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Friday 1 February 2019

For “Autism” just read “Special”






The entry to Bethlehem through the separation wall from the road to Jerusalem

We recently visited Jerusalem, but our return flight was cancelled due to snow at our return destination.  As a result, we got to experience the inflight TV on Turkish Airlines as we came home via Istanbul.  The TV is nearly all family friendly American programming.
I was surprised how many of the family programs now include characters with “autism” and even one character discussing her own IEP (Individual Education Plan). None of these characters would have been diagnosed with anything back in the days I was in school. My 15-year-old son with classic autism has never had an IEP; it feels like I am his IEP, but I am not complaining.
What I did find interesting was an episode in which, when confronted by a 10-year-old Aspie asking her annoying personal questions, a teenage cheerleader just said “oh, you’re one of those special kids”.
Special is a nice way of saying different and nobody would think of it as a biological diagnosis, as they very mistakenly do with autism.  
It looks like today at least 25% of kids are now seen as “special”, one way or another, and in the great majority of cases there really is no definitive biological reason why.  All 25% would benefit from special help at school, so no surprise some parents desperately seek out an autism diagnosis.  My son's assistant at school is often asked for help by the non-special kids, who find her notes very helpful and the teachers say to me how some of the non-special kids would benefit from the extra work my special son does regarding spoken and written communication.
Until recent decades you had to be extremely special to get any specific help. If you were deaf or blind you had your own school, often residential.
The 15% of the population with an IQ less than 85, all the people with AD(H)D, autism, bipolar, schizophrenia, dyslexia, dyspraxia, dysphasia, (gender) dysphoria etc should all count as special.
All the people with genetic or metabolic dysfunctions are special, but 99% of the population could not understand the detailed medical explanation of why, unless they are willing to sit down for a few hours and do some homework.
So, I think we should apply the teenage cheerleader’s simple explanation that they are all just special kids. No further explanation needed, unless she is aiming for a PhD, or he is her brother.
Nobody will feel upset if in the next decade psychiatrists define 30% of kids as special. Deep down most people would like to be special in one way or another.

What Kind of Special?
If someone really wants to know what kind of special a person is, that is like asking how a nuclear reactor works; it is possible to answer, but it takes a long time to explain.
Most people really do not want to know how a nuclear reactor works, they just assume that some clever people at the power company do know.
If you really want to know what causes a particular person’s severe autism, you will soon realize how dumb it is to use the word “autism” as a medical diagnosis.
Consider those dendritic spines that make a connection between neurons in the brain. The only thing different genetic autisms have in common is that they all vary from normal/typical, but they vary in all possible ways - too many/few spines, or just the “wrong” shape.

Typical dendritic spine (in grey) vs 5 "genetic" autisms 

Accept that 90% of people are not interested                   
Most people really are not interested in a “special” variation that does not affect them. Many such variations are very complicated to understand and so well-intentioned raising awareness may not be helping.  Just repeating the name of the disorder does little to explain it; it just means more people have heard of it.
My elder son recently asked his Grandparents what they would do if he had been gay. He knows that for them gay is even “worse” than autism. In fact, when going to study abroad one of the tips he received was to stay away from gay people.
I think the Grandparents would also have said stay away from autistic people, but now they have got to know one, and it is not so bad.  Even so, they do not themselves want to see other autistic people.
Creating this large “special” category has many advantages, everyone will almost inevitably already know someone who is “special”.
In our superficial world, where everyone seems to have an opinion on just about everything, regardless of whether they understand it, just keep it cheerleader simple, “special” is the way to go.






18 comments:

  1. Peter, I've checked some of the most important enzymes for drug metabolism through cytochrome 450 dna test, serotonin, dopamine polymorphism and found out he is an intermediate cyp2d6 metaboliser and ultra rapid cyp2c19. He is also heterozigous 5-htt(SLC6A4) and drd2 a2>a1. He is prone to tardive dyskinesia and prolactin accumulation if treated with antipsychotics. Drd3, 5ht2a and other cyps are ok. These cyps are not only in liver, they are also in the brain and metabolize both exogenous and endogenous chemicals, for example steroids, cholesterol , vitamin D, fatty acids etc. and research is still going on to identify and suggest possible treatments. Diabetes type II and glucose metabolism is implicated here. My simple reading says, his being an intermediate cyp2d6 metaboliser means defective detox system and ultra rapid cyp2c19 means vital substrates don't stay long in his system. This combimation leads to ineffective therapies and adverse effects.
    Petra

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  2. Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates.DOI: 10.2217/pgs.14.151
    Here is some relevant Swedish research.
    Petra

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    1. Petra, The efficiency of cytochrome enzymes that metabolize drugs and also, as your study highlights, endogenous substances, determines how quickly your body breaks down these substances.

