Dendritic Spines in Autism – Why, and potentially how, to modify them

This blog is getting rather more detailed than I had anticipated.  

Today’s post is about something very complex, but not fully understood by anyone, so I will be somewhat superficial in my coverage.  Just click on the links to learn more detail.

There are two words that may be new to you – Morphology and Dendritic Spines.

Morph in Twin Decks

Morphology, in biology, the study of the size, shape, and structure of animals, plants, and microorganisms and of the relationships of the parts comprising them.

For today it is really could be thought of as the variability in size and shape of something.

A dendritic spine is a small protrusion from a neuron's dendrite that typically receives input from a single synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head (the spine head), and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

Now we combine our two new words and have a better summary of what this post is about:

Morphology of dendritic spines and mental disease

It turns out that shape of dendritic spines may play a key role in mental disease, including autism.

The shape is not fixed and live imaging studies have revealed that spines are remarkably dynamic, changing size and shape over timescales of seconds to minutes and of hours to days.

The shape is important as it impacts on function, malformations lead to dysfunctions that can affect a myriad of brain functions.

Here are some variations in the shape of dendritic spines.

In case you are thinking this is all rather abstract, let’s jump forward to a patent for a possible new treatment for autism.

Afraxis Patent

Methods for treating autism 

  

SUMMARY OF THE INVENTION

Described herein are p21 -activated kinase (PA ) inhibitors that alleviate, ameliorate, delay onset of, inhibit progression of, or reduce the severity of at least one of the symptoms associated with autism.

Claims  

WHAT IS CLAIMED IS:

1. A method for treating autism comprising administering to an individual in need thereof a therapeutically effective amount of a p21 -activated kinase (PAK) inhibitor.

2. The method of claim 1, wherein the PAK inhibitor modulates dendritic spine morphology or synaptic function.

3. The method of claim 2, wherein the PAK inhibitor modulates dendritic spine density.

4. The method of claim 2 or 3, wherein the PAK inhibitor modulates dendritic spine length.

5. The method of any of claims 1-4, wherein the PAK inhibitor modulates dendritic spine neck diameter.

6. The method of any one of claims 1-5, wherein the PAK inhibitor modulates dendritic spine head volume.

7. The method of any one of claims 1-6, wherein the PAK inhibitor modulates dendritic spine head diameter.

8. The method of claim 1 or 2, wherein the PAK inhibitor modulates the ratio of the number of mature dendritic spines to the number of immature dendritic spines.

9. The method of claim 1 or 2, wherein the PAK inhibitor modulates the ratio of the dendritic spine head diameter to dendritic spine length.

10. The method of claim 1 or 2, wherein the PAK inhibitor modulates synaptic function.

Etc …

Of course, plenty of patents turn out to be worthless nonsense, but I think the people at Afraxis do know what they are doing; time will tell.

Morphology or Number of Dendritic Spines?

The PAK1 researchers and others believe the morphology (shape) of the dendritic spines is the problem, others believe the problem is that there are just too many of them.

Research has shown that a particular gene (NrCAM) can increase/decrease the number of dendritic spines.

Studies at University of North Carolina showed that knocking out the NrCAM gene caused mice to exhibit the same sorts of social behaviors associated with autism in humans.

Researchers from Columbia University found an overabundance of the protein MTOR in mice bred to develop a rare form of autism. By using a drug to limit MTOR in mice, the Columbia researchers were able to decrease the number of dendritic spines and thus prune the overabundance of synaptic connections during adolescence. As a result, the social behaviors associated with autism were decreased. However, the drug (Rapamycin) used to limit MTOR can cause serious side effects.

Children with Autism Have Extra Synapses in Brain

Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.

By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.

“It’s the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” Dr. Sulzer said, “although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviors.”

Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses, “Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”

“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”

Maness, a member of the UNC Neuroscience Center and the Carolina Institute for Developmental Disabilities, also said that there are likely many other proteins downstream of NrCAM that depend on the protein to maintain the proper amount of dendritic spines. Decreasing NrCAM could allow for an increase in the levels of some of these proteins, thus kick starting the creation of dendritic spines.

Knocking out the gene NrCAM increases the number of dendritic spines  

   

Gene linked to increased dendritic spines -- asignpost of autism

  

The view from Japan

RIKEN is a large research institute in Japan, with an annual budget of US$760 million.  Their Brain Science Institute (BSI) has a mission to produce innovative research and technology leading to scientific discoveries of the brain.  So RIKEN  BSI is like MIT just for the brain.

Science does tend to stratify by geography.  Just as we saw that NGF (Nerve Growth Factor) is the preserve of the Italians, when it comes to PAK it is the Japanese.

As you can see below the Japanese are firmly behind PAK1. 

 Pak1 regulates dendritic branching and spine formation.

Abstract

The serine/threonine kinase p21-activated kinase 1 (Pak1) modulates actin and microtubule dynamics. The neuronal functions of Pak1, despite its abundant expression in the brain, have not yet been fully delineated. Previously, we reported that Pak1 mediates initiation of dendrite formation. In the present study, the role of Pak1 in dendritogenesis, spine formation and maintenance was examined in detail. Overexpression of constitutively active-Pak1 in immature cortical neurons increased not only the number of the primary branching on apical dendrites but also the number of basal dendrites. In contrast, introduction of dominant negative-Pak caused a reduction in both of these morphological features. The length and the number of secondary apical branch points of dendrites were not significantly different in cultured neurons expressing these mutant forms, suggesting that Pak1 plays a role in dendritogenesis. Pak1 also plays a role in the formation and maintenance of spines, as evidenced by the altered spine morphology, resulting from overexpression of mutant forms of Pak1 in immature and mature hippocampal neurons. Thus, our results provide further evidence of the key role of Pak1 in the regulation of dendritogenesis, dendritic arborization, the spine formation, and maintenance.

SHANK3 and Dendritic Spines

Mutations of the SHANK3 gene are known to cause autism. 

Researchers in France found that SHANK3 mutations lead to modification of dendritic spine morphology and they identified the mechanism.

SHANK3 mutations identified in autism lead to modification of dendritic spinemorphology via an actin-dependent mechanism

You may recall in my earlier posts on growth factors that it was this type of autism that responded to treatment with IGF1.

SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients

If you take a broader look at today’s subject you will see that various growth factors are indeed closely involved.  Here is some comment from Wayman Lab at Washington State University:- 

"Not surprisingly, abnormalities in dendritic arborization and spinogenesis, which diminish neuronal connectivity, are a common feature of the cognitively compromised aging brain as well as numerous forms of mental retardation including Fragile X, Fetal alcohol, Downs and Retts syndromes.

It is clear that changes in synaptic activity and neurotropic factors (e.g., BDNF) are effective initiators of the remodeling process and result in long-term alterations in dendrite and spine structure. What is not known are the molecular mechanisms that underlie how they stimulate dendritic spine formation."

Take your pick

So it looks like three different methods may exist to potentially modify dendritic spine numbers and morphology:-

1.   PAK1

Much work is ongoing regarding PAK1.  It is my current favorite.

For those interested here is a recent study using FRAX486 on Fragile X mice.

Rescue of Fragile X Syndrome phenotypes in Fmr1 KO mice by the small molecule PAK inhibitor FRAX486

Abnormal dendritic spines are a common feature in FXS, idiopathic autism, and intellectual disability. Thus, this neuroanatomical abnormality may contribute to disease symptoms and severity. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect may also ameliorate behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). In a healthy brain, PAK and FMRP - the protein product of fmr1 - antagonize one another to regulate spine number and shape. Inhibition of PAK with a strategy utilizing mouse genetics reverses spine abnormalities as well as cognitive and behavioral symptoms in fmr1 KO mice, as we demonstrated in our previous publication. This discovery highlights PAK as a potential target for drug discovery research. In this thesis work, we build on this finding to test whether the small molecule FRAX486 - selected for its ability to inhibit PAK - can rescue behavioral, morphological, and physiological phenotypes in fmr1 KO mice. Our results demonstrate that seizures and behavioral abnormalities such as hyperactivity, repetitive movements, and habituation to a novel environment can all be rescued by FRAX486. Moreover, FRAX486 reverses spine phenotypes in adult mice, thereby supporting the hypothesis that a drug treatment which reverses the spine abnormalities can also treat neurological and behavioral symptoms.

