Autism research in 2023: a bit of a game-changing year

 So, autism research in 2023. It’s been quite a year. Let me (briefly) tell you why.

The autism numbers game: the only way is (still) up. Northern Ireland, where some great work is done to plot the annual (estimated) prevalence rate of autism spectrum disorder (ASD) in school-aged children, said 1 in 20 (or 5%) in 2023. The US CDC said an estimated 1 in 36 8-year olds (2.7%) were autistic in 2020. The CDC also said 1 in 47 4-year olds were autistic (2%). Scotland also recently produced data observing “The prevalence of autism was 2.60% (10,089 children) in 2022. This represents a 31.98% increase from the 2018 prevalence of 1.97% (7883 children).” That Scottish data, by the way, only covered those at primary school (aged 4ish-12ish years). Other sources too are still showing a growth in the prevalence of autism across other parts of the globe, including a near 5% rate of behaviours consistent with autism or ASD in the Hadza of Tanzania. All data on autism prevalence is still only heading in one direction: UP. 

Importantly, the old ‘all better awareness’ arguments are slowly fizzling out as the effects of those prevalence stats are starting to show on resources and infrastructure that seemingly haven’t kept pace with the growth in numbers. Indeed, one of the head people related to the CDC autism figures, went as far as to say that the stats don’t really support ‘better awareness’ as the primary driver given that the increase is showing across various different ‘levels’ of autism that are/were unlikely to be missed or thought to be something else. Certainly here in the UK, I don’t think I’ve ever read so many reports about school place shortages (particularly specialised school place shortages) as I have this year. And unfortunately, with an estimated 140,000 people (mostly children and young people) awaiting assessment in England alone, I fear the squeeze on resources is just going to get worse and worse. Anyone care to start asking ‘why the increase’ yet?

CDC says yes to ‘profound autism’. Speaking of autism ‘levels’ (as in DSM-5 autism levels of support or the ICD-11 condition combinations), the CDC did something else rather important this year: producing the first ever report on the rate of profound autism in the US. So, for data covering the years 2000-2016, and using the descriptor “classified as having profound autism if they were nonverbal, were minimally verbal, or had an intelligence quotient <50” they determined that 26.7% of those with autism fitted into the profound autism category. An estimated quarter of autistic people are profoundly autistic. That’s quite important.

There were mixed reactions to the CDC use of the term profound autism. Many people were happy to see it, given that it now lays the foundations for more research and more understanding that despite being united by a triad/dyad of symptom combinations, not everyone experiences autism in the same way. Look no further than the awful early mortality statistics following the deadly triad that is autism, wandering/elopement and water safety to see this in action. Of course autism by virtue of just being diagnosed, means support is required for everyone with the diagnosis. But that support will arguably differ depending on whether you possess things like communicative speech and language, present with things like self-injurious or aggressive behaviours and/or need 24-7 care to ensure that your daily needs are fulfilled. Indeed, I often think that the general lack of support post autism diagnosis is a big driver in the reticence to adopt the term profound autism in some quarters. But should people be so reticent? I mean we have similar distinctions when it comes to experiences of learning (intellectual) disability and nobody seemingly bats an eyelid there. 

There is however more to do on profound autism. This ties into other changes that are needed when it comes to assessing things like cognitive functions and communication (verbal or non-verbal) ability in relation to autism. That’ll follow as the term beds in and builds up more of a research base. Asperger syndrome gone, profound autism steps in.

What else? 

Non-persistence of autism in (some) young kids. 2023 also gave a lot more credence to the idea that the saying ‘all autism is lifelong’ probably isn’t as accurate as you might think. Looking at the developmental trajectories of around 200 kids, all diagnosed early with autism, saw about a third of them not continuing to meet the diagnostic threshold for autism/ASD at ages 5-7 years according to a big study. Other independent work also illuminated this topic and argued against the ‘just misdiagnosed’ suggestions that some people might make and that also the state of ‘autism free’ might have important implications for various other issues too.

