Autistic people have higher rates of chronic physical health conditions across the whole body and are more likely to have complex health needs, according to a study led by researchers at the University of Cambridge. Their findings, published in the journal Molecular Autism, have important implications for the clinical care of autistic people.

Previous studies have shown that autistic people are dying far younger than others and that they are more likely to experience a range of physical health conditions. Until now, it was believed that autistic people were more likely to have specific conditions, such as gastrointestinal pain, sleep problems, and epilepsy/seizure disorders.

The new study is different in that it investigated a much wider range of health risks than has been done before and shows that autistic people experience a much broader range of health vulnerabilities than was previously thought.

Specifically, autistic people are more likely to have physical health conditions across all organ systems, including the brain (such as migraine), the gastrointestinal system (for example coeliac disease), and the endocrine system (for example endometriosis), compared to non-autistic people.

Dr Elizabeth Weir, a Research Associate at the Autism Research Centre in Cambridge, who led the team, said: “This study emphasizes the increased health vulnerability of autistic people both in the types and number of conditions they may have. We now need to understand the causes of these increased risks, which are likely multifactorial in nature.”

This is the first study to show that autistic people are more likely than non-autistic people to experience ‘physical health multimorbidity’, meaning that they have at least two or more physical health conditions. These include co-occurring fibromyalgia (which causes chronic pain throughout the body) and polycystic ovarian syndrome (which causes irregular menstrual cycles, infertility, excess hair growth, and acne in women) across different organ systems.

The study was conducted by a team at the ARC and used an anonymized, self-report survey to compare the experiences of 1,129 autistic people with 1,176 non-autistic people aged 16-90 years. The participants were international, although 67% of participants were from the UK.  

The survey assessed risk of 60 physical health conditions across nine different organ systems (gastrointestinal, endocrine, rheumatological, neurological, ocular, renal/hepatic, otolaryngological, haematological, and dermatological). The analysis took into account other factors such as age, sex assigned at birth, country of residence, ethnicity, education-level, alcohol use, smoking, body mass index, and family medical history.

The team found that autistic people were more likely to have diagnosed medical conditions across all nine organ systems tested, compared to non-autistic people. Regarding specific conditions, autistic people had higher rates of 33 specific conditions compared to non-autistic peers. These included coeliac disease, gallbladder disease, endometriosis, syncope (fainting or passing out), vertigo, urinary incontinence, eczema, and iron deficiency anaemia.

Dr John Ward, a visiting research scientist at the ARC in Cambridge, who conducted the analysis, said: “This research adds to the body of evidence that the healthcare needs of autistic people are greater than those of non-autistic people. More research is required, particularly surrounding the early identification, and monitoring of chronic conditions.”

This is also the first epidemiological study to show that Ehlers-Danlos Syndrome (EDS) – a group of disorders that affects connective tissues and which cause symptoms such as joint hypermobility, loose joints that dislocate easily, joint pain and clicking joints, skin that bruises easily, extreme tiredness, digestive problems, dizziness, stretchy skin, wounds that are slow to heal, organ prolapse, and hernias – may be more common among autistic women than non-autistic women.

The new research also replicates previous findings to show that autistic people have higher rates of all central sensitivity syndromes, which are a varied group of conditions that are related to dysregulation of the central nervous system, compared to non-autistic people. Central sensitivity syndromes include irritable bowel syndrome (IBS), temporomandibular joint syndrome (TMJ), migraine, tinnitus, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia.

The new study also investigated risks of physical health multimorbidity with a novel application of ‘network analysis’, a technique used to understand relationships between different parts of a system. This analysis method is regularly used in neuroscience to understand how different regions of the brain interact with each other. In this study, the analysis assessed how often conditions from different organ systems occurred together in the same person. In addition to highlighting complex health needs, this analysis established for the first time that the combinations of medical conditions that frequently co-occur may be different between autistic and non-autistic adults.

These results are preliminary evidence that healthcare providers such as GPs or family physicians need to be monitoring the health care needs of autistic people much more closely.

Dr Carrie Allison, Director of Strategy at the ARC and a member of the team, added: “These findings highlight the acute need to adapt the healthcare system to better meet the needs of autistic people. These results must be confirmed in larger, population-based samples.”

Professor Sir Simon Baron-Cohen, Director of the ARC and another member of the team, said: “We are aware of the risks of mental health conditions in autistic people, but this new research identifies their risks of physical health conditions too. We need to urgently re-evaluate current health care systems to improve support for autistic people.”

The research team led by Professor Minsik Kim from the Department of New Biology at DGIST (President Kuk Yang) announced on the 17th (Thurs.) that they have identified the environmental factors affecting the occurrence mechanism of autism spectrum disorder through a joint study conducted along with the research teams led by Professor Yongsuk Lee at Seoul National University, Professor Junyong Ahn at Korea University, and Chanyeong Shin at Konkuk University.

□ Autism spectrum disorder is a neurodevelopmental disorder that typically occurs in early childhood, in which behavioral patterns, interests, and activity range are restricted and repeated due to the inability to perform normal social communications and interactions. According to certain studies, 1 out of every 50 to 60 children has a spectrum disorder, making them fairly common.

□ Autism spectrum disorder is known to be caused by genetic factors as well as various environmental factors such as severe infection or exposure to specific types of drugs during pregnancy.

□ Meanwhile, a previous study conducted by the research team of Professor Chan-yeong Shin at Konkuk University discovered that valproate may be potentially related to autism spectrum disorder since it may affect the brain development of a fetus when used during pregnancy. However, the development of therapeutic drugs has faced challenges due to a lack of research on the molecular target.

□ Thus, the research team of Professor Minsik Kim performed a multi-omics analysis with Professor Ahn’s research team at Korea University using the mouse model treated with valproate developed by Professor Shin’s research team. The results showed that expression of the Rnf146 gene, which is known to affect autism spectrum disorder, increased in the prefrontal lobe of the autism mouse model due to an adverse reaction to valproate. Furthermore, autistic behavioral patterns were observed using the Rnf146 gene expression model in a joint effort with Professor Lee’s research team at the College of Medicine of Seoul National University. It was discovered that the balance between excitatory and inhibitory neurotransmitters was disturbed in the frontal lobe of the mouse model. Professor Lee of Seoul National University said, “Since this phenomenon is commonly observed in other autistic models, this research significantly contributes to identifying the common cause of autism.”

□ The findings of this study are expected to help further understand the mechanism related to autism spectrum disorder, and even contribute to advancing early detection and treatment methods for autism spectrum disorder.

□ Professor Kim said, “We will continue our research on various developmental disorder models using multi-omics analysis through joint studies with other institutions and carry out comprehensive research on model organisms so as to identify the core network of autism spectrum disorder and discover treatment targets.”

□ Professor Shin of Konkuk University added, “The research results are expected to become the foundation of future research on the possibility of environmental pollution causing autism and the related mechanisms.”

□ Professor Ahn of Korea University stated, “In particular, the multi-omics technology is expected to be widely utilized in discovering a new molecular network in the brain development process and finding critical regulatory genes of various autistic models.”

Left half: Confocal image of a CHOOSE (CRISPR-human organoids-scRNA-seq) human brain organoid mosaic system showing cells carrying a mutation in red. Right half: a mosaic depiction of different colors representing single cells, each carrying a mutation in one high-confidence autism gene. ©Knoblich Lab / IMBA-IMP Graphics CREDIT ©Knoblich Lab / IMBA-IMP Graphics

Does the human brain have an Achilles heel that ultimately leads to Autism? With a revolutionizing novel system that combines brain organoid technology and intricate genetics, researchers can now comprehensively test the effect of multiple mutations in parallel and at a single-cell level within human brain organoids. This technology, developed by researchers from the Knoblich group at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences and the Treutlein group at ETH Zurich, permits the identification of vulnerable cell types and gene regulatory networks that underlie autism spectrum disorders. This innovative method offers unparalleled insight into one of the most complex disorders that challenge the human brain with implications that bring autism clinical research much-needed hope. The results were published on September 13 in Nature.

