Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation, 2025, Birch, Younger et al

[LizWorthey]

Oh, I clicked on the first every time so I didn’t see the second.

The AD one doesn’t say, but the liver cirrhosis is based on massive cohorts so you actually know that the rare variants are over-represented in the cases.

If you have that validation, I completely agree that the genes can be very relevant for figuring how the disease works.

Jnmaciuch put the rest better than me.

Where these are noted as pathogenic or risk factors; there is evidence. Happy to go through that some time for any of interest, but these are not just VUSs we claim to be pathogenic. I think the point being made is more that just having a rare disease variant with an overlapping disease phenotype doesn't mean that it explains ME/CFS; if I understand correctly. My (author's) take is that these are excellent hypotheses generators that can be followed up on experimentally or in the larger cohorts .

 

[Utsikt]

Just commenting on some parts:

Where milder/more moderate later onset forms (often with "milder" variants) have been noted presenting with exercise intolerance/early fatigability, chronic fatigue, weakness, peripheral neuropathy.

Lots of diseases present with exercise intolerance, weakness and fatigue. My relative with MS would fit this description. Peripheral neuropathy is also common (I’m not sure about the prevalence in ME/CFS).

Where SARS‐CoV‐2 has been shown to be a preceding event in the death of a patient with this variant (homozygous) - acute respiratory failure and refractory hypotension from severe cardiomyopathy, and a different variant (homozygous) with a second death.

What does covid have to do with ME/CFS in general? I think we have data demonstrating that ME/CFS isn’t more common after covid than other normal infections. And death from covid is different than ME/CFS. I think men are more likely to die from it, but women are more likely to get ME/CFS. So a predisposition towards more severe covid might be protective for ME/CFS.

I also think that we don’t have robust enough data on the link between severity of the infection and rate of getting ME/CFS.

Where the impacted mechanism of fatty-acid oxidation/long-chain FA metabolism, has been shown altered across a dozen or more ME/CFS/Long COVID/PASC studies.

Please share those studies, there might have threads on them already.

Where progressive disease worsening has been seen in HADHA associated disease with even low amounts of exercise due to rhabdomyolysis and where rhabdomyolysis has been published as a theory related to PEM in ME/CFS.

There is no rhabdo in ME/CFS, it would have been very obvious on all of the CPETs that have been done, or the countless people that have tried to exercise their way out of ME/CFS.

Where chronic fatigue and exercise intolerance is a core symptom of many mitochondrial diseases, including in a number like LHON where there is an early onset disorder with varied severe symptoms beyond those two symptoms, but also a extended phenotype in the carrier parents that is often very much focused on chronic fatigue, brain fog, and exercise intolerance.

Others will know more about this, but I think the broken mitochondria angle for ME/CFS hasn’t panned out. And ME/CFS does not look like the known mitochondrial diseases.

 

[Jonathan Edwards]

I would agree with @Utsikt for several of those points.

Peripheral neuropathy is not a known feature of ME/CFS. Nor is rhabdomyolysis. (There is one report which is at odds with a very long history of relevant negative data.) We don't have any evidence for mitochondrial malfunction being responsible for symptoms despite persistent claims. Susceptibility to acute Covid is not necessarily relevant. Evidence for altered fatty acid metabolism is I think pretty unclear except perhaps in some immune cells. Even weakness is hard to demonstrate in ME/CFS.

I think these rare gene variants are intriguing but to my mind someof the genes pulled out by DecodeME look more likely to be important clues - implicating maybe generic aspects of T cell behaviour and neural signalling. Much of the popular dogma on ME/CFS pathogenesis seems off target to research-based physicians in other fields and I think it is worth interrogating all these models very carefully. (Which I guess is what we have tried to do here for the last eight years.)

 

[jnmaciuch]

I'm not sure we will shift each other much off our current thinking in a slow back and forward here

Yup I think we might be at an impasse. I’m all for pulling pieces of information into a hypothesis, but the concern is that an analysis like this is structured to introduce multiple layers of confirmation bias where a different kind of analysis wouldn’t—from the way specific genes are picked out to the bias in the case studies that link often generic symptoms to a variant without due diligence.