2. mTOR

In spite of its noted toxicity, Rapamycin, is about to be tested in a clinical trial on a rare type of autism called TSC:-

Rapalogues for Autism Phenotype in TSC: A Feasibility Study (RAPT)

Funnily enough the trial is taking place at the Kennedy Krieger Institute.

When commenting on the use of Bumetanide for autism, I recall the President of the Institute was quoted as saying:-

"So many things cure cancer in mice and rats, and so many things cure all kinds of things and then when we give them to humans they have adverse effects and don't fix the problems we thought they could fix," says Gary Goldstein, president and CEO of the Kennedy Krieger Institute, a Baltimore-based clinic and research center. "I wouldn't give it to my child, I can tell you that."

I found it a little odd that he gave the green light to trialing Rapamycin in children, given the long list of very nasty side effects.

  

3.  NrCAM 

Manesslab at UNC is clearly the centre for research into finding therapeutic agents surrounding NrCAM.  It looks like this is still some way from trials in humans.

“Too many spines and too many excitatory connections that are not pruned between early childhood and adolescence could be one of the chief problems underlying autism. Our goal is to understand the molecular mechanisms involved in pruning and find promising targets for therapeutic agents.”

Conclusion

It should not be surprising that multiple pathways may have the same therapeutic benefit on dendritic spines.  We only need one to be safe and effective.

The link back to human growth factors is interesting since we know these are disturbed in autism and other mental conditions, but the dysfunction varies by sub-type.  In fact, Nerve Growth Factor (NGF) would likely be an effective therapy for dementia and perhaps even Retts syndrome.

In the next post we will learn some more interesting things about growth factor anomalies in autism.  It turns out that something called Akt, also known as protein kinase B (PKB), may be behind them all. A related protein called protein kinase C (PKC), is known to affect the morphology of dendritic spines. There is also protein kinase A (PKA).  Both PKA and PKB have been shown to have reduced activity in regressive autism, this will also be covered later. 

Mounting Evidence Regarding Autism, Neurofibromatosis and PAK1

When I google “autism” and “PAK1”, I keep seeing my own posts come up.  This is beginning to be a regular occurrence, when I research an idea.  Google “verapamil autism”, “clonazepam autism” “bumetanide autism” and even “NAC autism”, the same thing happens.

So it is nice to have some further studies that also show the possible importance of PAK1 in treating autism.  This time it is from the University of Indiana and more precisely, Anantha Shekhar, Professor of Psychiatry at the School of Medicine.

We have the study’s abstract and the more people-friendly press release.

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase (PAK1)

Abstract

Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1^+/−), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1^+/− mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1^+/− mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

Here is the very informative and readable press release.

 

Blocking one gene could aid social behavior in some forms of autism, IU scientists report

INDIANAPOLIS -- Blocking a single gene that is active in the brain could provide a means to lessen behavioral problems among children with a common genetic disease, many of whom are also diagnosed with an autism disorder, according to researchers at the Indiana University School of Medicine.

The genetic disorder, neurofibromatosis type 1, is one of the most common single-gene diseases, affecting about 1 in 3,000 children worldwide. Symptoms can range from café-au-lait spots on the skin to tumors that are disfiguring or that can press dangerously against internal organs.

"Physicians are increasingly recognizing that many children with the disorder have social and behavioral difficulties, and as many as one in five cases of autism may be associated with the same biochemical defects seen in neurofibromatosis type 1," said Anantha Shekhar, M.D., Ph.D., Raymond E. Houk Professor of Psychiatry at the IU School of Medicine.

The researchers used a mouse model of neurofibromatosis, examining both behavioral differences from normal mice and biochemical differences in the animals' brains, particularly in the amygdala, a brain structure associated with social behavior and emotional regulation.

Reporting their work in the journal Nature Neuroscience, the researchers found that the neurofibromatosis model mice had problems with long term social learning -- remembering important social cues involving interactions with other mice. Tests also showed that neurochemical pathways between structures of the brain involved with social behavior were disrupted by the neurofibromatosis mutation.

