Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods:We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different musclemanifesting mitochondrial dysfunctions.Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p , 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p , 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p , 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. Classification of evidence:This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies. Neurology ® 2016;87:2290-2299 GLOSSARY ALS 5 amyotrophic lateral sclerosis; CI 5 confidence interval; CK 5 creatine kinase; FGF21 5 fibroblast growth factor 21; GDF15 5 growth and differentiation factor 15; mCRC 5 metastasized colorectal cancer; MM 5 mitochondrial myopathy; mtDNA 5 mitochondrial DNA; PBC 5 primary biliary cirrhosis; PSC 5 primary sclerosing cholangitis; RC 5 respiratory chain; S-FGF21 5 serum FGF21; tRNA 5 transfer RNA.Mitochondrial diseases are the most common form of inherited metabolic disorders. The high variability in clinical manifestation, heterogeneity of genetic causes with .150 known disease genes, 1 and scarcity of sensitive and specific biomarkers make their diagnosis challenging. Our original multicenter analysis identified fibroblast growth factor 21 (FGF21) induction in *These authors contributed equally to this work.

The objective was to assess the prevalence and heritability of symptoms associated with fibromyalgia in a population-based working-age twin sample. The study was based on the 12,502 like-sexed twins of the Finnish Twin Cohort and 49 diagnosed fibromyalgia patients who answered the same questionnaire in 1990-1992. Questions that were considered to best match symptoms of fibromyalgia were validated between the twins and the fibromyalgia patients. Latent class analysis was used to classify the subjects into more homogeneous groups with respect to the symptom items. The pairwise distribution of symptom classes in relation to zygosity and gender was modelled using quantitative genetic models to estimate heritability. Responses to all fibromyalgia-related items were obtained from 10,608 twins. A similar proportion of men (12%) and women (13%) was placed in the third latent class, which best represented possible fibromyalgia patients. Subjects in this class had a similar symptom profile as the diagnosed fibromyalgia patient group, but they were less severely affected. The two other latent classes represented subjects that were virtually symptom free and subjects with some symptoms. The heritability of liability to symptom class membership was estimated to be 51% (95% CI 45-56%). The prevalence of symptoms associated with fibromyalgia in our population-based sample unselected for disease status was comparable to the prevalence of widespread pain reported in population based studies. The symptoms known to be associated with fibromyalgia seem to have a strong genetic background.

BackgroundFibromyalgia (FM) is a pain syndrome, the mechanisms and predictors of which are still unclear. We have earlier validated a set of FM-symptom questions for detecting possible FM in an epidemiological survey and thereby identified a cluster with “possible FM”. This study explores prospectively predictors for membership of that FM-symptom cluster.MethodsA population-based sample of 8343 subjects of the older Finnish Twin Cohort replied to health questionnaires in 1975, 1981, and 1990. Their answers to the set of FM-symptom questions in 1990 classified them in three latent classes (LC): LC1 with no or few symptoms, LC2 with some symptoms, and LC3 with many FM symptoms. We analysed putative predictors for these symptom classes using baseline (1975 and 1981) data on regional pain, headache, migraine, sleeping, body mass index (BMI), physical activity, smoking, and zygosity, adjusted for age, gender, and education. Those with a high likelihood of having fibromyalgia at baseline were excluded from the analysis. In the final multivariate regression model, regional pain, sleeping problems, and overweight were all predictors for membership in the class with many FM symptoms.ResultsThe strongest non-genetic predictor was frequent headache (OR 8.6, CI 95 % 3.8–19.2), followed by persistent back pain (OR 4.7, CI 95 % 3.3–6.7) and persistent neck pain (OR 3.3, CI 95 % 1.8–6.0).ConclusionsRegional pain, frequent headache, and persistent back or neck pain, sleeping problems, and overweight are predictors for having a cluster of symptoms consistent with fibromyalgia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-0873-6) contains supplementary material, which is available to authorized users.

Background Fibromyalgia (FM) patients are likely to differ from healthy controls in muscle activity and in reactivity to experimental stress. Methods We compared psychophysiological reactivity to cognitive stress between 51 female FM patients aged 18 to 65 years and 31 age- and sex-matched healthy controls. They underwent a 20-minute protocol consisting of three phases of relaxation and two phases of cognitive stress. We recorded surface electromyography normalized to maximum voluntary muscle contraction (%EMG), the percentage of time with no muscle activity (EMG rest time), and subjective pain and stress intensities. We compared group reactivity using linear modelling and adjusted for psychological and life-style factors. Results The FM patients had a significantly higher mean %EMG (2.2 % vs. 1.0 %, p < 0.001), pain intensity (3.6 vs. 0.2, p < 0.001), and perceived stress (3.5 vs. 1.4, p < 0.001) and lower mean EMG rest time (26.7 % vs. 47.2 %, p < 0.001). In the FM patients, compared with controls, the pain intensity increased more during the second stress phase (0.71, p = 0.028), and the %EMG decreased more during the final relaxation phase (-0.29, p = 0.036). Within the FM patients, higher BMI predicted higher %EMG but lower stress. Leisure time physical activity predicted lower %EMG and stress and higher EMG rest time. Higher perceived stress predicted lower EMG rest time, and higher trait anxiety predicted higher pain and stress overall. Conclusions Our results suggest that repeated cognitive stress increases pain intensity in FM patients. FM patients also had higher resting muscle activity, but their muscle activity did not increase with pain. Management of stress and anxiety might help control FM flare-ups. Trial registration Retrospectively registered on ClinicalTrials.gov (NCT03300635).