Genetic Mutations vs Differentially Expressed Genes (DEGs) in Autism

 

Genes make proteins and you need the right amount in the right place

at the right time.

I should start this post by confessing to not having carried out genetic testing on Monty, now aged 18 with autism.  When I did mention this to one autism doctor at a conference, I was surprised by her reply:- “ You did not need to.  Now there’s no point doing it”.

I got lucky and treated at least some of Monty’s Differentially Expressed Genes (DEGs) by approaching the problem from a different direction.

People do often ask me about what diagnostic tests to run and in particular about genetic testing.  In general, people have far too high expectations regarding such tests and assume that there will be definitive answers, leading to effective therapeutic interventions.

I do include an interesting example today where parent power is leading a drive towards an effective therapeutic intervention in one single gene type of autism.  The approach has been to start with the single gene that has the mutation and look downstream at the resulting Differentially Expressed Genes (DEGs). The intervention targets one of the DEGs and not the mutated gene itself.

This is a really important lesson.

It can be possible to repurpose existing drugs to treat DEGs quite cheaply.  Many DEGs encode ion channels and there are very many existing drugs that affect ion channels.

Entirely different types of autism may share some of the same DEGs and so benefit from the same interventions.

 

Genetic Testing 

Genetic testing has not proved to be the holy grail in diagnosing and treating autism, but it remains a worthwhile tool at a population level (i.e. maybe not in your specific case).  What matters most of all are Differentially Expressed Genes (DEGs), which is something different.

A paper was recently published that looked into commercially available genetic testing.  Its conclusion was similar to my belief that you risk getting a “false negative” from these tests, in other words they falsely conclude that there is no genetic basis for the person’s symptoms of autism. 

 

Brief Report: Evaluating the Diagnostic Yield of Commercial Gene Panels in Autism

Autism is a prevalent neurodevelopmental condition, highly heterogenous in both genotype and phenotype. This communication adds to existing discussion of the heterogeneity of clinical sequencing tests, “gene panels”, marketed for application in autism. We evaluate the clinical utility of available gene panels based on existing genetic evidence. We determine that diagnostic yields of these gene panels range from 0.22% to 10.02% and gene selection for the panels is variable in relevance, here measured as percentage overlap with SFARI Gene and ranging from 15.15% to 100%. We conclude that gene panels marketed for use in autism are currently of limited clinical utility, and that sequencing with greater coverage may be more appropriate.

 

To save time and money, the commercial gene panels only test genes that the company defines as autism genes.  There is no approved list of autism genes. 

You have more than 20,000 genes and very many are implicated directly, or indirectly, in autism and its comorbities. To be thorough you need Whole Exome Sequencing (WES), where you check them all.  

There are tiny mutations called SNPs ("snips") which you inherit from your parents; there are more than 300 million known SNPs and most people will carry 4-5 million.  Some SNPs are important but clearly most are not.  Some SNPs are very common and some are very rare. 

Even WES only analyses 2% of your DNA, it does not consider the other 98% which is beyond the exome.  Whole Genome Sequencing (WGS) which looks at 100% of your DNA will be the ideal solution, but at some time in the future.  The interpretation of WES data is often very poor and adding all the extra data from WGS is going to overwhelm most people involved. 

Today we return to the previous theme of treating autism by treating the downstream effects caused by Differentially Expressed Genes (DEGS).

Genetics is very complicated and so people assume that is must be able to provide answers. For a minority of autism current genetics does indeed provide an answer, but for most people it does not.

Early on in this blog I noted so many overlaps between the genes and signaling pathways that drive cancer and autism, that is was clear that to understand autism you probably first have to understand cancer; and who has time to do that!

Some people’s cancer is predictable. Chris Evert, the American former world No. 1 tennis player, announced that she has ovarian cancer.  Her sister had exactly the same cancer.  Examining family history can often yield useful information and it is a lot less expensive that genetic testing.  Most people’s cancer is not so predictable; sure if you expose yourself to known environmental triggers you raise its chances, but much appears to be random.  Cancer, like much autism, is usually a multiple hit process. Multiple events need to occur and you may only need to block one of them to avoid cancer. We saw this with a genetic childhood leukemia that you can prevent with a gut bacteria. 

