Fatigue in Ehlers-Danlos Syndrome (EDS)

By Pradeep Chopra, M.D.
Fatigue is a common yet often misunderstood symptom in individuals with hypermobile Ehlers-
Danlos Syndrome (hEDS). Unlike typical tiredness, which resolves with rest, fatigue in hEDS is
persistent and often resistant to conventional remedies. This chronic exhaustion is sometimes
misdiagnosed as Chronic Fatigue Syndrome (CFS), a vague label that can hinder further
investigation into the root causes of fatigue in hypermobility disorders.
Understanding the underlying factors contributing to fatigue in EDS can help patients and
healthcare providers develop targeted management strategies. Below are some key contributors
to fatigue in individuals with hEDS:

1. Orthostatic Intolerance and Poor Blood Flow
   Postural Orthostatic Tachycardia Syndrome (POTS) and other forms of dysautonomia are
   common in EDS. These conditions impair blood flow regulation, leading to insufficient oxygen
   delivery to tissues. Poor oxygenation can cause both muscular fatigue and cognitive impairment,
   often described as “brain fog.”
2. Medication-Induced Fatigue
   Many EDS patients take multiple medications to manage pain, dysautonomia, and MCAS. Some
   of these medications, such as antihistamines (e.g., Benadryl), sedatives, and beta-blockers,
   contribute to lethargy. While each medication alone may have a mild effect, the combination can
   significantly increase fatigue.
3. Ligament Laxity and Muscle Overuse
   People with EDS experience ligament laxity, meaning their ligaments are too loose to provide
   adequate joint stability. This forces their muscles to work harder to maintain posture and
   movement, leading to muscle fatigue. Unlike individuals with normal ligament support, EDS
   patients constantly engage their muscles, even while at rest, resulting in chronic fatigue.
4. Mast Cell Activation Syndrome (MCAS)
   MCAS is frequently seen in individuals with EDS and results in widespread inflammation.
   Patients often describe a constant flu-like feeling, which contributes to overall fatigue. Chronic
   inflammation from MCAS can exacerbate exhaustion and reduce daily functionality.
5. Sleep Disorders: Sleep Apnea and Non-Restorative Sleep
   EDS is associated with obstructive and central sleep apnea due to laxity in airway tissues.
   Tracheomalacia, or softening of the trachea, can further contribute to breathing difficulties during

sleep. Additionally, high sympathetic nervous system activity in EDS prevents restful sleep,
leaving individuals exhausted despite sleeping for a full night.

6. Mitochondrial Dysfunction
   In EDS, mitochondrial dysfunction impairs oxygen utilization, leading to exercise intolerance
   and muscle weakness. This dysfunction may stem from genetic factors, autoimmune issues, or
   chronic infections.
   Mitochondria, often referred to as the “powerhouses of the cell,” play a crucial role in energy
   production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. ATP
   serves as the primary energy currency for nearly all cellular processes, including muscle
   contraction, neurotransmission, and metabolic homeostasis. Dysfunction in mitochondrial
   function has been increasingly linked to fatigue, a symptom that is both prevalent and complex,
   affecting individuals with various medical conditions, including chronic fatigue syndrome (CFS),
   fibromyalgia, and mitochondrial diseases.
   Mitochondrial Function and ATP Production
   Mitochondria convert nutrients—primarily glucose and fatty acids—into ATP via the electron
   transport chain (ETC), a series of protein complexes embedded in the inner mitochondrial
   membrane. This process is highly efficient under normal physiological conditions, but
   disruptions can lead to impaired ATP synthesis and an increase in oxidative stress, both of which
   contribute to fatigue.
   Mitochondrial Dysfunction and Fatigue
   Several mechanisms link mitochondrial dysfunction to fatigue:
7. Reduced ATP Availability: Insufficient ATP production directly affects cellular energy
   demands, leading to muscle weakness, cognitive fatigue, and exercise intolerance.
8. Oxidative Stress: An imbalance between reactive oxygen species (ROS) production and
   antioxidant defenses damages mitochondrial DNA (mtDNA), proteins, and lipids, further
   impairing energy production.
9. Inflammatory Response: Chronic inflammation, commonly observed in conditions
   associated with fatigue, can lead to mitochondrial damage through cytokine-mediated
   effects on ETC function.
10. Dysregulated Mitochondrial Biogenesis: Impaired signaling pathways (e.g., PGC-1α, a
    key regulator of mitochondrial replication) may reduce the number of functional
    mitochondria, exacerbating energy deficits.
    Clinical Implications and Potential Interventions
    Addressing mitochondrial dysfunction may provide therapeutic avenues for fatigue management.
    Strategies include:

• Nutritional Support: Coenzyme Q10, L-carnitine, riboflavin, and magnesium have been explored for their roles in mitochondrial energy metabolism.
• Exercise Therapy: Moderate aerobic and resistance training can enhance mitochondrial efficiency and biogenesis, improving fatigue symptoms over time.
• Antioxidant Therapy: Targeting oxidative stress with compounds such as N-acetylcysteine (NAC) and alpha-lipoic acid (ALA) may support mitochondrial integrity.
• Metabolic Modulation: Interventions like intermittent fasting or ketogenic diets may enhance mitochondrial resilience by optimizing fatty acid oxidation.

Metabolic Modulation: Interventions like intermittent fasting or ketogenic diets may
enhance mitochondrial resilience by optimizing fatty acid oxidation.
Mitochondrial function is integral to cellular energy balance, and its impairment is a recognized
contributor to fatigue. Understanding the interplay between mitochondrial bioenergetics,
oxidative stress, and inflammation provides insights into fatigue-related disorders and potential
therapeutic strategies. Future research should continue exploring targeted mitochondrial
interventions to improve energy production and reduce fatigue-related symptoms.
7.Hormonal Dysregulation
People with EDS often experience hormonal imbalances, such as symptoms of hypothyroidism
despite normal lab results. Pituitary and adrenal insufficiency may also develop due to cerebral
hypoperfusion, leading to chronic fatigue and poor stress tolerance.

8. Intracranial Pressure Abnormalities
   EDS patients frequently experience abnormal intracranial pressure:
    High Intracranial Pressure (ICP): Restriction of venous blood flow can elevate
   pressure inside the skull, affecting pituitary function and hormone regulation. This
   condition, known as Empty Sella Syndrome, can contribute to fatigue.
    Low Intracranial Pressure (ICP): Cerebrospinal fluid (CSF) leaks, common in EDS,
   can lead to low ICP, causing severe headaches that worsen when upright and improve
   when lying down. This condition is also linked to profound fatigue.
9. Autoimmune Dysfunction
   A subset of EDS patients exhibit autoimmune-like symptoms, where their immune system
   mistakenly attacks their own tissues. Chronic pain and fatigue are hallmark symptoms of
   autoimmune involvement in EDS.
10. Nutritional Deficiencies
    Gastrointestinal dysmotility is prevalent in EDS, causing chronic nausea, constipation, diarrhea,
    and malabsorption. Patients often develop food intolerances and deficiencies in essential
    nutrients, including fat-soluble vitamins. Small Intestinal Bacterial Overgrowth (SIBO) is also
    common, further exacerbating fatigue.
11. Anemia and Low Ferritin Levels

Iron is crucial for oxygen transport in the blood. Many EDS patients have low ferritin levels,
indicating poor iron storage. Even when traditional anemia is not diagnosed, suboptimal ferritin
levels can contribute to persistent fatigue.

By recognizing the multifaceted nature of fatigue in EDS, healthcare professionals can move
beyond generic diagnoses like Chronic Fatigue Syndrome and provide more precise, effective
interventions.

For EDS patients, understanding the reasons behind their fatigue can be empowering, offering
hope for targeted management strategies that improve quality of life.

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