This was a particularly important finding for me given our paper from a few years back talking about inborn and lifelong not necessarily being the most accurate phrases for all autism. It also accords with various other studies in related areas observing that diagnoses like ADHD and depression for example, aren’t lifelong labels for absolutely everyone either. Although I noted some people tried to talk about ‘masking’ and ‘camouflaging’ as being the reasons why young kids in that JAMA study didn’t meet the thresholds for autism having previously done so, I do have to ask whether they’ve ever seen autistic kids at this age. Indeed, any child at this age, who generally aren’t renowned for their developed social etiquette abilities covering masking et al (this is also the reason that the gold-standard autism assessment instrument, the ADI-R, codes 4-5 years separately from ‘current behaviour’). As to why autism doesn’t persist for some, well, we don’t know exactly. There was talk of intervention potentially playing a role (behavioural intervention) but it’s probably going to be a bit more complicated than just that. For now, we await further studies on this important topic including more longitudinal ones and perhaps also looking at the biology behind this phenomenon. If I was to speculate about why there is autism non-persistence for some, I might be inclined to say ‘look to infection’ for some, and how, more and more, we’re learning that infection and immune responses to infection can manifest as behaviour and developmental issues as well as in immune biology. Just me speculating, so pay no mind (although that autism in Hadza children study did nicely reignite my interest in how infections like malaria can, through various mechanisms, also seemingly lead to autism).

The gut-brain axis is important to autism. I know a lot of people already appreciate this, but seeing it in a peer-reviewed mega paper in 2023 adds a lot more weight to it. Said paper trawled through huge amounts of data about gut bacteria and the like, and concluded that there is something to see both as observation and also as potential intervention. Authors even mentioned the words ‘faecal matter transplant’ (FMT) in the context that what goes on in the gut doesn’t necessarily stay in the gut, and something that is rising in some autism research and other circles. Allied to the gut-brain axis stuff was the reporting from other mega review papers observing that gastrointestinal (GI) symptoms are present in roughly 55% of children with autism, compared with about a quarter of non-autistic children. Constipation comes out on top. So fixed to clinical advice about treating such issues published over 10 years ago, maybe now is the time to preferentially screen and treat such issues in the context of autism? Perhaps recognise that the gut and brain are connected for quite a few labels/conditions? More on that shortly.

Various medical issues are over-represented in autism. More important data points to the various clusters of medical (somatic) issues that seem to accompany autism across the age ranges. Ranging from cardiovascular conditions to immune-mediated conditions, various studies confirmed what quite a few people already knew. With my gluten research hat on (I don’t actually have a hat made of gluten), I was glad to see that the archetypal gluten-related autoimmune condition called coeliac disease was given mention. Who knows, between coeliac disease and the slightly greyish area of non-coeliac gluten issues that seem to be over-represented alongside autism, there’s further hope for wider screening and use of a gluten-free diet in the context of autism? Oh, and just before you inquire about the research base in this area, here’s a couple of meta-analyses from the last few years - see here and see here - saying it might be worth a shot (minus any clinical or medical advice given or intended).

And there was yet more research on the psychiatric and behavioural issues that seem to be over-represented alongside autism. Importantly, and I do think needs a lot more investigation, one study out of Canada stressed the need to look at comorbid psychiatric issues as being an important driver of suicidal behaviours in the context of autism. I know such behaviours are complex and often very individual with a heavy biopsychosocial tilt, but there’s a wealth of evidence out there already suggesting that depression, bipolar disorder, personality disorder and schizophrenia spectrum disorders all convey a heightened risk for suicidal behaviours. All those conditions are well over-represented alongside a diagnosis of autism (yep, an estimated 1 in 10 autistic people will potentially ‘transition’ to schizophrenia). Screen, screen and treat (including, where appropriate, more clinical emphasis on the archetypal anti-suicidal agent that is lithium used in the right context).

