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Tuesday, 19 September 2017

Identifying your sub-type of Autism


Today’s post is very much a work in progress, so do not expect all the answers.
It has occurred to me and also some readers of this blog that you could produce a diagnostic decision tree that would narrow down each person’s sub-type of autism. This really does lend itself to a relatively simple computer model, meaning you could have a simple on-line diagnostic program/app. You do wonder why a tiny part of the hundreds of millions of dollars spent on autism research is not allocated in this direction.

A blank screen awaiting more case studies

A company called Verily, formerly Google Life Sciences, would be an appropriate partner for such a project.  Google is currently backing the approach that genetic testing will reveal all about autism, which looks unlikely.
The decision tree computing part of such a project could be done in an afternoon, what would like more time is creating the logical diagnostic steps.
One clever part, where Verily could help, would be the use of software to “read” the research and look for associations; this is after all what I do with the help of Google Scholar and Ctrl F. In this way you could quickly “read” many tens of thousands of research papers, books and case histories, if there were any.
Software can also be used to “read” all the personal data of any volunteer participants, such as genetic tests, MRIs, family history and all lab tests. As our reader Tyler pointed out, just relying on a pair of eyes to read the MRI means tiny variances go unnoticed and perhaps they do mean something.
You cannot automate everything, but technology certainly can help.
Even a primitive decision tree can help, because it pushes you to think logically and stops you wasting time potentially applying therapies that might help some biological dysfunctions, but clearly not yours.

Parent led initiatives have been successful in the past and have resulted in rare diseases or syndromes becoming treatable using so-called orphan drugs. Treating autism is a massive task and parent led initiatives are what exist today - they have not succeeded in making any impact on mainstream medicine. To make an impact in autism you need big money and big companies.


Start with severity
Ideally everyone would have autism diagnosed in early childhood.  In the case of mild autism this usually does not happen.  Ideally all children would be assessed using the same evaluation test, like CARS, but this also does not happen; most people have no evaluation test, just a subjective observational diagnosis.
So you would need unambiguous terminology to define how the person is affected by “autism”.  This would be how verbal they are; level of cognitive dysfunction and how “autistic” they are behaviorally.
Then you can add things like epilepsy, self-injury and adaptive behavior (toileting, feeding etc). 

Family History
While genetic testing is seen by many as the ultimate diagnostic test, in many cases family history tells you a great deal more. Similar family histories will very likely end up with similar sub-types of autism. This would include medical history of relatives, but also educational/job attainment. It would include health before and during pregnancy, type of delivery and health status at birth.
Genetic testing of your DNA can never be the holy grail of autism diagnosis; what matters is gene expression, when and where, and this is something much more complex.
Family history tells you what has happened in the past and most things happen for a reason.
Family history is by its nature very personal, but it is one of the richest areas to identify how people might be usefully grouped together. This may appear highly politically incorrect, but that does not stop it being useful. 

Physical Features
Until very recently even single gene types of disorder were actually diagnosed by their hallmark physical features. These are often facial, or on hands or feet, but can be anywhere.
One of the most useful physical markers is very simple, you just need to know at birth and for the next couple of years was there a tendency towards being big and/or muscular or small and more floppy?  The stronger the tendency to either extreme, the more important is the observation.

A recent study has even used 3D modeling to identify autism by analyzing people's faces. This apparently works particularly well in females with autism, who apparently tend to have more male features. I have no doubt Googlers could improve this.

Hypermasculinised facial morphology in boys and girls with Autism Spectrum Disorder and its association with symptomatology


Comorbidities
Other medical conditions in the child and also in the parents, and in particular in the mother during pregnancy, can help assign people to subgroups. 
In mothers thyroid disorders and diabetes during pregnancy look particularly relevant.
In the child, epilepsy, allergy and GI issues are important. There are many types of GI issue, some of which overlap with allergy and some do not.
Then you have sleep disorders, eating disorders, sensory disorders etc.  Some are only an issue when very young and then fade away, some may remain. 

Biological Markers
There are hundreds of possibly relevant biomarkers and many more that are likely totally irrelevant.  The most reliable tests will use samples taken from spinal fluid, which in effect is part of the central nervous system, and so tell you what is going on inside the blood brain barrier. Blood tests can be useful but often do not tell you what is going on inside the brain. 

The most immediately relevant biomarkers relate to treatable in-born errors of metabolism, each one of these syndromes may indeed be rare, but there are many of them and you would think it worth ruling them all out. 
The risk here is getting lost in hundreds of tests, rather like with genetic testing.
There will be some useful markers like for oxidative stress, inflammatory biomarkers, mitochondrial function etc. 

