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Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia Leading Research. Delivering Hope.Open Medicine Foundation® Canada

Genetic and Metabolic Markers
of BH4 Deficiency in Long COVID

The study expands on a previously-awarded proposal to thoroughly explore the underlying pathophysiology of post exertional malaise (PEM), the hallmark symptom of ME/CFS.

  • Laurel Crosby, PhD
  • Ronald W. Davis, PhD
  • 300 DNA genotyping test kits designed, assembled, and ready to ship.
  • Online signup and consenting procedures are ready to implement. Social media announcements are in development for OMF, Patient Led Research Collaborative.
  • For in-person visits:
    • VENDYS-II Digital Thermal Monitoring instrument has been acquired and tested on laboratory volunteers. Ready to implement.
    • We are testing whether urine may be a more accessible specimen than plasma for measuring the proposed signature of BH4 deficiency.
    • HPLC-electrochemical detector has been acquired and tested with BH4 standards. BH4 stabilization protocol from human plasma is still under development; in-person visits will commence when this step is complete.

Tetrahydrobiopterin (BH4) is a vitamin-like cofactor that is made in the body by a series of enzymatic steps. However, there are common mutations in the biosynthesis pathway that are associated with cofactor deficiency. BH4 is needed for metabolism of a small number of amino acids that are precursors to neurotransmitters, and deficiency leads to cognitive impairment and a wide variety of other symptoms associated with neurotransmitter imbalance. BH4 is also needed for the enzyme nitric oxide synthase, which is a major regulator of blood flow dynamics and immune cell function.

We have determined that individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are more likely to have pathogenic variants in BH4 synthesis genes compared to the general population, and we have also identified a corroborating metabolic signature that predicts BH4 deficiency. Oxidative stress during infection can also lead to BH4 deficiency, so there are many potential routes to the same problem. We propose to test whether these genetic markers and other indicators of BH4 deficiency are also present in subjects with Long Covid. If we are successful, we will show that ME/CFS and Long Covid have a common underlying disease mechanism that includes deficiency of BH4.


3D illustration. Genetic test in test tube.

  • Conduct a 1-year Genotyping study on 300 individuals with Long Covid, recruited from the Patient-Led Research Collaborative and other patient registries for Long Covid.
  • Invite 50 individuals with the affected GCH1 genotypes and 50 healthy age- and gender-matched controls to participate in tests to:
  • Measure plasma metabolites for a characteristic signature of BH4 deficiency
  • Conduct a physiology assessment of BH4-dependent Vascular Reactive Index using Digital Thermal Monitoring.