Late 2023 research entry: CM-AT results are really, really, really promising. I’ve been following the CM-AT story for quite a while on this blog and beyond. Basically, it concerns a pancreatic enzyme therapy designed for autism that has already crossed quite a few methodological trial hurdles. Then, in November 2023 lo and behold, the results of a double-blind, placebo-controlled trial that say, yes, following the gold-standard trial design, CM-AT is good for treating/managing irritability and agitation in the context of autism in pre-schoolers. Said treatment is also likely safe and effective. This is a potential game-changer and opens the door to things like regulatory approval. Also, exquisite evidence for the whole ‘behaviour is biology’ tenet and the important role of the gut-brain axis in autism, yet again.

There was so much more other science published this year, across all-manner of different topics. Certainly far too much for me to put into one blogpost. I’m a great believer in your citizen scientists and so would encourage everyone to look-see and take part. I can’t help but draw your attention to another paper that basically said the ‘person with autism’ vs ‘autistic person’ arguments typically seen on social media aren’t really worth a dime. Ask the person how they want to be addressed. Oh, and remember, people aren’t ‘neurotypes’ either. They’re people. 

And finally… Saying farewell to Donald.

Finally, [I can see you’re yawning] a non-sciency thing to mention. ‘Patient 1’ from the great Leo Kanner’s seminal paper describing autism - Donald Triplett - passed away. If you’ve ever read or watched ‘In a Different Key’ you’ll have read about him or seen him. Of all the things said about Donald in the various obituaries to him, I think the overwhelming idea that comes across is how much community was important to him; both being part of a supportive community and having a great community around him. Loads of lessons to be learned there. My advice: seek out those who wish to foster community, and there are lots of good people of this ilk. Here's to 2024 and beyond.

The rise and rise of CM-AT for autism

Today's post surrounds a poster presentation delivered at INSAR 2019, the (still) premier international autism conference, albeit not without its battles. The poster was delivered by Heil and colleagues [1] and talks about a compound / preparation that has been discussed a few years back on this blog: CM-AT (see here).

CM-AT is described as a "pancreatic enzyme preparation" with chymotrypsin - a digestive enzyme - seemingly placed quite prominently in its list of ingredients. CM-AT is, from what I understand, something that is still going through the research processes with regards to its use in the context of autism. Heil and colleagues presented data on part of that research agenda, specifically pertinent to ascertaining "whether or not behavior (e.g., symptoms of irritability, hyperactivity) in preschoolers with autism could be improved with CM-AT."

Bearing in mind a conference poster presentation is not necessarily the same as a published peer-reviewed research article, the Heil data was based on the use of a "randomized, placebo-controlled, 12-week clinical trial" methodology where 92 children, aged between 3-5 years, diagnosed with an autism spectrum disorder (ASD) received CM-AT "as granules sprinkled on food" and almost a hundred boys with ASD received a placebo "which consisted of visually identical inert sprinkles." The 'Irritability' scale of the Aberrant Behavior Checklist (ABC) was the primary outcome measure.

Results: "children receiving CM-AT (relative to those receiving placebo) demonstrated significant reductions in Irritability... Hyperactivity... Inappropriate Speech... over the 12 weeks of the trial." Researchers further reported that those children with higher levels of irritability at baseline tended to show a greater positive response than when the participant sample as a whole was analysed.

I think you can perhaps see why these results - preliminary as they are - are worthy blogging material. Irritability, perhaps listed as a 'challenging behaviour' in the context of autism is something that many, many people would love to be able to effectively tackle; if not just because of the impact it can have on those with autism and those around them who have to 'cope' with such behaviours. Indeed, given the other options for managing such behaviour such as the antipsychotic risperidone (see here) and the issues which that drug and its similars can bring (see here), the idea that there may be other, less side-effect heavy options (see here) is definitely something to consider.

I'm hopeful that soon, very soon, I can talk more about CM-AT in the context of irritability and beyond in relation to autism...

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[1] Heil MF. et al. Pancreatic Replacement Therapy with CM-at Is Associated with Reduction in Maladaptive Behaviors in Preschoolers with Autism. INSAR 2019.

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ALV003 glutenase and more

Today's post is a bit of mash-up but hopefully containing some common threads. If you're also reading the title of this post and wondering what it might have to do with autism research, stay with me...