I can acknowledge I might be overly skeptical compared to your enthusiasm for the relevance of these variants identified here. Or alternatively, your enthusiasm may be indicative of that confirmation bias. I would be happy to be proven wrong!

And it all depends on what this is intended to be used for—as a basis for hypothesis generation, sure (though I might like a stronger evidence base than we see in this study to justify resources). As something to be incorporated into hypothesis-testing studies or drug trials to define “subgroups” in the absence of a known mechanism or robust a priori subgroup categorization from a large study, absolutely not.

 

[LizWorthey]

Just commenting on some parts:

Keep trying to take a break, but getting asked questions . But appreciate the engagement.

LizWorthey said:
Where milder/more moderate later onset forms (often with "milder" variants) have been noted presenting with exercise intolerance/early fatigability, chronic fatigue, weakness, peripheral neuropathy.

Lots of diseases present with exercise intolerance, weakness and fatigue. My relative with MS would fit this description. Peripheral neuropathy is also common (I’m not sure about the prevalence in ME/CFS).

Yes and I made that exact point earlier. I agree that ALONE it doesn't make a mitochondrial role in ME/CFS certain. But as I said it is a datapoint of interest. Of interest; do you think that there is no role for a mito defect in ME/CFS?

LizWorthey said:
Where SARS‐CoV‐2 has been shown to be a preceding event in the death of a patient with this variant (homozygous) - acute respiratory failure and refractory hypotension from severe cardiomyopathy, and a different variant (homozygous) with a second death.

What does covid have to do with ME/CFS in general? I think we have data demonstrating that ME/CFS isn’t more common after covid than other normal infections. And death from covid is different than ME/CFS. I think men are more likely to die from it, but women are more likely to get ME/CFS. So a predisposition towards more severe covid might be protective for ME/CFS.

Not suggesting severe COVID equals ME/CFS; clearly not. From what I have seen; NIH-funded work has documented increased ME/CFS diagnoses following covid infection and increased rates of ME/CFS since COVID. If you have critiques of those studies, I’m genuinely interested. I’m not aware of evidence that severe COVID is protective for ME/CFS, and from what I have seen, reports suggest ME/CFS/Long-COVID risk isn’t tightly tied to acute-illness severity. Would love to know more there if that isn't what's noted here.

The specific reason I mentioned COVID here is mechanistic: SARS-CoV-2 can exacerbate cardiomyopathy in individuals with HADHA variants. That cardiomyopathy has been linked to impaired long-chain fatty-acid oxidation with toxic metabolite accumulation and tissue injury; biology that contributes to post-exertional and chronic fatigue. So an interesting data point.

LizWorthey said:
Where the impacted mechanism of fatty-acid oxidation/long-chain FA metabolism, has been shown altered across a dozen or more ME/CFS/Long COVID/PASC studies.

Please share those studies, there might have threads on them already.

Ok pulled together a starter set of both the studies and a few reviews of studies; not exhaustive. It’d be great if someone had already done a deep, post-hoc review of these papers with varied expertise. We’re slowly scanning pre-existing omics studies for signals that map to mitochondrial variants (including in supplement tables that may have been overlooked); if we ever finish, I’ll share it gladly.

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PubMed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is...

pubmed.ncbi.nlm.nih.gov

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal...

pubmed.ncbi.nlm.nih.gov

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and...

pubmed.ncbi.nlm.nih.gov

Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, poorly understood disease that has no effective treatments, and has long been underserved by scientific research and national health systems. It is a sex-biased disease towards females that is often triggered by an...

www.medrxiv.org

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids - PubMed

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma...

pubmed.ncbi.nlm.nih.gov

Metabolic adaptation and fragility in healthy 3D in vitro skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, no<i>in vitro</i>model exists to study skeletal muscle wasting, peripheral weakness, or...

pubmed.ncbi.nlm.nih.gov

The Omics Landscape of Long COVID-A Comprehensive Systematic Review to Advance Biomarker, Target and Drug Discovery - PubMed

An estimated 10% of coronavirus disease (COVID-19) survivors suffer from persisting symptoms referred to as long COVID (LC), a condition for which approved treatment options are still lacking. This systematic review (PROSPERO: CRD42024499281) aimed to explore the pathophysiological mechanisms...