Learning about Autism from the 3 Steps to Childhood Leukaemia

What is not random in cancer are the Differentially Expressed Genes (DEGs).

We all carry highly beneficial tumor suppressing genes, like the autism/cancer gene PTEN.  You would not want to have a mutation in one of these genes.

What happens in many cancers is that the individual carries two good copies of the gene like PTEN, but the gene is turned off. For example, in many people with prostate cancer, the tumor suppressor gene PTEN is turned off in that specific part of the body.  There is no genetic mutation, but there is a harmful Differentially Expressed Gene (DEG). If you could promptly turn PTEN expression back on, you would suppress the cancer.

Not surprisingly, daily use of drugs that increase PTEN expression is associated with reduced incidence of PTEN associated cancer.  Atorvastatin is one such drug.

 

DEGs are what matter, not simply mutations

 

In many cases genetic mutations are of no clinical relevance, we all carry several on average.  In some cases they are of immediate critical relevance.  In most cases mutations are associated with a chance of something happening, there is no certainty and quite often further hits/events/triggers are required.

A good example is epilepsy. Epilepsy is usually caused by an ion channel dysfunction (sodium, potassium or calcium) that is caused by a defect in the associated gene. Most people are not born with epilepsy, the onset can be many years later.  Some parents of a child with autism/epilepsy carry the same ion channel mutation but remain unaffected. 

 

Follow the DEGs from a known mutation 

There is a vanishingly small amount of intelligent translation of autism science to therapy, or even attempts to do so.  I set out below an example of what can be done.

 

Pitt Hopkins (Haploinsufficiency of TCF4) 

The syndrome is caused by a reduction in Transcription factor 4, due to mutation in the TCF4 gene.  One recently proposed therapy is to repurpose the cheap calcium channel blocker Nicardipine. Follow the rationale below.

 

↓  means down regulated

↑ means up regulated

1.     Gene/Protein TCF4 (Transcription Factor 4) ↓↓↓↓

2.     Genes SCN10a  ↑↑    KCNQ1 ↑↑

3.     Encoding ion channels  Na_v1.8   ↑↑     K_v7.1   ↑↑

4.     Repurpose approved drugs as inhibitors of K_v7.1 and Na_v1.8 

5.     High throughput screen (HTS) of 1280 approved drugs.

6.     The HTS delivered 55 inhibitors of K_v7.1 and 93 inhibitors of Na_v1.8

7.     Repurposing the Calcium Channel Inhibitor Nicardipine as a Na_v1.8 inhibitor 

           

The supporting science: 

Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1

  

Highlights

•TCF4 loss of function alters the intrinsic excitability of prefrontal neurons 

•TCF4-dependent excitability deficits are rescued by SCN10a and KCNQ1 antagonists 

•TCF4 represses the expression of SCN10a and KCNQ1 ion channels in central neurons 

•SCN10a is a potential therapeutic target for Pitt-Hopkins syndrome

  

Na_v1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene

K_v7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene.

  

Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated with schizophrenia and Pitt-Hopkins syndrome (PTHS).  

SNPs in a genomic locus containing TCF4 were among the first to reach genome-wide significance in clinical genome-wide association studies (GWAS) for schizophrenia  These neuropsychiatric disorders are each characterized by prominent cognitive deficits, which suggest not only genetic overlap between these disorders but a potentially overlapping pathophysiology.

We propose that these intrinsic excitability phenotypes may underlie some aspects of pathophysiology observed in PTHS and schizophrenia and identify potential ion channel therapeutic targets.

Given that TCF4 dominant-negative or haploinsufficiency results in PTHS, a syndrome with much more profound neurodevelopmental deficits than those observed in schizophrenia, the mechanism of schizophrenia risk associated with TCF4 is presumably due to less extreme alterations in TCF4 expression at some unknown time point in development

The pathological expression of these peripheral ion channels in the CNS may create a unique opportunity to target these channels with therapeutic agents without producing unwanted off-target effects on normal neuronal physiology, and we speculate that targeting these ion channels may ameliorate cognitive deficits observed in PTHS and potentially schizophrenia.