      Being an intermediate CYP2D6 metaboliser means he might require a lower dose of drugs using this enzyme

      Your paper states that CYP2D6 is implicated in metabolism of the endogenous compounds 5-methoxytryptamine, anandamide, progesterone and tyramine and in generation of serotonin and dopamine from trace amines

      Being an ultra rapid CYP2C19 metaboliser means he would require a higher dose of drugs using this enzyme.

      The paper states that CYP2C19 is implicated in the metabolism of endogenous substances during brain development seems to be a likely explanation for the phenotypes observed in the transgenic mouse model; however, the identities of these substances remain to be discovered. CYP2C19 has been shown to metabolize cannabinoid compounds.

      SLC6A4 and DRD2 are considered possible genes for bipolar disorder.
      https://www.researchgate.net/publication/258525774_Gender-specific_association_of_the_SLC6A4_and_DRD2_gene_variants_in_bipolar_disorder/download

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  3. Thank you Peter. I'll check the paper about bipolar,however, according to my reading so far, his being heterozygous SLC6A4 and DRD2 rescues things a bit and makes him candidate for anxiety, depression, PTSD and diabetes type II.

    Petra

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    1. Petra, did you ever try an L type calcium channel blocker, like Verapamil?

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  4. Yes, I used it some long time ago but I didn't have a stable mood improving effect and quitted. Recently I've thought of nifedipine as he shows signs of reynaud's phenomenon due to emotional stress.
    Lately my son had another throat infection and was found strep positive. He took a ten day course of augmentine and responded very well, I mean no behavioural issues, but after a while he presented with unbearable ocd and started fluvoxamine, 100mg divided into two doses.
    Fluvoxamine is a potent sigma 1 receptor agonist and once again I saw that this mechanism is really helpful in his case. Among sigma 1 receptors bind steroids and I suspect, without being able to prove, progesterone lowering effect which seems beneficial for him. Turmeric, oregano and various spices have a progesterone lowering effect, good and safe options for my son's daily nutrinion. You mention cyp2d6 processes progesteone, perhaps not being able to eliminate he gets aggressive, just a thought I want to mention.
    Petra

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    1. Petra, it is odd but the OCD seems to come after the infection, not during it. A 5 day course of prednisone seems to make the OCD go away, you may want to ask your doctor about it. It is likely classic PANS/PANDAS.

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  5. Roger, I am not aware of any genes that predispose you to PANS/PANDAS.

    In fact PANS can occur at any age and so really should be called ANS; Petra’s son for example is an adult.

    People with an over activated immune system (activated microglia) are likely to be prone to their body mistakenly attacking certain receptors in the brain.

    NMDA receptor encephalitis is another example and I would put it in the group of ANS disorders.

    https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

    Depending on which receptor is attacked, the neuro psychiatric symptoms will differ. If left untreated for a long time the symptoms will likely become permanent.

    I did coin the term “double tap autism” to describe people with severe but stable autism who in later years suddenly find their symptoms worsen. So an ABA responder suddenly becomes untreatable, for example.

    One part of those with a double tap or sharp regression undoubtedly had an undiagnosed and untreated ANS event. I think this is particularly likely with sudden onset tics and repetitive behaviour (dopamine receptors attacked), but as with NMDA encephalitis any other type of receptor could be mistakenly targeted.

    Treating the underlying immune activation is ultimately the solution, then when a genuine trigger for the immune system comes along there will not be an aberrant response in the brain.

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  6. Dr. Jennifer Frankovich just gave a webinar recently and will be published from Stanford (don't know when)w some emerging info. My understanding from the talk is that there is a strong association with HLA-Bw4-allele which she had said was preliminary data. Thes post-infection/inflammatory disorders show signs of systemic inflammation -- high rates of autoantibodies, complement activation, vasculitis. Conditions are mediated by inflammation. Those are my notes, so please take with a great of salt. MH

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    1. Also referred to data from Drs. Gledd and Chugani ---swelling and increased microglia activity in the basal ganglia, suggesting underlying activated microglia-mediated neuroinflammation, were found to be increased in bilateral caudate and bilateral lentiform nucleus in the PANDAS group MH

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  7. Here is some big research concerning fMRI autism research I read about last week but have been too busy to post about here until now:

    Press Release:

    https://www.sciencedaily.com/releases/2019/01/190130133120.htm

    Paper:

    https://www.biologicalpsychiatryjournal.com/article/S0006-3223(18)32090-0/fulltext

    This research is very important because it may suggest that many fMRI findings with respect to autism may actually be backwards in terms of what the findings happen to be.

    What the researchers did was first measure regional blood flow in various white matter and grey matter areas of the brain and then compared those findings with the N-Acetyl-Aspartate levels in those areas (NAA is a measure of neural activity, especially healthy neural activity). What they found was that in regions with hyperperfusion (higher than normal blood flow), the NAA levels were lower than normal. More blood flow in healthy neurons would suggest higher NAA levels, but the opposite was actually found. This suggests that it may be that neural support cells (astrocytes, oligodendrocytes) may be working harder to support unhealthy neuron axons to compensate for their dysfunction. The increased metabolism from the neuron support cells thereby raises the regional cerebral blood flow (rCBF) as an indirect measure of compensation.

