# Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Josef Finsterer, Sinda Zarrouk-Mahjoub

► To cite this version:

Josef Finsterer, Sinda Zarrouk-Mahjoub. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?. Journal of Translational Medicine, 2016, pp.182. 10.1186/s12967-016-0939-0. pasteur-01467096

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Submitted on 14 Feb 2017

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# Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Josef Finsterer<fnref n="1" />*† and Sinda Zarrouk-Mahjoub²†

**Keywords:** Mitochondrial DNA, Chronic fatigue syndrome, Exercise intolerance, Exhaustion, Respiratory chain

**Letter to the Editor**

With interest we read the article by Billing-Ross et al. [1] about 193 patients with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda or Canadian Consensus criteria and undergoing sequencing of the mtDNA, the DePaul Symptom questionnaire and the Medical Outcome Survey Short Form-36. The study showed that CFS is associated with mtDNA haplogroups J, U and H, that 8 mtDNA single nucleotide polymorphisms (SNPs) were associated with 16 symptom categories, and that three haplogroups were associated with six symptom categories [1]. We have the following comments and concerns.

The main limitation of this study is that only the mtDNA was investigated for sequence variants. Since it is well-known that mitochondrial disorders (MIDs) may be also caused by mutations in nDNA-located genes, particularly in children [2], disease-causing mutations or SNPs facilitating the development of CFS may have been missed. Furthermore, MIDs may not only be due to respiratory chain dysfunction but also due to disruption of other mitochondrial pathways, such as the beta-oxidation, the hem synthesis, the calcium handling, the coenzyme-Q metabolism, or the urea cycle. There is also consensus that investigations of mtDNA mutations or SNPs in mtDNA from lymphocytes may not be constructive since some mutations may not be present or

heteroplasmy rates may be lower than in more severely affected tissues [3].

A further limitation of the study is that neither immune-histological nor biochemical investigations of the muscle biopsy were carried out. Immune-histological investigations of the muscle biopsy may show NADH-, SDH-, or COX-deficiency. Biochemical investigations of the muscle homogenate may show reduced activity of one or several respiratory chain complexes or coenzyme-Q deficiency [4]. Morphological and functional studies are essential not to miss dysfunction of the respiratory chain or other mitochondrial pathways.

We also should be informed how causes of fatigue, exhaustion, and exercise intolerance other than CFS, were excluded. How many patients had muscle disease other than a MID, which may be also associated with fatigue, such as muscular dystrophies or congenital myopathies [5, 6]? How many had hypothyroidism, sleep apnea syndrome, malignancy, electrolyte disturbances, adrenal dysfunction, or pituitary insufficiency? Were any of the routine laboratory parameters abnormal in the 193 patients? How many had creatine-kinase (CK) elevation or lactacidosis? How many presented with features other than fatigue which could be attributed to a MID? How many had epilepsy, cognitive impairment, extra-pyramidal disease, or psychiatric disease? How many had a cataract, glaucoma, retinitis, or chronic progressive external ophthalmoplegia (CPEO)? It would be interesting to know if any of the patients had cardiac disease, gastrointestinal disease, renal impairment, endocrine disturbances, or lung disease indicative of a MID?

<footnote>*Correspondence: fifigs1@yahoo.de</footnote>

<footnote>†Josef Finsterer and Sinda Zarrouk-Mahjoub contributed equally to this work</footnote>

<footnote n="1">¹ Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria
Full list of author information is available at the end of the article</footnote>
Nothing is reported about the previous history of the
197 patients and their permanent medication [1]. How
often was the family history positive for CFS or a MID?

Overall, this interesting study may profit from provid-
ing more information about the individual patients and
their relatives and from carrying out more comprehen-
sive morphological, functional, and genetic studies not
to miss metabolic defects, which may be due to sequence
variations in nDNA located mitochondrial genes. There
is also a need to exclude cardiac, pulmonary, or systemic
disease not to miss differentials of CSF.

Author details

¹ Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria. ² Genomics Platform, Pasteur Institute of Tunis, Tunis, Tunisia.

Competing interests

The authors declare that they have no competing interests.

Received: 5 May 2016 Accepted: 3 June 2016

Published online: 18 June 2016

**References**

1. Billing-Ross P, Germain A, Ye K, Keinan A, Gu Z, Hanson MR. Mitochondrial DNA variants correlate with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome. J Transl Med. 2016;20(14):19. doi:10.1186/ s12967-016-0771-6.

2. Desguerre I, Hully M, Rio M, Nabbout R. Mitochondrial disorders and epilepsy. Rev Neurol (Paris). 2014;170:375-80.

3. Pallotti F, Binelli G, Fabbri R, Valentino ML, Vicenti R, Macciocca M, Cevoli S, Baruzzi A, DiMauro S, Carelli V. A wide range of 3243A>G/tRNALeu(UUR) (MELAS) mutation loads may segregate in offspring through the female germline bottleneck. PLoS One. 2014;9:e96663. doi:10.1371/journal. pone.0096663.eCollection2014.

4. Delonlay P, Rötig A, Sarnat HB. Respiratory chain deficiencies. Handb Clin Neurol. 2013;113:1651-66.

5. Hedermann G, Vissing CR, Heje K, Preisler N, Witting N, Vissing J. Aerobic training in patients with congenital myopathy. PLoS One. 2016;11:e0146036. doi:10.1371/journal.pone.0146036.

6. Pangalila RF, van den Bos GA, Bartels B, Bergen M, Stam HJ, Roebroeck ME. Prevalence of fatigue, pain, and affective disorders in adults with duchenne muscular dystrophy and their associations with quality of life. Arch Phys Med Rehabil. 2015;96:1242-7.

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