Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms

Abstract:

Earlier this year, we described an analysis of mitochondrial DNA (mtDNA) variants in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients and healthy controls. We reported that there was no significant association of haplogroups or singe nucleotide polymorphisms (SNPs) with disease status. Nevertheless, a commentary about our paper appeared (Finsterer and Zarrouk-Mahjoub. J Transl Med14:182, 2016) that criticized the association of mtDNA haplogroups with ME/CFS, a conclusion that was absent from our paper.

The aforementioned commentary also demanded experiments that were outside of the scope of our study, ones that we had suggested as follow-up studies. Because they failed to consult a published and cited report describing the cohorts we studied, the authors also cast aspersions on the method of selection of cases for inclusion. We reiterate that we observed statistically significant association of mtDNA variants with particular symptoms and their severity, though we observed no association with disease status.

You can read the rest of this rebuttal here:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175376/

 

Source: Hanson MR, Gu Z, Keinan A, Ye K, Germain A, Billing-Ross P. Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. J Transl Med. 2016 Dec 20;14(1):342. doi: 10.1186/s12967-016-1104-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175376/ (Full article)

 

Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome

Abstract:

Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia.

We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women.

This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied.

Copyright © 2016. Published by Elsevier B.V.

 

Source: Torrell H, Alonso Y, Garrabou G, Mulet D, Catalán M, Valiente-Pallejà A, Carreño-Gago L, García-Arumí E, Montaña E, Vilella E, Martorell L. Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome. Mitochondrion. 2016 Oct 27. pii: S1567-7249(16)30221-5. doi: 10.1016/j.mito.2016.10.007. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27989882

 

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity

Abstract:

Myalgic encephalomyelitis (ME) is a complex, heterogeneous illness of unknown etiology. The search for biomarkers that can delineate cases from controls is one of the most active areas of ME research; however, little progress has been made in achieving this goal. In contrast to identifying biomarkers that are directly involved in the pathological process, an immunosignature identifies antibodies raised to proteins expressed during, and potentially involved in, the pathological process. Although these proteins might be unknown, it is possible to detect antibodies that react to these proteins using random peptide arrays.

In the present study, we probe a custom 125,000 random 12-mer peptide microarray with sera from 21 ME cases and 21 controls from the USA and Europe and used these data to develop a diagnostic signature. We further used these peptide sequences to potentially uncover the naturally occurring candidate antigens to which these antibodies may specifically react with in vivo.

Our analysis revealed a subset of 25 peptides that distinguished cases and controls with high specificity and sensitivity. Additionally, Basic Local Alignment Search Tool (BLAST) searches suggest that these peptides primarily represent human self-antigens and endogenous retroviral sequences and, to a minor extent, viral and bacterial pathogens.

 

Source: Singh S, Stafford P, Schlauch KA, Tillett RR, Gollery M, Johnston SA, Khaiboullina SF, De Meirleir KL, Rawat S, Mijatovic T, Subramanian K, Palotás A, Lombardi VC. Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity. Mol Neurobiol. 2016 Dec 15. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27981498

 

Epistemic injustice in healthcare encounters: evidence from chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) remains a controversial illness category. This paper surveys the state of knowledge and attitudes about this illness and proposes that epistemic concerns about the testimonial credibility of patients can be articulated using Miranda Fricker’s concept of epistemic injustice. While there is consensus within mainstream medical guidelines that there is no known cause of CFS/ME, there is continued debate about how best to conceive of CFS/ME, including disagreement about how to interpret clinical studies of treatments.

Against this background, robust qualitative and quantitative research from a range of countries has found that many doctors (and medical students) display uncertainty about whether CFS/ME is real, which may result in delays in diagnosis and treatment for patients. Strikingly, qualitative research evinces that patients with CFS/ME often experience suspicion by healthcare professionals, and many patients vocally oppose the effectiveness, and the conceptualisation, of their illness as psychologically treatable.

We address the intersection of these issues and healthcare ethics, and claim that this state of affairs can be explained as a case of epistemic injustice (2007). We find evidence that healthcare consultations are fora where patients with CFS/ME may be particularly vulnerable to epistemic injustice. We argue that the (often unintentional) marginalisation of many patients is a professional failure that may lead to further ethical and practical consequences both for progressive research into CFS/ME, and for ethical care and delivery of current treatments among individuals suffering from this debilitating illness.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

 

Source: Blease C, Carel H, Geraghty K. Epistemic injustice in healthcare encounters: evidence from chronic fatigue syndrome. J Med Ethics. 2016 Dec 5. pii: medethics-2016-103691. doi: 10.1136/medethics-2016-103691. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27920164

 

High-frequency rTMS for the Treatment of Chronic Fatigue Syndrome: A Case Series

Abstract:

Structural and functional abnormalities of the prefrontal cortex seem to correlate with fatigue in patients with chronic fatigue syndrome (CFS). We consecutively applied facilitatory high-frequency repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) of seven CFS patients over three days. Five patients completed the 3-day protocol without any adverse events. For the other two patients, we had to reduce the stimulation intensity in response to mild adverse reactions. In most of the patients, treatment resulted in an improvement of fatigue symptoms. High-frequency rTMS applied over the DLPFC can therefore be a potentially useful therapy for CFS patients.

 

Source: Kakuda W, Momosaki R, Yamada N, Abo M. High-frequency rTMS for the Treatment of Chronic Fatigue Syndrome: A Case Series. Intern Med. 2016;55(23):3515-3519. Epub 2016 Dec 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216154/ (Full article)

 

Acupuncture and Moxibustion have Different Effects on Fatigue by Regulating the Autonomic Nervous System: A Pilot Controlled Clinical Trial

Abstract:

In order to investigate the different effects of acupuncture and moxibustion on chronic fatigue syndrome (CFS) and alterations in the autonomic nervous system by measuring heart rate variability (HRV).

Forty-five participants were recruited and randomly divided into 3 groups using a randomization schedule. The control group (CG, n = 15) and the acupuncture group (AG, n = 15) were treated by manipulation acupuncture, and the moxibustion group (MG, n = 15) was treated by indirect moxibustion. Primary outcomes were the scores of the Fatigue Assessment Instrument (FAI). Secondary outcomes were the HRV parameters which can reflect activity of the autonomic nervous system.

This trial considered both instantaneous changes and long-term effectiveness. FAI scores decreased after the 4th and 10th treatments in the 3 groups. The decrease in FAI in the MG was greater than that in the AG. Acupuncture was more effective in instantaneous changes of HRV and moxibustion in long-term aspects. Both acupuncture and moxibustion improved fatigue in CFS patients, but moxibustion was more effective.

The possible mechanism of the intervention may be through activation of the vagus nerve. Moxibustion was more effective than acupuncture in long-term treatment of CFS.

 

Source: Shu Q, Wang H, Litscher D, Wu S, Chen L, Gaischek I, Wang L, He W, Zhou H, Litscher G, Liang F. Acupuncture and Moxibustion have Different Effects on Fatigue by Regulating the Autonomic Nervous System: A Pilot Controlled Clinical Trial. Sci Rep. 2016 Nov 25;6:37846. doi: 10.1038/srep37846. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122953/ (Full article)

 

Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescence: Population Birth Cohort Study

Abstract:

Although many studies have investigated the overlap between pain phenotypes and chronic fatigue syndrome (CFS) in adults, little is known about the relationship between these conditions in adolescents. The study’s aim was therefore to identify whether a relationship exists between chronic widespread pain (CWP) and CFS in adolescents and investigate whether the two share common associations with a set of covariates.

A questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 17, asking about site, duration, and pain intensity, from which participants with CWP were identified. At the same research clinic, a computer-based Revised Clinical Interview Schedule was filled out, from which a classification of CFS was obtained. The relationship between selected covariates and CFS and CWP was investigated using a variety of logistic, ordinal logistic, and multinomial regressions.

We identified 3,214 adolescents with complete data for all outcomes and covariates. There were 82 (2.6%) individuals classified as CFS and 145 (4.5%) as CWP. A classification of CFS resulted in an increased likelihood of having CWP (odds ratio = 3.87; 95% confidence interval, 2.05-7.31). Female adolescents were approximately twice as likely to have CFS or CWP, with multinomial regression revealing a greater sex effect for CWP compared with CFS.

Those with exclusive CFS were more likely to report higher levels of pain and greater effect of pain compared with those without CFS, although associations attenuated to the null after adjustment for covariates, which did not occur in those with exclusive CWP. Multinomial regression revealed that relative to having neither CFS nor CWP, a 1-unit increase in the depression and anxiety scales increased the risk of having exclusive CFS and, to a greater extent, the risk of having comorbid CFS and CWP, but not exclusive CWP, which was only related to anxiety.

