By Stéphane Daens, MD
For a long time, certain symptoms frequently reported by people with hypermobile Ehlers-Danlos syndrome (hEhlers-Danlos syndrome, hEhlers-Danlos) or a hypermobility spectrum disorder (HSD) have been difficult to explain. Fatigue, intolerance to standing, palpitations, difficulty concentrating or remembering things, and“brain fog” are not, however, merely anecdotal symptoms. Recent research is gradually providing a better understanding of the mechanisms behind them.
POTS and “brain fog”: The mechanisms are starting to become measurable
Postural orthostatic tachycardia syndrome (POTS) is a form of autonomic dysfunction commonly seen in hypermobile patients. The “brain fog” that may accompany it is now a major area of research.
Studies show that these difficulties do not necessarily correspond to an overall decline in intellectual abilities. They appear to affect, in particular, attention, information-processing speed, working memory, and certain executive functions. They can vary considerably depending on body position, fatigue, and hemodynamic status.
Above all, recent studies using cerebral blood flow measurements, Doppler, SPECT, and now functional MRI provide objective evidence. In some patients with POTS, abnormalities in cerebral perfusion and in the response of the brain networks involved in autonomic regulation have been observed. A study published in 2026 thus reports a simultaneous decrease in cerebral blood flow, changes in certain cerebral parameters, and an abnormal response of the central autonomic network during various physiological stressors.
Other studies show that a decrease in cardiac output, changes in CO₂, sympathetic hyperactivity, and abnormalities in cerebrovascular regulation may contribute to these phenomena.
This does not mean that a single mechanism explains brain fog in all patients. On the contrary, the emerging model is likelymultifactorial, involving—to varying degrees—dysautonomia, cerebral perfusion, vascular regulation, fatigue, sleep, and potentially immune or inflammatory mechanisms.
But a significant change is underway:a symptom that was once described primarily by patients is gradually becoming a phenomenon that can be studied and objectively measured.
microRNAs: Another Window into the Biology of the SED
Another particularly interesting area of research involvesmicroRNAs (miRNAs). These very small RNA molecules do not directly produce proteins; rather, they help regulate the expression of many genes and can therefore alter the functioning of entire biological networks.
Abnormal profiles of certain microRNAs have already been found in fibroblasts from patients with SED/hypermobility. The pathways potentially involved include the extracellular matrix, Wnt/β-catenin signaling, inflammation, and fibroblast transformation mechanisms. In vascular SED, recent transcriptome andmiRNomeanalyses have also revealed abnormalities involving, in particular, autophagy, proteostasis, and mTOR signaling.
These findings are stillpreliminary. We currently have no validated “microRNA test” that can be used in routine clinical practice to diagnose hypermobile Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type hypermobile), and it would be premature to present these molecules as the cause of hypermobile Ehlers-Danlos syndrome. However, they represent an important avenue for understanding how a connective tissue abnormality can be associated with much broader biological consequences.
This research is part of a broader trend: genomics, transcriptomics, proteomics, and biomarker research are beginning to provide new tools for studying SEDh and hypermobility spectrum disorders.
SEDh or HSD: A Distinction That Is Increasingly Being Questioned
Another important change concerns the distinction betweenhypermobile SED and HSD.
The 2017 international classification was essential for standardizing diagnoses and research. However, it established a relatively strict clinical distinction between SEDh and HSD, even though there are currently no validated biological markers available to confirm or rule out SEDh.
As more data has been collected, this distinction now appearsless clear-cut than was initially thought. Patients classified as SEDh and HSD may present with very similar clinical pictures, not only in terms of musculoskeletal symptoms but also with regard to pain, fatigue, and various systemic manifestations and comorbidities.
Current international efforts to revise the criteria are specifically aimed at determining which signs, symptoms, and comorbidities truly distinguish these populations from one another. Initial data suggest thatno single clinical characteristic, taken in isolation, completely distinguishes SEDh from HSD, and support the hypothesis of a biological and clinical spectrum with significant areas of overlap.
