A still mysterious chronic illness keeps patients bedridden after the slightest effort, while leaving their routine check-ups almost normal. The authors of a review published in 2025 in the journal DNA estimate that it affects between 0.4 and 2.5% of the world’s population, with three women for every man and up to 91% of cases undiagnosed. For decades, this pathology was reduced to simple fatigue or a psychological disorder, which fueled suffering and medical wandering.
This disease is myalgic encephalomyelitis (ME), also called
chronic fatigue syndrome. At CHU Sainte-Justine and the University of Montreal, Professor Alain Moreau devotes his work to deciphering its intimate mechanisms, from the genome to mitochondria. His research, crossed with that synthesized in the journal DNApaint a new picture: anomalies ofMitochondrial DNAdisturbances ofepigenetic and emergence of the first biomarkers blood. For millions of patients, it is finally a concrete prospect of objective diagnosis and targeted treatments.
A multi-systemic illness: what people with chronic fatigue syndrome experience
ME/CFS affects several systems of the body and causes muscle pain and weakness, digestive and sleep disorders and annoying “brain fog”, explains the University of Montreal. Its central symptom remains post-exercise discomfort, a lasting worsening of all signs after sometimes minimal effort. “Myalgic encephalomyelitis is not a single disease but rather a spectrum composed of several subgroups“, declared Alain Moreau, professor at the University of Montreal and researcher at the CHU Sainte-Justine Research Center.
The diagnosis remains delicate, the symptoms fluctuating and often overlapping with those of fibromyalgia. “An accurate diagnosis is difficult because ME and fibromyalgia have very similar symptoms that can fluctuate over time. Our molecular analyzes have shown that up to 40% of people diagnosed with ME actually have fibromyalgia, and it is possible to have both at the same time.“, explained Professor Alain Moreau. His teams point out that around 75% of cases begin after a viral infection such as mononucleosis, influenza or SARS-CoV-2.
Thus, according to Professor Moreau, “Long COVID is not an entirely new disease, but rather a convergence of different post-infectious mechanisms. Among those with the most persistent and severe symptoms, a significant proportion eventually meet the criteria for myalgic encephalomyelitis (ME).”.
DNA, mitochondria and epigenetics: a change in perspective on ME/CFS
The work of Wesam Elremaly and Alain Moreau published in
DNA confirm a predisposition and less efficient mitochondria to produce ATP, with excess oxidative stress and damage to theMitochondrial DNA. For certain patients, variants of this DNA would mainly modulate the severity of symptoms, which helps to understand why the disease remains so heterogeneous.
The review describes abnormal epigenetic marks on immunity and metabolism genes and shows that more than 95% of symptoms of ME/CFS and
Long Covid overlap, with 58% of long Covid patients meeting ME criteria. These epigenetic “scars”, left by infections or toxins (including heavy metals and molds) would provide a missing link between genetic background, viral trigger and chronicization of symptoms.
Biomarkers and clinical trials in preparation for chronic fatigue syndrome
Moreau’s team also discovered various markers of myalgic encephalomyelitis that could be used to refine diagnosis and serve as targets for treatments. Among these markers are specific patterns of circulating microRNAs, also called “molecular signatures,” that can accurately differentiate myalgic encephalomyelitis from similar diseases like fibromyalgia.
Another avenue: a blood marker particularly attracts attention, the SMPDL3B protein. “Circulating SMPDL3B concentration is directly linked to disease severity, with higher levels of this protein correlating with more intense symptoms“, explained Professor Alain Moreau. Ultimately, measuring this protein could be used to objectify the severity and monitor the response to future treatment. After identifying the enzyme which increases SMPDL3B, the team is testing its blockade with antidiabetics associated with myo-inositol, with clinical trials planned, while the rise of long Covid makes ME/CFS a scientific priority.
For patients, seeing their disease finally studied at the molecular level opens the prospect of more precise medicine and less contested medical recognition. “This validation is crucial because patients have long suffered from a lack of understanding, even within the medical community. Myalgic encephalomyelitis (ME) remains difficult to define, but recent progress is gradually changing the situation.”concludes Professor Moreau.