However, blocking the activity of another gene -- called Pak1, which is involved with those neurochemical pathways -- improved the social behaviors of the mice. Mice bred to have both the neurofibromatosis mutation and the deletion of the Pak1 gene engaged in social behavior similar to normal mice. In addition, mice with the neurofibromatosis mutation that were injected with a compound known to block Pak1 gene activity had normal social behavior restored.

"These findings could lead to novel approaches to treating behavioral problems that are seen in NF1 patients and some patients with autism spectrum disorders," said D. Wade Clapp, M.D., Richard L. Schreiner Professor of Pediatrics at the IU School of Medicine.

Implications

The researchers from Indiana are suggesting that 20% of people with autism may have the same dysfunction as the very much rarer condition of neurofibromatosis type 1.  Those 20% are likely to benefit from treatments shown to be effective in NF-1.

How do you know whether you are in the 20%?  A little genetic testing might tell you, or maybe not (see below).

In the absence of such testing, you could possibly deduce something from looking at the comorbidities.

It might seem odd that NF-1, a rare disorder affecting 1 in 3,000 children could share its underpinnings with 20% of children with autism, which would roughly equate to 6 in 3,000 children.

This reminds me of a question I raised earlier:-

Just How Rare are the Known Genetic Causes of Autism?

In that post it became clear that you can have a partial dysfunction of a “rare” genetic disorder.  I wonder if that partial dysfunction will show up on today’s genetic tests.

Comorbidities

The comorbidities of autism that most intrigue me are asthma, allergies and ulcerative colitis.  I have a suspicion that they are all linked by mast cell degranulation and further, that what is underlying autism is promoting mast cells to degranulate.

A recent study showed how PAK1 is involved in modulating mast cell degranulation:-

A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells

 

And another one:- 

PAK1 AS A THERAPEUTIC TARGET

Fortunately, the effects of PAK1-deficiency on the immune system have a very encouraging up-side. As demonstrated by otherwise relatively healthy PAK1-/- mice, Pak1 is critical for disassembly of cortical F-actin upon allergen stimulation, and PAK1 deficiency prevents the release of pro-inflammatory molecules from the granules of mast cells during the IgE-associated allergic responses

I have already shown the effectiveness of Verapamil as a therapy for autism and mast cell degranulation.  I suspect that a further improvement may follow with a potent PAK1 inhibitor.

I think the Indiana research also points in the same direction.

There is also the issue of malformed dendritic spines, which will be fully addressed in a later post.  This appears in autism and schizophrenia and may explain much of why autistic brains function differently to other peoples.  It is thought that this malformation is also linked to PAK1.

So while treating mast cell degranulation will help some people’s autism, you could also go one step backwards up the chain and address the signal that was prompting them to degranulate.  This same signal may trigger an unrelated damaging cascade of events elsewhere in the brain.

Which PAK1 inhibitor?

In earlier post we saw that the choices of PAK1 inhibitor are:-

1.     Experimental drugs still under development by Afraxis, the MIT spin-off  

2.     Ivermectin, an old anti-parasite drug, used with some success by fringe alternative doctors in the US.  At least one reader of this blog is a fan of Ivermectin for autism.
 
3.     Certain types of Propolis, like the one containing CAPE (Caffeic Acid Phenethyl Ester) that comes from New Zealand
 

The question remains whether the Propolis is potent enough to have the same effect as Ivermectin.  In the NF-1 and NF-2 community, opinion is split as to whether Propolis can shrink existing tumours.  This issue of stopping new tumours developing, versus shrinking existing ones does seem to crop up quite often in cancer research as well.  Drugs are, not surprisingly, most effective when used very early on.

Ivermectin cannot be used long term continuously, since it is toxic.  It can be used “on and off” for decades as an anti-parasite therapy.