MRI
It does make sense for everyone with autism to have an MRI, including those with Asperger’s. People who break their arm get an X-ray by default, is an MRI for autism too much to expect?
The brain may appear entirely normal, but there is a significant chance of identifying a relevant variation, albeit small.
There are also some specific tests that can be carried by Functional Magnetic Resonance Imaging (fMRI) at the same time as the basic MRI.  


EEG
Many people with autism, but without epilepsy, do have an abnormal EEG, with so-called epileptiform activity.  Medicine does not have a consensus opinion regarding what to do, but some neurologists, like Dr Chez, believe it should be treated and can reduce the severity of autism.  Detailed knowledge of such epileptiform activity might be useful when defining sub-groups of autism.


Genetic Testing
The tests usually offered are microarray, whole exome and whole genome sequencing.  These tests may reveal something useful or may just reveal a list of variances that do not seem to have any relation to autism.

If funds are unlimited, then whole genome sequencing of the child and both parents is the best choice.  Then you need someone very methodical to review and interpret the results.

What matters is gene expression locally and even whole genome sequencing does not tell you this, it is however a part of the picture.

Nature of Onset
People tend to consider autism as either early onset or regressive. Here it is important to extract the group who were born entirely neurotypical, met all their milestones and then regressed.
Most people’s autism started long before birth but it manifests itself differently over time. This is like the progression of a disease. Indeed one therapeutic idea is that by very early pharmacological intervention you can affect this progression and improve the final outcome.
The point here is that you can have early onset autism that appears to “get worse”, this is not regressive autism.
People with regressive autism need to split into those who profoundly regressed and those who were always different and then became more so.
For people with mild autism the time/nature of onset is likely much less of an issue. 

Variability of Symptoms
Some people with autism exhibit the same severity of symptoms every day, but many do not.  In people with highly variable autism it is very useful to understand what makes it worse.  Many lay people refer to autism as being the result of the brain being "wired-up" differently, as if it was static condition. In those with highly variable autism, the condition is clearly not fixed. Something is making autism worse, you just have to find out what it is. It could very likely be allergy, but could potentially be many things even microorganisms affecting gene expression.

The Goal - Why would you want to collect all this personal data?
As I have noted in this blog, there clearly are groups of people who respond to the same therapies. It is remarkable and it is not a matter of chance.  I do not just mean one therapy, like NAC or bumetanide, but a whole string of them, even the ones that may appear odd to some readers.
If you could predict who fits into which subgroup of autism based on answering a long list of questions on an app on your smartphone and sending some data to Google, widespread treatment of autism would become a reality.
You do need a lot of data and most of it does not yet exist.
I know a lot about one subtype of autism and there is a substantial overlap with the son of one regular commenter. Bumetanide, Potassium, NAC, Atorvastatin, Verapamil, Potassium Bromide etc all appear to have the same (beneficial) effect.
Once you have more data, you look what all these children have in common and then you can try and predict which other people will have a similar drug response. 
You just need a lot of well documented case studies and a lot of experimentation with possible therapies. In other words not just Peter’s Polypill, Tyler’s Polypill, Alli’s Polypill or Dr Kelley’s mito-cocktail,  but very much more.
There does seem to be an effective therapy for regressive autism caused by mitochondrial disease, which is likely to be one of the larger subgroups. Given all the attention given to PANDAS/PANS, I cannot understand why the mitochondrial sub-group has not been similarly “mainstreamed”. The therapy is Dr Kelley’s (from Johns Hopkins) plus add-ons.  One potential add-on being calcium folinate (Leucoverin) to reduce peroxynitrite (ONOO) from nitrosative stress, but there are undoubtedly other add-ons waiting to be discovered, or perhaps just documented.


Conclusion

Trying to match effective drugs to a long list of markers and other criteria, does have something in common with tracking individuals web browsing to generate personalized relevant advertising. So I do think that the likes of Google/Verily would do a much better job than medical researchers alone. They would of course automate the process, which is not what many doctors are going to like. 

If you happen to know Larry Page or Sergey Brin from Google, you can suggest it. Brin's former wife incidentally is the founder of 23andMe. I am sure both companies employ plenty of people with Asperger's and so likely have some kids with autism. Brin apparently is interested to find a Parkinson's cure, he has a mutation in the gene LRRK2; since this gene is also associated with Crohn's disease, he might want to fund that too. Why does Brin have a LRRK2 mutation? You only need a glance at his family history.




