Fatigue in hEDS

Fatigue is one of the most common and disabling symptoms experienced by people with hypermobile Ehlers-Danlos syndrome (hEDS). It is much more than simply feeling tired after a busy day. Many people describe overwhelming physical exhaustion, reduced stamina, slowed thinking, difficulty recovering after activity, and an inability to sustain everyday tasks. Even routine activities such as showering, grocery shopping, or preparing a meal may require significant effort.

Research over the past decade has shown that fatigue in hEDS is a complex, multisystem symptom rather than the result of a single problem. A useful way to understand fatigue is as an imbalance between the body's energy demands and its ability to produce, conserve, and restore energy. While pain, poor sleep, and reduced physical activity all contribute, newer evidence suggests that underlying abnormalities in connective tissue, autonomic nervous system regulation, immune function, and cellular energy production also play important roles. Together, these interacting biological systems help explain why fatigue can be severe, persistent, and difficult to overcome.

Large studies estimate that approximately 75–85% of people with hEDS experience clinically significant fatigue, compared with roughly 10–20% of healthy individuals, depending on the measurement tool used. Fatigue severity in hEDS is often comparable to that seen in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and is substantially greater than that experienced by the general population.

Although fatigue affects nearly every aspect of daily life, it has historically received less attention than joint instability and chronic pain. As research has expanded, however, fatigue is increasingly recognized as one of the core manifestations of hEDS and one of the greatest contributors to disability and reduced quality of life.

Fatigue and sleepiness are not the same. Sleepiness is the tendency to fall asleep, whereas fatigue is a persistent lack of physical or mental energy that is not necessarily relieved by sleep. Many people with hEDS feel profoundly fatigued even after a full night's sleep because the biological processes contributing to fatigue continue around the clock.

Empirical Evidence of Fatigue Severity and Persistence

Most research examining fatigue in hEDS has been based on cross-sectional studies (single time-point assessments) rather than long-term studies following patients over many years. Even so, the findings have been remarkably consistent: people with hEDS report significantly greater fatigue than healthy individuals across nearly every validated fatigue measurement scale.

In one well-characterized study, participants with hEDS had an average score of approximately 98 out of 140 on the Checklist Individual Strength (CIS), compared with approximately 46 among healthy controls—more than twice the fatigue burden. Fatigue severity in hEDS was comparable to that reported by individuals with fibromyalgia and ME/CFS.

Long-term studies specifically tracking fatigue progression remain limited. However, research examining muscle strength, exercise capacity, physical functioning, and quality of life suggests that many of the biological factors contributing to fatigue persist over time. Although some individuals improve with appropriate treatment, fatigue often remains one of the most challenging symptoms to manage.

Fatigue is also common in children and adolescents with hEDS, where it is strongly associated with pain, autonomic symptoms, anxiety, depression, reduced participation in school and sports, and poorer overall quality of life. Research on pediatric chronic pain conditions suggests that fatigue beginning early in life may continue into adulthood, particularly when pain, sleep disturbance, and autonomic dysfunction remain untreated.

Overall, current evidence indicates that fatigue in hEDS is highly prevalent, frequently severe, and often persistent. Individual experiences vary considerably, but complete resolution is uncommon without addressing the multiple biological systems contributing to fatigue.

The Biology of Fatigue in hEDS: A Multisystem Disorder

Fatigue in hEDS does not have a single cause. Instead, it results from multiple interacting biological systems that influence circulation, energy production, nervous system regulation, musculoskeletal function, immune activity, sleep, and recovery from physical activity. Some of these mechanisms have been recognized for many years, while others have only recently begun to emerge through genetic and physiological research. Together, they help explain why fatigue affects nearly every aspect of daily life and why recovery from even modest physical or mental activity may be prolonged.

Historically, fatigue was thought to result primarily from chronic pain, poor sleep, and physical deconditioning. While these factors remain important, newer research suggests that they represent only part of the picture.

Recent genetic studies suggest that variants involving three major biological systems may be more common in some people with hEDS:

• Connective tissue (collagen) pathways, which influence joint stability, blood vessel function, and circulation.

• Immune-related pathways, including human leukocyte antigen (HLA) genes involved in immune regulation and inflammatory responses.

• Mitochondrial pathways, which are responsible for producing most of the body's cellular energy.

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These findings provide a possible biological framework for understanding fatigue. Rather than acting independently, these systems likely interact with one another. For example, connective tissue abnormalities may contribute to dysautonomia and increased muscular workload, immune dysregulation may amplify inflammation and autonomic dysfunction, and impaired mitochondrial function may reduce the body's ability to generate and sustain cellular energy. Together, these overlapping mechanisms may explain why fatigue is one of the most common and disabling symptoms of hEDS.

Increasing evidence suggests that fatigue is not simply a consequence of living with chronic pain or reduced activity but may also represent a direct manifestation of the underlying biology of hEDS.

Connective Tissue, Circulation, and Dysautonomia

Connective tissue provides structural support throughout the body, including the walls of blood vessels. In hEDS, abnormalities in connective tissue are thought to make veins more elastic than normal. When standing, gravity causes a greater volume of blood to pool in the legs and abdomen rather than returning efficiently to the heart. This reduces the amount of blood pumped with each heartbeat and decreases blood flow to the brain and muscles.

To compensate, the autonomic nervous system often increases heart rate and activates other mechanisms to maintain blood pressure and circulation. Although these responses help keep a person upright, they require additional work from the cardiovascular system and increase the body's energy demands.

Many people with hEDS develop dysautonomia, a disorder of the autonomic nervous system that affects automatic body functions such as heart rate, blood pressure, digestion, temperature regulation, and sweating. The most common form is postural orthostatic tachycardia syndrome (POTS), but other forms of orthostatic intolerance are also common. Symptoms such as rapid heart rate, dizziness, lightheadedness, brain fog, exercise intolerance, and profound fatigue often worsen when standing for prolonged periods or during hot weather.

Research suggests that orthostatic intolerance is one of the strongest predictors of fatigue in hEDS. One study found that orthostatic intolerance, chronic pain, reduced physical activity, and sedating medications together explained nearly half of the variation in fatigue severity among individuals with hEDS. More recent imaging studies have also shown that many people with dysautonomia have smaller cardiac chamber volumes and reduced stroke volume, changes thought to result from chronic cardiovascular deconditioning. These findings help explain why even routine daily activities may require substantially more effort than they do for healthy individuals.

Mitochondrial Dysfunction and Cellular Energy Production

Mitochondria are often described as the "energy factories" of the cell because they produce most of the body's adenosine triphosphate (ATP), the molecule that powers nearly every biological process. Muscles, nerves, and the brain are especially dependent on efficient mitochondrial function because of their high energy demands.

Emerging evidence suggests that mitochondrial dysfunction may contribute to fatigue in at least a subset of people with hEDS. Recent genetic research identified variants in several mitochondrial respiratory chain genes significantly more often in individuals with hEDS than in healthy controls. Although these findings require confirmation in larger studies, they support earlier hypotheses that impaired cellular energy production may play a role in exercise intolerance and persistent fatigue.

When mitochondria function less efficiently, cells produce less ATP and more reactive oxygen species, increasing oxidative stress and reducing the energy available to muscles, nerves, and the brain. Muscle cells may also rely more heavily on less efficient metabolic pathways, contributing to earlier fatigue, slower recovery after activity, and reduced exercise tolerance.

Researchers have also proposed that the chronic muscular overwork required to stabilize hypermobile joints may place additional stress on mitochondria over time. If so, mitochondrial dysfunction may both contribute to fatigue and be further aggravated by the increased energy demands created by joint instability, producing a self-reinforcing cycle of fatigue and reduced endurance.

Immune Dysregulation and Mast Cell Activation

Emerging evidence suggests that abnormalities of the immune system may also contribute to fatigue in some individuals with hEDS. Recent genetic studies have identified an increased frequency of variants involving human leukocyte antigen (HLA) genes, which play an important role in regulating immune responses. These findings may help explain why immune-related conditions appear to occur more frequently in people with hEDS than in the general population.

One immune-related condition reported more frequently in people with hEDS is mast cell activation syndrome (MCAS), although the exact relationship between the two conditions continues to be investigated. Mast cells release histamine, cytokines, and other inflammatory chemicals that help coordinate immune responses. When these cells become inappropriately activated, they can affect multiple organ systems, producing symptoms such as flushing, gastrointestinal problems, itching, headaches, rapid heart rate, and fatigue.

Several mechanisms may explain how immune dysregulation contributes to fatigue. Histamine and inflammatory signaling molecules can influence brain function, alter autonomic nervous system activity, disrupt sleep, impair gastrointestinal function, and interfere with normal cellular energy production. Together, these effects may increase the body's overall energy demands while reducing its ability to recover from physical or mental exertion.

Although researchers continue to investigate these relationships, immune dysregulation is increasingly recognized as another important contributor to the complex biology of fatigue in hEDS.

Small Fiber Neuropathy

Small fiber neuropathy has emerged as another important contributor to fatigue in hEDS. Small nerve fibers transmit pain signals and regulate many automatic body functions, including blood vessel constriction, heart rate, sweating, and temperature regulation.

Skin biopsy studies have found reduced numbers of these small nerve fibers in a substantial proportion of individuals with hEDS. Damage to these nerves may contribute to fatigue in two important ways. Because many small nerve fibers are part of the autonomic nervous system, small fiber neuropathy may contribute simultaneously to dysautonomia, chronic pain, and fatigue, helping explain why these symptoms frequently occur together.

First, impaired autonomic nerve function can worsen dysautonomia by reducing the body's ability to rapidly adjust blood vessel tone and maintain adequate circulation when changing position. Second, injury to pain-sensing nerve fibers may contribute to chronic neuropathic pain, increasing nervous system activity and further draining physical and mental energy.

The exact cause of small fiber neuropathy in hEDS remains uncertain. Researchers have proposed that abnormalities in connective tissue surrounding peripheral nerves may reduce structural support or alter the local environment needed for normal nerve function, but additional research is needed to better understand this relationship.

Chronic Pain and Central Sensitization

Pain is one of the most consistent contributors to fatigue in hEDS. Joint instability, recurrent soft tissue injuries, muscle overuse, and nerve irritation require the nervous system to process persistent pain signals throughout the day. Persistent pain places continuous demands on the nervous system, contributing to physical fatigue, mental fatigue, and reduced ability to recover from exertion.

Over time, persistent pain may also contribute to central sensitization, a condition in which the brain and spinal cord become increasingly responsive to pain signals. As central sensitization develops, the nervous system may amplify pain even in response to relatively minor stimuli, increasing the body's energy requirements while further reducing the capacity for physical activity, restorative sleep, and recovery.

Musculoskeletal Inefficiency

The musculoskeletal system in hEDS often requires substantially more energy to perform everyday activities than it does in people without the condition. Because joints are more flexible and less stable, muscles often must remain active for longer periods to provide the support that ligaments and other connective tissues would normally supply.

This constant muscular effort occurs even during simple activities such as standing, walking, maintaining posture, or reaching overhead. Over time, repeated muscle overuse can lead to earlier fatigue, soreness, prolonged recovery, and reduced endurance.

Many people with hEDS also experience reduced muscle strength, impaired proprioception (the body's ability to sense joint position and movement), and altered movement patterns. These changes make movement less efficient, meaning more energy is required to perform the same task. As fatigue increases, muscles may become less effective at stabilizing joints, further increasing the effort needed for movement and creating another self-reinforcing cycle.

When fatigue, pain, or autonomic symptoms limit activity, cardiovascular fitness and muscle conditioning may gradually decline. Although deconditioning can significantly worsen fatigue, it is generally considered a consequence of the underlying disorder rather than its primary cause. Appropriate rehabilitation can improve strength and endurance, but it does not eliminate the underlying biological factors contributing to fatigue.

Sleep Disruption

Restorative sleep is essential for repairing tissues, regulating the immune system, consolidating memory, and restoring physical and mental energy. Unfortunately, sleep disturbance is extremely common in hEDS.

