Today’s post is a summary of a small part of the recent autism research. I am constantly amazed how much autism related research is churned out every day. To anyone who says more autism research is needed, just take a look at how much there already is !!
Facial recognition of Autism?
Those working every day with special needs children have long known that you can pretty quickly spot a child with autism, without any lengthy diagnostic procedure.
Some advocates like to see autism as a hidden disability and believe you cannot “look autistic.” They had better not read this post.
I did write about facial recognition of single gene autisms and rare diseases where a commercialized product (Face2Gene) can now identify 200 conditions with 91% accuracy. This is from a single photo of the face.
Now Chinese researchers have produce software that can predict autism in pre-schoolers with 94% accuracy based on automated analysis of a video.
Risk assessment and automatic identification of autistic children based on appearance
The diagnosis of Autism Spectrum Disorder (ASD) is mainly based on some diagnostic scales and evaluations by professional doctors, which may have limitations such as subjectivity, time, and cost. This research introduces a novel assessment and auto-identification approach for autistic children based on the appearance of children, which is a relatively objective, fast, and cost-effective approach. Initially, a custom social interaction scenario was developed, followed by a facial data set (ACFD) that contained 187 children, including 92 ASD and 95 children typically developing (TD). Using computer vision techniques, some appearance features of children including facial appearing time, eye concentration analysis, response time to name calls, and emotional expression ability were extracted. Subsequently, these features were combined and machine learning methods were used for the classification of children. Notably, the Bayes classifier achieved a remarkable accuracy of 94.1%. The experimental results show that the extracted visual appearance features can reflect the typical symptoms of children, and the automatic recognition method can provide an auxiliary diagnosis or data support for doctors.
The ASD group were all pre-school children, aged between 20 and 60 months, with an average age of 33.4 months for males and 31.5 months for females.
Like it or not, it seems that autistic toddlers do look different and so it is not a hidden disability. Nobody should be waiting years for a diagnosis.
Bullying
Most autism diagnosed today is mild, level 1 autism. Some of this group really do struggle and can genuinely benefit from pharmacologic therapies.
Bullying is one very common issue that is faced and does not need drug therapy, it needs a different kind of intervention.
Children diagnosed with autism spectrum disorder are at high risk of being bullied, but research on teaching children with autism self-protection skills for bullying situations is scant. We taught five children self-protection skills for two types of bullying (threats and unkind remarks) and consecutive bullying occurrences. We first evaluated behavioral skills training and a textual prompt to teach children to report threats of physical or material harm, provide a disapproving statement after a first unkind remark, and occupy themselves with an activity away from a bully after a second unkind remark. Additional tactics were necessary to aid in the discrimination of bullying situations for two children. There were increases in the self-protection skills with all children. Results further support that an active-learning approach is efficacious in teaching responses to bullying in simulated situations. Considerations for teaching these skills while maintaining trust and rapport with children and caregivers are discussed.
Having a sibling in the same school can be an effective defence against bullying. It might be an older brother, as was the case for Monty, but a younger sister can also be very effective. One episode, of many, I witnessed at school was a young Swedish girl intervening on behalf of her older Aspie-like brother. It really shocked the older boys and certainty impressed me.
I think most bullying affects those with level 1 autism. Those with severe autism would tend to have a 1:1 assistant and if he/she is doing their job there should not be the possibility bullying. I am told that out in the real world kids with level 3 autism do get bullied, which means the system has failed.
From the school’s perspective there is also the opposite issue of the pupil with autism/ADHD attacking other pupils or staff. This does happen and if the child is a large fully-grown male can lead to very serious injury. It is not just those with level 3 autism who can do this.
I think the best strategy to protect against bullying is to ensure your child is in a caring environment at school and is well integrated. This may be easier said than done, but it is possible for many people. Then the other pupils will look out for the one with special needs. This assumes you do not overdo it with who gets to be "special".
Special needs are not so special any more, as was highlighted recently in the UK. For the most privileged group of pupils, those going to private fee-paying schools, 41% are getting special treatment in their exams due to their various special needs. Even in the regular state schools, which for sure have a higher percentage of kids with actual special needs, 26% of pupils get extra time in exams.
Nearly one in three pupils in England given extra time in exams, says regulator
Nearly a third of pupils in England were given 25% extra time to complete their GCSEs and A-level exams following a surge in special exam access arrangements being granted, data from Ofqual has shown.
The figure is higher again among exam candidates in private schools where more than two in five received 25% extra time in the last academic year, according to England’s exams regulator.
The total number of approved special access arrangements for GCSE, AS and A-level exams rose by 12.3% in the 2023/24 school year compared to the year before, the data has revealed.
· Independent centres 41.8%
· Sixth form and FE colleges 35%
· Non-selective state schools 26.5%
It comes as education leaders have suggested more pupils are seeking support after the pandemic due to a rise in young people with special educational needs and disabilities (Send) and mental health issues.
