Category: Etiology

Dr. Bell on ME/CFS Symptom Variation: Illness or Host?

ProHealth.com
by David S Bell, MD, FAAP
March 7, 2012

This information is excerpted from the Nov 1999 issue of the Lyndonville Journal – a bi-monthly newsletter from Dr. Bell’s medical office that preceded the Lyndonville News. It is reproduced here with kind permission,* and offers still-relevant insights, as research to identify proper case definitions, potential ME/CFS subsets, and causes continues.

Reprinted with the kind permission of ProHealth: 3/7/12

Symptom Variation: Illness or Host?

Roughly 70% of the persons I see in the office have a pattern of symptoms that is “typical of” chronic fatigue syndrome (CFS). The remaining 30% have variations where doubt can be raised as to the diagnosis. This variation in symptoms is the main reason that researchers may see CFS as a variety of differing illnesses that produce fatigue as a symptom…. But I feel that the vast majority have a single illness, rather than CFS being a mish-mash of different illnesses. The issue here is the debate of illness versus host.

What exactly comes from the cause, and what comes from the host response? To look at this conflict, let us look at chicken pox.

Chicken pox is an everyday, run of the mill, simple illness. Every clinician makes the diagnosis with ease. You seen one chicken pox, you have seen a thousand. It is simple and it is one single illness. That is because it is an illness that affects a distant target organ – the skin. A five-year-old comes in with a fever and little blisters that look like a “dew drop on a rose petal.” And that is exactly what a perfect chicken pox looks like. (I have no idea where the chicken part comes in.)

There may be some minor variations. A child may have 30 pox or 300. Some pox (or poxes?) may get infected or scabbed over. Big deal, it is still chicken pox, one illness. The host (or person with the illness) does not affect it much.

But wait. In some cases the host is critical and the illness can be different. Some people have chicken pox without a rash, or have a pneumonia, or worse yet, have a neurologic complication. Is it still chicken pox? Yes, because we are able to culture the virus from the lung or brain, and it is the same as the regular chicken pox in the skin.

In CFS we do not have this luxury. The situation is different.

Whatever CFS is, it affects a very central mechanism within the body, not an end organ like the skin. And this central mechanism, probably the brain, can manifest the symptoms of an insult very differently. With the brain, the same injury or illness causes a variety of symptoms. (Brain tumors, for example. The symptoms of a one-inch area of brain injury depend entirely upon the location of this injury. In one area, there may be minor if any symptoms. In another it might cause arm weakness, in another area, behavior or emotional symptoms.)

Let us suppose for one minute that a single neurotropic virus – one that affects brain tissue – causes CFS. If this virus affects only a small part of the brain, the symptoms will be uniform (post-encephalitic Parkinson’s). But if it affects more than one area, then a multitude of symptoms may result, with clear variations from person to person (Post polio syndrome). The issue is the competition between agent specificity and how the host responds to it (host versus illness).

The enormous complexity of both genetic and environmental factors makes people different. By itself, this is an interesting discussion, and probably a good thing. But science would be easier if we were all clones. (We would probably get along better as well.) The complexity of host response, differences in immunity, emotional vulnerability, and environment makes it so that the same injury may cause a variety of responses, particularly if that injury is to a central or primitive part of the brain.

In CFS, we can trace the symptoms to this primitive part of the brain where hormones are produced, where sleep and alertness are regulated, where blood pressure and heart rate are controlled, where pain is modified.

One person with CFS may have asthenia [lack of energy and strength] as the worst symptom. In another, pain is the worse symptom. Are these two illnesses, or are they the same?

The answer is seen not by looking at one or two symptoms, but by examining the entire symptom pattern. For now, it is reasonable to define CFS broadly without being picky. A clinical, symptom-based diagnosis is appropriate, with the understanding that other fatigue-causing illnesses have been excluded. The pattern of symptoms rather than the specific worst symptom defines the diagnosis. And this pattern may vary from person to person. I do not see this variation as due to differing illnesses. Rather I see the same illness having differing host responses.

The roots of my bias are easy to spot.

In Lyndonville, many persons developed severe fatigue and other symptoms due to something. Because this took place in an isolated rural community, I feel that it must have been a single event. [The 1985 ‘Lyndonville outbreak’ of CFS affected 210 persons, 60 of whom were children, a patient group that Dr. Bell continues to track.(1)] I do not think that 15 different cause of CFS hit all at the same time. For this reason, the variation of symptom severity and even emphasis must be due to host responses rather than cause.

Two children in the same family become ill: One has acute onset, one gradual; one with fatigue as the worst symptom, one with headache. But it is too much of a coincidence that these would be different illnesses within the same family at the same time.