 

 

Disordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression

Pitt-Hopkins syndrome (PTHS) is a rare autism spectrum-like disorder characterized by intellectual disability, developmental delays, and breathing problems involving episodes of hyperventilation followed by apnea. PTHS is caused by functional haploinsufficiency of the gene encoding transcription factor 4 (Tcf4). Despite the severity of this disease, mechanisms contributing to PTHS behavioral abnormalities are not well understood. Here, we show that a Tcf4 truncation (Tcf4^tr/+) mouse model of PTHS exhibits breathing problems similar to PTHS patients. This behavioral deficit is associated with selective loss of putative expiratory parafacial neurons and compromised function of neurons in the retrotrapezoid nucleus that regulate breathing in response to tissue CO₂/H⁺. We also show that central Nav1.8 channels can be targeted pharmacologically to improve respiratory function at the cellular and behavioral levels in Tcf4^tr/+ mice, thus establishing Nav1.8 as a high priority target with therapeutic potential in PTHS. 

 

Repurposing Approved Drugs as Inhibitors of K_v7.1 and Na_v1.8 To Treat Pitt Hopkins Syndrome

Purpose:

Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K_v7.1 and Na_v1.8 which triggers an increase in after-hyperpolarization and altered firing properties.

Methods:

We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K_V7.1) or HEK293 (Na_v1.8) cells and the HTS used either ⁸⁶Rb⁺ efflux (K_V7.1) or a FLIPR assay (Na_v1.8).

Results:

The HTS delivered 55 inhibitors of K_v7.1 (4.2% hit rate) and 93 inhibitors of Na_v1.8 (7.2% hit rate) at a screening concentration of 10 μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Na_v1.8.

Conclusions:

This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na_v1.8, as there are currently no approved treatments for this rare disorder.

  

Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Na_v1.8 inhibitor in vivo for Pitt Hopkins Syndrome

Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Na_v1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Na_v1.8 through a drug repurposing screen.

 

All of the above was a parent driven process.  Well done, Audrey!

Questions remain.

Is Nicardipine actually beneficial to people with Pitt Hopkins Syndrome? Does it matter at what age therapy is started? What about the K_v7.1 inhibitor?

 

Conclusion 

Genetics is complicated, ion channel dysfunctions are complicated; but just a superficial understanding can take you a long way to understand autism, epilepsy and many other health issues.

There is a great deal in this blog about channelopathies/ion channel dysfunctions.

https://epiphanyasd.blogspot.com/search/label/Channelopathy

Almost everyone with autism has one or more channelopathies. Most channelopathies are potentially treatable.

Parents of children with rare single gene autisms should get organized and make sure there is basic research into their specific biological condition.  They need to ensure that there is an animal model created and it is then used to screen for existing drugs that may be therapeutic.  I think they also need to advocate for gene therapy to be developed.  This all takes years, but the sooner you start, the sooner you will make an impact.

Very likely, therapies developed for some single gene autisms will be applicable more broadly.  A good example may be the IGF-1 derivative Trofinetide, for girls with Rett Syndrome. IGF-1 (Insulin-like growth factor 1) is an important growth factor that is required for proper brain development. In the brain, IGF-1 is broken down into a protein fragment called glypromate (GPE). Trofinetide is an orally available version of GPE.

The MeCP2 protein controls the expression of several genes, such as Insulin-like Growth Factor 1 (IGF1), brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA).  All three are implicated in broader autism. 

https://rettsyndromenews.com/trofinetide-nnz-2566/

In girls with Rett Syndrome the genetic mutation is in the gene MeCP2, but one of the key DEGs (differentially expressed genes) is the FXYD1; it is over-expressed. IGF-1 supresses the activity of FXYD1 and hopefully so does Trofinetide.  Not so complicated, after all!

Medicine is often driven by the imperative to do no harm.

In otherwise severely impaired people, perhaps the imperative should be to try and do some good.

