Peter Hypothesis Regarding the Cause of Autism

Peter Hypothesis Regarding the Cause of Autism,

 The Predisposition of some Children towards it and Implications for Treatment

Autism is a spectrum of behaviours and disorders that result from damage and subsequent malformation of the developing cerebellum.  The damage in classic autism occurs in utero, whereas in the case of regressive autism, there is a second oxidative shock that occurs around a key point in brain development, triggering the onset of autism.  The cause of the cerebral damage is an oxidative shock from one or more of a variety of possibilities, not limited to, maternal stress and infection during pregnancy and toxins such as mercury crossing the blood brain barrier (BBB).  Individuals with autism, and many of their close relatives, have a predisposition to the condition, due to an inherited over-reactive immune system.

The immune system may have become over-reactive to infection partly due to a lack of the on-going attacks, for which it has evolved.  This may be another case for the well documented “Hygiene Hypothesis”, in which a little bit of dirt, rather than an apple a day, keeps the doctor away.

The result is that while in modern society the likelihood of an oxidative shock has increased, the immune system has become so relaxed, due to a sterile environment, that it becomes over-activated when confronted by a severe oxidative shock.  A cytokine storm then rages and the resulting severe neuroinflammation and oxidative damage causes permanent brain damage.  The brain tries to repair itself, but as it continues to grow, it deforms.  A milder neuroinflammation typically continues throughout life and this aggravates the observed autistic behaviours.

In very rare individuals with mild autism, a “recovery” can be observed.  This is most likely the result of successful behavioural therapy of some kind and the on-going neuroinflammation subsiding, for reasons unknown.    In cases where brain damage is substantial, as is generally reported to be the case in classic autism, “recovery” is somewhat fanciful; optimal outcome is the realistic goal of therapy.

A secondary inherited/genetic factor may eventually be proved to be the permeability of the BBB (blood brain barrier).  This would play a role in both the initial oxidative shock reaching the cerebellum and in the following cytokine storm.  Cytokine molecules are particularly large and those released from outside the brain should struggle to enter it.

Vaccination damage is just one of many possible causes of oxidative shock that could trigger regressive autism; it cannot be the cause of classic early onset autism.  Milder cases of autism, and indeed ADHD, are caused by milder cerebral damage and milder on-going neuroinflammation.

Implications of the Hypothesis

1.       At risk mothers should avoid possible oxidative attack

The overactive immune system is measurable (the simplest and cheapest test is the C-reactive protein test; but cytokine testing would be conclusive) and this knowledge could be used to reduce further cases of autism, by identifying at risk mothers.  The threat of oxidative damage could be reduced by de-sensitizing the immune system during pregnancy (risky, but possible), or perhaps better, by meticulously avoiding oxidative damage during pregnancy, in those in the high risk group.  Most likely, the lack of a “successful” oxidative attack during pregnancy would reduce the likelihood of a secondary shock later on that could tip the balance towards regressive autism.

2.       Reset the immune system

Increased exposure to pets, mild intestinal parasites and dirt in general, would reverse the modern trend towards an unprepared and then over-reactive immune system.

This would have the secondary benefit of reducing the prevalence of a wide range of 21^st century conditions including asthma, food allergies, eczema and even gastrointestinal sensitivity and arthritis.  These are all linked to neuroinflammation and/or an overactive immune system.

3.       Therapy & Treatment

Once the brain damage has occurred we are left with the challenge of how best to manage it and achieve “optimal outcome”.  Now that we have a plausible hypothesis, this will greatly help us (me) finding effective therapies, some of which will be novel.

Therapy needs to take advantage of neuroplasticity, particularly in the very early years, to maximize the potential of the damaged brain.  Intensive early behavioural intervention has been proved to be effective and neurological explanation is that the brain’s own plasticity is being exploited to develop new pathways within it.  In other words, start an ABA programme.

Targets for pharmacological intervention:- 

•     Reduce the on-going neuroinflammation / oxidative stress   

•    Treat secondary issues arising from the malformation of the brain

            ·         Ion channel and neurotransmitter (GABA, glutamate etc.)  malfunction

            ·         Hippocampus malfunction, leading to a cascade of hormone errors (CRH, 
                      TRH, AVP, Oxytocin, Cortisol etc.)

Tapas Time - Statins Part 4

Today’s post is bite-sized, as opposed to the occasional shock to the digestive system that I serve up.

You may have been wondering how come a few American researchers have managed to keep a lid on the neuroprotective power of statins; or even that Peter and Monty are making it all up.

Well, for a change from the usual Anglo-Saxon research, today I present you a paper from Granada in Spain.

 

Statins as neuroprotectants: acomparative in vitro study of lipophilicity, blood-brain-barrier penetration,lowering of brain cholesterol, and decrease of neuron cell death.

