Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome Bart Smits a, ⁎, Lambert van den Heuvel b , Hans Knoop c , Benno Küsters a, d , Antoon Janssen b , George Borm e , Gijs Bleijenberg c , Richard Rodenburg b , Baziel van Engelen a a Neuromuscular Center Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands b Nijmegen Center for Mitochondrial Disorders and Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands c Expert Center Chronic Fatigue, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands d Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands e Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands abstract article info Article history: Received 30 November 2010 Received in revised form 18 May 2011 Accepted 25 May 2011 Available online xxxx Keywords: Chronic fatigue syndrome Chronic progressive external ophthalmoplegia Diagnostic test assessment Mitochondrial medicine Respiratory chain complexes We studied the extent of mitochondrial involvement in chronic fatigue syndrome (CFS) and investigated whether measurement of mitochondrial respiratory chain complex (RCC) activities discriminates between CFS and mitochondrial disorders. Mitochondrial content was decreased in CFS compared to healthy controls, whereas RCC activities corrected for mitochondrial content were not. Conversely, mitochondrial content did not discriminate between CFS and two groups of mitochondrial disorders, whereas ATP production rate and complex I, III and IV activity did, all with higher activities in CFS. We conclude that the ATP production rate and RCC activities can reliably discriminate between mitochondrial disorders and CFS. © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. 1. Introduction Patients with non-specific neuromuscular complaints, such as fatigue, myalgia and exercise intolerance can pose a diagnostic dilemma. These complaints can be the sole features of a mitochondrial disorder but can also occur in the absence of any recognizable somatic disorder (Andreu et al., 1999). In the latter case, the patient is often diagnosed with chronic fatigue syndrome (CFS) (Reeves et al., 2003). When in doubt between a mitochondrial disorder and CFS, a skeletal muscle biopsy can be performed for further differentiation (Rahman and Hanna, 2009). Skeletal muscle is highly suitable for histological examination and is the tissue of choice for the measurement of the activities of the four mitochondrial respiratory chain complexes (RCC) involved in adenosine triphosphate (ATP) production. Decreased activity of one or more RCCs is suggestive of a mitochondrial disorder but is also reported in physically inactive, otherwise healthy subjects (Brierley et al., 1996; Rimbert et al., 2004). Since physical inactivity is common both in mitochondrial disor- ders and in CFS, the diagnostic value of measuring skeletal muscle RCC activities is unsure. Here, we determined the diagnostic value of RCC activities for the discrimination between mitochondrial disorders and CFS. For this purpose, we first determined the extent of mitochondrial involvement in CFS by comparing skeletal muscle biopsies of CFS patients to those of healthy controls. Next, to determine the diagnostic value of RCC activities we compared muscle biopsies between CFS patients and two groups of patients with genetically confirmed mitochondrial disorders. We focused on CFS patients with additional symptoms of myalgia and/or exercise intolerance, since differentiation between CFS and mitochondrial disorders is particularly difficult in these patients. 2. Methods 2.1. CFS patients To determine the extent of mitochondrial involvement in CFS we compared RCC activities in skeletal muscle biopsies between CFS patients and healthy controls. The CFS group was recruited from patients who had undergone a muscle biopsy with measurement of RCC activity for evaluation of a suspected neuromuscular or mitochondrial disorder between 2005 and 2007. All patients met the US Center for Disease Mitochondrion xxx (2011) xxx–xxx Abbreviations: A3243G, m.03243A →G mutation; AUC, area under the receiver operating characteristic curve; CFS, chronic fatigue syndrome; CS, citrate synthase; CPEO, chronic progressive external ophthalmoplegia; RCC, mitochondrial respiratory chain complex. ⁎ Corresponding author at: Neuromuscular Center Nijmegen, Department of Neurology Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 3613542; fax: +31 24 3541122. E-mail address: b.smits@neuro.umcn.nl (B. Smits). MITOCH-00637; No of Pages 4 1567-7249/$ – see front matter © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2011.05.005 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito Please cite this article as: Smits, B., et al., Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome, Mitochondrion (2011), doi:10.1016/j.mito.2011.05.005