21 comments:

  1. Peter

    This is all very interesting and the diagnostic decision tree would be so helpful.

    I am lucky that my son responds to most drugs of your PolyPill and I wonder what would such detailed analysis show for him and Monty, how many features do they share? Apparently there are significant differences. Would such analysis be enough to recommend treatments similar to Monty's for my son with his (history of) intellectual disability, multiple slow regressions, different lab results, GI issues and PANS symptoms?

    For the time being, it seems to me that the marker which might predict future treatment success quite well is previous drug response. Would it be a part of such analysis as well? Including serendipitous findings e.g. autism improvement on antibiotic given for common infections?

    Also I wonder if an algorithm can be created for lab testing in autism. How to include all relevant treatable conditions and avoid "diagnostic overkill"? Are there any tests which should be offered to everyone? Should there be proactive screening in case of disorders overrepresented in autism e.g. celiac, if it is well known that things may present atypically (=behaviorally) in ASD?

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    1. To do this properly would require much more data and from far more participants. Then you could decide which inputs are significant and which others, might be interesting, but do not matter.

      We talk about subgroups, but actually there will be clusters and any one person might be in more than one. So for some things your son will respond in the same way as mine, but perhaps in another key area he will respond like Tanya’s son.

      As it stands, only a handful of people have tried all the interventions that your son and my son have tried. There needs to be far more data.

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  2. similar concept here: autism360.org. I registered there couple of years ago, but didn't enter the detail data. Not sure if it is still actively used.

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    1. It looks like the DAN doctor Sidney Baker's project with $1million of donated software/IT support. I wonder how many people entered data.

      I think there is a need for a mainstream initiative (NIH, Google, Simons Foundation etc). I don't expect it to happen any time soon, but it is worth raising the idea. People are far more likely to support this kind of initiative.

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  3. Some cases of autism,like mine,can fit into more than one subtype.In my case,both an inborn error of metabolism,and a unique chromosomal disorder,which may be the true underlying cause.Inborn errors of metabolism,and neuroimmune disorders like PANDAS and PANS are more common than most people think.Widespread testing and diagnosis is sadly lacking.I am one of the lucky few that have gotten diagnoses and treatments.

    Coeliac,which I have been diagnosed with,is something everybody with autism who has GI symptoms should be tested for.There is no such thing as diagnostic overkill,especially in autism with multiple comorbidities.The more tests the better to unravel what is going in.The conditions related to autism are complex.It is possible,as it was with me,to treat a metabolic disorder,and reverse autism,learning disabilities,and other cognitive,and behavioural disorders,but leave all medical problems untouched.

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    1. Roger I totally agree with you about leaving no stone unturned in autism and your story proves that - thank you for sharing. But in my country if one needs more in-depth diagnostics it is paid by parents, so a stepwise evidence based algorithm would be of help in case of limited resources.

      With regard to celiac I rather thought of going further and recommending the test to every child with autism and challenging behaviors regardless of frank GI symptoms - based on celiac over-representation and behavioral manifestations of physical symptoms in autism. At one stage, behaviors misdiagnosed as mood disorder were the only visible sign of mast cell disorder in my son.



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  4. @Roger Kulp
    Could you please let us know the symptoms of Cerebral Folate Deficiency?
    Did you have muscle weakness or any other signs visible to others without doing any diagnostic tests?
    I heard that CFD makes the leg muscle weak and people who have it cannot walk or run well.
    Thanks
    SB

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    1. Unknown,
      That is very interesting.I have had muscle wasting in my arms and legs,and poor coordination all of my life,but I never chalked it up to CFD.I always assumed it was due to my combination of coeliac,and inflammatory bowel disease.

      Poor motor coordination can be a symptom of CFD,as it was for me,but otherwise the symptoms can be pretty universal,and hard to distinguish without testing.Autism,seizures,intellectual disability (mental retardation),learning disability (I had severe nonverbal learning disorder.),self abusive behaviour (I used to head bang.I wonder if it was seizures.),sensory issues,all the usual autism stuff.This was what I had.

      True cerebral folate deficiency autism rarely exists in a vacuum,and rarely occurs with Asperger's.It can occur with any number of conditions.Intellectual disability,mitochondrial disease,PANDAS/PANS,inborn errors of metabolism,chromosomal disorders,cerebral palsy,Ehrlers-Danlos,and many more.

      Also,once you start treatment,you no longer regress when you get sick,as I used to.