pubmed.ncbi.nlm.nih.gov

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome - PubMed

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome

pubmed.ncbi.nlm.nih.gov

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep...

www.medrxiv.org

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and...

pubmed.ncbi.nlm.nih.gov

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC) - PubMed

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded...

pubmed.ncbi.nlm.nih.gov

Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study - PubMed

LCLs generated from circulating B cells from people with ME/CFS show accumulation of lipids, skewed lipid profiles and altered activity of related metabolic enzymes such as PTDSS1. These findings will inform future hypothesis-driven studies of primary lymphoid cell populations from people with...

pubmed.ncbi.nlm.nih.gov

Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms - PubMed

The observed sex-specific pattern of dysregulated PL, NL, HexCer and oxylipins in ME/CFS patients suggests a possible role of these lipids in promoting immune dysfunction and inflammation which may be among the underlying factors driving the clinical presentation of fatigue, chronic pain, and...

pubmed.ncbi.nlm.nih.gov

Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients - Metabolomics

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term multisystem disorder with a central and inexplicably persistent fatigue symptom that is unable to be relieved by rest. Energy metabolism and oxidative stress have been recent focal points of ME/CFS research...

link.springer.com

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or "PEM"), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the...

pubmed.ncbi.nlm.nih.gov

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics...

pubmed.ncbi.nlm.nih.gov

NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome - PubMed

Chronic fatigue syndrome (CFS) is a debilitating multisystem disorder characterised by long-term fatigue with a variety of other symptoms including cognitive dysfunction, unrefreshing sleep, muscle pain, and post-exertional malaise. It is a poorly understood condition that occurs in ~5 in every...

pubmed.ncbi.nlm.nih.gov

Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK biobank - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility toward a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in patients with...

pubmed.ncbi.nlm.nih.gov

Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic...

pubmed.ncbi.nlm.nih.gov

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PubMed

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the...

pubmed.ncbi.nlm.nih.gov

Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism - PubMed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains a continuum spectrum disease without biomarkers or simple objective tests, and therefore relies on a diagnosis from a set of symptoms to link the assortment of brain and body disorders to ME/CFS. Although recent studies show...

pubmed.ncbi.nlm.nih.gov

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and...

pubmed.ncbi.nlm.nih.gov

Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O …

pubmed.ncbi.nlm.nih.gov

Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review - PubMed

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue...

pubmed.ncbi.nlm.nih.gov

LizWorthey said:
Where progressive disease worsening has been seen in HADHA associated disease with even low amounts of exercise due to rhabdomyolysis and where rhabdomyolysis has been published as a theory related to PEM in ME/CFS.

There is no rhabdo in ME/CFS, it would have been very obvious on all of the CPETs that have been done, or the countless people that have tried to exercise their way out of ME/CFS.

If mitochondrial dysfunction is only one pathway to ME/CFS, you’d expect related findings in just a subset of cases; not seeing it in everyone doesn’t refute the hypothesis. In heterogeneous cohorts, rare events like rhabdomyolysis could be missed (could be underpowered for this group of folks, testing to see the issue could be time-point specific, etc.). I’m not claiming it’s common or even proven; only that its absence at group level doesn’t disprove the hypothesis. I looked hard at rhabdo for a while, and there are case reports of rhabdo in ME/CFS/Long COVID patients - one I recall was an autopsy case from the UK; there were some other mentions on reddit and ME/CFS long hauler sites. So like all of these; they remain to be proven, but IMO anyway remain a plausible, if uncommon, path.

Others will know more about this, but I think the broken mitochondria angle for ME/CFS hasn’t panned out. And ME/CFS does not look like the known mitochondrial diseases.

Interesting. Even within trifunctional protein/β-oxidation/fatty-acid oxidation/OXPHOS, there are published findings; and many more across mitochondrial biology generally. If the hypothesis is that mitochondrial defects are one of several paths to ME/CFS, we wouldn’t expect to see them in everyone, which could explain why some larger studies don’t pan out. I’d be genuinely interested to hear whether others think mitochondrial defects plausibly account for a subset of patients. How do you (or others who discussed it) define broken mitochondria? I also have thought a lot about when samples were taken. In the mitochondrial disease world, we do see instances of people passing testing one day and not the next when they end up having a defect; mito/metabolomics can be like that.