They study which statin should be the most neuroprotective.  Their choice is Simvastatin, which is also known as Zocor.  In the UK, Zocor is now an over the counter (OTC) drug, meaning no prescription required.


The previous posts on Statins are here:-

Statins Part 1
Statins Part 2
Statins Part 3

 


 

Finished switching ears off!

I had another surprise a couple of days ago; I was standing with Monty outside the entrance to a very noisy ice-cream bar.  There were babies crying, a lady begging rather aggressively and an orderly queue to enter the shop.  Finally, the noise abated and I heard Monty say:-

“Finished switching ears off!”

Is there more to this than the emergence of spontaneous and appropriate speech?

Selective Hearing, Elective hearing and (S)elective mutism

I once did a course called Noise Control as part of my Engineering degree.  I recall that at the start of the course, the Professor confessed his desire to be able to turn his hearing on and off; clearly there were some noises he would prefer not to hear.

If you have children you will have discovered “selective hearing”; whenever you want them to come for a meal, they just do not seem to hear you.  If you offer ice cream though, they will hear the first time you call.

There is also the relatively common case of selective mutism, in people with anxiety disorders, they lose the ability to speak in stressful situations.

I think that many non-verbal autistic children probably have elective mutism; they just decide not to speak, or perhaps there is a barrier inside them that they just cannot get over.

Many people with autistic children initially go through a phase of thinking their child is deaf.  I know a child who lost his hearing and then a couple of years later regained it.  I met him just after his hearing was restored and I was convinced he had autism; he had all the characteristics.

Maybe some autistic children have elective deafness and/or elective mutism and perhaps a little pharmacological intervention could actually help them overcome this barrier?

For Monty, thankfully, these problems are in the past.  For him ABA and PECS did the job.

 

 

 

By Jupiter! - Satins Part 3

Makes more sense if you have read:-
Statins Part 1
Statins Part 2

 

For most of you Jupiter is the fifth planet from the Sun, or maybe the largest planet in the Solar System.  To a young boy like Monty, Jupiter is a red fire engine, normally driven by Fireman Sam.

If you are a cardiologist you will have heard of the JUPITER trial. (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial)

It was a huge study looking into the possible benefits of giving statins to older people with low cholesterol.  All the 17,802 subjects had elevated levels of high-sensitivity C-reactive protein (CRP) levels, which is a marker for cardiac (and neuro) inflammation.  Half were given 20mg of a statin and the other half had a placebo.  The study measured their cholesterol, CRP levels and whether they later had a cardiac incident.  The group with the statin lowered their already okay LDL and triglycerides level and also lowered their CRP level by a thumping 37%.

At the time of study termination (median follow up, 1.9 years; maximal follow-up, 5.0 years), 142 first major cardiovascular events had occurred in the statin group, as compared with 251 in the placebo group.

This was interpreted by the authors as evidence that even older people without elevated cholesterol could benefit from statins to reduce their risk of cardiovascular events.

 

 

JUPITER and autism

What JUPITER tells me is that statins were highly effective at reducing inflammation as measured by CRP.

 

Autism and CRP

Now we just need some data on the level of CRP in Autism.  Thanks to those nice people in Iran we have a study called: - The complementary role of high sensitivity C-reactive protein in the diagnosis and severity assessment of autism.

 They concluded:-

► Inflammatory process can play key role in the pathophysiology of autism.
► Higher levels of hs-CRP are detected in autistic children.

► A correlation exists between hs-CRP level and autism severity.

► Hs-CRP can be considered a complementary diagnostic test for autism.
►These findings affirm the role of inflammation in autism.

I guess because Iran is public enemy number two, nobody took much note of this study, except Paul Whiteley of course.

 
 

Autism & Statins

So it looks pretty likely that statins will reduce CRP in autistic subjects and if statins can do this, they will reduce both the neuroinflammation and, by inference, the severity of autistic behaviours.

 

Peter Research

While in the Astra Zeneca-funded JUPITER study there were 17,802 subjects and five years of research; here in the Peter Research Institute we have one subject and one week of research.

As with my Bumetanide research, I am shocked by the almost immediate effect of the drug.  In terms of lowering cholesterol, statins are supposed to take two weeks to reach full effect.  In terms of reducing neuroinflammation the effect appears to be much faster – very encouraging but, to be honest, quite unexpected.  

Back to Cholesterol & Autism

The important thing is that statins appear to reduce autistic behaviours, at least in my subject; it would however also be nice to fully understand why.  The research shows the presence of dyslipidemia (abnormal amounts of lipids) in boys with autism.

 

Alterations in lipid profile of autistic boys: a case control study

The findings were: - LDL normal, HDL low, Triglycerides high, Total cholesterol normal.  The current benchmark used is that Total Cholesterol divided by HDL should be less than 4.5.  With low HDL and high triglycerides, this could put many autistic subjects in the zone of elevated risk.

