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Neurology. 2016 Nov 29;87(22):2290-2299. Epub 2016 Oct 28.

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders.

Author information

1
From the Research Programs Unit, Molecular Neurology (J.M.L., S.F., H.L., M.A., P.I.), Faculty of Medicine/Clinicum, Oncology (P.O.), and Finland Genome Scale Biology Program (S.L.), University of Helsinki, Finland; Mitochondrial Medicine Group (E.B., C.V., M.Z.), Medical Research Council Mitochondrial Biology Unit, Cambridge, UK; Center for Physiology and Pathophysiology (O.R.B., R.J.W.), Institute of Vegetative Physiology, University of Köln, Germany; Transplantation and Liver Surgery Clinic (H.I., K.H.), Department of Oncology (P.O., S.L.), and Heart and Lung Center, Department of Cardiology (T.H.), Helsinki University Hospital; School of Medicine (M.H., J.J., R.L.), University of Tampere; Anaesthesiology, Intensive Care and Pain Medicine (R.M.), Clinical Neurosciences, Neurology (H.L., M.A., A.S.), and Child Neurology, Children's Hospital (P.I.), University of Helsinki and Helsinki University Hospital, Finland; Dyslipidemia Center (G.M.), Cardiotoracovascular Department, Niguarda Hospital, Milan, Italy; PEDEGO Research Unit (J.U.) and Biocenter Oulu (J.U.), University of Oulu; Finnish Clinical Biobank Tampere (R.L.), Tampere University Hospital, Finland; Nijmegen Centre for Mitochondrial Disorders (J.S.), Radboud University Medical Centre, Nijmegen, the Netherlands; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) (R.J.W.), Köln; Center for Molecular Medicine Cologne (R.J.W.), CMMC, University of Köln, Germany; Faculty of Life and Environmental Sciences (K.N.), University of Tsukuba, Japan; and Medical Research Center Oulu (J.U.), Oulu University Hospital and University of Oulu, Finland.
2
From the Research Programs Unit, Molecular Neurology (J.M.L., S.F., H.L., M.A., P.I.), Faculty of Medicine/Clinicum, Oncology (P.O.), and Finland Genome Scale Biology Program (S.L.), University of Helsinki, Finland; Mitochondrial Medicine Group (E.B., C.V., M.Z.), Medical Research Council Mitochondrial Biology Unit, Cambridge, UK; Center for Physiology and Pathophysiology (O.R.B., R.J.W.), Institute of Vegetative Physiology, University of Köln, Germany; Transplantation and Liver Surgery Clinic (H.I., K.H.), Department of Oncology (P.O., S.L.), and Heart and Lung Center, Department of Cardiology (T.H.), Helsinki University Hospital; School of Medicine (M.H., J.J., R.L.), University of Tampere; Anaesthesiology, Intensive Care and Pain Medicine (R.M.), Clinical Neurosciences, Neurology (H.L., M.A., A.S.), and Child Neurology, Children's Hospital (P.I.), University of Helsinki and Helsinki University Hospital, Finland; Dyslipidemia Center (G.M.), Cardiotoracovascular Department, Niguarda Hospital, Milan, Italy; PEDEGO Research Unit (J.U.) and Biocenter Oulu (J.U.), University of Oulu; Finnish Clinical Biobank Tampere (R.L.), Tampere University Hospital, Finland; Nijmegen Centre for Mitochondrial Disorders (J.S.), Radboud University Medical Centre, Nijmegen, the Netherlands; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) (R.J.W.), Köln; Center for Molecular Medicine Cologne (R.J.W.), CMMC, University of Köln, Germany; Faculty of Life and Environmental Sciences (K.N.), University of Tsukuba, Japan; and Medical Research Center Oulu (J.U.), Oulu University Hospital and University of Oulu, Finland. anu.wartiovaara@helsinki.fi.

Abstract

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 muscle-manifesting 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.

PMID:
27794108
PMCID:
PMC5270510
DOI:
10.1212/WNL.0000000000003374
[Indexed for MEDLINE]
Free PMC Article

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