As an aside the CFC has stated that CFS does not run in families. This is because all may not fit the CDC research criteria. But most clinicians feel that there is a clear familial component. If three family members develop chronic fatigue at the same time, host response is more likely to explain the differences in symptoms than the possiblity of separate illnesses.

At the time of the CFS ‘outbreak’ in Lyndonville, there were those with viral infections that caused two months of fatigue. Lucky individuals. And there were siblings who got full-blown CFS. My hunch is that it is the same initiating event expressing itself differently in separate individuals.

We will know the answer to host versus illness only when an an underlying cause is known in a few persons. Then we can see if the others have evidence of the same underlying cause. This was the case with HIV infection. Some persons would have cancer, some bad pneumonias. Only when a specific initiating event was found was it possible to understand the full spectrum of HIV infection.

So now we have to wait. We can create a definition, and start from there. It is my hunch that we will soon define appropriate subgroups of CFS. And it remains to be seen whether these subgroups are artificial or will accurately define different causes of CFS.

But until this occurs, persons with CFS should not be denied appropriate diagnosis, treatment, or disability benefits if warranted. The definition of CFS now must be broad. Whether due to host response or initiating cause will be answered eventually with research.

I am going to put my money on:

• A few different initiating events,

• Causing a specific physiological injury,

• In persons with varying host response.

And I keep wondering why I am broke.

– Dr. David S Bell, MD, FAAP, Nov 1999

____

1. See Dr. Bell’s presentation on his tracking of the Lyndonville outbreak patients (“25 Year Follow-up on Chronic Fatigue Syndrome: Rising Incapacity,”), delivered Apr 16, 2011 as part of the Massachusetts CFIDS/ME & FM Association’s lecture series. (Allow ample time for the video download.) He discusses symptom variation, and theorizes that ‘fibromyalgia’ is a term people use when they’re able to be up and around, but their pain is considerable.

* Reproduced with kind permission of the author from the paper archives of the Lyndonville Journal, © Bell, Pollard, Robinson, 2000. All rights reserved.

Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy.

In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1-dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP).

While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation.

We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases.

Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets.

Source: Rusin A, Cocchetto A, Mothersill C. Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade. Int J Mol Sci. 2026 Jul 22;27(14):6535. doi: 10.3390/ijms27146535. PMID: 42511874; PMCID: PMC13411118. https://pmc.ncbi.nlm.nih.gov/articles/PMC13411118/ (Full text)

Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum

Abstract:

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome is a disease of uncertain aetiology that affects up to 400,000 individuals in the UK. Exposure of cultured cells to the sera of people with ME has been proposed to cause phenotypic changes in these cells in vitro when compared to sera from healthy controls. ME serum factors causing these changes could inform the development of diagnostic tests.

In this study, we performed a large-scale, pre-registered replication of an experiment from Fluge et al (2016) that reported an increase in maximal respiratory capacity in healthy myoblasts after treatment with serum from people with ME compared to serum from healthy controls.

We replicated the original experiment with a larger sample size, using sera from 67 people with ME and 53 controls to treat healthy cultured myoblasts, and generated results from over 1,700 mitochondrial stress tests performed with a Seahorse Bioanalyser. We observed no significant differences between treatment with ME or healthy control sera for our primary outcome of interest, oxygen consumption rate at maximal respiratory capacity.

Results from our study provide strong evidence against the hypothesis that ME blood factors differentially affect healthy myoblast mitochondrial phenotypes in vitro.

Source: Ryback AA, Hillier CB, Loureiro CM, Ponting CP, Dalton CF. Indistinguishable mitochondrial phenotypes after exposure of healthy myoblasts to myalgic encephalomyelitis/chronic fatigue syndrome or control serum. PLoS One. 2026 Feb 3;21(2):e0341334. doi: 10.1371/journal.pone.0341334. PMID: 41632778; PMCID: PMC12867253. https://pmc.ncbi.nlm.nih.gov/articles/PMC12867253/ (Full text)

ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis

Highlights:

  • Subset of ME/CFS cases proposed to be caused by a ‘noisy’ latent HSV-1 infection within the brain.
  • HSV-1 proposed to cause local sickness behaviour-like response in the brain.
  • IL-1β, IL-6, TNF-α in the brain proposed to increase sensations of fatigue and pain.

Abstract:

This work presents the hypothesis that a Herpes Simplex Virus 1 (HSV-1) infection in the brain is a significant contributor to the symptoms experienced by a subset of ME/CFS patients. In these patients, an HSV-1 infection has spread from the trigeminal ganglia to the brain, leading to a sickness behaviour-like response that amplifies sensations such as fatigue, pain, and nausea. The hypothesis proposes that ME/CFS is a heterogeneous condition, with a ‘noisy’ latent HSV-1 infection of the brain, and an enduring sickness behaviour-style immune response, an underlying factor for a subset of patients.
Source: John Campbell. ME/CFS as a sickness behaviour-like response to HSV-1 infection within the brain: A hypothesis. Medical Hypotheses, Volume 204, 2025, 111788. ISSN 0306-9877 https://doi.org/10.1016/j.mehy.2025.111788. https://www.sciencedirect.com/science/article/abs/pii/S0306987725002270 (Full text)

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules, 15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).

Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Source: Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One. 2023 Dec 29;18(12):e0296060. doi: 10.1371/journal.pone.0296060. PMID: 38157384; PMCID: PMC10756525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756525/ (Full text)

Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study

Abstract:

Background: Previous serological studies have indicated an association between viruses and atypical pathogens and Chronic Fatigue Syndrome (CFS). This study aims to investigate the correlation between infections from common pathogens, including typical bacteria, and the subsequent risk of developing CFS. The analysis is based on data from Taiwan’s National Health Insurance Research Database.

Methods: From 2000 to 2017, we included a total of 395,811 cases aged 20 years or older newly diagnosed with infection. The cases were matched 1:1 with controls using a propensity score and were followed up until diagnoses of CFS were made.

Results: The Cox proportional hazards regression analysis was used to estimate the relationship between infection and the subsequent risk of CFS. The incidence density rates among non-infection and infection population were 3.67 and 5.40 per 1000 person-years, respectively (adjusted hazard ratio [HR] = 1.5, with a 95% confidence interval [CI] 1.47-1.54). Patients infected with Varicella-zoster virus, Mycobacterium tuberculosis, Escherichia coli, Candida, Salmonella, Staphylococcus aureus and influenza virus had a significantly higher risk of CFS than those without these pathogens (p < 0.05). Patients taking doxycycline, azithromycin, moxifloxacin, levofloxacin, or ciprofloxacin had a significantly lower risk of CFS than patients in the corresponding control group (p < 0.05).

Conclusion: Our population-based retrospective cohort study found that infection with common pathogens, including bacteria, viruses, is associated with an increased risk of developing CFS.

Source: Chang H, Kuo CF, Yu TS, Ke LY, Hung CL, Tsai SY. Increased risk of chronic fatigue syndrome following infection: a 17-year population-based cohort study. J Transl Med. 2023 Nov 11;21(1):804. doi: 10.1186/s12967-023-04636-z. PMID: 37951920. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04636-z (Full text)

Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis

Abstract:

Background: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients.

Methods: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections’ contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased).

Results: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a “moderate association” by Cohen’s d test) compared to both healthy and diseased controls.

Conclusion: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

Source: Hwang, JH., Lee, JS., Oh, HM. et al. Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis. J Transl Med 21, 763 (2023). https://doi.org/10.1186/s12967-023-04635-0 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04635-0 (Full text)

Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue

Abstract

Background: Causative genetic variants cannot yet be found for many disorders with a clear heritable component, including chronic fatigue disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These conditions may involve genes in difficult-to-align genomic regions that are refractory to short read approaches. Structural variants in these regions can be particularly hard to detect or define with short reads, yet may account for a significant number of cases. Long read sequencing can overcome these difficulties but so far little data is available regarding the specific analytical challenges inherent in such regions, which need to be taken into account to ensure that variants are correctly identified.

Research into chronic fatigue disorders faces the additional challenge that the heterogeneous patient population likely encompasses multiple aetiologies with overlapping symptoms, rather than a single disease entity, such that each individual abnormality may lack statistical significance within a larger sample. Better delineation of patient subgroups is needed to target research and treatment.

Methods: We use nanopore sequencing in a case of unexplained severe fatigue to identify and fully characterise a large inversion in a highly homologous region spanning the AKR1C gene locus, which was indicated but could not be resolved by short-read sequencing. We then use GC-MS/MS serum steroid analysis to investigate the functional consequences.

Results: Several commonly used bioinformatics tools are confounded by the homology but a combined approach including visual inspection allows the variant to be accurately resolved. The DNA inversion appears to increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory neurosteroids and impaired progesterone metabolism.

Conclusions: This study provides an example of how long read sequencing can improve diagnostic yield in research and clinical care, and highlights some of the analytical challenges presented by regions containing tandem arrays of genes. It also proposes a novel gene associated with a specific disease aetiology that may be an underlying cause of complex chronic fatigue and possibly other conditions too. It reveals biomarkers that could be assessed in a larger cohort, potentially identifying a subset of patients who might respond to treatments suggested by the aetiology.

Source: Julia Oakley, Martin Hill, Adam Giess, Mélanie Tanguy, Greg Elgar. Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of unexplained severe fatigue. ResearchSquare [Preprint] https://www.researchsquare.com/article/rs-3218228/v2 (Full text)