    So for instance, many fMRI autism studies now have found hyperperfusion in the salience network which comprises the dorsal anterior cingulate cortex with the right ventral anterior insular cortex which has to date been assumed to mean that the neurons in the salience network are hyperactive. What this new research may suggest is that the axonal connections (white matter) between these two nodes/regions in the salience network may be dysfunctional and/or unhealthy and therefore hypoactive, and that the hyperperfusion that consistently shows up in fMRI studies is merely the increased metabolism of the axon support cells requiring additional blood flow to support their activities.

    In terms of treatment, this may suggest that axon support interventions and drugs such as what has been developed for Multiple Sclerosis may warrant a closer look with respect to autism as it improving the health of the white matter may reduce the strain on the neuron support cells whose hypermetabolism could be causing secondary problems (inflammation, low rates of autophagy, etc.)

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    1. Tyler, very interesting and I recommend other people to read your first link.

      I guess Maja and other readers who obtained Clemastine will be feeling thankful.

      I think in the US readers seeking Clemastine should just go and ask a pharmacist. The generic producer Teva also seems to sell it in the US. It is even sold on eBay.

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    2. Also forgot to mention that the researchers hypothesized that mitochondrial inefficiency was the primary culprit in the dysfunction of the axons. Of course it could be many different issues contributing to the low NAA levels relative to regional blood flow, but I just thought I would point that out, especially since unlike all other cells in the body, mitochondria in neurons have to migrate vast distances from the soma to get to the distal parts of the cell.

      In fact, a recent paper I just read even suggested there is a process whereby mitochondria can be delivered from neural stem cells to neurons themselves directly from membrane to membrane contact since most neurons need to live up to 120 years and mitochondria need to turnover readily in cells with a high metabolism. If there is a problem with this process, one can envision problems with axons, especially very long ones like the kind that traverse other sides of the brain such as what you find with the corpus callosum and the anterior commissure.

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  8. Peter,

    This is a brilliant explanation of PANS. What about expanding your ANS name to AINS, with "I" for immune-mediated then?

    The problem is that PANS criteria from the US are behavioral and just yesterday I was told by a parent in Poland that her child cannot be diagnosed with PANS/PANDAS by the immunologist here as "there are no criteria" at all. Cunnigham Pannel use as biomarker has mixed results in the published studies and in my opinion, the immune activation does not necessarily need to be antibody mediated anyway. So how to diagnose/prove immunological nature of PANS?

    Obviously, the next (million dollar) question is how to treat underlying immune activation - a broad term in fact ?

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  9. Roger,

    Not sure if you still look back to this comment, but there is a clear relation between PANS symptoms and genetics in my son. He was indeed suspected of PANS/PANDAS and he fulfills most of PANS criteria with his episodic behavioral symptoms in addition to autism.

    Recently WES revealed CACNA1A variant in him, which is likely contributing to his manifestation in a polygenic/multifactorial manner – to quote the geneticist. This kind of calcium channelopathy is associated with abnormal glutamate synaptic release, which can be triggered by infection, allergy and even emotional stress – just like it is described in PANS. In most people pathogenic mutations will cause complicated migraines or ataxia, but psychiatric symptoms of wax and wane pattern have also been reported. This is what happens to my son. He has confirmed mast cell activation syndrome and possibly other types of immune dysregulation as well, which possibly triggers his aberrant P/Q calcium channels from time to time resulting in what is a textbook PANS flare.

    I guess that there may be many paths leading to PANS or A(I)NS, just as Peter explained, and some of them may have a genetic background.

    Coming back to the title of this blog post, until most people for “autism” just read “special”, such things will not be explained soon. That’s why I think this way of presenting autism to the public is really detrimental for those in need.

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  10. Agnieszka, thinking long term, you encourage your daughter to enjoy household pets, particularly dogs and visits to farmyards and not to be obsessed with living in a super clean home. Then when she becomes a mother and maintains her exposure to animal bacteria, this will help calibrate her children’s immune system.

    For someone already with autism re-calibrating their immune system is not possible, but it should be possible to modify it.

    In the brain, minocycline, BHB and clemastine can all shift activated Microglia (M1) back to resting (MO) or perhaps over to M2.

    I actually believe in the crosstalk with the rest of the body and that activated microglia is at least partially a consequence of immune activation elsewhere in the body. This means all kinds of things might help, which will even include those gut bacteria that seem to modulate inflammation (Th1,Th2, Th 17 etc).

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  11. Agnieszka, I just saw this paper:

    Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome
    https://www.ncbi.nlm.nih.gov/pubmed/31468518

    /Ling

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  12. Hi Ling,

    Thanks for the paper, not many is published on CACNA1A.

    At the moment I can't access the full text, but I like the conclusion:
    "functional validation [of the gene function] is required to clarify the underlying molecular mechanisms and to guide therapies."

    If only it was easier to have it done...

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