Crossing the Blood Brain Barrier

Once question arose in an earlier post as to how Ivermectin could be effective in autism, since it does not readily cross the blood brain barrier.  According to the experts it does not have to, see below:-

PAK1 AS A THERAPEUTIC TARGET

11. Expert opinion: Is PAK1 a suitable target for therapy?

As discussed above, there is growing evidence that PAKs are involved in the phenomena that are clinically significant for various cardio-vascular disorders, but the specificity of PAK1 involvement is still uncertain. Studies indicate that even closely related PAKs (e.g. PAK1 and PAK2) have non-identical sets of substrates. The issue is further complicated because of the multiple and sometimes opposing roles of PAKs in these processes and certainly merits further investigation.

The reports on the involvement of PAK1 in various diseases of the brain indicate that both up- and down-regulation of this enzyme may be associated with pathological changes. This, along with the uncertainty about the relative contribution of other isoforms, clouds the prospect of targeting PAK1 for therapeutic intervention in these conditions. Furthermore, these observations necessitate a close attention to the affects that any anti-PAK therapy targeted at other organs might have on the nervous system, including the cognitive functions and the memory. In this regard, failure of an anti-PAK1 agent to penetrate the blood-brain barrier may not be a detriment to its therapeutic utility. Similarly complicated is the question of PAK1 targeting in infections: while it may partially attenuate certain viruses, it would also negatively impact some functions of the immune system. In fact, the recent report of PAK1-deficient animals having IgE-mediated responses to allergens may indicate that, at least, for such acute life-threatening conditions as anaphylaxis the benefits of suppressing PAK1 may outweigh the risks.

My PAK-1 inhibitor Trial

I am practicing what I preach, so to speak.  Only once the pollen allergy season is well and truly over, will I trial my PAK-1 inhibitor.  I want a genuine result, free from external effects, like degranulating mast cells.

Since Ivermectin is known to react with other drugs in my PolyPill, I will be using the Propolis from New Zealand. 

Autism Drugs - Horses for Courses and Safety over Assured Efficacy?

Only a few months goes by without there being an uplifting report in the media of some breakthrough drug for autism.  These reports usually relate to research on mice.

So where are the resulting approved drugs for use on humans?

There still are no drugs approved for the core symptoms of autism.  It is quite likely that in spite of all the ongoing research, the situation will not change anytime soon.

I was reading about yet another potential wonder treatment, based on research into a very old drug called Suramin.   This rather toxic drug has been shown to be effective in a particular mouse model of autism call MIA (Maternal Immune Activation).  There is some doubt as to whether the researchers have got the method of action correct, but nobody doubts the positive effect it had on some mice.

Today’s post does not look at the science of Suramin, which is, by the way, another anti-parasite drug like Ivermectin, which I looked at earlier.  The subject of this post is much more down to earth and practical.

There is a problem with all Autism Clinical Trials

It is not just me that thinks something is amiss with Autism Clinical Trials, first read what the head of Medical Research at Autism Speaks has to say.  He is talking about this in the context of Naviaux’s recent trials of Suramin on “autistic” mice:-

Need to work harder on trials

Paul Wang, Head of Medical Research, Autism Speaks :-

Hedging bets: “Animal models of autism, such as the maternal immune activation (MIA) model studied here by Naviaux and his colleagues, are the best tools that researchers have for examining the cellular and molecular pathophysiology of autism and for testing experimental treatments before they can be advanced to human trials.

“But, of course, none of the models can be considered valid until treatment effects in them are proven to be predictive of effects in people. In the case of the MIA mouse, the authors here candidly hedge their bets by calling it a model of both autism and schizophrenia. Meanwhile, the field of autism research wisely hedges its own bets by studying multiple treatments of the MIA mouse, including probiotics as well as antipurinergic therapy.”

Precedent lacking: “Although milestones in the initial stage of testing basic research findings for translational research continue to accumulate — from mGluR5-targeted rescue of the FMR1 knockout mouse to suramin reversal of social deficits in the MIA mouse — we appear to be making little headway on the hurdles of clinical trials. From arbaclofen to oxytocin to Trichuris suis ova, clinical trial results have been tepid at best. This should not be surprising. We have no successful precedent to guide the design of clinical trials in autism.