In medicine, time is of the essence; doctors in the ER can be heard to say "Stat!", from the Latin word for immediately, statim.  

How about some urgency in translating autism science into therapy? But then, what's the hurry? Why rock the boat?

On an individual basis, much is already possible, but you will have to do most of the work yourself - clearly a step too far for most people.

   

 

Thymosin alpha 1 (Thymalfasin/Zadaxin) for auto-immune autism flare-ups?

 

Today’s post is about a drug originally proposed by Wayne State University in the US, but so far approved and widely used mostly in Asia.  China is the big producer/user and Italy is the outlier where it is also used.

 

Therapeutic Developed in United States Benefits Many in Asia

Since Wayne State University gastroenterologist Milton Mutchnick, M.D., first proposed using the hormone-like peptide thymosin alpha 1 to combat Hepatitis B in the mid-1980s, the drug has seen both outstanding success and somber letdown. Overseas, thymosin has become an important tool for fighting Hepatitis B, cancers and infections. Within the United States, its promise remains in doubt decades later.

 

Today we consider repurposing a naturally occurring peptide from the thymus to restore balance/homeostasis to the immune system in people with autism.

It has been well documented in the research (for example by Paul Ashwood at the MIND Institute) that the immune system can be dysfunctional in many people with autism, but in different ways.

Some people with autism suffer from flare-ups when their symptoms get much worse.  These flare-ups can be immune mediated, meaning that the rather complicated pro-inflammatory / anti-inflammatory balance has been disrupted.  A reset is needed.

In some cases, a short course of oral steroids is enough to provide the reset, but often it does not work.

One reader of this blog was proposed by his Italian doctor to try Thymosin alpha 1 shots to treat his son’s autism flare up.  Not surprisingly, living in the UK, he had never heard of Thymosin alpha.

 

 

Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747025/figure/F2/

 

 

 

What is Thymosin alpha 1?

 

The following paper provide an excellent explanation:

 

Thymosin alpha 1: A comprehensive review of the literature

 

Thymosin alpha 1 is a peptide naturally occurring in the thymus that has long been recognized for modifying, enhancing, and restoring immune function. Thymosin alpha 1 has been utilized in the treatment of immunocompromised states and malignancies, as an enhancer of vaccine response, and as a means of curbing morbidity and mortality in sepsis and numerous infections.

Thymosin alpha 1 has long been recognized as an immune enhancing, immune modulating, as well as an immune restoring agent, and as such it has been utilized in several clinical and research settings. The synthetic form of thymosin alpha 1, thymalfasin, is approved in more than 35 countries for the treatment of hepatitis B and C and as an immune enhancer in several other diseases

 

Thymosin alpha 1 functions as a toll-like receptor (TLR)-9 and TLR-2 agonist in both myeloid and dendritic cells, the professional antigen-presenting cells. By targeting TLRs, thymosin alpha 1 can stimulate the adaptive immune response, which is essential for fighting viral, bacterial, and fungal infections and cancers, as well as stimulation of posterior humoral immunity. Additionally, thymosin alpha 1 can increase levels of IL-2, IL-10, IL-12, interferon (IFN)-α, and IFN-γ. The role of thymosin alpha 1 in stimulating T-cell dependent antibody production is also the reason why it has been considered as a vaccine adjuvant for enhancing response to vaccines.

Thymosin alpha 1 has a wide range of biological activities that range from anti-tumor to immune-modulating properties. The immune response of thymosin alpha 1 is due to its action in elevating the activity of T cell maturation into CD4+/CD8+ T cells. It works to directly activate natural killer cells as well as CD8+ T cells through which it kills virally infected cells. Thymosin alpha 1 has a negative effect on IL-1β and tumor necrosis factor-α, which in turn leads to a decreased inflammatory response and is quite beneficial in conditions such as chronic hepatitis and acute pancreatitis.

  

 Thymosin alpha 1 has a wide range of biological activities. IL: Interleukin; IFN: Interferon; TLR: Toll-like receptors.