Multiple factors can interfere with sleep, including chronic musculoskeletal pain, autonomic dysfunction, gastrointestinal symptoms, anxiety, restless legs syndrome, periodic limb movements during sleep, and breathing disorders such as upper airway resistance syndrome or obstructive sleep apnea. Even when individuals spend an adequate number of hours in bed, sleep may remain fragmented or nonrestorative, leaving them feeling as though they never fully recovered from the previous day.

Poor sleep not only increases daytime fatigue but also heightens pain sensitivity, worsens cognitive function, impairs mood, and reduces the body's ability to recover from physical activity. Because sleep disturbance affects so many biological systems, identifying and treating sleep disorders can be an important component of fatigue management.

How These Systems Interact

Although each of these biological mechanisms contributes to fatigue in different ways, they rarely occur in isolation. Instead, they interact with one another to create a cumulative energy burden.

For example, connective tissue abnormalities can impair circulation, requiring the autonomic nervous system to work harder to maintain blood flow when standing. Joint instability increases the workload placed on muscles, while chronic pain and small fiber neuropathy further increase nervous system activity and interfere with restorative sleep.

Immune dysregulation may amplify inflammation and autonomic symptoms, and impaired mitochondrial function may reduce the efficiency with which cells produce energy. Together, these processes increase the body's energy demands while limiting its ability to restore energy reserves.

This interaction helps explain why relatively modest activities may produce disproportionately severe fatigue in people with hEDS. A task that requires only modest effort for one person may require substantially greater physical and mental energy for someone with hEDS. Recovery may take hours or even days because multiple biological systems must return to baseline rather than just the muscles alone.

Rather than being caused by a single abnormality, fatigue in hEDS reflects the combined effects of increased energy demands and reduced capacity to generate, conserve, and restore energy. This multisystem model is increasingly supported by both clinical research and emerging genetic evidence.

Not every person with hEDS experiences fatigue for the same reasons. One individual may be affected primarily by dysautonomia, while another may experience greater contributions from chronic pain, sleep disruption, mast cell activation, or musculoskeletal instability. Others may experience several of these problems simultaneously. Understanding which biological systems contribute most to fatigue in each individual can help guide evaluation and treatment. The relative contribution of each mechanism likely varies considerably from person to person, which may explain why fatigue responds differently to treatment among individuals with hEDS.

Although many aspects of this biological model continue to be investigated, the evidence increasingly suggests that fatigue is not simply a consequence of chronic pain or reduced activity. Instead, it appears to arise from multiple interacting biological systems that together create a cumulative energy burden.

Major Biological Contributors to Fatigue in hEDS

Why Fatigue Often Becomes More Limiting Over Time

Many people with hEDS report that fatigue becomes more limiting as they age. Although long-term studies following fatigue over decades are limited, current research and clinical experience suggest that several overlapping biological processes likely contribute to this pattern.

Years of joint instability, repetitive micro-injuries, and compensatory movement patterns gradually increase the workload placed on muscles and supporting tissues. Even when injuries are relatively minor, repeated mechanical strain may accumulate over time, increasing pain, reducing endurance, and making everyday activities more physically demanding.

Many people also develop additional medical conditions that contribute to fatigue. Dysautonomia, gastrointestinal dysmotility, mast cell activation syndrome, sleep disorders, chronic migraine, neuropathic pain, and other comorbidities often emerge or become more noticeable over time. Each condition adds its own physiological demands, increasing the body's overall energy burden.

Reduced activity may further contribute to fatigue. People naturally limit activities that provoke pain, dizziness, or prolonged recovery, which can gradually reduce cardiovascular fitness and muscle strength. Although appropriate exercise remains an important part of treatment, rehabilitation is often challenging because excessive activity may temporarily worsen symptoms. Finding the right balance between activity and recovery is therefore essential.

Normal aging may also reduce the body's physiologic reserve—its ability to adapt to physical stress and recover from exertion. While this affects everyone to some degree, individuals with hEDS often begin with a greater baseline energy burden, making age-related changes more noticeable.

Psychological factors can also contribute to fatigue, although they are not considered its primary cause. Living with chronic pain, repeated medical appointments, uncertainty, functional limitations, and the emotional demands of managing a lifelong multisystem disorder requires considerable cognitive and emotional energy. These stresses can amplify fatigue without fully explaining it.

