Editorial: Autism beyond the brain: the overlooked role of connective tissue

Guest Editorial by Emily Casanova, PhD

For decades, autism research and clinical care have understandably focused on the brain and behavior. Yet autistic people and their families have long reported something that does not fit neatly within that framework: high rates of chronic pain, gastrointestinal problems, fatigue, sleep disturbance, autonomic symptoms, and other complex physical health concerns.

Increasingly, research suggests that connective tissue may be one important piece of this puzzle.

Ehlers-Danlos syndromes (EDS) are heritable connective tissue disorders, while hypermobility spectrum disorders (HSD) describe symptomatic joint hypermobility that does not meet criteria for EDS. Hypermobile EDS (hEDS), the most common form of EDS, and HSD can involve much more than flexible joints. People may experience joint instability and injury, chronic pain, profound fatigue, gastrointestinal problems, dysautonomia, sleep difficulties, and immune-related symptoms, among other health concerns. Strikingly, many of these same problems occur disproportionately in autistic people.

The association between autism and hypermobility-related conditions is no longer based simply on anecdotal reports. A nationwide Swedish study found that people diagnosed with EDS were more than seven times as likely to have an autism diagnosis as matched controls (Cederlöf et al., 2016). Studies approaching the question from the opposite direction have found a similar pattern. In one large study of autistic adults, 28% had generalized joint hypermobility, compared with only 11% of non-autistic adults. Symptomatic hypermobility showed an even stronger association with autism. But an especially important finding from this study receives less attention: Asymptomatic hypermobility was also significantly associated with autism (Glans et al., 2022).

This suggests that we may need to think beyond EDS and HSD diagnoses alone. Instead, there may be a broader spectrum of connective tissue variation enriched within the autistic population. For some people, that variation may amount to little more than unusually flexible joints. For others, it may be accompanied by pain, instability, fatigue, or the multisystem features that characterize HSD or hEDS.

Why does this matter?

Many of the health conditions associated with EDS/HSD can profoundly affect quality of life. Cardiovascular involvement can include mitral valve prolapse and aortic root dilation, both of which are recognized features of hEDS (Rashed et al., 2022). Connective tissue differences may also affect the mechanical properties of blood vessels. Increased vascular compliance has been proposed as one factor contributing to blood pooling and orthostatic intolerance (a form of dysautonomia) in EDS/HSD, although the mechanisms underlying this relationship are still being investigated (Miller et al., 2020; Roma et al., 2018).

Dysautonomia, including orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS), can cause dizziness, rapid heart rate, anxiety-like symptoms, weakness, brain fog, exercise intolerance, and debilitating fatigue. Heightened activation of the sympathetic, or “fight-or-flight,” nervous system can also produce feelings of internal agitation and anxiety and may heighten sensitivity to sensory input. For an autistic person already prone to sensory overload, this additional physiological stress may intensify feelings of overwhelm and potentially contribute to shutdowns or meltdowns. What appears to be worsening anxiety or autistic distress may therefore sometimes be influenced by an underlying physical stressor.

Chronic musculoskeletal pain can interfere with sleep, concentration, mobility, school, employment, and everyday activities. Gastrointestinal dysregulation and immune abnormalities, including mast cell-related disorders, are also frequently reported in hypermobility-related populations (Casanova et al., 2020).
Importantly, these conditions do not merely appear on two separate lists of “autism comorbidities” and “EDS comorbidities.” There is emerging evidence that the relationships may be interconnected. Researchers have found that joint hypermobility statistically mediates part of the relationship between neurodivergence and both orthostatic intolerance and musculoskeletal pain (Csecs et al., 2022). More recent research in people with chronic pain and fatigue has produced similar findings (Quadt et al., 2026).We do not yet know why autism and connective tissue differences overlap. One possibility is shared genetics. Genes do not necessarily perform a single job in a single organ: The same gene may play important roles in both brain development and the cells that produce and maintain connective tissue. Genetic variation affecting such a gene could therefore have effects on both neurodevelopment and connective tissue. Other possibilities include shared developmental pathways and immune-related mechanisms. These possibilities are increasingly being studied, but we do not yet know which mechanisms—or combination of mechanisms—account for the association. But uncertainty about mechanism should not become an excuse for overlooking what we already know clinically.

