Reassessing Cognitive Impairment in Autism – Improving the Prognosis

When Monty, now aged 11 with ASD, was diagnosed aged three and a half we were told that he had autism and “this may be indicative of the presence of an associated learning disability, but it is impossible at this stage to give a prognosis as to his future difficulties” and also “he is not yet able to take part in formal assessments of his cognitive ability. When his skills and ability to share interests with adults and to follow direction/instruction develop, it will be possible to formally assess his cognitive skills using standard measures.”

Off the record, we were also told that he might develop epilepsy.

We never measured his IQ and he has never had a seizure.

With hindsight, it is interesting what they said about it being pointless to try and measure his IQ.  Apparently it is not uncommon to do just that.

Improving Cognitive Function

This post is about cognitive improvement, so do not be put off by the introduction to MR/ID.  Several regular readers who are using some of the suggested drugs discussed in this blog are now also commenting on the resulting cognitive improvement, so it really is not just a case of N=1.

Nobody here is measuring the change in their child’s IQ, so these remain anecdotes.

To start on a happy note

Monty, aged 11 and diagnosed with classic autism, has been learning the piano for three years.  At the start he was not very cooperative with his teacher and after a few months the lessons stopped.  

27 months ago he started on bumetanide, the first part of his autism Polypill.  After years of ABA, slow but solid development appeared to have reached a plateau; but then he began to accelerate.  We restarted piano lessons again, with a new teacher.  Having added Atorvastatin, from the very next day he began to practice daily, playing without his teacher.  He has had two 40 minutes lessons most weeks since.  Two years later this is the result:-

 Click the image to play, turn up the volume (video may not work on Apples)

  

  

So there is no doubt that Monty got smarter.  When I heard him playing this piece, I thought it was the piano teacher, but she was recording Monty on her phone.

Big brother also did not believe little brother was playing this, until he saw the full video (with moving fingers).

Reading, writing, and numeracy have all improved and are now at a similar level to those of many of his NT classmates (who are 2 to 3 years younger than him).  Rather unexpectedly, he was recently the only one in class who understood how to multiply fractions; this was never taught at home.   

Prior to starting the Polypill drugs, I had spent three years, on and off, trying to teach Monty prepositions, without much progress.  This is almost always a difficult area for those with classic autism.  In the end he figured it all out by himself, with a little help from Bumetanide.

Recently yet another cognitive step forward seems to have have occurred, which appears to be the result of PAK 1 inhibiting propolis and/or the tangeretin flavonoid.  Monty's assistant in school was today proudly showing me his latest school test result, "73% and it was all his own work".  She thinks it is the tangeretin.

In earlier years school was for “socialization”, not learning.  This is fine as long as the learning takes place at home, otherwise inclusion means no education.

Cognitive Function, IQ, MR/ID

I prefer to talk about cognitive function, and its improvement or enhancement.  Drugs that achieve this are usually called Nootropic.

I think that many people remain skeptical about Nootropics.

Psychiatrists, Pediatricians and Psychologists prefer to think about IQ, MR/ID.

People affected do not like the old term of Mental Retardation (MR) and so quite recently, in English speaking countries, it was replaced by the term Intellectual Disability (ID).  The World Health Organization still use the old term, as does almost everybody else.

Somebody is diagnosed with MR or ID if their IQ is below 70.  In a typical group of 100 people, two people (2.2%) would be expected to fall into that category.  The average IQ (mean, median and mode) is 100.

In theory as you progress through childhood and into adulthood your IQ is expected to stay the same.  So the tests used adjust for your age.  There are special non-verbal tests.

If you acquire new skills at a lower rate than typical, your IQ would appear to fall over time.  This does not mean that you have lost skills just that you are acquiring new skills at a slower rate than your peers.  This explains why parents of kids with ASD, who do have their IQ tested, often find their score goes down as they get older.

Measuring IQ in Autism

I think it is generally a bad idea to measure IQ in people with autism.

There is anecdotal evidence to show that the results are often not valid, because the test is based on the assumption of compliance and that the child is actually doing his/her best.  Not surprisingly, the experts have found that children undergoing an ABA program improve their measured IQ by 10s.  After a few months of ABA the previously unfocused child has been trained to sit down, sit still, pay attention and work.  Of course they then get a higher score, but are they now more intelligent?

One reason put forward for not measuring IQ, is that while people will go a long way to help a child with autism to learn, once you add a diagnosis of MR/ID, some people will try much less hard.

Nonetheless people do measure IQ in autism and it is worth a quick look at what is known.

Some people are saying that 50% of people with autism have MR/ID.  I always found that odd, and what exactly do they mean by autism?

Using the previous US DSM definitions, Asperger’s was a part of the autistic spectrum but had the precondition that there was no MR/ID and no language delay.  Then you had the middle group with the odd name of PDD-NOS    (Pervasive Developmental Disorder Not Otherwise Specified).  This groups the people with more issues than Asperger’s, but without many of the problems experienced by those diagnosed with Autism.

So in the old US system there were 3 main categories, plus 2 minor ones:-

1.     Asperger’s

2.     PDD-NOS

3.     Autism

4.     Retts Syndrome

5.     Childhood Disintegrative Disorder (CDD)

Very few people have Retts or CDD.

The Autistic Spectrum was, in effect, also called PDD (Pervasive Developmental Disorder) just to confuse people a little more.  PDD = ASD = the above five conditions.

The latest version DSM5 went several steps backwards.  Everybody affected in the US is now just ASD, all five categories were merged.  

Hopefully nobody else in the world will pay any attention.