Not everyone with hEDS experiences progressive worsening. Some individuals remain relatively stable for many years, while others improve substantially with early diagnosis, targeted rehabilitation, effective management of comorbid conditions, and appropriate lifestyle modifications. Nevertheless, the underlying biology of hEDS creates an ongoing vulnerability to fatigue, particularly when several contributing mechanisms occur simultaneously.

How Fatigue in hEDS Compares with Other Conditions

Fatigue in hEDS is substantially greater than that experienced by healthy individuals and is among the most disabling symptoms reported by people with the condition. Studies consistently show that fatigue severity approaches that seen in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), despite differences in the underlying biology of these disorders.

Unlike inflammatory autoimmune diseases, in which fatigue often parallels disease activity, fatigue in hEDS appears to arise primarily from the combined effects of connective tissue abnormalities, autonomic dysfunction, musculoskeletal inefficiency, chronic pain, sleep disruption, immune dysregulation, and altered cellular energy production. Because these mechanisms interact with one another, improvement is often gradual rather than immediate.

Individuals with overlapping conditions such as POTS, mast cell activation syndrome, small fiber neuropathy, fibromyalgia, or ME/CFS frequently experience even greater fatigue and reduced quality of life. This reflects the additive effects of multiple conditions affecting many of the same biological systems.

Age-Related Considerations

Children and Adolescents

Fatigue is common even during childhood and adolescence. Young people with hEDS often report reduced endurance, difficulty participating in sports or physical education, and increased fatigue after school or other activities. Fatigue is closely associated with pain, autonomic symptoms, sleep disturbance, anxiety, depression, and reduced quality of life. Early recognition and appropriate management may help reduce long-term disability by preventing avoidable deconditioning and improving symptom control.

Adults

In adults, fatigue commonly affects employment, parenting, household responsibilities, and participation in social and recreational activities. Fatigue often correlates with pain severity, autonomic symptoms, physical activity levels, and the presence of additional medical conditions. Many adults describe carefully budgeting their energy throughout the day to avoid prolonged symptom flares.

Older Adults

Research involving older adults with hEDS remains limited. However, normal age-related changes in muscle mass, cardiovascular function, tissue repair, and physiologic reserve likely interact with long-standing connective tissue abnormalities and comorbid conditions to increase fatigue vulnerability. Additional research is needed to better understand fatigue later in life.

Major Comorbid Contributors

Several conditions commonly seen in hEDS can significantly worsen fatigue, including:

• Dysautonomia, including POTS and other forms of orthostatic intolerance

• Chronic pain syndromes

• Mast cell activation syndrome

• Gastrointestinal dysmotility and nutritional deficiencies

• Sleep disorders

• Small fiber neuropathy

• Migraine

• Mood and anxiety disorders

Because these conditions often interact, evaluating and treating each contributor individually may substantially reduce overall fatigue, even when fatigue itself does not completely resolve.

Management Strategies, Measurement, and Research Gaps

Effective Management

Because fatigue in hEDS arises from multiple interacting biological systems, no single treatment addresses every contributing mechanism or is effective for everyone. The greatest improvements are usually achieved by identifying the factors contributing to fatigue in each individual and addressing them together.

Management often includes:

• Physical therapy focused on improving joint stability, movement efficiency, and endurance

• Individually tailored exercise programs that emphasize gradual progression while avoiding excessive symptom flares

• Activity pacing to balance exertion with recovery and reduce post-exertional worsening of symptoms. Pacing does not mean avoiding activity altogether. Instead, it involves balancing physical and mental activity with planned recovery periods to reduce symptom flares while maintaining function over time.

• Evaluation and treatment of dysautonomia, including strategies to improve blood volume, circulation, and autonomic regulation

• Effective management of chronic pain using a multidisciplinary approach

• Identification and treatment of sleep disorders, including sleep apnea, upper airway resistance syndrome, restless legs syndrome, and periodic limb movement disorder when present

• Evaluation and treatment of gastrointestinal disorders and nutritional deficiencies that may contribute to fatigue

• Assessment and treatment of mast cell activation syndrome and other significant comorbid conditions when clinically indicated

• Psychological support to help individuals cope with chronic illness, improve stress management, and reduce the emotional burden of living with a lifelong multisystem disorder

  
  

Many individuals find that modest improvements in several contributing factors produce greater overall benefit than attempting to treat only one symptom. For example, improving sleep quality, optimizing management of dysautonomia, reducing pain, and increasing movement efficiency may each provide a small improvement individually, but together they can significantly reduce fatigue and improve daily functioning.