For mash get smash... @ Wikpedia 

The chopping up duties of ALV003
To start, we have the paper by Lähdeaho and colleagues [1] who reported results based on the "ability of ALV003, a mixture of 2 recombinant gluten-specific proteases given orally, to protect patients with celiac disease from gluten-induced mucosal injury". Those with their ear to the coeliac (celiac) disease research ground will probably have heard something about ALV003 from Alvine Pharmaceuticals before. This glutenase mix - a protease compound designed to degrade gluten - comprising cysteine endoprotease B-isoform 2 and prolyl endopeptidase has already started to make some scientific waves following the results of a couple of studies reporting tolerability [2] and initial efficacy [3] in cases of coeliac disease (CD). The theory behind it being that chopping up those dastardly gluten proteins/peptides might break an important link in the chain of biological events observed in coeliac disease.

The data from Lähdeaho et al suggest that "the glutenase ALV003 appears to attenuate gluten-induced small intestinal mucosal injury in patients with celiac disease in the context of an everyday gluten-free diet containing daily up to 2 g gluten". In other words, taking ALV003 together with a gluten-supplemented meal seemed to have some protective effect on the state of the gut mucosa compared to the effects of a placebo.

With my autism research hat on, and particularly the green beret marked gluten and casein-free (GFCF) diets, I did wonder whether there may be something to be potentially learned from these results. I'm not for one minute implying that ALV003 should be indicated for autism nor am I suggesting that autism is coeliac disease despite some potential overlap. But I did wonder in light of something like the opioid-excess theory of autism [4] and some continued interest in all-things digestive enzymes and autism (see here), whether there may be some investigations to do in this area.

IgA deficiency and autoimmunity
Next up is the paper by Ludvigsson and colleagues [5] who observed that: "Individuals with IgA deficiency have a higher prevalence of several other autoimmune disorders". IgA deficiency is something that has cropped up on this blog before, again with an autism slant (see here). Harking back to some potentially important work by the late Reed Warren [6] suggestive that some on the autism spectrum may present with an IgA deficiency, extrapolating the results from Ludvigsson (yes, he of the 'not quite coeliac disease but something close in cases of autism' study) might have some important implications.

In particular, Ludvigsson et al  report quite a dazzling connection between IgA deficiency and the risk of various autoimmune conditions, such that there was: "a 35-fold higher PR [prevalence ratio] for celiac disease and 10-fold higher for type 1 diabetes". I'm only an amateur statistician but even I understand that a frequency of CD in IgA deficient vs. non-deficient population controls amounting to 6.7% and 0.2% respectively, is something potentially very important. Outside of the fact that IgA deficiency can affect the serological diagnosis of CD [7] I find these results to be interesting. That some people on the autism spectrum presenting with IgA deficiency may similarly find themselves in the cycle of greater risk of autoimmune conditions potentially offers some important lessons for screening and management of such issues. Also noted in a fairly recent presentation from one Alessio Fasano (see here for the video), science could do a lot worse than look to something like gluten as also being one of the important [modifiable] drivers in this autoimmunity relationship too.

I've probably bored you enough with this post and the speculations contained within. As per my recent ramblings on disappearing anti-gliadin antibodies following use of a gluten-free diet (see here) the important point to get across is that alongside a diagnosis of autism (and other comorbidity) there may be some important biochemistry that needs to be examined at least for some on the autism spectrum. Looking past the presented behavioural symptoms to see the person first and the autism label second is a pretty important part of this strategy so as to ensure that such health issues if present for some on the autism spectrum, don't disadvantage individuals further.

Now, how about some light reading paralleling pathogens and gluten peptides in CD [8] with suitable musical accompaniment by Sheryl Crow. Have some fun!

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[1] Lähdeaho ML. et al. The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology. 2014 Feb 25. pii: S0016-5085(14)00242-X.

[2] Siegel M. et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci. 2012 Feb;57(2):440-50.

[3] Tye-Din JA. et al. The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo. Clin Immunol. 2010 Mar;134(3):289-95.

[4] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[5] Ludvigsson JF. et al. Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. J Clin Immunol. 2014 Mar 2.