“How should we quantitate clinical improvement — or deterioration? How long must treatment be provided before effects are evident? At what age will each treatment be most effective: 6 years? 16 years? 6 months? Which individuals will benefit most from each treatment: those with more severe or more mild symptoms? Those with regression or not? Those with or without comorbidities? Results in Phelan-McDermid syndrome (presented by Joseph Buxbaum at the 2014 International Meeting for Autism Research) represent a rare but preliminary exception to the frustrations of clinical trials.”

Clearing the hurdles: “As basic research continues to generate more candidate treatments for autism, we need to work harder on clinical trials. Most especially, we need to identify measures of improvement that emerge early, potentially within a few weeks of treatment initiation and well before the broad functional improvement that the U.S. Food and Drug Administration is likely to require for drug approval.”

 

Multiple mouse models, suggests multiple human types of autism

The fact that researchers have created multiple types of mutant mice that mimic autistic behaviour does rather suggest that numerous distinct dysfunctions in humans might also result in autistic behaviour. 

In fact it is now a widely held belief, in the scientific community, that there are numerous sub-types of autism, each with its own biological dysfunction(s).

Clinical trials doomed to fail?

Since no effort is made to stratify the autistic population by sub-type, clinical trials are likely doomed to fail.  They usually just require that participants fall into the vague autism behavioral category of DSMIV, or now DSM V.

While a trial drug may indeed have a positive effect in one sub-type of autism, it may have no effect, or worse still a negative effect in other subtypes.  This is exactly what happed with Arbaclofen, and Roche pulled the plug on that one.

Horses for Courses

Perhaps a more pragmatic approach is required.  “Horses for courses”, was suggested to me the other day by that prolific autism science blogger from Sunderland.

Just accept that one Alzheimer’s drug may work for Fragile X, but be totally in-effective in broader autism.  Or maybe it only works in some people with Fragile-X?

This sound fine, but what if you do not know which “course” your horse (child) is running on?

Science may indeed have the answer in the form of something called micro RNA analysis, which is a way of looking for a large number of known genetic dysfunctions quickly and therefore relatively cheaply.  It just needs a blood sample. It is available to autism researchers today.

In the meantime we are left with that reliable old workhorse called trial and error, which does seem to work, if you do your homework.

Safety over Assured Efficacy

While clinical trials may not be able to guarantee which drugs are helpful in autism, they can tell us which are safe to use.  Fortunately many of the interesting drugs for autism are existing ones that have been in use for decades, but for other conditions.

One interesting point I noticed in the autism trials of Alzheimer’s drugs was that the drugs were very well tolerated.  Not surprisingly, older patients claim to have far more frequent side effects, since they likely have multiple ailments and may attribute their various ills to the new drug.

So what is required to treat autism is a range of drugs that are known to be safe for long term use; and then some indication of effectiveness in some people with autism.

Last year, when reading the very detailed critique of most recent clinical trials into autism, produced  by the UK’s National Institute for Health and Care Excellence (NICE), it was clear that they are looking for a level of success in clinical trials that will likely never materialize.  This was a 700 page document produced in advance of the final 40 page report.  Only the 40 page report seems to be available now.

A “one size fits all” approach will fail, because “autism” is a vague behavioral diagnosis and not a precise biological one.

Any particular drug might be effective in only 10% of what psychiatrists rather arbitrarily define as “autism”, but if your child is in that 10%, you would be delighted.

The logical way forward is blocked for most people, since they cannot access even very safe prescription drugs.  This is of course for the “greater good” of society and avoids doctors worrying about getting prosecuted for malpractice.

Back to School and “Learning Years”

School for Monty, aged 11 with ASD, did start a couple of weeks ago but then a nasty virus swept through school, sending him back home again.

To recap, Monty attends a very small mainstream international school with his own assistant. The school uses the English system. To get the equivalent US grade, you subtract one from the English year.  He comes home after lunch and then has one-to-one, ABA-inspired, home schooling for another three hours.    In school holidays he has eight hours a day of ABA-inspired one-to-one home program.  This has been going on for seven years so far.

Following all these years of ABA, schooling at home and 20 months of his PolyPill he is now able to learn at school, follow the rules and interact with staff and other children.  He now initiates play with the other kids.