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    2. Just to bring up the head circumference correlation Peter mentions - except the other end, the smaller head circumference - I remember sitting at a talk given by Dr Rossignol 5-6 yrs ago about CFD and some symptoms he listed was smaller head circumference. He also mentioned intolerance to dairy.

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  5. Hi, Peter. I've been reading your blog and I am impressed; you appear to be very intelligent. I was hoping that you could have a discussion with me. I could also give you my email if that would be easier for further discussion, but I will start by giving you some background information about me. I am a 20 year old female with Aspergers. I found out I had Aspergers at around age 17. Since I was 10 years old I presented with several symptoms and medical problems. I have peripheral neuropathy (I even get tingling in my scalp, lips, and face), migraines, vestibular dysfunction, vertigo, and chronic fatigue. I am hypersensitive to sounds and have to wear specially molded noise reducing ear plugs to be able to handle normal environmental noises. I've had Eustachian tube dysfunction for 5 years and tinnitus for 6 years. I also have chronic allergies (I was allergic to over 90% of what was tested for environmentally, plus food allergies that include beef, corn, wheat, and brewer's yeast). I have had "out of body feelings" since I was 10, and recently after more research it has occurred to me that I have all of the symptoms of depersonalization disorder. I feel like I'm walking through an illusion and I constantly question reality to the point it feels like madness. I also have "mind chatter" of random phrases, words, and melodies jumbled together that are intrusive and not coherent; this is something I thought was a sign of schizophrenia. I am trying to reach out to someone intelligent and caring enough who may have some information or suggestions.

    I need more lab work, however, finding out what to get has been difficult. I have a wide array of symptoms... I even recently had an MRI to rule out a tumor. I also had an MRI with and without contrast back in 2012 when I was 15, but I am not for sure that I can trust that the people who looked at it would have enough in depth knowledge to look for even slight differences. There is a lot more to explain as well, including some lab work I've already had. I hope that you read this and get back with me. We could discuss this more privately by email if possible. It would be interesting to converse with you; I am also a research and science enthusiast and I have been researching this topic for years given both its importance and relevance. I wish to improve and this first starts with understanding.


    Thank you

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  6. Hey Peter have you ever come across Calcipotriol in your research before on TH1/TH17 immune suppression?

    https://en.wikipedia.org/wiki/Calcipotriol

    I came across it on a paper related to autophagy and it was mentioned briefly for this ability. I looked into it further and noticed its method of action was mostly via activating the Vitamin D receptor without causing excessive calcium to be dumped into the blood. Activating the Vitamin D receptor is thought to help suppress TH1/TH17 activation.

    It is a drug, but it sounds like it might be good for some autism profiles.

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    1. It is interesting, but I think the drug form is only as a cream for applying to the skin. Many people with autism do have psoriasis.

      Perhaps an oral version of this vitamin D analog would indeed be helpful.

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    2. I'm confused about autophagy. I have read that autophagy can be pro virus and causes certain viruses to replicate. Does that just mean that those particular viruses (I think coxsackie is one) manipulate autophagy process to their advantage and the virus alone is responsible for that effect? And that taking any supplement that boosts autophagy makes no difference with those viruses? Or can viruses remain dormant and once you start taking anything that triggers autophagy, they awaken and start replicating?

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    3. Oops you are right. Oral use I suppose degrades too fast to be useful. Maybe a lipophilic form or something related.would do the trick.

      Tanya, I have.never read that autophagy increases viral activity, and on top of that there are so many different types of viruses that infect cells so many different ways that it boggles the mind.

      Autophagy roughly means that various organelles and proteins within a cell are packaged up by autophagosomes and degraded into simpler molecules that can be reused for building proteins or else as energy.

      Viruses typically are less active during fasting as their activity is energy dependent, just as the cells which host them.

      I am generalizing here, and just because I have never read about certain types of viruses becoming more active during nutrient inhibition, does not mean it does not exist, though a virus that further stresses it's host during periods of nutritional stress would seem to be anti-evolutionary since it would be more likely to kill the host and thereby weaken the transmission of the virus.

