title: FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study.
abstract: BACKGROUND
  Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders.
  
  
  METHODS
  We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers.
  
  
  RESULTS
  We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132·0 (95% CI 38·7-450·3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92·3% (95% CI 81·5-97·9%) and specificity was 91·7% (84·8-96·1%). The positive and negative predictive values for FGF-21 were 84·2% (95% CI 72·1-92·5%) and 96·1 (90·4-98·9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0·95; by comparison, the values for other biomarkers were 0·83 lactate (p=0·037, 0·83 for pyruvate (p=0·015), 0·72 for the lactate-to-pyruvate ratio (p=0·0002), and 0·77 for creatine kinase (p=0·013).
  
  
  CONCLUSIONS
  Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy.
  
  
  BACKGROUND
  Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppö Foundation.
authors.affiliation: Research Programmes Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. anu.wartiovaara@helsinki.fi
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.forename: Jenni M
authors.initials: JM
authors.lastname: Elo
authors.forename: Kirsi H
authors.initials: KH
authors.lastname: Pietiläinen
authors.forename: Anna H
authors.initials: AH
authors.lastname: Hakonen
authors.forename: Ksenia
authors.initials: K
authors.lastname: Sevastianova
authors.forename: Mari
authors.initials: M
authors.lastname: Korpela
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.forename: Sanna K
authors.initials: SK
authors.lastname: Marjavaara
authors.forename: Tiina
authors.initials: T
authors.lastname: Tyni
authors.forename: Sari
authors.initials: S
authors.lastname: Kiuru-Enari
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.forename: Niklas
authors.initials: N
authors.lastname: Darin
authors.forename: Katrin
authors.initials: K
authors.lastname: Õunap
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Jana
authors.initials: J
authors.lastname: Buzkova
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Johanna
authors.initials: J
authors.lastname: Annunen-Rasila
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Mar
authors.initials: M
authors.lastname: Tulinius
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000097:blood* / Q000175:diagnosis* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D015415:Biomarkers; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors