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A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.

ABSTRACT: BACKGROUND:Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literature on mitochondrial changes in ME/CFS/SEID patients compared to healthy controls. METHODS:Embase, PubMed, Scopus and Medline (EBSCO host) were systematically searched for articles assessing mitochondrial changes in ME/CFS/SEID patients compared to healthy controls published between January 1995 and February 2020. The list of articles was further refined using specific inclusion and exclusion criteria. Quality and bias were measured using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. RESULTS:Nineteen studies were included in this review. The included studies investigated mitochondrial structural and functional differences in ME/CFS/SEID patients compared with healthy controls. Outcomes addressed by the papers include changes in mitochondrial structure, deoxyribonucleic acid/ribonucleic acid, respiratory function, metabolites, and coenzymes. CONCLUSION:Based on the included articles in the review it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID.

SUBMITTER: Holden S

PROVIDER: S-EPMC7392668 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.

Holden Sean S Maksoud Rebekah R Eaton-Fitch Natalie N Cabanas Hélène H Staines Donald D Marshall-Gradisnik Sonya S

Journal of translational medicine 20200729 1

<h4>Background</h4>Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) present with a constellation of symptoms including debilitating fatigue that is unrelieved by rest. The pathomechanisms underlying this illness are not fully understood and the search for a biomarker continues, mitochondrial aberrations have been suggested as a possible candidate. The aim of this systematic review is to collate and appraise current literatu ...[more]

PMID: 32727475

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Project description:BACKGROUND:Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) is a complex illness that has an unknown aetiology. It has been proposed that metabolomics may contribute to the illness pathogenesis of CFS/ME/SEID. In metabolomics, the systematic identification of measurable changes in small molecule metabolite products have been identified in cases of both monogenic and heterogenic diseases. Therefore, the aim of this systematic review was to evaluate if there is any evidence of metabolomics contributing to the pathogenesis of CFS/ME/SEID. METHODS:PubMed, Scopus, EBSCOHost (Medline) and EMBASE were searched using medical subject headings terms for Chronic Fatigue Syndrome, metabolomics and metabolome to source papers published from 1994 to 2020. Inclusion and exclusion criteria were used to identify studies reporting on metabolites measured in blood and urine samples from CFS/ME/SEID patients compared with healthy controls. The Joanna Briggs Institute Checklist was used to complete a quality assessment for all the studies included in this review. RESULTS:11 observational case control studies met the inclusion criteria for this review. The primary outcome of metabolite measurement in blood samples of CFS/ME/SEID patients was reported in ten studies. The secondary outcome of urine metabolites was measured in three of the included studies. No studies were excluded from this review based on a low-quality assessment score, however there was inconsistency in the scientific research design of the included studies. Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent. CONCLUSION:The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ME/SEID. Further research using the same CFS/ME/SEID diagnostic criteria, metabolite analysis method and control of the confounding factors that influence metabolite levels are required.

Project description:BackgroundOrthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).Methods and resultsIn 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65-85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.ConclusionThis study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.

Project description:Changes in the terminology and diagnostic criteria for chronic fatigue syndrome/myalgic encephalomyelitis are explained in this paper. This syndrome is a complex and controversial entity of unknown origins. It appears in the medical literature in 1988, although clinical pictures of chronic idiopathic fatigue have been identified since the nineteenth century with different names, from neurasthenia, epidemic neuromyasthenia, and benign myalgic encephalomyelitis up to the current proposal of disease of intolerance to effort (post-effort). All of them allude to a chronic state of generalised fatigue of unknown origin, with limitations to physical and mental effort, accompanied by a set of symptoms that compromise diverse organic systems. The International Classification of Diseases (ICD-10) places this syndrome in the section on neurological disorders (G93.3), although histopathological findings have not yet been found to clarify it. Multiple organic alterations have been documented, but a common biology that clarifies the mechanisms underlying this disease has not been established. It is defined as a neuro-immune-endocrine dysfunction, with an exclusively clinical diagnosis and by exclusion. Several authors have proposed to include CFS/ME within central sensitivity syndromes, alluding to central sensitisation as the common pathophysiological substrate for this, and other syndromes. The role of the family doctor is a key figure in the disease, from the detection of those patients who present a fatigue of unknown nature that is continuous or intermittent for more than 6 months, in order to make an early diagnosis and establish a plan of action against a chronic disease with high levels of morbidity in the physical and mental sphere. OBJECTIVE: To carry out a bibliographic review of the terminology and diagnostic criteria of the chronic fatigue syndrome/myalgic encephalomyelitis, in order to clarify the pathology conceptually, as a usefulness in the diagnosis of Primary Care physicians.

Project description:Purpose: ME/CFS is a lifelong debilitating disease that affects approximately 1% of the global population. Previous studies have identified dysfunctional activity in metabolic, immune and neurological pathways. The goal of this study is to identify ME/CFS specific variations in DNA methylation to determine whether the patient specific epigenetic patterns provide insight into the disease pathophysiology. Methods: DNA was extracted from the PBMCs of 10 ME/CFS patients and age/gender matched controls. After performing RRBS the sequence was aligned to hg19 genome using Bismark. The data was analyzed using first an ANOVA F test through DMAP in order to determine variation between the patient and control groups across 40-220bp fragments of the genome. Additional analysis was performed following a MethylKit pipeline, which analyzed the variation on a single CpG basis using a Fishers test. Results: From a total of 146,575 DMAP fragments we identified 76 differentially methylated fragments (P <0.05, Diff meth +/- 15%). A total of 31 were associated with gene regions (intronic/exonic). MethylKit analysis also identified a total of 394 differentially methylated cytosines (FDR corrected P <0.05, Diff meth +/- 15%) from a total of 196,172 individual analyzed cytosines, 91 of the statistically significant cytosines fell within gene regions. Comparison of both methylomes and regions where both the DMAP fragments and multiple MethylKit cytosines fell highlighted areas of the genome containing regulatory elements associated with metabolic and immune activity. Gene body pathway enrichment additionally identified immune metabolic and neurological related functions. Conclusions: Our study represents the first investigation of ME/CFS patients using reduced representation bisulfite sequencing. We identified a number of major differences between patients that distinguished them from healthy controls. Our results identified a number of differentially methylated regulatory elements and gene bodies that highlight the disturbed pathophysiology in ME/CFS. In particular the large number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology in patients.

Project description:Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients frequently show autonomic symptoms which may be associated with a hypothalamic dysfunction. This study aimed to explore circadian rhythm patterns in rest and activity and distal skin temperature (DST) and their association with self-reported outcome measures, in CFS/ME patients and healthy controls at two different times of year. Ten women who met both the 1994 CDC/Fukuda definition and 2003 Canadian criteria for CFS/ME were included in the study, along with ten healthy controls matched for age, sex and body mass index. Self-reported measures were used to assess fatigue, sleep quality, anxiety and depression, autonomic function and health-related quality of life. The ActTrust actigraph was used to record activity, DST and light intensity, with data intervals of one minute over seven consecutive days. Sleep variables were obtained through actigraphic analysis and from subjective sleep diary. The circadian variables and the spectral analysis of the rhythms were calculated. Linear regression analysis was used to evaluate the relationship between the rhythmic variables and clinical features. Recordings were taken in the same subjects in winter and summer. Results showed no differences in rhythm stability, sleep latency or number of awakenings between groups as measured with the actigraph. However, daily activity, the relative amplitude and the stability of the activity rhythm were lower in CFS/ME patients than in controls. DST was sensitive to environmental temperature and showed lower nocturnal values in CFS/ME patients than controls only in winter. A spectral analysis showed no differences in phase or amplitude of the 24h rhythm, but the power of the second harmonic (12h), revealed differences between groups (controls showed a post-lunch dip in activity and peak in DST, while CFS/ME patients did not) and correlated with clinical features. These findings suggest that circadian regulation and skin vasodilator responses may play a role in CFS/ME.

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A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.

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A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease.

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