PERSPECTIVE: In this cohort, 14.6% of adolescents with CFS have comorbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared with those attending specialist services. Clinicians should be aware of the overlap between the 2 conditions and carefully consider treatment options offered.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

 

Source: Norris T, Deere K, Tobias JH, Crawley E. Chronic Fatigue Syndrome and Chronic Widespread Pain in Adolescence: Population Birth Cohort Study. J Pain. 2016 Nov 12. pii: S1526-5900(16)30308-X. doi: 10.1016/j.jpain.2016.10.016. [Epub ahead of print] http://www.jpain.org/article/S1526-5900(16)30308-X/fulltext (Full article)

 

Experiences of general practitioner continuity among women with chronic fatigue syndrome/myalgic encephalomyelitis: a cross-sectional study

Abstract:

BACKGROUND: Continuity of care is important for patients with chronic illness in need of coordinated healthcare services from multiple providers. Little is known about how patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) experience continuity of GP care. This study explores how women with CFS/ME experience GP care across the three dimensions of continuity: informational, management, and relational continuity.

METHODS: This cross-sectional study uses questionnaire data collected from members of The Norwegian ME Association. Descriptive statistics and logistic regressions were used to estimate experiences of continuity, and associations with age, education, self-rated degree of CFS/ME, duration of the GP relation (GP duration), and number of GP visits for CFS/ME-related issues during the previous year (GP frequency).

RESULTS: Almost two-thirds of participants reported positive experiences across all three dimensions of GP continuity of care; 64.4% for informational, 64.1% for management, and 77.2% for relational continuity. Lower educational attainment was associated with more negative experiences of informational continuity (primary school only compared to university educated: odds ratio [OR] 0.12, confidence interval [CI] 0.03-0.49, p = 0.003). Compared to participants aged 40-59 years, those aged 60+ years were significantly less likely to have experienced poor (negative) management continuity (OR 0.25, CI 0.09-0.76, p = 0.014). A GP relationship of three or more years was associated with positive experiences of relational continuity (OR 2.32, CI 1.09-4.95, p = 0.030). Compared to those with moderate CFS/ME, those who graded their CFS/ME as severe or very severe were significantly more likely to have negative experiences of relational continuity (OR 0.38, CI 0.14-0.99, p = 0.047).

CONCLUSIONS: A large proportion of participants experienced all three aspects of continuity of GP care (especially the relational dimension) positively. Informational and management continuity scores were moderately lower. Our results suggest greater emphasis on information giving, feedback, and better coordination of care to be good strategies for practice improvement for this patient group.

 

Source: Hansen AH, Lian OS. Experiences of general practitioner continuity among women with chronic fatigue syndrome/myalgic encephalomyelitis: a cross-sectional study. BMC Health Serv Res. 2016 Nov 14;16(1):650. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109710/ (Full article)

 

A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

BACKGROUND: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME) is a debilitating condition of unknown aetiology. It is characterized by a range of physiological effects including neurological, sensory and motor disturbances. This study examined candidate genes for the above clinical manifestations to identify single nucleotide polymorphism (SNP) alleles associated with CFS/ME compared with healthy controls.

METHODS: DNA was extracted and whole genome genotyping was performed using the HumanOmniExpress BeadChip array. Gene families for transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors, and acetylcholinesterase were targeted. The frequency of each SNP and their association between CFS/ME and healthy controls was examined using Fisher’s exact test, and to adjust for multiple testing, False Detection Rate (FDR) and Bonferroni corrections were applied (p < 0.05).

RESULTS: The study included 172 participants, consisting of 95 Fukuda defined CFS/ME patients (45.8 ± 8.9; 69 % female) and 77 healthy controls (42.3 ± 10.3; 63 % female). A total of 950 SNPs were included for analysis. 60 significant SNPs were associated with CFS/ME compared with healthy controls. After applying FDR and Bonferroni corrections, SNP rs2322333 in adrenergic receptor α1 (ADRA1A) was higher in CFS/ME compared with healthy controls (45.3 % vs. 23.4 %; p = 0.059). The genotype class that was homozygous minor (AA) was substantially lower in CFS/ME compared with healthy controls (4.2 % vs. 24.7 %).

CONCLUSIONS: This study reports for the first time the identification of ADRA1A and a possible association between CFS/ME and genotype classes. Further examination of the functional role of this class of adrenergic receptors may elucidate the cause of particular clinical manifestations observed in CFS/ME

 

Source: Johnston S, Staines D, Klein A, Marshall-Gradisnik S. A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. BMC Med Genet. 2016 Nov 11;17(1):79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105265/ (Full article)

 

Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

OBJECTIVE: The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients.

METHODS: A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software.

RESULTS: Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group.

CONCLUSION: This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

© The Author(s) 2016.

 

Source: Marshall-Gradisnik S, Johnston S, Chacko A, Nguyen T, Smith P, Staines D. Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Int Med Res. 2016 Nov 10. pii: 0300060516671622. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27834303