An autistic child with chronic leg pain, frequent joint injuries, fatigue, gastrointestinal problems, or dizziness when standing should not automatically have these difficulties attributed to autism, anxiety, behavior, or deconditioning. Even changes in anxiety, sensory tolerance, or episodes of shutdown or meltdown may warrant asking whether an underlying physical problem is contributing. Likewise, an autistic adult whose physical health progressively limits work, exercise, self-care, or family participation deserves investigation of those symptoms on their own merits.

This does not mean that every autistic person has EDS, or that every flexible autistic person needs a medical diagnosis. Rather, autism should increase clinicians’ awareness of the possibility of generalized joint hypermobility and related physical health problems. Asking a few additional questions about joint instability, chronic pain, fatigue, orthostatic symptoms, gastrointestinal problems, and family history could identify people who warrant further evaluation.
Research must broaden its perspective as well. We need large, carefully characterized studies that examine connective tissue traits across the autism spectrum—not only people who already carry an EDS or HSD diagnosis. We need to understand why some hypermobile autistic people remain relatively asymptomatic while others develop chronic pain, dysautonomia, immune problems, and substantial disability. And we need to investigate the biological pathways that may connect neurodevelopment, connective tissue, autonomic regulation, and immune function.

Most importantly, physical health must become a more central part of how we think about autistic quality of life. For families struggling with pain, fatigue, dizziness, gastrointestinal problems, sleep disruption, and declining physical function, understanding the biology behind these problems is not an academic exercise. Recognition can lead to appropriate evaluation, better symptom management, and, potentially, a very different quality of life.
True, autism involves the brain. But autistic people live in bodies. Our research—and our healthcare—must give those bodies the attention they deserve.

References

Casanova, E. L., Baeza-Velasco, C., Buchanan, C. B., & Casanova, M. F. (2020). The relationship between autism and Ehlers-Danlos syndromes/hypermobility spectrum disorders. Journal of Personalized Medicine, 10(4), 260.
Cederlöf, M., Larsson, H., Lichtenstein, P., Almqvist, C., Serlachius, E., & Ludvigsson, J. F. (2016). Nationwide population-based cohort study
of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings. BMC Psychiatry, 16(1), 207.
Csecs, J. L., Iodice, V., Rae, C. L., Brooke, A., Simmons, R., Quadt, L., … & Eccles, J. A. (2022). Joint hypermobility links neurodivergence to dysautonomia and pain. Frontiers in Psychiatry, 12, n786916.
Glans, M. R., Thelin, N., Humble, M. B., Elwin, M., & Bejerot, S. (2022). The relationship between generalised joint hypermobility and autism spectrum disorder in adults: a large, cross-sectional, case-control comparison. Frontiers in Psychiatry, 12, 803334.
Miller, A. J., Schubart, J. R., Sheehan, T., Bascom, R., & Francomano, C. A. (2020). Arterial elasticity in Ehlers-Danlos syndromes. Genes, 11(1), 55.
Quadt, L., Savage, G., Bond, R., Davies, K. A., Critchley, H. D., & Eccles, J. A. (2026). Rates of likely neurodivergence and variant connective tissue in patients with chronic pain/chronic fatigue: a case-control study. Journal of Psychiatric Research, 197, 125-132.
Rashed, E. R., Ruiz Maya, T., Black, J., Fettig, V., Kadian-Dodov, D., Olin, J. W., … & Kontorovich, A. R. (2022). Cardiovascular manifestations of hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders. Vascular Medicine, 27(3), 283-289.
Roma, M., Marden, C. L., De Wandele, I., Francomano, C. A., & Rowe, P. C. (2018). Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. Autonomic Neuroscience, 215, 89-96.

This editorial originally appeared in Autism Research Review International, Vol. 40, No. 3, 2026