Compared to other animal species, the human brain has a mind of its own. To develop, the human brain relies on processes unique to humans, allowing us to build an intricately layered and connected cortex. These unique processes also make neurodevelopmental disorders more likely in humans. As an example, many genes conferring a high risk of developing autism spectrum disorder (ASD) are crucial for cortex development. Although clinical studies have shown causality between multiple genetic mutations and autism, researchers still do not understand how these mutations lead to brain developmental defects – and because of the uniqueness of human brain development, animal models are of limited use. “Only a human model of the brain can recapitulate the complexity and particularities of the human brain,” says IMBA Scientific Director Jürgen Knoblich, one of the study’s corresponding authors.

To help crack this black box open, researchers from Jürgen Knoblich’s and Barbara Treutlein’s research groups at IMBA and ETH Zurich developed a technique to screen a complete set of key transcriptional regulator genes linked to autism. This development is especially impactful since the genes of interest can be examined simultaneously within a single mosaic organoid, marking the beginning of an era of intricate, efficient, and expedient genetic screening in human tissue. In the newly developed system, called “CHOOSE” (CRISPR-human organoids-scRNA-seq), each cell in the organoid carries at most one mutation in a specific ASD gene. The researchers could trace each mutation’s effect at a single-cell level and map each cell’s developmental trajectory. “With this high-throughput methodology, we can systematically inactivate a list of disease-causing genes. As the organoids carrying these mutations grow, we analyze the effect of each mutation on the development of each cell type,” says the study’s first and co-corresponding author Chong Li, a postdoctoral fellow in the Knoblich group.

A high-throughput systematic approach

With the CHOOSE system, the IMBA and ETH Zurich teams advance research on disease-causing genes by a whole leap, providing researchers with access to a versatile and high-throughput method that can be applied to any disease and in any human model system. Importantly, CHOOSE considerably speeds up the analysis in comparison to traditional genetic loss-of-function approaches. “We can see the consequence of every mutation in one experiment, thus shortening the analysis time drastically when compared to traditional methods, using an approach that for decades was only possible in organisms like the fruit fly”, explains Knoblich. “Additionally, we can still benefit from a hundred years of scientific literature about disease-causing genes.”

Mutating several genes in parallel and tracking their effects generates an enormous amount of data. To analyze this complex dataset, co-corresponding author Barbara Treutlein and her team at ETH Zurich used quantitative bioinformatics and machine learning approaches. “Using this high-throughput single-cell expression data, we can quantify whether a given cell type is more or less abundant due to a given mutation, and we can also identify sets of genes that are commonly or distinctly affected by each mutation. By comparing across all the gene mutations, we can reconstruct the phenotypic landscape of these disease-linked genetic perturbations,” explains Treutlein.

Learning about autism during development

Using the CHOOSE system, the researchers show that mutations of 36 genes, known to put carriers at high risk of autism, lead to specific cell type changes in the developing human brain. They identified critical transcriptional changes regulated through common networks, called “gene regulatory networks” or GRNs. A GRN is a set of molecular regulators that interact with each other to control a specific cell function, explains Li. “We demonstrated that some cell types are more susceptible than others during brain development and identified the networks that are most vulnerable to autism mutations,” he adds.

“With this approach, we learned that autism-causing genes share some common molecular mechanisms,” says Knoblich. Yet, these common mechanisms can lead to markedly distinct effects in different cell types. “Some cell types are more vulnerable to mutations that lead to autism, especially some neural progenitors- the founder cells that generate neurons. This is true to the point that the pathology of autism could already emerge early during brain development. This indicates that some cell types will necessitate more attention in the future when studying autism genes,” says Li.

To confirm whether these findings are relevant to human disorders, the researchers teamed up with clinicians from the Medical University of Vienna and generated brain organoids from two patient stem cell samples. Both patients had mutations in the same gene that caused autism. “The organoids generated from both patients showed marked developmental defects linked to a specific cell type. We could validate these in vitro observations by comparing the organoid structures to the prenatal MRIs of one of the patients’ brains,” says Knoblich, showing that the organoid data closely matched clinical observations.

Beyond the brain and autism…

In addition to gaining unparalleled insights into the pathology of autism, the team underlines the versatility and transferability of the CHOOSE system. “We anticipate that our technique will be widely applied beyond brain organoids to study various disease-associated genes,” says Knoblich. With this new technique, scientists and clinicians gain a robust and precisely controlled high-throughput screening tool that considerably shortens analysis time and provides invaluable insights into disease mechanisms.

