Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice.

Alireza Morovat,Victoria Nesbitt,Geralrine Quaghebeur,Gayani Weerasinghe,Carl Fratter,Kate Sergeant,Monika Hofer,Mehdi Mirzazadeh,Joanna Poulton,Nishan Guha,Thomas Agnew

doi:10.3390/jcm6080080

Abstract

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway.

Highlights

Mitochondrial disease (MD) is common, with 1 in 400 individuals harbouring the m.3243A>G mutation that usually causes mild disease such as presbycusis [1]
In 2013, the Department of Clinical Biochemistry at the John Radcliffe Hospital in Oxford started offering fibroblast growth factor-21 (FGF-21) assay to specialist clinicians for assessing patients who were being investigated for mitochondrial disease
There was no difference between FGF-21 values in men and women (p = 0.907), but FGF-21 showed an increase with age (mean 3.0 ng/L per year; p < 0.0001)

Summary

Introduction

Mitochondrial disease (MD) is common, with 1 in 400 individuals harbouring the m.3243A>G mutation that usually causes mild disease such as presbycusis [1]. Mitochondrial diseases are notoriously difficult to diagnose because of their heterogeneity, the presence of mitochondrial heteroplasmy, poor genotype-phenotype relationships, and the bluntness of the generally used laboratory tests for assessing mitochondrial dysfunction. The diagnosis of mitochondrial disease often involves an invasive muscle biopsy for studies of mitochondrial function. Respiratory chain enzyme studies are technically demanding and available only in a few specialist centres. They may generate false positive results if tissue samples are poorly preserved [4]

Methods

Results

Conclusion