Also, be aware of the very rare condition called Smith-Lemli-Opitz Syndrome (SLOS), caused by low levels of cholesterol;  it is explained in this open-access paper:-

Abnormalities of Cholesterol Metabolism in Autism Spectrum Disorders

In one of the studies I read that CRP always drops before the fall in cholesterol.  This would imply that in the case of ASD, the cholesterol issue is just a consequence; it is the precursors that actually matter.  At least to me, that makes a lot of sense.



In case you missed the prequels:

Statins Part 1
Statins Part 2


and now there is Part 4  http://epiphanyasd.blogspot.com/2013/05/tapas-time-statins-part-4.html



 

More Music!

I have been helping 12 year old Ted with his algebra, or perhaps, more accurately stated, I have been doing Ted’s homework while he goes “A-ha”.

 
With 9 year Monty, I have been doing algebra of a different kind, this time I get a bit more than an “A-ha” in return.  We have now established the following completely unscientific statement to be true:-

1mg Bumetanide + 3g NAC + 10mg Atorvastatin  =  More Music + More Parties  + More Hugs

Monty has always liked music, but he only wanted to play the piano during a lesson and at first, even during the lessons, he only wanted to escape.  This year he has moved from playing with two fingers to playing with all fingers of both hands. He now plays the piano spontaneously all by himself and the little colour stickers came off the piano keys yesterday, without a comment.

More parties, because if you behave nicely in class, you get invited to parties and even though they are very noisy and full of strangers, you stay calm and under self-control, so nothing can get in the way of having fun and you no longer have to leave early.

More hugs, because now it is easy to express yourself and with tantrums and obsessive behaviour gone, it is possible for spontaneous emotional behaviour to emerge.

 

Disorders leading to Autistic-like Symptoms

When you read the research it eventually becomes clear that "autism" is just a bunch of symptoms, rather than a single disease. So autism, as such, has no cure. A specific cause of autistic symptoms in a particular person, may indeed have a remedy, but most sadly do not.

Many causes of autistic symptoms though will have therapies that can reduce and help manage the symptoms. Combine this with the neuroplasticity of the brain and behavioural therapies and a clear way forward emerges.

You will see below that oxidative damage is the main culprit. In the more rare disorders, a genetic mutation is invariably the cause, but even a mosquito can be guilty.

This blog is focused at finding effective therapies for Classic Autism.  In spite of what could be reasonably expected, this is proving very fruitful and genuinely effective therapies actually do exist.

Notes

Oxidative Brain Injury					Comments
	Classic Autism				In utero malformation of cerebellum following oxidative shock.
					Ongoing neuroinflammation. Mixed outcome.
	Regressive Autism				As for classic autism, but with a shock event that triggers inceased inflammation and prompts regression.  Mixed outcome.
	Asperger's				Mild case of classic autism. Prognosis if usually good.
	ADHD				Mild case of classic autism. Prognosis is good.
Neurological Complication of Parasitic Disease
	Cerebral Malaria				Shock inflammation of the cerebellum causes massive damage.
					Treatable if detected early
Unknown
	Childhood disintegrative disorder				Cause unknown, causes complete loss of all skills
					onset between 2 and 10 years old
Genetic mutations/malfunctions
	tuberous sclerosis complex (TSC)				Multi organ genetic disorder
					Rapamycin is used to shrink the tumors.
	Rett Syndrome				Subjects are mainly girls, male fetuses rarely survive.
					Prognosis is often poor.
	Fragile X				Neurodegeneration increases in middle age.
	Phenylketonuria				Treatable if detected early
	Adenylosuccinate lyase deficiency				Viewed as untreatable
	Guanidinoacetate Methyltransferase Deficiency (GAMT)
					Creatine deficiency syndromes
	Arginine: Glycine Amidinotransferase Deficiency (AGAT)				Treatment of oral creatine supplementation can improve
					symptoms, if initiated early, in GAMT and AGAT patients.
					Treatment for CRTR patients, oral creatine supplementation’s
	Creatine Transporter Deficiency (CRTR)				therapeutic effects are limited.
	Smith–Lemli–Opitz Syndrome				inability to produce or synthesize cholesterol due to
					mutation of the DHCR7 gene. Treatable with cholesterol
	Biotinidase deficiency				treatable with biotin
	Infantile Neuronal Ceroid Lipofuscinoses				very rare and fatal
	Sanfilippo syndrome				possible treatment with flavonoid GENISTEIN
	Histidinemia				Rare generally, except in Japan
	Succinic semialdehyde dehydrogenase deficiency (SSADHD)				Defect in ALDH5A1 gene, causes defect in GABA pathway
	Dihydropyrimidine dehydrogenase deficiency (DPD deficiency)				Genetic mutation of DPYD gene