FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children

Lisa G Riley; Michael Nafisinia; Minal J Menezes; Reta Nambiar; Andrew Williams; Elizabeth H Barnes; Arthavan Selvanathan; Kate Lichkus; Drago Bratkovic; Joy Yaplito-Lee; Kaustuv Bhattacharya; Carolyn Ellaway; Maina Kava; Shanti Balasubramaniam; John Christodoulou

doi:10.1016/j.ymgme.2021.12.001

FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children

Mol Genet Metab. 2022 Jan;135(1):63-71. doi: 10.1016/j.ymgme.2021.12.001. Epub 2021 Dec 8.

Authors

Affiliations

¹ Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia; Rare Diseases Functional Genomics, The Children's Hospital at Westmead, Sydney, NSW, Australia. Electronic address: lisa.riley@health.nsw.gov.au.
² Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia; Westmead Institute for Medical Research, Storr Liver Centre, Sydney, NSW, Australia.
³ Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia.
⁴ Immunopathology Laboratory, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁵ Immunopathology Laboratory, The Children's Hospital at Westmead, Sydney, NSW, Australia; Central Clinical School, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁶ NHMRC Clinical Trials Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁷ Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁸ Metabolic Clinic, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁰ Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
¹¹ Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia; Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
¹² Metabolic Unit, Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital for Children/Perth Children's Hospital, Perth, WA, Australia; Department of Neurology, Princess Margaret Hospital for Children/Perth Children's Hospital, Perth, WA, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
¹³ Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Metabolic Unit, Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital for Children/Perth Children's Hospital, Perth, WA, Australia.
¹⁴ Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.

PMID: 34991945
DOI: 10.1016/j.ymgme.2021.12.001

Abstract

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.

Keywords: Biomarker; Diagnosis; FGF21; GDF15; Mitochondrial disease; Pediatric.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Child
Fibroblast Growth Factors / genetics
Growth Differentiation Factor 15* / genetics
Humans
Mitochondrial Diseases* / diagnosis
Mitochondrial Diseases* / genetics

Substances

Biomarkers
GDF15 protein, human
Growth Differentiation Factor 15
fibroblast growth factor 21
Fibroblast Growth Factors