When his assistant leaves at 2pm, the teachers now want him to stay by himself for afternoon classes like art and physical education.  This is quite a change, until quite recently the teachers did not want him there if his assistant was unable to be at school, or got delayed in traffic.

The clever move turned out to be holding him back two years, a while back; so that he is now in a group of 8 year olds.  This makes sense for many reasons; most importantly, he is at the academic level of classmates.  Since he did not speak a word until he was three and half years old and for most of 2012 he was raging and regressing, it also makes sense.  In “learning years” he is, at best, a seven year old.

Until a couple of years ago, all learning (speaking, reading, writing, numeracy) was acquired at home; school was just for practice and socialization.

Socialization is the main point of inclusion, but even that needs a lot of managing.  Socialization without any learning does not seem a clever choice.

The Wider World

In some countries there is a very developed system of Special Education, with the US being far ahead, partly because it diagnoses so many kids to have a special need.

Most other countries now seem to have adopted elements of what is seen as best practice, like having an IEP (Individual Educational Plan) and some interpretation of “inclusion”.  Unless the IEP is well thought out, it is just another stack of paper.  If inclusion is not accompanied by plenty of training and supervision, the results will not be good.

Given the resources for 1:1 education, much can be achieved, but this is rarely going to be possible; only very expensive private schools or home schooling can provide this.

In a large inclusive classroom, I do not see how children with classic autism can make any academic progress, except with the help of a very good 1:1 assistant (but when is there 1:1 time in a noisy inclusive classroom?).  In many inclusive schools, the teachers have had no special training, and quite often, neither has the 1:1 assistant.

Parents often make great efforts to avoid their child going to special education, due to the perceived stigma.  Readers from the US may find this odd, but in most of the world autism remains hidden.  People turn down free intensive early years support, preferring the child to be with typical children.

I see plenty of parents writing commenting things like, “I wish the school would teach my child to read and write”.  Without individual tuition at school and/or home it is easy to see how such kids will not get far at all.

From what appears in the media, most people are not happy with schooling for classic autism.  If you want better, you will have to take on much of the job yourself.

There are plenty of good ideas you can use.

Extended School Year and Duration

In some countries kids with autism have an extended school year, i.e. very short holidays.  This seems a very good idea for both the kids and the parents.  It means that the learning year is more like 11 months long, rather than the typical 9 months.

In most developed countries school finishes when you are 18.  In the US special education in high school continues to 22.  That is quite a big difference, which brings me on to the next point.

Final Academic Level with Classic Autism

I was interested to see what range of academic levels is typical for people with classic autism to achieve when they finish their school education.  It is very hard to find this anywhere and I only found one range, which was between 2^nd grade and 6^th grade, on leaving “high school”, using the US system.  This seems plausible.

It is clear that many special schools are really focused on living skills rather than academics. 

If you manage to progress academically all the way through school, then it must have been a case of High Functioning Autism or Asperger’s. 

What Monty did

Monty, now aged 11 with ASD, started out un-able to learn in the conventional sense, like most kids with classic autism.

Using an ABA-inspired home program, he did gradually start to learn.  He went to school for socialization and fun.

We have no external agencies, Education Authorities etc. involved in Monty’s education.  We have a nice, responsive, mainstream private school, which has always tried to help, although they have no special needs resources or knowledge.  The class sizes are tiny; this year there are 13 in the group. 

From the age of about 10, things changed sufficiently for school to be about learning.  By that stage he had acquired the academic skills of a typical 7-8 year old, based almost entirely on his supplemental 1:1 tuition.

The home program continues and will be needed for years to come.

  

Monty has three school years left in Primary before moving on to Secondary/High School.  Primary school is a nice place to be if you have ASD, the same may not be true for Secondary School. 


In the UK system, Secondary school starts when you are 11 years old.  In other countries it starts much later; where we live Secondary school is normally from 14 to 18 years old.

Summertime is no longer developmentally lost, due to the odd effect of allergy and some key neurological autism issues have been identified and treated; more are likely to follow.

I am optimistic that we will see three years of uninterrupted development, twelve months a year.  Every calendar year should be a “learning year”.