes that should be “off” are turned on and vice versa.

These events have recently been a new name “Epigenopathies”

Just as we can look at many dysfunctions in autism as Channelopathies; those dysfunctions in ion channels and ion transporters, we will be able to consider others as Epigenopathies.

Who first came up with this terminology is not certain, but it might be a clever Frenchman called Mark Millan who works at the Unit for Research and Discovery in Neuroscience, Institut de Recherches Servier, beside the river Seine.

The good news is that here is a very clever neuroscientist with an interest in autism, but not obsessed by it.

France generally has quite an old fashioned view of autism, you will not find much in the way of ABA in France, and the State is certainly not going to be the one paying for it.

An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy

Millan nicely summarizes the implications:-

Neurodevelopmental Disorders (NDDs) are accompanied by aberrant "epigenetic" regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatin-modelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy …

In the next post on epigenetics we will look at the research that is specific to  neurodevelopmental disorders.  It is interesting, but does not really have any obvious therapeutic implications.  One point I will highlight in this current post is the following:-

ASD is not associated with systemic differences in global DNA methylation

What this means is that, as far as one key type of epigenetics is concerned, autism is not characterized by too many or too few epigenetic tags; the problem is that they are not all in the right place.  Many alternative therapies in autism are rather simplistic.  It is not a case of too much methylation, or too little.

In the twin study the ASD Twin and his unaffected sibling has almost the same amount of total DNA methylation.