  

Thymosin alpha 1 has exhibited the ability to restrain tumor growth, hence its use in the treatment of various cancers. It has anti-proliferative properties which have been exhibited in lung and liver tumor metastases.

Since thymosin alpha 1 is a polypeptide naturally present in the thymus, it plays a fundamental role in the control of inflammation, immunity, and tolerance. Thymosin alpha 1 has an immune-modulating action through its interaction with toll-like receptors. Due to the action of thymosin alpha 1 on other cell types, it is used as a therapeutic agent for diseases with evident immune dysfunction. Clinical trials with thymosin alpha 1 for diseases like DiGeorge syndrome, non-small cell lung cancer, hepatocellular carcinoma, hepatitis B and C, HIV, and melanoma have been conducted and yielded promising results. FDA approved the orphan drug thymalfasin (Zadaxin) for treatment of malignant melanoma, chronic active hepatitis B, DiGeorge anomaly with immune defects, and hepatocellular carcinoma due to its immunomodulatory and anti-tumor effect.

 

  

Thymosin alpha 1 for auto-immune autism flare-ups? 

Thymosin alpha 1 is no wonder drug for autism, but it looks like it has a place in the autism toolbox, for when symptoms take a sharp turn for the worse and you need a reset back to your baseline autism.

If it solves the flare-up, great.  If not, you just move on to the next option. 

 

Conclusion 

Italy does seem to have a different view of medicine.  They are big on the medical use of probiotic bacteria. They have treatments for GI problems that seem to be unheard of in other countries. It is home to the novel idea, that I found appealing, to use nerve growth factor (NGF) eyedrops to prevent dementia.

Italy is also home to the use of Thymosin alpha 1 shots, to reset the immune system after an immune-related autism flare-up.  I think it is a great idea and I doubt it is expensive.

Most readers of this blog are in North America, where Thymosin alpha 1 is not an approved drug. In China, India, Italy and another 30 countries it is widely available. 

As Zadaxin, Thymosin alpha 1, is produced by SciClone Pharmaceuticals in China.  They provide the following summary:

http://www.shijiebiaopin.net/upload/product/2011121219115812.PDF

 

It looks like our readers who have an autism doctor in Italy have some interesting options. 

Wayne State University never sought patent protection for Thymosin alpha 1 in China, which they now regret.

The Semantics of Autism - how the meaning has changed over time

 

A couple of weeks ago I took Monty, aged 18 with ASD, for his Covid booster injection. Since I was accompanying an adult and filling in his paperwork, I thought I should explain why I was needed there. I just said he has autism and prefers to speak English.

Where we live, autism still means severe autism and I for one would be very wary about trying to stick a needle in an unknown person with that diagnosis.

Monty is no problem at all at the doctor or dentist, he has figured all this out.

Moves are afoot to reintroduce the term “profound autism” to describe older children and adults who are severely disabled.

 

The Lancet Commission on the future of care and clinical research in autism (free to access full paper)

Awareness of autism has grown monumentally over the past 20 years. Yet, this increased awareness has not been accompanied by improvements in services to support autistic individuals and their families. Many fundamental questions remain about the care of people with autism—including which interventions are effective, for whom, when, and at what intensity. The Lancet Commission on the future of care and clinical research in autism aims to answer the question of what can be done in the next 5 years to address the current needs of autistic individuals and families worldwide. 

Available to watch on-demand / webinar

 

The term profound autism is not appropriate for young children. It might begin to be useful, with the consent and participation of families, from early school age (e.g., from the age of 8 years) for children with autism and severe to profound intellectual disability or minimal language, given the evidence that these factors are not likely to change. The term might be most helpful in adolescence and adulthood. It is not intended to describe other severe difficulties related to autism that might apply to individuals with extraordinary life circumstances, trauma, family conflict, scarcity of resources, or those with co-occurring mental health problems. We acknowledge that the word profound can have different connotations and other terms might be more appropriate in other languages. For example, in Spanish, the words severo or grave might be more appropriate because of different meanings of profundo (ie, deep).

