Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?, 2025, A. F. M. Towheedur Rahman et al

Published January 10, 2025


Abstract: Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a chronic multisystem disease characterized by severe muscle fatigue, pain, dizziness, and brain fog. The two most common symptoms are post-exertional malaise (PEM) and orthostatic intolerance (OI). ME/CFS patients with OI (ME+OI) suffer from dizziness or faintness due to a sudden drop in blood pressure while maintaining an upright posture. Clinical research has demonstrated that patients with OI display severe cardiovascular abnormalities resulting in reduced effective blood flow in the cerebral blood vessels. However, despite intense investigation, it is not known why the effective cerebral blood flow is reduced in OI patients.

Based on our recent findings, we observed that tetrahydrobiopterin (BH4) metabolism was highly dysregulated in ME+OI patients. In the current review article, we attempted to summarize our recent findings on BH4 metabolism to shed light on the molecular mechanisms of OI.
LINK

 

Even though this is a review article it still would be helpful to have some data in the abstract to demonstrate how highly disregulated the metabolism is.

 

I know this is a symptom experienced by a proportion but it seems weird tho put it as the first symptom. I doubt it affects everyone with ME and it certainly isn’t what defines the disease.

 

Would it be the main symptom that their hypothesis would explain ? ......

 

Tetrahydrobiopterin: Beyond It's Traditional Role as a Cofactor

Figure 5. Tetrahydrobiopterin (BH4) metabolism as a central hub regulating physiological and toxic pathways. Normal BH4 levels (green circle): Physiological levels of BH4 sustain the traditional coenzyme activity of the pathway, favoring the correct metabolism of aromatic amino acids and ether lipids, and the biosynthesis of nitric oxide. Under these conditions, appropriate BH4 levels activate energy metabolism, enhance cellular resistance to oxidative stress, modulate the inflammatory response, facilitate learning and memory, regulate immune system activity, increase vascular activity, and exert neuroprotective effects. Reduced BH4 levels (orange circle):

When BH4 levels are perturbed, ATP synthesis and brain lipid signaling are impaired, an oxidant status is induced, neurotransmission is compromised, and inflammation is favored. Pathologically augmented BH4 levels (brown circle): Excessive intracellular BH4 levels induce mitochondrial dysfunction, compromise memory and learning, increase the aggressivity of the immune system, promote the progression of inflammatory and autoimmune diseases, and elicit chronic pain. Thus, BH4 metabolism can be considered a double-edged sword: too little or too much results in cytotoxicity.

 

1. Could be related to Stanford doing a BH4 study with at home cheek swab kit, it plans to enroll 1,000 ME/CFS patients, 1,000 LC patients and 100 healthy controls. A 4 year long study

https://studypages.com/s/study-to-i...h4-deficiency-in-mecfs-and-long-covid-525299/

2. For context: same researchers published study in 2024 on BH4

• Study examines ME/CFS metabolic and biochemical pathways focusing on tetrahydrobiopterin (BH4) metabolism and its interactions with the pentose phosphate pathway (PPP)
• https://journals.sagepub.com/doi/full/10.1177/11795735241271675

ChatGTP summary findings of this previous study 2024:

1. Elevated BH4 Levels:
- BH4 levels were found to be significantly elevated in ME/CFS patients, including those with orthostatic intolerance (OI) and small fiber polyneuropathy (SFPN).
- This increase is associated with systemic responses to metabolic stress rather than a straightforward benefit to vascular or metabolic function.

2. Pentose Phosphate Pathway (PPP) Dysregulation:
- Dysregulation of the PPP, a critical pathway for producing NADPH, was highlighted. NADPH is essential for the recycling of BH4 and maintaining redox balance.
- Impairments in the PPP may contribute to oxidative stress by limiting the availability of NADPH necessary to counteract reactive oxygen species (ROS) and regenerate BH4.

3. Interplay Between Oxidative Stress and BH4 :
- The study suggests that elevated BH4 levels occur in response to increased oxidative stress. However, the lack of sufficient NADPH from the PPP may exacerbate this stress, creating a dysfunctional feedback loop.
- BH4 metabolism in this context does not translate into improved nitric oxide (NO) production due to potential enzymatic decoupling, leading instead to increased ROS generation.
-

What could be possible future Clinical Implications ?