Research on microRNAs, gene expression, proteins, and the extracellular matrix could also help advance this classification. However, these biomarkers remain experimental:at present, they do not allow for the individual reclassification of an HSD patient as SEDh, nor vice versa.
Thus, the diagnosis can probably no longer be viewed as simply interpreting a hypermobility score. The Beighton score remains useful, but its limitations are recognized, and current research is focusing in particular on evaluating additional joint examinations. Clinical history, systemic manifestations, comorbidities, and—perhaps in the future—certain biomarkers could contribute to a much more detailed characterization of patients.
That is precisely why the 2017 international diagnostic criteria are currently being revised. A new international classification is scheduled for December 2026.
Therefore, it is not a matter of asserting today that“SEDh and HSD are the same disease”: the data do not yet support that conclusion. However, the notion of a rigid boundary between two biologically distinct populations is increasingly being called into question.
A key message: We don't know everything yet, but we know a lot more
We must remain cautious. Many of these studies still involve small sample sizes, and their results need to be replicated by independent research teams. They do not yet provide a definitive diagnostic biomarker or a treatment specifically targeted at brain fog.
But the scientific understanding is evolving.
POTS is now the focus of specific international research. The cerebrovascular mechanisms underlying brain fog are being studied directly. microRNAs, the transcriptome, the extracellular matrix, and other biomarkers are opening up new avenues of research. And even the very way we define and distinguish between SEDh and HSD is being reexamined today in light of new findings.
To patients, the message is this: your symptoms deserve to be studied, assessed, and understood. To doctors: mechanisms that we could previously only speculate about are now becoming accessible to scientific investigation.
Research does not yet have all the answers. But it is advancing rapidly. It is gradually establishing a scientific understanding of certain phenomena, challenging certain diagnostic boundaries, and developing new models.
Classification describes the state of our knowledge at a given point in time; it should not be confused with biological reality, which research continues to explore.
Limitations That Have Already Been Identified: From the Beighton Score to a Broader Biological Perspective
This evolution in our understanding has also led to a reexamination of certain historical tools. As early as 2020, we drew attention to the limitations of an approach that places decisive weight onthe Beighton scorein the assessment of hypermobility. This score remains a useful, simple, and reproducible clinical tool, but it assesses only a limited number of joints, does not, on its own, describe the history of hypermobility, and does not account for the full connective tissue phenotype or associated systemic manifestations.
This caution is particularly important when drawing a line between SEDh and HSD. A difference of a few points on a clinical score does not necessarily reflect a fundamental biological difference between two patients whose systemic manifestations may be very similar.
As early as 2020, we also discussed the possibility that understanding Ehlers-Danlos syndrome (EDS) cannot be limited to the search for a single genetic mutation and that it is necessary to consider the mechanismsregulating gene expression, particularly epigenetic ones (“Understanding EDS,” 2020, and “Transforming Ehlers-Danlos Syndrome,” 2022).
Current research on microRNAs, the transcriptome, fibroblasts, and the extracellular matrix makes this question particularly relevant today. While this research has not yet demonstrated a causal epigenetic mechanism for SEDh, nor does it currently allow for the use of microRNAs as diagnostic biomarkers in clinical practice, it does highlight how the traditional distinction between “genetic disease” and “absence of identified genetic abnormalities” may be insufficient to describe the biological complexity of these syndromes.
Thus, several insights put forward a few years ago—the limitations of the Beighton scale, phenotypic heterogeneity, the importance of systemic manifestations, and the possible role of mechanisms regulating gene expression—are now at the heart of the questions being explored by international research.
Caution remains essential:anticipating a scientific question is not the same as demonstrating its mechanism. However, the current shift in research—from a primarily clinical classification toward a clinical, molecular, and functional characterization of patients—represents a significant development.
Take care,
Stéphane Daens and GERSED Belgium