 

Figure 4 shows the potential effect of differing levels of service, formal recognition of autism, active support, and community adaptation on the outcomes and functioning of the heterogeneous population of autistic individuals.

Societal response and services can optimise outcomes for all people with autism The green line indicates the hypothetical degree to which the environment supports the adaptive potential of autistic people with different cognitive abilities.

 

Many of those who were behind the drive to create the idea of the autism spectrum now acknowledge that the term autism is so broadly applied that it has little meaning.  It looks like they want to go back to the ways things used to be when different diagnoses were used, based on how disabled the person is.

When Kanner and Asperger were studying children in the 1930s, they were mainly interested in those without intellectual disability.

From his landmark paper in 1943, Kanner’s subject #1, later identified as Donald Triplet, grew up, went to College, learned to drive and was a keen golfer.

Today, when people talk of Kanner’s autism or classic autism, they are referring to something very different to much of what Kanner was studying.  They are talking about people with no hope of graduating real high school, let alone driving a car.

Kanner’s autism was not originally profound autism, but nowadays it is.

 

Can you have severe autism and normal IQ?

I would have been one of those saying it is impossible to have severe autism and a normal IQ, but I fully admit that it depends on whose definition you are using.

A retired neurodevelopmental pediatrician called James Coplan has some interesting thoughts.

Coplan wrote a short paper called “Counselling Parents Regarding Prognosis in Autistic Spectrum Disorder”. https://pubmed.ncbi.nlm.nih.gov/10799629/

It is only three pages long.  In one of his videos on his YouTube channel he comments that autism is 130 years behind most areas of medical science, since it is not diagnosed biologically, merely based on observations relative to an ever-moving benchmark, the US DSM (Diagnostic and Statistical Manual of Mental Disorders).

He points out that back in the 1980s under DSM version 3, the only kind of autism was severe autism with MR/ID. So only a few people were diagnosed.  In 1994 version 4 appeared and it included milder autism, with Asperger’s as a sub-type. In 2013 in DSM version 5, Asperger’s disappeared as a sub-type.

Coplan went from working with a rare, but severe disorder to a common but generally much mild one.

 

Coplan considers three variables:

 

·        Atypicality (how autistic you are) occurring along a spectrum from mild to severe.

·        Intelligence, with the centre point being an IQ of 70, the boundary of MR/ID

·        Age

  

Autism of any degree of severity can occur with any degree of general intelligence.

The long-term prognosis represents the joint impact of autism severity and cognitive ability; higher IQ leads to better outcome. 

The observed severity of autism in the same individual varies with age.  Many children with higher IQ do experience significant improvement over time. 

The ideal outcome is child B, in the chart, whose atypical symptoms were always mild and whose intelligence is above cut-off for mental retardation / intellectual disability (MR/ID).  The core features of ASD break up into fragments, which diminish in severity with the passage of time, until only traces of autism remain. 

A less favourable outcome is child A, who has severe autism, plus mental retardation MR/ID.  As time goes by, he continues to exhibit the same level of autism.

Clearly most children will be somewhere in between child A and child B. 

Dr Coplan says that there is little evidence that the prognosis today is different to that in the 1970s or 80s. That suggests little impact from the twenty year surge in expensive ABA interventions in the US.

   

Childhood Schizophrenia 

The original term for what became autism, was childhood schizophrenia, which started being used in the 1920s.

I did mention in an earlier post that I came across an interesting comment written by Michael Baron; back in 1962 he headed the world’s first parent organisation for autism, the UK's National Autistic Society.

Baron’s main point was to highlight how autism has completed morphed in 60 years to a quite different condition.  It is not the same autism. 

When his organisation was originally founded, it was called The Society for Psychotic Children.  That was the name the parents came up with themselves, before later substituting the word Autistic.  

The old name has well and truly been erased from the records.  Definitely not politically correct these days.

Autism may now be a cool diagnosis to some people in 2021, but being psychotic still is not. Perhaps bipolar will be the next cool diagnosis.

Note that the only approved drugs for autism in 2021 are actually antipsychotic drugs!

