Preliminary Determination of a Molecular Basis to Chronic Fatigue Syndrome

doi:10.1006/bmme.1996.0012

Biochemical and Molecular Medicine

Volume 57, Issue 2, April 1996, Pages 73-80

Biochemical and Mole...

DEDICATED TO PROFESSOR F. R. WHATLEY, F.R.S., AND DR. W. GREENAWAY

https://doi.org/10.1006/bmme.1996.0012 Get rights and content

Abstract

Chronic fatigue syndrome (CFS/ME) is a debilitating fatigue illness that has an unknown etiology. We studied 20 chronic fatigue syndrome (CFS) patients, who complied with the Oxford and American CDC definitions, and 45 non-CFS subjects. Participants completed questionnaires, were clinically examined, and had first morning urine specimens collected, which were screened by gas chromatography–mass spectrometry for changes in metabolite excretion. Multivariate analysis of the urinary metabolite profiles differed significantly in the CFS patients compared to the non-CFS patients (P< 0.004). The CFS patients had increases in aminohydroxy-N-methylpyrrolidine (P< 0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (P< 0.02), β-alanine (P< 0.02), aconitic acid (P< 0.05), and succinic acid (P< 0.05) and reductions in an unidentified urinary metabolite, CFSUM2 (P< 0.0007), alanine (P< 0.005), and glutamic acid (P< 0.02). CFSUM1, β-alanine, and CFSUM2 were found by discriminant function analysis to be the first, second, and third most important metabolites, respectively, for discriminating between CFS and non-CFS subjects. The abundances of CFSUM1 and β-alanine were positively correlated with symptom incidence (P< 0.01 andP< 0.001, respectively), symptom severity, core CFS symptoms, and SCL-90-R somatization (P< 0.00001), suggesting a molecular basis for CFS.

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Cited by (34)

Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain
2018, Biochimica et Biophysica Acta - Molecular Basis of Disease
Citation Excerpt :
In patients with RA, increasing fatigue scores were associated with a metabolic pattern characterised by down-regulation of metabolites from the urea cycle, fatty acids, tocopherols, aromatic amino acids, and hypoxanthine [24]. Urine metabolome studies showed a significant correlation between aminohydroxy-N-methylpyrrolidine and beta-alanine with CFS expression [20,21]. In a rat model of fatigue, distinctive changes in plasma metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism in the fatigued group were discovered [19].
Fatigue is a sensation of unbearable tiredness that frequently accompanies chronic widespread musculoskeletal pain (CWP) and inflammatory joint disease. Its mechanisms are poorly understood and there is a lack of effective biomarkers for diagnosis and onset prediction. We studied the circulating metabolome in a population sample characterised for CWP to identify biomarkers showing specificity for fatigue.
Untargeted metabolomic profiling was conducted on fasting plasma and serum samples of 1106 females with and without CWP from the TwinsUK cohort. Linear mixed-effects models accounting for covariates were used to determine relationships between fatigue and metabolites. Receiver operating curve (ROC)-analysis was used to determine predictive value of metabolites for fatigue.
While no association between fatigue and metabolites was identified in twins without CWP (n = 711), in participants with CWP (n = 395), levels of eicosapentaenoate (EPA) ω-3 fatty acid were significantly reduced in those with fatigue (β = − 0.452 ± 0.116; p = 1.2 × 10^− 4). A significant association between fatigue and two other metabolites also emerged when BMI was excluded from the model: 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), and C-glycosyltryptophan (p = 1.5 × 10^− 4 and p = 3.1 × 10^− 4, respectively). ROC analysis has identified a combination of 15 circulating metabolites with good predictive potential for fatigue in CWP (AUC = 75%; 95% CI 69–80%).
The results of this agnostic metabolomics screening show that fatigue is metabolically distinct from CWP, and is associated with a decrease in circulating levels of EPA. Our panel of circulating metabolites provides the starting point for a diagnostic test for fatigue in CWP.
Metabolism in chronic fatigue syndrome
2014, Advances in Clinical Chemistry
Citation Excerpt :
The following describes what is understood about metabolism in CFS. There have been a number of studies on metabolites within the CFS disorder, though only a few with the aim to study the state of metabolism [117–120]. The majority of studies into metabolites have focused on testing specific hypotheses or aspects of CFS through measuring a few metabolites [94,121–127].
Chronic fatigue syndrome (CFS) is a poorly understood condition that presents as long-term physical and mental fatigue with associated symptoms of pain and sensitivity across a broad range of systems in the body. The poor understanding of the disorder comes from the varying clinical diagnostic definitions as well as the broad array of body systems from which its symptoms present.
Studies on metabolism and CFS suggest irregularities in energy metabolism, amino acid metabolism, nucleotide metabolism, nitrogen metabolism, hormone metabolism, and oxidative stress metabolism. The overwhelming body of evidence suggests an oxidative environment with the minimal utilization of mitochondria for efficient energy production. This is coupled with a reduced excretion of amino acids and nitrogen in general.
Metabolomics is a developing field that studies metabolism within a living system under varying conditions of stimuli. Through its development, there has been the optimisation of techniques to do large-scale hypothesis-generating untargeted studies as well as hypothesis-testing targeted studies. These techniques are introduced and show an important future direction for research into complex illnesses such as CFS.
β-Alanine and γ-aminobutyric acid in chronic fatigue syndrome
2007, Clinica Chimica Acta
Citation Excerpt :
In contrast Jones et al. [15] found no abnormal excretion of β-alanine among CFS patients. In agreement with Jones et al., we were unable to detect the two substances CFSUM1 and CFSUM2, described by McGregor et al. [14], in the urine of patients or controls. Chalmers et al. [23] claim that CFSUM1 and CFSUM2 are artefacts from derivatization and not true endogenous metabolites.
Due to the occurrence of sleep disturbances and fatigue in chronic fatigue syndrome (CFS), an investigation was performed to examine if there is an abnormal excretion of γ-aminobutyric acid (GABA) and/or its structural analogue β-alanine in the urine from CFS patients. Both GABA and β-alanine are inhibitory neurotransmitters in the mammalian central nervous system.
The 24 h urine excretion of GABA and β-alanine was determined by isotope dilution gas chromatography mass spectrometry in 33 CFS patients and 43 healthy controls. The degree of symptoms in both patients and controls was measured by grading of three typical CFS symptoms using a Visual Analogue Scale.
Men had a significantly higher excretion of both β-alanine and GABA than women. Comparing CFS patients with healthy controls showed no significant difference in excretion of neither β-alanine nor GABA. No correlation was found between the excretion of β-alanine or GABA and any of the three characteristic CFS symptoms measured. However, two female and two male CFS patients excreted considerably higher amounts of β-alanine in their 24 h urine samples than control subjects.
Increased excretion of β-alanine was found in a subgroup of CFS patients, indicating that there may be a link between CFS and β-alanine in some CFS patients.
CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts
2006, Clinica Chimica Acta
McGregor et al. reported increased levels of an unidentified urinary compound (CFSUM1) in patients with chronic fatigue syndrome (CFS), with reduced excretion of another unidentified compound (CFSUM2), and suggested the possibility of chemical or metabolic ‘markers’ for CFS. The identity of CFSUM1 as reported was erroneous and the identities of these compounds have remained unknown until now. Urine samples were obtained from 30 patients with ME/CFS, 30 age- and sex-matched healthy controls, 20 control patients with depression and 22 control patients with rheumatoid arthritis. Samples were prepared using the published methods of McGregor et al. to produce heptafluorobutyryl-isobutyl derivatives of urinary metabolites. Alternative preparations utilised isopropyl, n-butyl and trifluoroacetyl derivatives. These were separated and identified using gas chromatography–mass spectrometry. CFSUM2 was identified as being partially derivatised [isobutyl ester-mono-heptafluorobutyryl (HFB)] serine. CFSUM1 was identified as partially derivatised pyroglutamic acid, being the isobutyl ester without formation of a HFB derivative. Both CFSUM1 and CFSUM2 are artefacts of the sample preparation procedure and previously reported quantitative abnormalities of CFSUM1 and CFSUM2 in urine from patients with ME/CFS are also artefactual. Pyroglutamic acid may be of primarily dietary origin. The methods used cannot provide reliable qualitative or quantitative data on urinary metabolites. No clinical or biochemical significance can be drawn between these compounds in ME/CFS or any other clinical conditions.
Urinary and plasma organic acids and amino acids in chronic fatigue syndrome
2005, Clinica Chimica Acta
Previous work by others have suggested the occurrence of one or more chemical or metabolic ‘markers’ for ME/CFS including specific amino acids and organic acids and a number of unidentified compounds (CFSUM1, CFSUM2). We have shown elsewhere that CFSUM1 is partially derivatised pyroglutamic acid and CFSUM2 partially derivatised serine and have suggested and demonstrated that the analytical methods used were unsuitable to identify or to accurately quantify urinary metabolites. We have now made a detailed analysis of plasma and urinary amino acids and of urinary organic acids from patients with ME/CFS and from three control groups. Fasting blood plasma and timed urine samples were obtained from 31 patients with CFS, 31 age and sex-matched healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Plasma and urinary amino acids and urinary organic acids were determined using established and validated methods and data compared by statistical analysis. None of the previously reported abnormalities in urinary amino acids or of organic acids could be confirmed. Results however provide some evidence in patients with ME/CFS for underlying inflammatory disease and for reduced intramuscular collagen with a lowered threshold for muscle micro-injury. These factors in combination may provide a basis for the fatigue and muscle pain that are the major symptoms in these patients.
Assessment of Nutritional Status
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Regular ArticlePreliminary Determination of a Molecular Basis to Chronic Fatigue Syndrome

Abstract

Regular Article
Preliminary Determination of a Molecular Basis to Chronic Fatigue Syndrome