Just How Rare are the Known Genetic Causes of Autism?

"Gene" by Courtesy: National Human Genome Research

As we have seen so far in this blog, a great deal is already known about various causes of autism.  It is claimed that only 5-8% of cases are caused by the mutation of a single gene, as in Fragile-X and Retts syndrome.

When I was researching the new drug Arbaclofen, that was being trialed as a therapy for Fragile-X, and autism in general, I was surprised to learn that within Fragile-X there is a wide spectrum.  Some people are very severely affected, both mentally and physically and others are quite mildly affected.

It turns out the same spectrum effect applies to other known genetic causes of autism, including Neurofibromatosis, Tuberous Sclerosis Complex (TSC) and Timothy Syndrome.

We also have the case of Anderson-Tawil syndrome, which was drawn to my attention by a reader of this blog.  This, supposedly extremely rare, syndrome appears to run in families with a high incidence of autism.  Some of the symptoms do overlap with autism.  As with Fragile X, there can be visible physical differences.  The reader informed us that sufferers are often initially misdiagnosed with Fibromyalgia.  This blog did already look at Fibromyalgia, which also seems to run in families where autism is present and particularly affects females.  Doctors tend to diagnose Fibromyalgia when they cannot identify any other cause of the patient’s reported aches and pains, and they want to put an end to the matter.

Further Observations

There is a general perception that people with autism “look different” and I do not mean just act differently, or walk funny.

Indeed, one of the things those rare doctors specialized in autism look for, is a big head (Macrocephaly) as an indicator of possible autism and possible MR.

When Monty, aged 11 with ASD, went to visit the parents of his afternoon assistant, who is a special educator in training, there was an unexpected, but interesting comment:-  “he looks normal”.

I was recently discussing my blog with a relative who works for the UK National Health Service (NHS).  I was asking why children diagnosed with autism were not routinely screened for known genetic causes, like Retts, Fragile-X etc.  I suggested that perhaps if more people were screened, we would find that these “rare” conditions might be more common that we think.

What the Science Tells Us

Since this blog is supposed to be based on science, let’s go see what those clever scientists can tell us.

It pretty much fits in with what I am saying.  They have a new term, “Mendelian diseases” – diseases caused by a single gene.

The Broad Institute (Ivy League types) has found that milder forms of otherwise severe “Mendelian” diseases can be found in autism.  Only a partially-disabling mutation has occurred in those genes.

  

New research investigates inherited causes of autism

One study, led by Mark Daly, a senior associate member of the Broad and co-director of its Medical and Population Genetics program, found that approximately 5% of autism cases could be linked to inherited, recessive mutations that completely disrupt gene function. A second study, led by Broad associate member Christopher A. Walsh, found that autism risk could also be attributed to inherited mutations that resulted in only a partial loss of gene function. Moreover, Walsh’s team found that many of these partially-disabling mutations occurred in genes in which a complete disruption of the gene has been known to cause more severe or even fatal inherited diseases. This suggests that milder forms of some severe, Mendelian diseases – diseases caused by a single gene – may present as autism spectrum disorders.

Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

Tuberous Sclerosis Complex (TSC), as an example

An example of a known genetic mutation leading to autism is Tuberous Sclerosis Complex (TSC).

TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

The graphic below shows the symptoms of TSC and the age at which they tend to present themselves.

  

Source: Wikipedia

The symptom that caught my attention was “Facial angiofibromas”, since these little marks on the face can be easily noticed, if you look at people when you talk to them.

These marks tend to make a butterfly shaped pattern on the face and vary from highly noticeable to nearly invisible,

Here is an example from Wikipedia:-

In the case of Fragile X, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, and low muscle tone.

Why does this matter?

If you are a parent, don’t go worrying about a new syndrome to deal with.

As time goes by, certain types of autism will eventually be matched to effective drug therapies.  So it makes sense to know who is mildly affected by these single-gene disorders, as well as those with the full-blown version, only some of whom have already been diagnosed.

So, if you are mildly TSC, you would follow the TSC research and if you have low muscle tone and a long face, then the forthcoming Fragile X therapies could be relevant.

Since genetic testing is extremely uncommon, the logical way to go is to look at the outward symptoms of these conditions, starting with the very obvious ones.

I do not know many people with autism, but even I can notice some tell-tale physical features, once you know what to look for. As these features are inherited, the physical manifestation may be more visible in siblings, even though the behavioural symptoms are absent.

So those single gene disorders may not be as rare as we thought.

The Cost of Approving an Old Generic Drug as a New Autism Drug

Some readers of this blog are commenting how hard it is to obtain prescription only drugs for “off-label” use in autism.

None of the drugs mentioned in this blog are actually approved for use in autism.  There is some science showing that they might be effective, but there is no mention of autism on the “label” approved by the regulator.

This means that your doctor will not know how to prescribe it and your insurer will not want to pay for it.

So how do I access these drugs?

This is a frequent question.  In theory you do not need to wait for the drug to be approved, you can apply to the national drug agency in your home country for permission to use a drug based on the experimental use that showed it might be effective.

Better still, in many countries like the USA, doctors are not banned from prescribing “off-label” drugs.  If the doctor follows the new research, he is permitted to apply it on his own patients.  If he does it recklessly, he might eventually lose his license.

In cancer therapy, many drugs are used off-label.

Why not just approve a new use for an old drug?

This would seem an obvious question and this is what is being done with bumetanide, one of drugs described in this blog.

The problem is the cost and the time taken: EUR 4 million  (USD 5 million) and four years.

As you can see below, in the case of Bumetanide, the French Government will contribute EUR 1 million and it appears the Simons Foundation another EUR 1.5 million.

RECHERCHES PARTENARIALES ET INNOVATION BIOMEDICALE (RPIB) 2012 : projet CURE AUTISM

Curing autism with the diuretic bumetanide 

Since Bumetanide is available today as a cheap generic drug, they cannot really ever get their money back.  Only if they modified the molecule slightly, patented it, and got that new drug approved could they recoup their USD 5 million, which would then be even more, since they would have even higher costs.

The last I heard, Bumetanide will only be approved for autism in Europe, not the USA, due to cost issues.

So with this kind of financial logic, you can see why off-label uses of old generic drugs are likely to stay off-label.  

Best find yourself an off-label doctor.

NAC for Long Term Use in Autism

One of the post popular subjects on this blog is the use of NAC (N-acetyl cysteine) for autism. There are numerous earlier posts explaining how and why it works.

Just look up NAC in the index by subject; there are 19 posts, for those with plenty of time. (the labels function just gives the recent posts)

NAC was shown in a clinical trial at Stanford to be an effective treatment for autism.  You might have expected that this would be quickly followed by further research, but since NAC is widely available as a cheap supplement, there is not much financial incentive for further research.  Without that research, mainstream doctors will never prescribe it.

Beginner's guide to NAC 

Highly respected researchers have shown that in many types of autism, oxidative stress is present and considered that NAC might be an effective therapy.

In the past, some DAN-type doctors have used NAC, but the Stanford trial was the first mainstream trial for autism.

For oxidative stress in asthma and in particularly severe types, like COPD, NAC has long been used.  Oxidative stress stops asthma drugs from working, which is why NAC is used.

In autism, as in asthma, it appears that oxidative stress is a long term condition.  NAC controls oxidative stress, but it does not cure it.

Just as asthma research has shown that smoking triggers irreversible oxidative stress, the same appears to be true for autism.  NAC will rebuild the level of body’s own antioxidant, GSH, but as soon as you stop taking the NAC, oxidative stress reappears.  Many years after people quit smoking, the asthma research showed that oxidative stress remains, and so the asthma drugs do not work.

Will NAC be effective?

In cases of classic autism, NAC has been effective for almost everyone who has given me feedback.

The effect is usually noticed as being a reduction/elimination of stereotypy/stimming and obsessive compulsive behavior.  Other people have seen a reduction in aggression and even in sleeping problems.  The reduction in stereotypy makes way for good behaviours, like increased speech and better mood.

Some types of autism are not associated with oxidative stress; anecdotally, it seems to be some regressive types of autism.

When effective, NAC should change behaviour within a couple of days.  Equally, when you stop taking it, the same behaviours should return with a day or two.  This is a good way to check that you are not just imagining the effect.

NAC has “stopped working”

After a period of months you may find, as I did, that NAC has “stopped working”.  If this happens, most likely it is not that NAC has stopped working, but rather that something else has started working and is making the autism worse.  You need to identify what has happened, treat it, and then NAC will appear to start working again.

Possible reasons for NAC appearing to stop working include:-

·        Effect of an allergy (pollen or food)
·        Flare-up in an existing auto-immune disease
·        New auto-immune condition

For example, if the person has a history of GI problems and these get worse just as NAC “stops working”, you would know what to do.

NAC dosage

From what people tell me, in a three year old children 600mg once per day is effective.

In older children higher doses, going up to 2,400 mg or 3,000 mg are being used. 

There will come a point where increasing NAC will have no further behavioural effect and then there will be more likelihood of side effects.

You can experiment to find the lowest effective dose.  It is logical to split larger doses over the day, to maximize effectiveness and minimize any side effects.

In my son (33kg/73 lbs) I give 1,200mg at breakfast, 600mg at lunch and 600mg in the evening.  I started about 20 months ago.

Quality of NAC

There is both cheap NAC in gelatin capsules and foil-packed NAC.  Over time NAC will react with the air and lose its potency; as this happens a smell of rotten eggs is produced.  The foil-packed NAC is called Fluimucil in Europe and PharmaNAC in the US.

Side effects

Almost everything has side effects of some kind, but in the doses used for autism, NAC does not seem to cause anything troubling to occur.  

NAC will also reduce homocysteine, which is linked to various heart problems in adults.  As an antioxidant, NAC will also help remove any metals that should not be present. NAC has also been shown to improve outcomes in some types of cancer.

Double-tap Autism – perhaps an important variant

In spite of the recent drive to improve autism awareness, mainly in North America, very much more could be done to understand the condition itself.  

Rather than just giving it different names (now ASC rather than ASD, for example) and broadening the “catchment area” of the autism diagnosis, would it not be wise to better study the “disease” itself?

In most countries, people with autism are not treated by any doctor, so a huge pool of possible information is lost forever.  We just have anecdotal evidence, and much of that can be emotionally distorted by care givers.

Whether I want to or not, I just can’t keep noticing things in the media that make me take note.  I do get lots of people writing to me, sending me links to articles and I do admit to looking at some other people’s blogs.

The clever researchers studying autism, and the handful of clinicians writing about it, do not seem to notice the same things as me.  So I will go a little further and define a new type of autism that I would have thought must have been noticed many times before.

Double-tap Autism

I am here referring to the more severe types of autism, not high functioning autism (HFA) and definitely not Asperger’s.  Double-tap autism is a variant of what I call “disabling autism”.

The younger generation of gamers, will all know where I got the name from.  So in my case, Ted, aged 14 and very neurotypical, is the inspiration.

There does seem to be a substantial group of children who are diagnosed with autism (very) early, i.e. younger than 36 months and sometimes younger than 24 months.  They then start their intensive ABA program, since they are either North American, affluent, or both.  All goes well and little Charlie, or Billy, is responding well to his therapy and the parents are even beginning to think that autism is not as bad as they had feared.  Then along comes a viral, perhaps flu-like, infection and all of a sudden things go into reverse and Charlie is no longer the little ABA star he once was and he regresses further. Progress thereafter remains painfully slow.

I do keep noticing very similar descriptions in blogs and newspaper reports.  I just read another example in the UK’s Daily Telegraph, with a father describing his son’s double-tap and descent thereafter. Hence this post.

Rapha boss Simon Mottram: my life with autism

Understanding the Underlying Science

While your family doctor likely knows absolutely nothing about autism, there is actually a great deal of scientific knowledge out there in the literature.

By observing clinical changes in the progression of a disease, you really should be able to learn something about it.  But if nobody is making observations, little progress can be made.

Monty, aged 11 with autism, has only ever seen a doctor, with some knowledge of autism, once in his life; indeed his regular paediatrician believes that a child has the “right not to speak” until he is five years old.  For Europe, once in a lifetime would be average and for much of the world, that would be one more than normal.  In parts of North America the situation is very much better, with EEGs, neurologists, genetic testing, diagnosis before 24 months and even free early intensive behavioural intervention on request.

I am certainly not the most qualified to hypothesize as to what is going on in double-tap autism; my son has “single-tap” autism, after all.  Nonetheless I think it would very interesting to understand the mechanism behind the second tap, and then to reverse it.  I do not believe you can necessarily reverse damage caused years ago in utero, but the effects of a viral infection aged 3-4 should be treatable, if you know what to treat.

The term “regressive autism” means very different things to different people, just as the term “autism” has now been devalued by the ever widening of its definition by, not so clever, psychiatrists in the US.   

             

Regressive autism is something different to double-tap autism.  Double-tap autism is like a further regression, after classic autism has already been noticed, diagnosed and become stable.

It is possible that in some cases nobody noticed the first tap and then you would confuse severe regressive autism with double-tap autism.  I think that regressive autism, where initial development was genuinely “normal”, is a different phenomenon to early-onset classic autism. 

I do not believe the brain abnormalities found in post mortem autism studies are necessarily present in regressive autism.  In fact I believe that science has got a distorted view from the post mortem studies, since they are by definition hugely skewed towards severe classic autism, with seizures and indeed MR.  Think where they get the samples from.  

All this does matter; the current scientific belief, based on post-mortem brain samples, is that the autistic brain is damaged prior to birth.  As a result any kind of therapy is based on optimizing the function of a fundamentally damaged brain and hoping to take advantage of the plasticity of the young brain.

If the brain has developed normally to the age of 3 years old, it has already substantially completed its development.  If thereafter things go wrong, it cannot be because of the kind of malformations found in the post-mortem samples.  So there is a much higher chance of being able to reverse those changes.  Just as in PANDAS and PANS, a perfectly developed brain can, in certain circumstances, produce odd autistic-like behaviours.  PANDAS and PANS are treatable and autistic-like behaviours can be reversed.

So serious thought should be given to treating people with double-tap autism.  It should be treatable and it should be possible to revert to the state the child was in, prior to the second tap.

Possible Treatment

I would think that the immunomodulatory therapy that I have been talking about in recent posts would be a good place to start.  Somebody like Dr Swedo, the PANDAS lady, would be needed to do some experiments.  Therapies for PANDAS already include:-

·        Steroids

·        IVIG

·       Plasmapheresis

and, if all that is claimed about it was really true:-

·        Gc-MAF (Gc protein-derived macrophage activating factor)

Another possibility is that the virus is just a trigger for a genetic or epigenetic process.  If it is an inherited genetic anomaly, it was always present, like the gene that often leads to breast cancer, it is like a ticking time bomb; it may or may not explode in your lifetime.  If it is epigenetic then the process is like a bookmark, rather than a genetic defect, that turns on something that should be off, or vice versa.  Regardless of genetic or epigenetic, once you know what gene is affected, you may be able to figure out a way to counter it.  Just like in my PolyPill research, I read that it was already known in autism there may be a defect in the CACNA1C gene. The CACNA1C gene produces the calcium channel Cav1.2.  So I just needed to look at this Cav1.2 channel and figure out how to modify its behavior, just in case it was linked to my son’s particular type of autism.  This only took a few hours to figure out; it took longer to test it and even longer to write about it.

It is quite likely that many of the people with double-tap autism have the same underlying dysfunctions, and so what helps one could help many.  This was also the case with PANDAS/PANS.

I hope somebody, vaguely scientific, eventually does try and help people with this kind of autism.  It should be less difficult than classic autism, which turns out to be treatable after all.  But don’t hold your breath and, as I tell my older son, if a job is worth doing, best do it yourself.  That is unless you have Dr Swedo on your case.

Immunomodulatory Therapy in Autism - Potassium Channel Kv1.3, Parasitic Worms, and their ShK–related peptides

Regular readers of this post will know that I believe that Immunomodulatory therapy has great promise for treating various subtypes of autism.  In effect, I want to bring the over-activated immune system back under control.  Two methods that appeal are:-

·        The steroid, Prednisone, because it is cheap and though it has side effects, they are very well understood. It also has been shown to be effective in autism and related conditions like PANDAS and Landau-Kleffner syndrome (LKS)

·        Parasitic worms appeal because they are known to have beneficial effect in many auto-immune conditions ranging from arthritis to autism, but nobody really understood why.  Until now.

This post is about the worms and recent research which has established that it is likely that they work by blocking the potassium channel Kv1.3.

You will have noted that this blog keeps going on about ion channel dysfunctions and autism.  We already know that Cl^-, Ca²⁺ , K⁺ and Na²⁺ are all implicated.

When researching calcium channel blockers for autism, one reason I picked Verapamil was that it is also a potassium channel blocker.  My earlier experiments have shown that hypokalemic sensory overload exists in autism, I showed that oral potassium could treat sensory overload.

Hypokalemic Autistic Sensory Overload

 

This blog is (slowly) working its way through the ion channel dysfunctions known to exist in autism.

Well, it appears that Verapamil also blocks Kv1.3.

