FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

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 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 Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study

“…The significant correlation between abnormal MRC activities and plasma FGF21 confirms that this protein is a good marker for MRC dysfunction in accord with previously reported findings [19]. Moreover, the finding that elevated FGF21 was prevalent in the combined group and suspected of mitochondrial translation or maintenance defects is certainly consistent with the recent report by Lehtonen et al [20]. Nevertheless, as some discrepancies were observed between plasma FGF21 and urine organic acids, it seems that the combination of these two tests would be more informative than each one alone.…”

“…Among these are growth differentiation factor 15, amino acids, liver function tests, pyruvate, muscle pathology, etc. [5,20,21]. Nevertheless, according to our findings, testing patients suspected of a mitochondrial diseases, for organic acids in urine and FGF21 in plasma is informative and the results facilitate the decision whether to perform a biopsy or not.…”

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

“…We therefore consider IBM a secondary mitochondrial disease. As “non‐mitochondrial disease controls”, we analysed serum metabolomes from 15 patients with different neuromuscular diseases (NMDs; Suomalainen et al , ; Lehtonen et al , ): Becker's muscle dystrophy ( DMD ), myotonic dystrophy type I ( DMPK ) and II ( ZNF9 ), motoneuron disease (unknown), muscle weakness ( CAPN3 ), oculopharyngeal muscular dystrophy ( PABPN1 ), late‐onset Pompe's disease ( GAA ), spinal muscular atrophy type II ( SMN1 ) and III (unknown), and Welander's muscular dystrophy ( TIA1 ; Table ). To compare the parallel disease‐specific signatures of all available genetically defined mitochondrial disease groups, we also re‐analyse metabolomic data from blood and muscle of patients with progressive external ophthalmoplegia (PEO) and infantile‐onset spinocerebellar ataxia (IOSCA; Nikkanen et al , ).…”

“…MIRAS is an autosomal recessive disorder affecting mainly the central nervous system (CNS). The MIRAS patients in this study manifested typically with progressive gait disturbance, polyneuropathy, ataxia, and some with epilepsy, but signs of muscle pathology were absent or mild (respiratory chain-deficient muscle fibres, mtDNA deletions and blood FGF21 concentration; Table 1; Hakonen et al, 2005;Lehtonen et al, 2016). We also collected plasma from 16 non-manifesting MIRAS family members heterozygous for the MIRAS allele ("MIRAS carriers", Dataset EV1).…”

Biomarker changes associated with clinical symptoms in MELAS patient

“…Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) represents the most common subtype of mitochondrial myopathy, with affected patients characterized by stroke‐like episodes (SLEs) . Recently, new biomarkers for diagnosis and severity were reported, including FGF21, shown to be a useful indicator of a muscle manifesting mitochondrial disorder, and GDF15, which was found to be a genetic indicator of mitochondrial disorders regardless of clinical phenotype.…”