TGI Friday! Our weekly round-up of recently published research abstracts | 24 March 2017

March 24, 2017

From BMC Medical Genetics (open access), 16 March 2017

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome

Elizna M. Schoeman (1, ^), Francois H. Van Der Westhuizen (2, ^), Elardus Erasmus(1, 3), Etresia van Dyk(1), Charlotte V. Y. Knowles(2), Shereen Al-Ali (4,5), Wan-Fai Ng (4, 6), Robert W. Taylor(3), Julia L. Newton(4,6) and Joanna L. Elson(1,3)
1. Centre for Human Metabolomics, North-West University
2. Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University
3. Institute of Genetic Medicine, Newcastle University
4. Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University
5. Department of Biology, College of Science, University of Basrah
6. Newcastle Hospitals NHS Foundation Trust
^ contributed equally to the study



Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations.


MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.


We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.


The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

From Fatigue: Biomedicine, Health & Behavior, 13 March 2017

SEID, ME and CFS: Patients diagnosed with Myalgic encephalomyelitis/chronic fatigue syndrome also fit systemic exertion intolerance disease criteria

Lily Chua(a), Jane L. Norris(a), Ian J. Valencia(b) and Jose G. Montoya(a)
a) Stanford ME/CFS Initiative, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA;

b) Formerly of Stanford ME/CFS Initiative, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA



Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) remains undiagnosed in up to 91% of patients. Recently, the United States-based Institute of Medicine (IOM) developed new diagnostic criteria, naming it systemic exertion intolerance disease (SEID).


We examined how subjects fit SEID criteria and existing ME/CFS case definitions early in their illness.


A total of 131 subjects fitting 1994 Fukuda CFS criteria at the time of study recruitment completed a survey of symptoms they experienced during their first 6 months of illness.

Symptoms were drawn from SEID and existing criteria (1994 Fukuda, 2003 Canadian Consensus Criteria (CCC), and 2011 Myalgic Encephalomyelitis-International Consensus Criteria (ME-ICC)).

We calculated and compared the number/percentage of subjects fitting single or combinations of case definitions and the number/ percentage of subjects with SEID experiencing orthostatic intolerance (OI) and/or cognitive impairment.


At 6 months of illness, SEID criteria identified 72% of all subjects, similar to when Fukuda criteria (79%) or the CCC (71%) were used, whereas the ME-ICC selected for a significantly lower percentage (61%, p < .001).When severity/frequency thresholds were added to the Fukuda criteria, CCC and ME-ICC, the percentage of these subjects also fitting SEID criteria increased to 93%, 97%, and 95%.Eighty-seven percent of SEID subjects endorsed cognitive impairment and 92%, OI; 79% experienced both symptoms.CONCLUSIONSSEID criteria categorize a similar percentage of subjects as Fukuda criteria early in the course of ME/CFS and contain the majority of subjects identified using other criteria while requiring fewer symptoms.The advantage of SEID may be in its ease of use.

From the Journal of Translational Medicine, 16 March 2017

Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study

Brett A. Lidbury (1,2), Badia Kita(3), Donald P. Lewis(4), Susan Hayward(5), Helen Ludlow(6), Mark P. Hedger(5) and David M. de Kretser(5,7)
1. Pattern Recognition and Pathology, Department of Genome Sciences, The John Curtin School of Medical Research, The Australian National University
2. The National Centre for Epidemiology and Public Health, The Research School of Population Health, ANU
3. Paranta Biosciences Limited
4. CFS Discovery, Donvale Medical Specialist Centre
5. The Hudson Medical Research Institute, Monash University
6. Centre for Proteins and Peptides, School of Life Sciences, Oxford Brookes University
7. Department of Anatomy and Developmental Biology, Monash University



Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available.


A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals.


Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma.


Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

From the Journal of Neurological Science, published online 22 February 2017

Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity.

Natelson BH(1), Mao X(2), Stegner AJ, Lange G(1), Vu D(1), Blate M(1), Kang G(2), Soto
E(3), Kapusuz T(3), Shungu DC(2).
1. Department of Neurology, Mount Sinai Beth Israel, New York, NY, United States
2. Department of Radiology, Weill Cornell Medicine, New York, NY, United States
3. Department of Pain Management, Mount Sinai Beth Israel, New York, NY, United States


• Patients have higher brain ventricular lactate, more abnormal spinal fluids, lower brain GSH, and reduced cerebral blood flow than controls
• Psychiatric comorbidity does not influence any of these potential biological markers of CFS
• 50% of the patients had more than one of these abnormalities
• The subgroup of patients with brain abnormalities may have an underlying encephalopathy producing their illness


The purpose of this study was to investigate whether CFS patients without comorbid psychiatric diagnoses differ from CFS patients with comorbid psychiatric diagnoses and healthy control subjects in neuropsychological performance, the proportion with elevated spinal fluid protein or white cell counts, cerebral blood flow (CBF), brain ventricular lactate and cortical glutathione (GSH).

The results of the study did not show any differences in any of the outcome measures between CFS patients with and without psychiatric comorbidity, thus indicating that psychiatric status may not be an exacerbating factor in CFS.

Importantly, significant differences were found between the pooled samples of CFS compared to controls. These included lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls.

Thirteen of 26 patients had abnormal values on two or more of these 4 brain-related variables. These findings, which replicate the results of several of our prior studies, support the presence of a number of neurobiological and spinal fluid abnormalities in CFS.

These results will lead to further investigation into objective biomarkers of the disorder to advance the understanding of CFS.

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