  

Autism first appeared as an official diagnosis in 1980 

In 1980 the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) includes criteria for a diagnosis of infantile autism for the first time.

In 1994 Asperger’s Disorder was added in DSM-IV as a separate disorder from autism.

In 2013 DSM-5 was published and it combined autism, Asperger’s, and childhood disintegrative disorder into autism spectrum disorder (ASD). 

Hopefully, in DSM-6 there will be more intelligent science-based subdivisions of conditions within autism spectrum disorder (ASD); but, probably not!

 

Autism without impaired speech or cognition

In 2006, before the introduction of Asperger’s as a diagnosis, Ari Ne'eman established the Autistic Self Advocacy Network (ASAN).

These people are a subset of Dr James Coplan’s high intelligence plus mild to severe atypicality.

Many of this group regard intellectual impairment and lack of speech as unrelated to autism.  They see them as just unrelated comorbidities.

The Moms with a case of profound autism at home might counter that the suicidal thoughts that plague the #actuallyautistic people are also not part of autism either, rather a comorbidity.

  

Who is right?

I suppose the science can tell us who is right.

But language is not about science and being right does not really matter.

The meaning of words can change.  The words “gay” and “queer” are no longer usable in their original meanings.

In the school yard, “autistic” is now used as an insult, like all the LGBT words are/were, depending on where you live.

  

Profound Autism

Now let us come back to the proposed definition of profound autism:

·        IQ<50

·        Age>8

·        Severe autism/atypicality

This fits perfectly into Dr Coplan’s framework.

It is the stubborn “block A”.

Far removed from the Elon Musk “block B” type, that was treated in childhood by explaining social cues etc and the result was the symptoms receded into the background; they are only there if you want to see them. 

It looks like some people are desperate for those little cubes not to melt away; they actually find they give them identity and purpose.  Musk just wants to make a lot of money and get to Mars, which looks a better life mission.

 

 

 

You might wonder why you have to wait to the age of 8 for this proposed new diagnosis.  The panel includes Catherine Lord, who conducts the ongoing longitudinal study of autism running now for 20 years. She fully understands that things can change along the way as toddlers grow up.

·       Some people are misdiagnosed with autism at a very early age.  Indeed the well known autism epidemiologist Eric Fombonne found that when you recheck the diagnosis, about a third of people have been misdiagnosed. Doctors over-diagnose to help delayed children access the better services, available to those with an autism diagnosis.  

·       Some toddlers are just late bloomers and after a period of delayed development, do catch up

·        Some people unfortunately have an event in childhood, usually after the age of 5, that causes a (further) regression.  This is what I term “double tap” autism; you survive the first tap, but then along comes the second. The second event can lead to profound disability.

   

Conclusion

You can certainly make the case that the old DSM-IV terminology was much more useful.  People with normal IQ and no speech delay were Aspies and people with low IQ and limited speech had autism.

Many parents do not like now having to say their grown-up child has severe autism, for them autism was sufficient. They see severe as an unnecessary pejorative term.

Once self-advocates tell the world that autism is neither a disorder, nor a disability, it is hard for the wider public not to conclude that autism is nothing more than the new ADHD.  You pay some money, get the diagnosis you want and join the club. 

As Uta Frith, who brought us the well-intentioned idea of autism as a spectrum recently commented, the word autism is now meaningless.

Professor Uta Frith of University College London recently spoke out about autism spectrum disorder (ASD) diagnosis, saying urgent changes are needed in how the condition is diagnosed as it “has been stretched to breaking point and has outgrown its purpose”.

I think one of the underlying problems is that most people do not like any terminology that refers to low IQ.  Don’t dare mention mental retardation. The English language is full of pejorative terms for people with low IQ. Eventually, as their child becomes an adult, some parents start to use the term intellectual disability as a descriptor to distinguish their case from Elon, Greta, Temple Grandin and those cute Netflix depictions.

As Catherine Lord and others have shown from their longitudinal studies, IQ is the best predictor of a better outcomes in adulthood.

There is much in this blog about raising cognitive function and as I have been saying for a while, treating ID/MR is much less controversial than treating autism.