So can I ask; what would be your take on rare causes of ME/CFS? honestly interested in general.

 

[LizWorthey]

Yup I think we might be at an impasse. I’m all for pulling pieces of information into a hypothesis, but the concern is that an analysis like this is structured to introduce multiple layers of confirmation bias where a different kind of analysis wouldn’t—from the way specific genes are picked out to the bias in the case studies that link often generic symptoms to a variant without due diligence.

I can acknowledge I might be overly skeptical compared to your enthusiasm for the relevance of these variants identified here. Or alternatively, your enthusiasm may be indicative of that confirmation bias. I would be happy to be proven wrong!

And it all depends on what this is intended to be used for—as a basis for hypothesis generation, sure (though I might like a stronger evidence base than we see in this study to justify resources). As something to be incorporated into hypothesis-testing studies or drug trials to define “subgroups” in the absence of a known mechanism or robust a priori subgroup categorization from a large study, absolutely not.

Yes agree; a good discussion we can maybe continue as we see how things go

 

[LizWorthey]

Keep trying to take a break, but getting asked questions . But appreciate the engagement.

Yes and I made that exact point earlier. I agree that ALONE it doesn't make a mitochondrial role in ME/CFS certain. But as I said it is a datapoint of interest. Of interest; do you think that there is no role for a mito defect in ME/CFS?


Not suggesting severe COVID equals ME/CFS; clearly not. From what I have seen; NIH-funded work has documented increased ME/CFS diagnoses following covid infection and increased rates of ME/CFS since COVID. If you have critiques of those studies, I’m genuinely interested. I’m not aware of evidence that severe COVID is protective for ME/CFS, and from what I have seen, reports suggest ME/CFS/Long-COVID risk isn’t tightly tied to acute-illness severity. Would love to know more there if that isn't what's noted here.

The specific reason I mentioned COVID here is mechanistic: SARS-CoV-2 can exacerbate cardiomyopathy in individuals with HADHA variants. That cardiomyopathy has been linked to impaired long-chain fatty-acid oxidation with toxic metabolite accumulation and tissue injury; biology that contributes to post-exertional and chronic fatigue. So an interesting data point.


Ok pulled together a starter set of both the studies and a few reviews of studies; not exhaustive. It’d be great if someone had already done a deep, post-hoc review of these papers with varied expertise. We’re slowly scanning pre-existing omics studies for signals that map to mitochondrial variants (including in supplement tables that may have been overlooked); if we ever finish, I’ll share it gladly.

Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PubMed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is...

pubmed.ncbi.nlm.nih.gov

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal...

pubmed.ncbi.nlm.nih.gov

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and...

pubmed.ncbi.nlm.nih.gov

Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, poorly understood disease that has no effective treatments, and has long been underserved by scientific research and national health systems. It is a sex-biased disease towards females that is often triggered by an...

www.medrxiv.org

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids - PubMed

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma...

pubmed.ncbi.nlm.nih.gov

Metabolic adaptation and fragility in healthy 3D in vitro skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, no<i>in vitro</i>model exists to study skeletal muscle wasting, peripheral weakness, or...

pubmed.ncbi.nlm.nih.gov

The Omics Landscape of Long COVID-A Comprehensive Systematic Review to Advance Biomarker, Target and Drug Discovery - PubMed

An estimated 10% of coronavirus disease (COVID-19) survivors suffer from persisting symptoms referred to as long COVID (LC), a condition for which approved treatment options are still lacking. This systematic review (PROSPERO: CRD42024499281) aimed to explore the pathophysiological mechanisms...

pubmed.ncbi.nlm.nih.gov

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome - PubMed

Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome

pubmed.ncbi.nlm.nih.gov

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogeneous, and systemic disease defined by a suite of symptoms, including unexplained persistent fatigue, post-exertional malaise (PEM), cognitive impairment, myalgia, orthostatic intolerance, and unrefreshing sleep...

www.medrxiv.org

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and...

pubmed.ncbi.nlm.nih.gov

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC) - PubMed

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded...

pubmed.ncbi.nlm.nih.gov

Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study - PubMed

LCLs generated from circulating B cells from people with ME/CFS show accumulation of lipids, skewed lipid profiles and altered activity of related metabolic enzymes such as PTDSS1. These findings will inform future hypothesis-driven studies of primary lymphoid cell populations from people with...

pubmed.ncbi.nlm.nih.gov

Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms - PubMed

The observed sex-specific pattern of dysregulated PL, NL, HexCer and oxylipins in ME/CFS patients suggests a possible role of these lipids in promoting immune dysfunction and inflammation which may be among the underlying factors driving the clinical presentation of fatigue, chronic pain, and...

pubmed.ncbi.nlm.nih.gov

Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients - Metabolomics

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating long-term multisystem disorder with a central and inexplicably persistent fatigue symptom that is unable to be relieved by rest. Energy metabolism and oxidative stress have been recent focal points of ME/CFS research...

link.springer.com

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or "PEM"), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the...

pubmed.ncbi.nlm.nih.gov

A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics...

pubmed.ncbi.nlm.nih.gov

NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome - PubMed

Chronic fatigue syndrome (CFS) is a debilitating multisystem disorder characterised by long-term fatigue with a variety of other symptoms including cognitive dysfunction, unrefreshing sleep, muscle pain, and post-exertional malaise. It is a poorly understood condition that occurs in ~5 in every...

pubmed.ncbi.nlm.nih.gov

Exploring a genetic basis for the metabolic perturbations in ME/CFS using UK biobank - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a clinically heterogeneous disease lacking approved therapies. To assess genetic susceptibility toward a specific metabolic phenotype, we performed a genome-wide association study on plasma biomarker levels (mGWAS) in patients with...

pubmed.ncbi.nlm.nih.gov

Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic...

pubmed.ncbi.nlm.nih.gov

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PubMed

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the...

pubmed.ncbi.nlm.nih.gov

Metabolic profiling of a myalgic encephalomyelitis/chronic fatigue syndrome discovery cohort reveals disturbances in fatty acid and lipid metabolism - PubMed

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains a continuum spectrum disease without biomarkers or simple objective tests, and therefore relies on a diagnosis from a set of symptoms to link the assortment of brain and body disorders to ME/CFS. Although recent studies show...

pubmed.ncbi.nlm.nih.gov

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and...

pubmed.ncbi.nlm.nih.gov

Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways - PubMed

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O …

pubmed.ncbi.nlm.nih.gov

Conceptual foundations of acetylcarnitine supplementation in neuropsychiatric long COVID syndrome: a narrative review - PubMed

Post-acute sequelae of COVID-19 can present as multi-organ pathology, with neuropsychiatric symptoms being the most common symptom complex, characterizing long COVID as a syndrome with a significant disease burden for affected individuals. Several typical symptoms of long COVID, such as fatigue...

pubmed.ncbi.nlm.nih.gov

If mitochondrial dysfunction is only one pathway to ME/CFS, you’d expect related findings in just a subset of cases; not seeing it in everyone doesn’t refute the hypothesis. In heterogeneous cohorts, rare events like rhabdomyolysis could be missed (could be underpowered for this group of folks, testing to see the issue could be time-point specific, etc.). I’m not claiming it’s common or even proven; only that its absence at group level doesn’t disprove the hypothesis. I looked hard at rhabdo for a while, and there are case reports of rhabdo in ME/CFS/Long COVID patients - one I recall was an autopsy case from the UK; there were some other mentions on reddit and ME/CFS long hauler sites. So like all of these; they remain to be proven, but IMO anyway remain a plausible, if uncommon, path.


Interesting. Even within trifunctional protein/β-oxidation/fatty-acid oxidation/OXPHOS, there are published findings; and many more across mitochondrial biology generally. If the hypothesis is that mitochondrial defects are one of several paths to ME/CFS, we wouldn’t expect to see them in everyone, which could explain why some larger studies don’t pan out. I’d be genuinely interested to hear whether others think mitochondrial defects plausibly account for a subset of patients. How do you (or others who discussed it) define broken mitochondria? I also have thought a lot about when samples were taken. In the mitochondrial disease world, we do see instances of people passing testing one day and not the next when they end up having a defect; mito/metabolomics can be like that.

So can I ask; what would be your take on rare causes of ME/CFS? honestly interested in general.

Oops did not know the site would pull all the papers out like that. Very cool. But LMK if I need to do something here. Just learning the formatting!

 

[LizWorthey]

I would agree with @Utsikt for several of those points.

Peripheral neuropathy is not a known feature of ME/CFS. Nor is rhabdomyolysis. (There is one report which is at odds with a very long history of relevant negative data.) We don't have any evidence for mitochondrial malfunction being responsible for symptoms despite persistent claims. Susceptibility to acute Covid is not necessarily relevant. Evidence for altered fatty acid metabolism is I think pretty unclear except perhaps in some immune cells. Even weakness is hard to demonstrate in ME/CFS.

I think these rare gene variants are intriguing but to my mind someof the genes pulled out by DecodeME look more likely to be important clues - implicating maybe generic aspects of T cell behaviour and neural signalling. Much of the popular dogma on ME/CFS pathogenesis seems off target to research-based physicians in other fields and I think it is worth interrogating all these models very carefully. (Which I guess is what we have tried to do here for the last eight years.)

Devil's advocate; one of those genes pulled out by DecodeME is mito FBXL4. And we did see a number of neuronal signalling genes too. I'm bad, I know . I don't disagree that the power of a large study is incredibly important. I sent a note to Chris to see if he is willing to hunt with us . Did try to comment on the other points. Again; not at all defensive. Just sitting here with the flu and wasting time/procrastinating grant critiques..

 

[Kitty]

There are a couple of ways of posting links, Liz. One method is to copy the URL from the address bar and paste it straight into the comment box, like so:

Foinn Seisiún from Comhaltas on The Session

thesession.org

...which automatically creates a preview.

The other method is to paste the address into the URL field in the Insert Link tool, accessed via the chain icon:

...which produces a bare link:

https://thesession.org/tunes/collections/5

 

[voner]

@LizWorthey,

I am reading your interchanges with great interest. Thanks for participating. FYI, here is the thread on S4ME on FBXL4:

Thread 'Genetics: FBXL4'

Aug 7, 2025

DecodeME candidate ME/CFS gene

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this...

• Hutan
• decodeme fbxl4 genetics mitochondria
• Replies: 15
• Forum: Possible causes and predisposing factor discussion

• 

 

[LizWorthey]

@LizWorthey,

I am reading your interchanges with great interest. Thanks for participating. FYI, here is the thread on S4ME on FBXL4:

Thread 'Genetics: FBXL4'

Aug 7, 2025

DecodeME candidate ME/CFS gene

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this...

• Hutan
• decodeme fbxl4 genetics mitochondria
• Replies: 15
• Forum: Possible causes and predisposing factor discussion

• 

Very interesting. One might imagine that IF there are any or various defects predisposing or causing ME/CFS (I know, I know ), that this type of variant in FBXL4 with its functions could be buffering against the other genetic vulnerabilities - so a protective variant by more quickly removing dysfunctional mitochondria accumulated from oxidative stress, infection, or inflammatory signaling. Or maybe could be protective by slowing down the natural mitophagy process.. All supposition of course. Very interesting.

 

[LizWorthey]

There are a couple of ways of posting links, Liz. One method is to copy the URL from the address bar and paste it straight into the comment box, like so:

Foinn Seisiún from Comhaltas on The Session

thesession.org

...which automatically creates a preview.

The other method is to paste the address into the URL field in the Insert Link tool, accessed via the chain icon:
View attachment 30170
...which produces a bare link:

https://thesession.org/tunes/collections/5

Ta!

 

[Hutan]

I'd just like to encourage more detailed family genetics studies, where there are multiple family members with ME/CFS diagnoses, as a half way house between n=1 and big studies. There can be an element of prediction in those, so they provide more reliable evidence that a variant (or combinations of variants) are relevant to symptoms than the n=1 approach.

Obviously the age of the participants is an issue (reduced chance for onset in younger people), but, time goes by quickly and there could be followup studies. And, increasingly, there will be generations who have stored genetic information and medical records.

 

[LizWorthey]

I'd just like to encourage more detailed family genetics studies, where there are multiple family members with ME/CFS diagnoses, as a half way house between n=1 and big studies. There can be an element of prediction in those, so they provide more reliable evidence that a variant (or combinations of variants) are relevant to symptoms than the n=1 approach.

Obviously the age of the participants is an issue (reduced chance for onset in younger people), but, time goes by quickly and there could be followup studies. And, increasingly, there will be generations who have stored genetic information and medical records.

If folks are interested in this, we can enroll you in our studies. We have a wee bit of a back log currently - but getting through cases. We are doing all of this work without any grants at the moment, so currently we can only work with people who have already had their sequencing done. But - I'm trying to come up with some ways to cover costs for people to get sequenced costs covered - fingers crossed. And definitely interested in family studies.

 

[mariovitali]

How about identical twin studies where one has MECFS and the other doesn't?

 

[Jonathan Edwards]

Devil's advocate; one of those genes pulled out by DecodeME is mito FBXL4.

But Chris made a point of saying that the variant seemed to be in the wrong direction for implicating a mitochondrial metabolic defect. Things might be more complicated but I do think that if one tries to model things on the basis of multiple alternative key pathways the opportunities for coincidences become fairly overwhelming. But lets see what further studies show.

 

[hotblack]

There was also a few other genes (as well as FBXL4) from PrecisionLife’s combinatorial analysis around metabolism, more implicating lipid and cell membrane systems than clearly saying mitochondria I think though (my clustering results here too). Having more knowledgeable and experienced minds take a look would be useful though. Maybe fits in with the @DMissa paper more than a straight mitochondria problem?

 

[Jonathan Edwards]

Ok pulled together a starter set of both the studies and a few reviews of studies; not exhaustive. It’d be great if someone had already done a deep, post-hoc review of these papers with varied expertise. We’re slowly scanning pre-existing omics studies for signals that map to mitochondrial variants (including in supplement tables that may have been overlooked); if we ever finish, I’ll share it gladly.

I think we probably have individual threads for all those studies, or at least nearly all. The analysis is usually fairly penetrating!

There are lots of papers on mitochondrial function but that probably just reflects a presupposition that mitochondria are relevant (which mitochondrial experts have questioned). And at the end of the day it is hard to see much of a story fitting together from all the different stuff.

 

[hotblack]

There are lots of papers on mitochondrial function but that probably just reflects a presupposition that mitochondria are relevant (which mitochondrial experts have questioned). And at the end of the day it is hard to see much of a story fitting together from all the different stuff

How about more predisposition rather than presupposition?

So if biological systems ABCD and E somehow involved in the disease state and different people have different susceptibilities within these systems caused by small genetic differences and it is those which we are seeing in the results of DecodeME then wouldn’t it be helpful to have information from people with rare variants which cause larger or more clear susceptibilities in one of those systems? Couldn’t this help confirm or clarify if those systems are involved for other people and give us more information pointing us in the direction of causes and treatment? Could one or those systems be mitochondrial?

I guess I’m asking, where do these rare variants fit in with other results? Do they ‘slot in’ to other potential mechanisms and pathways from studies like DeccdME or PrscisionLife? Is it worth looking at them alongside the data from those studies, perhaps with tissue expression or protein interaction data?

Sorry if I’m going over the old ground, still catching up with all of the posts. And I know I often see plots for stories everywhere!

 

[Sasha]

If folks are interested in this, we can enroll you in our studies. We have a wee bit of a back log currently - but getting through cases. We are doing all of this work without any grants at the moment, so currently we can only work with people who have already had their sequencing done. But - I'm trying to come up with some ways to cover costs for people to get sequenced costs covered - fingers crossed. And definitely interested in family studies.

Thanks very much for engaging with the forum, @LizWorthey! Great to have you here.

On your above point, would it be worth trying to recruit online people with multiple family members with ME/CFS who have already had their genome sequenced via 23andMe or whatever? Maybe commercial testing isn't good enough, though, or maybe some bias will be introduced in this way. I don't know enough about it.

Or, if better-quality sequencing is needed and no money is easily/rapidly available via grants, how about a crowdfunder? I can see one being very successful, since we wouldn't be talking about hundreds of thousands, presumably, and people are keen on genetics after DecodeME. Speed is of the essence. We all want our lives back (you included!).