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  7. thanks Tyler for the reply. Here is just one paper:

    https://www.karger.com/Article/FullText/346388

    "Viral Exploitation of the Autophagy Pathway and/or the Autophagy Machinery
    The proviral activity was first discovered in poliovirus-infected cells, in which autophagy promotes both viral replication and nonlytic release [58]. There are several possible ways in which intact or incomplete autophagy might benefit viral infection. As an essential mechanism to maintain nutrient and energy homeostasis in response to stress, autophagy may help supply building blocks for viral replication. As a prosurvival mechanism, autophagy may help keep virally infected cells alive, allowing more prolonged replication. As a pathway that mediates dynamic membrane rearrangements, autophagy (and/or specific autophagy proteins) may facilitate the formation of intracellular membranes required for viral replication. As a process that involves many enzymatic complexes, including the ubiquitin ligase protein conjugation systems and the class III phosphatidylinositol-3 kinase complex, some of the biochemical functions of these complexes might be co-opted for use in viral replication. Many of these, and likely other, features of autophagy may be utilized to foster viral replication. In this review, we focus on selected recent studies that have not previously been discussed in other published reviews [for a more complete discussion of this topic, we refer readers to [3,4,5,6,7]]."

    Peter and Tyler,
    So I go back to my original question - if you give something in supplement/drug form that triggers autophagy, and you do not see a benefit but see worsening symptoms, could it be a dormant virus that hijacks autophagy is behind the negatives?

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  8. https://www.ncbi.nlm.nih.gov/m/pubmed/24251670/

    "There is a considerable bulk of information supporting the connection between autophagy and human diseases, including IBD, and although autophagy is actually considered more a pro-survival than a pro-death pathway, these two features of its action are relevant in human diseases, having therapeutic potential for both activators and inhibitors of autophagy. Some of the opposite effects than have been reported for melatonin in IBD could be related to the duality of its effects on autophagy, which itself can be beneficial or detrimental."

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  9. Without autophagy, cells get clumped up with debris and stop functioning properly. Same goes with damaged mitochondia not getting recycled. Most supplements/drugs with the exception of perhaps rapamycin do not promote autophagy as well as fasting does. If you want to prevent autophagy, eat like a typical American who literally is on average stuffing food down their mouth 19 hours a day which is wholly unnatural and likely is a main contributor to the diabetes epidemic.

    Too much autophagy like in some diseases will cause the death of otherwise healthy cells. Those diseases are rare so with respect to autism, I would worry more about cellular homeostasis than some hypothetical virus. The vast majority of our genome is from viruses and if you consider how many bacteria we have in and around us and then factor in how many phages infect those bacteria and change their function, you are dealing with quadrillions of virii in and around you at any moment, not to mention your genetic code mostly being remnants of viruses that infected the germline of your many many ancestors.

    When discussing virii in the context you have provided, you need to ask yourself if the virii are even pathogenic or not and very, very few virii happen to cause direct negative health problems. Most are benign and some are even healthful, otherwise life on earth would have likely evolved beyond a ball of protoplasm.

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  10. This recent paper might be a step forward in the discussion whether subclinical epileptiform discharges should be treated in autism:

    "Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder"

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587198/

    It was an RCT type of study, so one cannot now say that there is no evidence. The question remains: what is the best way to treat such epileptiform discharges in autism?

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    1. Hi Agnieszka,I hope you and your child are well, from what I can say, I am surprised and don´t understand, why yet is not clear that epileptiform activity should be treated with antiepileptics.Constant epileptiform activity, like that of our children,has caused more damage in our children´s brains than epilepsy in neurotypical people. The question of what happened first,if the egg or the chicken is opened in this matter. What I can tell you is that without valproate my son had no chance of being what he is now. Regards, Valentina

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    2. Hi Valentina,

      I totally agree with you and my first thought when epileptiform pattern was diagnosed on EEG in my son was that it's logical that having clear EEG must be better than epileptiform and will get him further from seizures, which are common in severe autism. But four neurologists denied helping me with AED for him then, because of 'no evidence'.

      Unfortunately some people think that evidence based medicine equals randomized, blinded trials only, which is wrong. But I was told by the head of pediatric neurology literally to bring her RCT while I showed her Dr Chez papers on valproate. So, here it is, four times later. I hope it might be helpful for doctors and parents in such situation.

      Valentina, I am happy to read that your son is doing well on your interventions. Are you still using valproate? I sometimes consider trialling it back although my son EEG is normal now.

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    3. Agnieszca, yes, he is taking 500 mg a day, I tried to stop it a few months ago, for almost a month, but was a very bad experience. Had tried some time ago with the same result. May be you could do a trial only with valproate and leave bumetanide for the moment and see which have better effect.I don´t think that my son´s EEG would continue normal for long time without an antiepileptic,for me is valproate.I didn´t try bumetanide, tried diamox but no effect, if my son hadn´t epileptiform activity I would try bumetanide and or diamox for prevention.Epileptiform discharges do more harm than everyone thinks. Valentina

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