Left half: Confocal image of a CHOOSE (CRISPR-human organoids-scRNA-seq) human brain organoid mosaic system showing cells carrying a mutation in red. Right half: a mosaic depiction of different colors representing single cells, each carrying a mutation in one high-confidence autism gene. ©Knoblich Lab / IMBA-IMP Graphics CREDIT ©Knoblich Lab / IMBA-IMP Graphics

Does the human brain have an Achilles heel that ultimately leads to Autism? With a revolutionizing novel system that combines brain organoid technology and intricate genetics, researchers can now comprehensively test the effect of multiple mutations in parallel and at a single-cell level within human brain organoids. This technology, developed by researchers from the Knoblich group at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences and the Treutlein group at ETH Zurich, permits the identification of vulnerable cell types and gene regulatory networks that underlie autism spectrum disorders. This innovative method offers unparalleled insight into one of the most complex disorders that challenge the human brain with implications that bring autism clinical research much-needed hope. The results were published on September 13 in Nature.

Compared to other animal species, the human brain has a mind of its own. To develop, the human brain relies on processes unique to humans, allowing us to build an intricately layered and connected cortex. These unique processes also make neurodevelopmental disorders more likely in humans. As an example, many genes conferring a high risk of developing autism spectrum disorder (ASD) are crucial for cortex development. Although clinical studies have shown causality between multiple genetic mutations and autism, researchers still do not understand how these mutations lead to brain developmental defects – and because of the uniqueness of human brain development, animal models are of limited use. “Only a human model of the brain can recapitulate the complexity and particularities of the human brain,” says IMBA Scientific Director Jürgen Knoblich, one of the study’s corresponding authors.

To help crack this black box open, researchers from Jürgen Knoblich’s and Barbara Treutlein’s research groups at IMBA and ETH Zurich developed a technique to screen a complete set of key transcriptional regulator genes linked to autism. This development is especially impactful since the genes of interest can be examined simultaneously within a single mosaic organoid, marking the beginning of an era of intricate, efficient, and expedient genetic screening in human tissue. In the newly developed system, called “CHOOSE” (CRISPR-human organoids-scRNA-seq), each cell in the organoid carries at most one mutation in a specific ASD gene. The researchers could trace each mutation’s effect at a single-cell level and map each cell’s developmental trajectory. “With this high-throughput methodology, we can systematically inactivate a list of disease-causing genes. As the organoids carrying these mutations grow, we analyze the effect of each mutation on the development of each cell type,” says the study’s first and co-corresponding author Chong Li, a postdoctoral fellow in the Knoblich group.

A high-throughput systematic approach

With the CHOOSE system, the IMBA and ETH Zurich teams advance research on disease-causing genes by a whole leap, providing researchers with access to a versatile and high-throughput method that can be applied to any disease and in any human model system. Importantly, CHOOSE considerably speeds up the analysis in comparison to traditional genetic loss-of-function approaches. “We can see the consequence of every mutation in one experiment, thus shortening the analysis time drastically when compared to traditional methods, using an approach that for decades was only possible in organisms like the fruit fly”, explains Knoblich. “Additionally, we can still benefit from a hundred years of scientific literature about disease-causing genes.”

Mutating several genes in parallel and tracking their effects generates an enormous amount of data. To analyze this complex dataset, co-corresponding author Barbara Treutlein and her team at ETH Zurich used quantitative bioinformatics and machine learning approaches. “Using this high-throughput single-cell expression data, we can quantify whether a given cell type is more or less abundant due to a given mutation, and we can also identify sets of genes that are commonly or distinctly affected by each mutation. By comparing across all the gene mutations, we can reconstruct the phenotypic landscape of these disease-linked genetic perturbations,” explains Treutlein.

Learning about autism during development

Using the CHOOSE system, the researchers show that mutations of 36 genes, known to put carriers at high risk of autism, lead to specific cell type changes in the developing human brain. They identified critical transcriptional changes regulated through common networks, called “gene regulatory networks” or GRNs. A GRN is a set of molecular regulators that interact with each other to control a specific cell function, explains Li. “We demonstrated that some cell types are more susceptible than others during brain development and identified the networks that are most vulnerable to autism mutations,” he adds.

