Expanding and validating the biomarkers for mitochondrial diseases

Alessandra Maresca,Mariantonietta Capristo,Chiara La Morgia,Maria Lucia Valentino,Valerio Carelli,Lidia Di Vito,Martina Romagnoli,Valentina Del Dotto

doi:10.1007/s00109-020-01967-y

Abstract

Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase.Key messages• FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes.• The novel ccf-mtDNA is associated with MELAS and increases during acute events.• Creatine only discriminates severe mitochondrial patients.• FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.

Highlights

Mitochondrial medicine, the field investigating mitochondrial diseases, just crossed 30 years of its existence [1]
Ccf-mitochondrial DNA (mtDNA) was evaluated in plasma samples, amplifying two different regions of mtDNA (MT-ND2 shown in Fig. 1 and MT-ND1 shown in Supplementary Fig. 1)
Separating the mitochondrial disease patients (MD) group into mtDNA genetic defects (MDD) and nuclear DNA defects (NDD), we found that ccf-mtDNA levels were

Summary

Introduction

Mitochondrial medicine, the field investigating mitochondrial diseases, just crossed 30 years of its existence [1]. Mitochondrial diseases affect primarily organs and tissues with a high-energy requirement, usually causing encephalomyopathies [4]. J Mol Med (2020) 98:1467–1478 multi-systemic with a constellation of symptoms and signs, which may include cardiomyopathy and heart conduction defects, liver or kidney dysfunctions, diabetes mellitus, sensorineural deafness, isolated myopathy with ophthalmoplegia and ptosis, peripheral neuropathy, central nervous system manifestations such as stroke-like episodes (SLEs), epilepsy, ataxia and cognitive dysfunction, gastrointestinal dysmotility, retinal pathology, and optic nerve atrophy [2, 4] They usually lead to major disability and, frequently, to premature death but may present as a relentless, slowly progressive chronic condition or as an acute, life-threatening event needing an emergency treatment. The minimum birth prevalence of mitochondrial diseases in children has been estimated of 13.1/100,000, again remarking that they are more common than lysosomal storage diseases and many other well-known neurogenetic diseases [8]

Methods

Results

Conclusion