Announcing OMF's First ME/CFS Clinical Trial!

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

Driving research of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS),
Post Treatment Lyme Disease Syndrome (PTLDS), Fibromyalgia and Long COVID.

Donate
Sign Up
Main Menu

Genetic and Metabolic Markers
of BH4 Deficiency in Long COVID

Study AIM

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.

LEAD INVESTIGATORS
  • Laurel Crosby, PhD
  • Ronald W. Davis, PhD
Updates and Potential
  • 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.
STUDY HYPOTHESIS AND DESCRIPTION

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.

OBJECTIVES

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.

Consent management

Consent Preferences

Data Subject Access Request (DSAR) Form 

Microvesicles and viral sequencing
Microvesicles are a type of extracellular vesicle that is released from the cell membrane. Vesicles are small, fluid-filled sacs or vacuoles within the body. Sequencing is a technique used to determine the exact sequence of bases (A, C, G, and T) in a DNA (or viral) molecule.
NMR Metabolomics
NMR (Nuclear Magnetic Resonance) is an instrument/tool used to perform metabolic studies, metabolic profiling, and metabolomics in biofluids and tissues for more than 40 years using magnetic fields. There is a very close connection between metabolic measurements and NMR. This connection has flourished because of NMR’s many unique strengths for characterizing complex mixtures’ chemical composition.
Proteomics
The large-scale study of proteins, which are large, complex molecules that are required for structure, function, and regulation of the human body's tissues and organs.
Immune cell profiling
The immune system has many important regulatory roles in disease development and progression. Given the emergence of effective immune therapies, reliable predictors of response are needed. Immune cell profiling determines response by evaluating immune cell populations from treated and untreated samples. For our purposes, we will evaluate the white blood cell response to the viral infection using a process called “Cytof.”
Leukocyte Genomics
A leukocyte is a colorless cell circulating in the blood and body fluids and is involved in counteracting foreign substances and disease. A genome is all genetic material of an organism. Genomics is a biology field focusing on the structure, function, evolution, mapping, and editing of genomes. Therefore, leukocyte genomics is the study of all genetic material of leukocytes.
Metabolomics
Metabolomics is a way to study metabolism – that is, through measuring amounts of the metabolites (small molecules) produced by our bodies as we convert food into energy and other molecules that our cells need to survive. Metabolomics technology is ‘large-scale,’ meaning that several thousand metabolites can be measured from a single sample of e.g., blood or urine.
Micro RNA
Cells use Micro RNA to control whether a particular gene is making too much, too little or the normal amount of its protein at a particular time.
Autoantibodies
Antibodies that react with self-molecules and that occur in healthy individuals and are referred to as natural antibodies or autoantibodies.
Extracellular DNA for viral reactivation and Mitochondrial DNA
exDNA (extracellular DNA), exDNA is often secreted actively and is used to perform several tasks, thereby offering an attractive target or tool for biotechnological, medical, environmental, and general microbiological applications. Viruses are intracellular parasites that rely to a significant extent on the host cell for replication. Viral reactivation occurs when an active replication of the viral genome results in a lytic (degradation of the cell) infection characterized by the release of new progeny (descendant) virus particles.