Requests for 25% extra time in exams was the most common approved access arrangement for pupils with learning difficulties or disabilities, followed by computer readers, scribes and speech recognition.
Folate supplementation in mothers prevent pesticides causing neurodevelopmental disorders in offspring
There is a lot of research about folate (vitamin B9), birth defects and autism. From the early 1990s women were encouraged to take folate supplements during pregnancy to avoid neural tube defects and other congenital abnormalities.
Some individuals have mutations in the MTHFR gene that impair their ability to convert folic acid into its active form, L-methylfolate. For such individuals, taking methylated folate supplements will be necessary.
More recently we have learned that some people with adequate folate intake can lack folate inside their brain. They have antibodies that block the transmission of folate across the blood brain barrier.
We saw how one clinician is prescribing high dose calcium folinate to couples wishing to reduce the risk of autism in their future offspring, if they test positive themselves for folate receptor auto-antibodies.
As we already know exposure to pesticides and some other unnatural chemicals during pregnancy can lead to neurodevelopmental disorders (NDDs) that include autism.
The paper below is interesting because it looks as how to minimize the potential damage caused by exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US.
Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and NDDs. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams to vehicle or deltamethrin (3 mg/kg every 3 days) with or without folate supplementation (5 mg/kg methylfolate every 3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to NDDs; increased plasma folate concentrations; and increased neural expression of SHMT1, a cellular folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotype (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two other folate-related proteins. We conclude that DPE causes NDD-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.
A round-up of therapies to treat mouse autism
Treating human autism is not yet mainstream, but treating autism in mice has been going on for decades. Of course the idea is to use mouse models with a view to later treating humans.
The paper below is about mice, but it is actually a very good summary of the current status of treatment options more broadly.
It even covers the use of HDAC inhibitors to use epigenetics as a treatment tool. Click on the link to read the full text for free.
The Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of secondary complications, among which include anxiety, ADHD (attention deficit hyperactivity disorder), cognitive impairment, sleep disorders, sensory alterations, and gastrointestinal issues. So far, no treatment for the core symptoms of ASD has yielded satisfactory results in a clinical setting. Consequently, medical and psychological support for ASD patients has focused on improving quality of life and treating secondary complications. Despite no single cause being identified for the onset and development of ASD, many genetic mutations and risk factors, such as maternal age, fetal exposure to certain drugs, or infections have been linked to the disorder. In preclinical contexts, these correlations have acted as a valuable basis for the development of various murine models that have successfully mimicked ASD-like symptoms and complications. This review aims to summarize the findings of the extensive literature regarding the pharmacological and nutraceutical interventions that have been tested in the main animal models for ASD, and their effects on core symptoms and the anatomical, physiological, or molecular markers of the disorder.
The body of research here summarized suggests that many therapeutic strategies have yielded positive results for ASD core symptoms and ASD-linked cellular, anatomical, and metabolic alterations at the preclinical level. These results ultimately confirm clinical and in vitro evidence regarding the main pathways involved in ASD pathogenesis and hint at the potential for the combination of different types of treatment. The studies reviewed here showed that a treatment’s success or failure in these models usually depends on administration timing. The best results are commonly achieved when protective treatment is given in the first weeks after birth or prenatally. Unfortunately, this is not easily translatable into clinical practice as ASD diagnosis, at the moment, postdates this time window. Moreover, it is notable that most of the treatments employed in these studies did not achieve significant improvements in all the behavioral tests or definitive success in clinical trials. Despite the exact causes for the disparity between promising preclinical results and modest or negative clinical outcomes remaining unknown, a few hypotheses can be formulated. The results of many tests commonly employed to measure sociability and repetitive behaviors in mice can be altered by other symptoms known to be observed in these murine models, such as altered motor coordination, cognitive impairment, and anxiety, which may lead scientists to overestimate the effect of certain treatments on social behavior. Moreover, poor translatability may also be ascribed to the heterogeneity in symptoms and genetic backgrounds found in ASD human patients which, conversely, is far more limited in these mice strains. Ultimately, other possible confounding factors such as interactions with concurrent medications, socio-economic elements, patient lifestyle, or concomitant diseases are significantly more frequent and variable in the human population. Poor translatability may be potentially alleviated by precision medicine approaches in clinical practice and by preclinical testing of single treatments in a variety of ASD murine models. Ultimately, the present literature shows that, despite the limited clinical translational success, murine models can be a valuable tool for testing a variety of treatments in ASD research.
Figure 2. Schematic representation of key elements of the mTOR pathway and of therapeutic interventions considered in murine models for ASD. Abbreviations: PIP2: phosphatidylinositol 4,5-bisphosphate PIP3: phosphatidylinositol 3,4,5-bisphosphate PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; TSC1: tuberous sclerosis 1; TSC2: tuberous sclerosis 2; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; S6K: Ribosomal protein S6 kinase beta-1; eIF4E: eukaryotic Initiation Factor 4E; ULK complex: Unc-51-like kinase 1 complex; PKCa: protein kinase C alpha; P: phosphate group
You can see all the amino acids that have been trialed to modify mTOR (taurine, lysine, histidine and threonine) plus metformin and the potent rapamycin.
Also mentioned is the WHEN in what I call the what, when and where in autism treatment. This is the idea of treatment windows, when a specific therapy can potentially be beneficial.
This very concept was discussed in a recent paper on Rett syndrome.
Protein Loss Triggers Molecular Changes Linked to Rett Syndrome
Key Facts
· Early Gene Changes: Loss of MeCP2 leads to immediate gene expression dysregulation, affecting hundreds of genes.
· Neuronal Impact: Dysregulated genes are linked to neuronal function, causing downstream circuit-level deficits.
· Therapeutic Window: The study reveals a time frame between molecular changes and neurological symptoms, enabling early intervention opportunities.
Another transcription factor (TCF) that causes autism
There is a lot in this blog about TCF4 (transcription factor 4). Loss of this gene leads to Pitt Hopkins syndrome. Disruption of the gene is associated with schizophrenia and intellectual disability.
Mutations in TCF20 lead to a kind of autism plus intellectual disability called TCF20-Related Neurodevelopmental Disorder. Like Pitt Hopkins, this is a rare disorder, but milder misexpression of the gene is likely much more common. In the recent paper below we see which are the downstream effector genes.
Our old friends the sub-units of GABAa receptors are there. In this case it is GABRA1 and GABRA5 that are reduced.
Both GABRA1 and GABRA5 play essential but distinct roles in regulating neuronal inhibition. GABRA1 primarily contributes to synaptic inhibition and is critical in seizure and anxiety regulation, while GABRA5 is involved in tonic inhibition and cognitive processes.
Malfunctions in GABRA1 and GABRA5 can lead to autism, anxiety, schizophrenia, intellectual disability, epilepsy etc
Regulation of Dendrite and Dendritic Spine Formation by TCF20
Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.
Based on these results, we analyzed the expression of neuronal proteins in TCF20-deficient neurons and found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates (Figure 5) and in synaptosomal preparations (Figure 5) of shTCF20 rat cortical cultures. Additionally, GluN2B and GABRA5 were significantly downregulated, and GluA2 was significantly upregulated in synaptosomal preparations of shTCF20 rat cortical cultures (Figure 5).
On the subject of GABA type A receptor, we have a very recent paper from Poland that delves into this subject in great detail.
Molecular mechanisms of the GABA type A receptor function
The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia.
And finally …
Dr Frye has published a study that assessed the effect of his friend Dr Boles’ mitochondrial cocktail.
I did meet Dr Boles a while back at a conference in London. He came with his wife and a stock of NeuroNeeds products for sale, including SpectrumNeeds which was the subject of today’s paper. He was telling me all about the great food just across the border in Mexico and how he learnt Spanish.
Autism spectrum disorder (ASD) is associated with mitochondrial dysfunction but studies demonstrating the efficacy of treatments are scarce. We sought to determine whether a mitochondrial-targeted dietary supplement designed for children with ASD improved mitochondrial function and ASD symptomatology using a double-blind placebo-controlled cross-over design. Sixteen children [Mean Age 9y 4m; 88% male] with non-syndromic ASD and mitochondrial enzyme abnormalities, as measured by MitoSwab, received weight-adjusted SpectrumNeeds and QNeeds and placebos matched on taste, texture and appearance during two separate 12-week blocks. Which product received first was randomized. The treatment significantly normalized citrate synthase and complex IV activity as measured by the MitoSwab. Mitochondrial respiration of peripheral blood mononuclear cell respiration, as measured by the Seahorse XFe96 with the mitochondrial oxidative stress test, became more resilient to oxidative stress after the treatment, particularly in children with poor neurodevelopment. The mitochondrial supplement demonstrated significant improvement in standardized parent-rated scales in neurodevelopment, social withdrawal, hyperactivity and caregiver strain with large effect sizes (Cohen’s d’ = 0.77-1.25), while changes measured by the clinical and psychometric instruments were not significantly different. Adverse effects were minimal. This small study on children with ASD and mitochondrial abnormalities demonstrates that a simple, well-tolerated mitochondrial-targeted dietary supplement can improve mitochondrial physiology, ASD symptoms and caregiver wellbeing. Further larger controlled studies need to verify and extend these findings. These findings are significant as children with ASD have few other effective treatments.
Conclusion
Plus ça change, plus c'est la même chose.
The more things change, the more they stay the same.
There isn’t much new that we don’t already know. This is probably good news.
I think for Dr Boles and our Spanish speaking readers you would say "Cuanto más cambian las cosas, más siguen igual." Correct me if I am wrong.