New tools for mitochondrial disease diagnosis : FGF21, GDF15 and next-generation sequencing
Year: 2017
Type: dissertation
Study design: Observational Study
Abstract: Mitochondrial diseases are inheritable, often progressive diseases, where the function of the ATP producing organelle of the cell, is compromised. This leads to a wide variety of phenotypes, known to arise from defects in over 200 genes. Typically manifesting organs are brain, heart, muscle, liver, endocrine organs and sense organs. Careful clinical assessment with investigation of family history helps to predict the cause, but other diagnostic assessments play a central role in diagnosis. Elevation of blood or cerebrospinal fluid lactate has traditionally been an indicator of mitochondrial dysfunction, but this biomarker lacks sensitivity and specificity, and more accurate biomarkers are required. Muscle biopsy sample is the gold standard of mitochondrial disease diagnosis. Cytochrome c oxidase (COX) negative, succinate dehydrogenase (SDH) positive fibers and ragged-red fibers (RRFs) are hallmarks of mitochondrial dysfunction. Reduced respiratory chain enzyme activity in tissue verifies diagnosis. Solid diagnosis requires genetic evidence, but the expanding number of disease-causing genes makes it difficult to choose which genes to sequence. We report here a novel diagnostic serum biomarker, fibroblast growth factor 21 (FGF21), which is more sensitive and specific to muscle-manifesting mitochondrial disorders than any of the conventional biomarkers used before. It correlates with COX-negative muscle fibers and is most likely produced and secreted by them. We also studied another recently discovered serum biomarker, growth differentiation factor 15 (GDF15). We report that both FGF21 and GDF15 correctly distinguish mitochondrial myopathies from non-mitochondrial myopathies and controls, making them the most accurate biomarkers for mitochondrial myopathies to date. The trigger for induction of these biomarkers seems to be upstream of respiratory chain defect, most likely initiates from the mitochondrial translational machinery. In another study, we used next generation sequencing to search for a pathogenic mutation in a patient with fatal infantile Alpers hepatoencephalopathy. We identified two compound heterozygous mutations in a novel disease gene, FARS2. This gene encodes for a protein, mitochondrial phenylalanyl-tRNA synthetase (mtPheRS), responsible for the charging of mitochondrial phenylalanyl-tRNA with its cognate amino acid. Structural prediction of the mutated proteins together with functional studies in E. coli showing decreased activity of mutant mtPheRS, verified the diagnosis. Our results strongly support the use of FGF21 and GDF15 as first line diagnostic assessments. Rapid progression to next-generation sequencing is advised if both of these biomarkers are elevated, with positive predictive value being 95%. This would reduce the need for invasive diagnostic tests.
Source: Työväentutkimus Vuosikirja
Author: Jenni M. Lehtonen
Institution: University of Helsinki
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2747036377