Block of the lymphocyte K+ channel mKv1.3 by the phenylalkylamine verapamil

Research Down Under

Researchers in Australia have identified the chemicals released by parasitic worms that have the effect of subduing the immune system.  They identified a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms, they showed that these peptides acted to inhibit Kv1.3 channels in human T cells.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases

Abstract

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar–micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7⁻ effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases

A less heavy summary is here:-

'Wormpill' could ease autoimmune disease symptoms

  

The researchers noted that Kv1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.

So it seems that they have identified the mechanism of action of the worms.

Earlier posts have mentioned intentionally swallowing TSO parasites (Helminthic therapy) for autism and the trials now ongoing by Coronado Biosciences.   Here is part of one post:-

I think that TSO is very interesting.  It is now being developed by Coronado Biosciences as a therapy for several inflammatory conditions including:-

·        Crohn’s disease

·        Ulcerative Colitis

·        Autism

Here is a link to all the clinical trials they are running.

The idea behind TSO is that the parasites have evolved a method of ensuring their survival in their host, by subduing the immune system, so that they are not killed/ejected.  By down-regulating the immune system, they become a therapy for diseases featuring an over active immune system.

This all started a few years ago when one autism Dad figured all this out and tried it on his own son.  Then began the long process of clinical trials, which then ended up with Coronado Biosciences.  The Dad’s website is here.

The Australians have the idea of making their (ShK)–related peptides into a drug therapy.  So no need to swallow those worms after all.

Verapamil or Stichodactyla helianthus toxin (ShK)–related Peptides

Just as the Australians may have trumped Coronado Bioscience with their better-than-a-worm peptide pill, has Verapamil the ability to trump the Ozzies?

We know that Verapamil is neutralizing many allergic reactions affecting autism all over the body.  This appears to be a combination of mast cell stabilization and a possible effect on pancreatic function that reduces GI problems.  But is Verapamil’s inhibitory effect on Kv1.3 also providing a broader immunomodulatory effect as well?  It does indeed look possible.

We would need somebody using TSO worms for autism, to see if Verapamil was effective for them too.  Any volunteers?

Unlike the TSO worms and the ShK peptides, Verapamil is cheap and sitting on the shelf in your local pharmacy.

Cognitive Function Restored, with Bumetanide

Regular readers will know that every summer Monty, aged 11 with ASD, has a “flare-up” in his autism.  Behaviour gets very much worse and now we notice that also cognitive function is impaired.

In my last post I repeated how the aggression and SIB (self-injurious behaviour) was very effectively suppressed by Verapamil and I was pondering how to solve the, now visible, cognitive decline.

I suppose some readers may be thinking all this sounds fanciful.  Once a child with autism is verbal and has got as far as basic maths, it is very easy to measure cognitive function.  For years I have asked Monty what he had for lunch at school that day, to check how “switched-on” he was.  Now, I just need to ask him something like “what is five times five”.

Ted, Monty’s older brother, has also noticed these changes and has recently delighted in showing how his brother does not know six times six, or even twelve plus five.  He would ask him questions when we are all in the car, and then I would have to start making excuses for his brother.  Well with Verapamil, at least Ted is not going to get punched by Monty, as they sit in the back of the car.

We know that for most of the year Monty knows the right answer to all these questions, but from July to early October he may get them wrong, or does not answer.  This was all traced back to the effect of a mild pollen allergy.

Rather than look for something new, I decided that as a first step I would just increase the dose of one of his existing Polypill ingredients and “hey presto” the problem was solved.  A nice surprise, indeed.

I increased the Bumetanide dose from 1mg once a day, to 1mg twice a day.

Every time since that I ask Monty five times five, or six times four he gets the right answer, even if he is in the middle of doing something else, like jumping into the swimming pool.  That is proof enough for me.  Even Ted has noticed.

In previous posts I did complain about the effectiveness of autism rating scales and suggested that measuring academic performance (in older kids) might be more reliable.   In the case of Bumetanide this really is the case.

As to the relationship between bumetanide and allergy, there are various possibilities.  I did yesterday highlight this impact to the French researchers currently working to get Bumetanide approved officially as drug for autism, since it could be useful for them to know.

Conclusion

So, the current summertime allergy solution is:-

Aggression and SIB – Verapamil three times a day

Cognitive impairment – Bumetanide one extra daily dose of 1mg

All that is left of the “autism flare-up” is a very occasional rapid mood swing from happy to sad.

Compared to last summer, the difference is profound and now the difference between behaviour in summer and winter is very small.