Unfortunately being Psychiatrists, they again have to muddy the water and all the future data/statistics.  A portion of people formerly diagnosed with PDD-NOS, will now get diagnosed with SCD (Social Communication Disorder) which is set outside the new definition of ASD.

“Congratulations you are off the Spectrum” 

I really do wonder about the IQ of these Psychiatrists.

Reliable Data on ASD

I do like to have some reliable data.  The quality of data in the field of autism is usually very poor and incompatible (i.e. rubbish).  Most data, like that from the CDC in the US, is unreliable.  It seems that richer “Ethnic European” parents push to get an autism diagnosis much harder than poorer “Hispanic” and “African American” parents.  Perhaps hard to believe as an outsider, but in the US poverty equals low diagnosis of autism and wealth equals high diagnosis.  Incidence does not equal diagnosis.  CDC data is just who got diagnosed; in the US many poorer people do not get diagnosed.  If you live in a country with free socialized healthcare, as in Europe, this will look strange.

I have chosen a highly regarded, and very highly cited, Canadian source for my data.

Éric Fombonne  is a French psychiatrist and epidemiologist based at McGill University in Montreal.  He co-authored a pair of studies in 2001 and 2005 with Suniti Chakrabarti, that examined the entire preschool and early school population of one large area of the United Kingdom (falling under the South Staffordshire Health Authority).

There is a stable population of indigenous British people with a small (1.4%), mostly Asian, immigrant population. The total population living in the area was 320 000 people.

The studies are:-

Pervasive Developmental Disorders in Preschool Children, 2001

Pervasive Developmental Disorders in Preschool Children: Confirmation of High Prevalence, 2005

All children from 2.5 to 6.5 years old were screened, a total of 15,500 children in total 97 children (79.4% male)  were found to have a PDD (i.e. be somewhere on the autistic spectrum)

Of the 97 children, 29 (29.9%) had no functional use of language defined as the daily spontaneous use of 3-word phrases. The proportion of children without functional language was however strongly associated with diagnostic subtype (AD, 69.2%; Asperger syndrome, 0%; PDD-NOS, 16.1%).

Of the 97 children, 37 children underwent Merrill-Palmer testing and 56, Wechsler Preschool and Primary Scale of Intelligence testing. Four children could not be tested for practical reasons. Overall, 24 (25.8%) of 93 children had some degree of mental retardation. The 2 children with childhood disintegrative disorder and Retts syndrome scored in the moderate range of mental retardation.

Side-note about shoddy research

To show those of you still unconvinced that published, and moderately highly cited, autism research can be rubbish, the authoritative sounding paper written by a Professor of Psychology below also reviewed the above research data.

Are the Majority of Children With Autism Mentally Retarded? A Systematic Evaluation of the Data

The author commented:-

“Recent epidemiological surveys have shown that the prevalence rates of MR in children with autism is between 40% and 55% (e.g., Chakrabarti & Fombonne, 2001), much lower than the typical rates cited in the literature.”

The Chakrabarti & Fombonne 2001 paper clearly shows 69% of people with the narrow diagnosis of “autism” had MR whereas 25.8% of those with the broader diagnosis of ASD/PDD.

More than 100 other papers now cite the author’s incorrect readings of the original research.

I do not know what IQ you need to have to be a Professor of Psychology, but it clearly needs to be increased.

Back to the Fombonne studies

Four years later they repeated the same study on the next cohort of English school children:-

The rate of mental retardation in the autistic disorder group was 66.7%, compared to 12.0% in the group with pervasive developmental disorder not otherwise specified and 0.0% in the Asperger's disorder group

So I will take the average of the two studies

            Autism                       68% with MR/ID

            PD-NOS                     10% with MR/ID

            Asperger’s                    0% with MR/ID

What surprised me was the breakdown of the children by PDD.  Most kids (>50%) were PD-NOS, I did not expect that.

  Autism                        31%

            PD-NOS                     52%

            Asperger’s                  16%

            CDD/Retts                    1%

So the percentage all PDD (i.e. all ASD) with MR was 27%

Combining this as a graphic:-  

  

So now when people tell me that 50% of kids with autism have MR/ID, at least I know the likely reality.  It is either more, or less, depending on what you mean by “autism”; but is not 50%.

Conclusion

Most people think you cannot change your IQ.

The reality is that testing a young child with severer ASD is highly likely to underestimate their IQ, since the test assumes that the child will comply with the tester.  Most young children with autism do not comply with their parents, let alone an IQ tester.

ABA will improve compliance and hence improve an IQ test result.

Long term ABA use will, in many cases, gradually improve the child’s ability to learn and hence boost cognitive function and by implication an IQ test result.  You will find references to people saying ABA raised their kids IQ score by one or two dozen.

Correcting the biological dysfunctions underlying autism undermines the whole shaky DSM system.

PDD-NOS is, in effect, milder classic autism without the stereotypy .

Take some N-acetyl cysteine pills, you lower oxidative stress and you can stop the stereotypy.  So then your “expert” diagnosis would change from classic autism to PDD-NOS?

Take a few more pills and instead being in the 68%, with an IQ of less than 70, you can move up to 85 and, who knows, maybe much higher.

But it has to be said that the concept of IQ is something many people think they understand.

If one day, I were to make a clinical trial of my autism Polypill, I would definitely include a before and after measurement of IQ, alongside all the usual behavioral measures that most people would not understand.

And then …

“Wonder drug rescues people with autism from mental retardation”

In the meantime, we can continue correcting the remaining biological dysfunctions underlying autism and thus improving cognitive function.

Note the rocket, for those with classic autism doing just this and changing their prognosis.

“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.