“With this approach, we learned that autism-causing genes share some common molecular mechanisms,” says Knoblich. Yet, these common mechanisms can lead to markedly distinct effects in different cell types. “Some cell types are more vulnerable to mutations that lead to autism, especially some neural progenitors- the founder cells that generate neurons. This is true to the point that the pathology of autism could already emerge early during brain development. This indicates that some cell types will necessitate more attention in the future when studying autism genes,” says Li.

To confirm whether these findings are relevant to human disorders, the researchers teamed up with clinicians from the Medical University of Vienna and generated brain organoids from two patient stem cell samples. Both patients had mutations in the same gene that caused autism. “The organoids generated from both patients showed marked developmental defects linked to a specific cell type. We could validate these in vitro observations by comparing the organoid structures to the prenatal MRIs of one of the patients’ brains,” says Knoblich, showing that the organoid data closely matched clinical observations.

Beyond the brain and autism…

In addition to gaining unparalleled insights into the pathology of autism, the team underlines the versatility and transferability of the CHOOSE system. “We anticipate that our technique will be widely applied beyond brain organoids to study various disease-associated genes,” says Knoblich. With this new technique, scientists and clinicians gain a robust and precisely controlled high-throughput screening tool that considerably shortens analysis time and provides invaluable insights into disease mechanisms.

Researchers are calling for new approaches to reduce healthcare inequalities for Autistic people when they need medical treatment after identifying serious flaws in NICE-recommended health passports.

Autistic people die between 16 and 30 years before their non-Autistic peers and inaccessible healthcare may be a contributory factor. Health passports such as that designed by the National Autistic Society, were developed to help Autistic people communicate their needs to doctors, nurses and other healthcare professionals. Recommended by NICE guidance, these passports allow people to list their personal details and medical history as well as information about their communication and sensory needs.

Similar tools – such as the asthma self-management plans– have been found to help reduce mortality when used properly.

Researchers based at Swansea University’s Faculty of Medicine, Health and Life Science wanted to find out how effective Autism Health Passports actually are and if the infrastructure surrounding them is fit for purpose.

For their study, the team analysed previous research relating to health passports that had been published in scientific journals around the world. Their findings have just been published by prestigious online journal PLOS ONE and include:

• Evaluation of healthcare settings that were using the passports revealed a lack of staff knowledge and training in Autism;
• how staff lack of awareness of Autistic communication styles and how to amend their communication were often a barrier to providing equitable care;
• how Autism Health Passports varied not only in terms of their contents, but also in the infrastructure around them such as staff training and reminders to use them; and,
• although many papers stated that the health passports improved care, for example by saying that they increased trust or improved communication, it was not clear how this was supposed to happen, and it was rare that anything was measured to assess if healthcare quality or satisfaction had improved, because of this, we cannot currently say that Autism Health Passports are effective.

Dr Aimee Grant, senior lecturer in public health at Swansea University stated: “NICE guidance and UK policy recommend that Autism Health Passports are used, with the aim of reducing known health inequalities for Autistic people. 

“However, at its most basic a health passport is a piece of paper, and unless the environment is carefully crafted to give that piece of paper status – like the status granted to an actual passport that allows people to cross borders between countries – that piece of paper can achieve nothing.”

The researchers say there is an urgent need for new interventions to improve health care accessibility and quality for Autistic people to reduce early death and increase quality of life. 

They are calling for interventions that are specifically designed to remove the many barriers they identified, including lack of staff time and knowledge of Autism, including Autistic communication.

Lead researcher on the project, Dr Rebecca Ellis, public health research assistant at Swansea University, added: “All new interventions to reduce health inequalities for Autistic people should be evidence based, and co-produced both with the Autistic and wider neurodivergent community, and with health professionals who will be responsible for implementing them.

“It is also essential that they are adequately funded, to avoid the tokenism seen with Autism health passports, and to create meaningful change.”

For their study the research team worked with Autistic UK. The organisation’s research director Kathryn Williams added: “Autistic adults often ask for our advice about how to receive better healthcare and for links to Autism Health Passports recommended by other organisations.

“We were not convinced of their efficacy, yet we had no access to evidence to either support or refute their helpfulness as stated in NICE guidelines. This research provides much-needed evidence and will hopefully enable organisations supporting Autistic people to provide improved guidance and signposting.”