[6] Warren RP. et al. Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord. 1997 Apr;27(2):187-92.

[7] Shahnaz A. et al. Tissue transglutaminase antibody levels predict IgA deficiency. Arch Dis Child. 2013 Nov;98(11):873-6.

[8] Bethune MT. & Khosla C. Parallels between Pathogens and Gluten Peptides in Celiac Sprue. PLoS Pathog 2008; 4(2): e34.

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Lähdeaho ML, Kaukinen K, Laurila K, Vuotikka P, Koivurova OP, Kärjä-Lahdensuu T, Marcantonio A, Adelman DC, & Mäki M (2014). The Glutenase ALV003 Attenuates Gluten-Induced Mucosal Injury in Patients with Celiac Disease. Gastroenterology PMID: 24583059



Ludvigsson JF, Neovius M, & Hammarström L (2014). Association Between IgA Deficiency & Other Autoimmune Conditions: A Population-Based Matched Cohort Study. Journal of clinical immunology PMID: 24584841

Just wondering about CM-AT and autism

CM-AT. Ever heard of it? Well, if you haven't before you certainly might be hearing a lot more about it in the near future with autism in mind. I will from the outset stress that I am not writing this entry as some kind of 'advertorial' for CM-AT or anything like that, but rather because I am genuinely interested in this enzyme-replacement preparation developed by Dr Joan Fallon and how it might link in with some other favourite topics included on this blog. I would also refer you to a previous mention for CM-AT by MJ over at Autism Jabberwocky.


The details are still a little but sketchy about CM-AT in terms of exactly what it is and how it is supposed to benefit people with autism, some people with autism, but there are some clues in the literature so far. We know for example, that the formulation is intended as an enzyme-replacement therapy with autism in mind (see this excerpt published in Nature) which is probably designed to act on/supplement one or more enzymes; perhaps enzymes used in protein/peptide/amino acid metabolism? The digestive enzyme chymotrypsin seems to be a fairly big component of CM-AT as per the recent abstract reporting results at IMFAR 2012* and some details about the patent which has been filed (here). We even know that the results of a phase III randomised, placebo-controlled trial of CM-AT have been completed according to the ClinicalTrials.gov entry.


No doubt there will be other sides to CM-AT - other pancreatic enzymes? - but at the moment I have little or no clue what exactly the preparation is aside from a few patent applications which I assume are related, including the enzyme delivery system (here) and a patent titled 'Methods of treating pervasive developmental disorder' (here). I note that Dr Fallon has previously published quite a speculative article on antibiotics and autism a few years back** but whether this is related to CM-AT or not is not known yet.


Without wishing to seem like I am vying for position as and when the CM-AT splash finally touches the beach, I'd like to think that there is some common sense in looking at things like enzyme function in cases of autism bearing in mind the results produced so far (see Munasinghe and colleagues***) and recent history related to molecules like secretin. I'm also thinking back to a post which attempted to look at stomach acid and autism and the potential consequences of hypochlorhydria for both enzyme function and things like gut bacteria. Speculative but potentially interesting (at least to me). 


While we are on the topic of food and enzymes, let us also not forget the important links being forged between carbohydrate metabolism and enzyme function in cases of autism. Once again I am taken back to the Brent Williams paper on autism, carbs and dysbiosis as a central case in point, bearing in mind that the topic of carbohydrates and the various enzymes involved in their digestion is quite a broad area. 


I'll be keeping my eyes and ears open for any further developments on CM-AT and will update accordingly. To finish, and for all the Wannabes out there, some Spice from the 1990s.


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* Fallon J. & Heil M. The role of a biomarker in the double blind placebo - controlled study of CM-AT in children with autistic disorder ages 3-8. IMFAR 2012.

** Could one of the most widely prescribed antibiotics amoxicillin/clavulanate "augmentin" be a risk factor for autism? Medical Hypotheses. 2005; 64: 312-315.

*** Munasinghe SA. et al. Digestive enzyme supplementation for autism spectrum disorders: a double-blind randomized controlled trial. JADD. 2010; 40: 1131-1138.