Although some people experience substantial improvement, complete resolution of fatigue is uncommon because many of the underlying biological mechanisms remain present.

Measuring Fatigue

Fatigue is difficult to measure because it affects many aspects of physical and mental functioning. Most research in hEDS uses general fatigue questionnaires developed for other medical conditions, such as the Checklist Individual Strength (CIS) or the Fatigue Severity Scale (FSS). While these instruments provide valuable information, they do not fully capture the unique combination of physical fatigue, cognitive fatigue, prolonged recovery after activity, autonomic symptoms, and fluctuating daily function commonly experienced by people with hEDS.

Developing fatigue measures specifically designed for hEDS may improve both research and clinical care by providing a more accurate picture of symptom severity and treatment response.

Future Research

Research into fatigue in hEDS is advancing rapidly. Recent genetic studies have identified potential abnormalities involving connective tissue, immune regulation, and mitochondrial energy production that may help explain why fatigue is so common and disabling. Although these findings require confirmation in larger and more diverse populations, they represent an important step toward understanding the biological basis of fatigue.

Future research will likely focus on clarifying how these biological systems interact, identifying distinct subgroups of patients, developing better tools to measure fatigue, and evaluating treatments that target specific mechanisms rather than fatigue as a single symptom. As our understanding improves, more personalized approaches to treatment may become possible.

Summary

Fatigue is one of the defining manifestations of hypermobile Ehlers-Danlos syndrome and one of the greatest contributors to reduced quality of life. Rather than resulting from a single abnormality, fatigue reflects the combined effects of connective tissue dysfunction, autonomic dysregulation, musculoskeletal inefficiency, chronic pain, sleep disturbance, immune abnormalities, small fiber neuropathy, and, in some individuals, impaired cellular energy production.

These biological systems interact in ways that increase the body's energy demands while reducing its ability to generate, conserve, and restore energy. This helps explain why everyday activities may require substantially more effort for people with hEDS and why recovery often takes much longer than expected.

Although no single treatment addresses every contributor to fatigue, identifying and treating the factors that are present in each individual can significantly improve function, endurance, and quality of life. Early recognition, individualized management, and treatment of associated conditions such as dysautonomia, sleep disorders, gastrointestinal disorders, chronic pain, and mast cell activation syndrome are particularly important.

Our understanding of fatigue in hEDS has evolved considerably over the past decade. Historically, fatigue in hEDS was often attributed primarily to chronic pain, sleep disruption, and reduced physical activity. More recent research suggests these factors remain important but represent only part of a much more complex biological picture. Ongoing research continues to improve our understanding of the biology of fatigue while creating opportunities for more targeted and effective treatments in the future.

Although many questions remain, recent advances have fundamentally changed our understanding of fatigue in hEDS. Rather than viewing fatigue as simply the result of chronic pain, poor sleep, or reduced physical activity, researchers increasingly recognize that fatigue may be a direct manifestation of the disorder's underlying biology. Connective tissue abnormalities, autonomic dysfunction, immune dysregulation, altered neuromuscular function, and less efficient cellular energy production appear to interact in complex ways, producing a cumulative energy burden that affects nearly every organ system.

This evolving understanding has important implications for both patients and healthcare providers. Fatigue should not be dismissed as an expected consequence of living with chronic pain or attributed solely to stress, anxiety, or deconditioning. Instead, it should be recognized as a legitimate, biologically based symptom that deserves careful evaluation and individualized treatment.

While no single therapy can eliminate fatigue for everyone with hEDS, addressing its many contributing factors can meaningfully improve daily functioning, quality of life, and long-term health. As research continues to uncover the biological mechanisms underlying hEDS, there is growing hope that future therapies will target the causes of fatigue more directly rather than simply helping people cope with its effects.