The Dimensions of Primary Mitochondrial Disorders

Abstract

The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

Integration of proteomics with genomics and transcriptomics increases the diagnostic rate of Mendelian disorders

“…An overview of our multiplexed, time-efficient, RNA-seq and proteomic sample workflow is depicted in Supplementary Fig. 1a-c. b , Proportion of protein-coding genes detected by RNA-seq (blue) and proteomics (red), genome-wide and among mitochondrial disease genes (Schlieben and Prokisch 2020), Neuromuscular and Neurology genes (Frésard et al, 2019), and OMIM disease genes (https://omim.org). c , Protein z-score distribution for disease-causing genes in WES/WGS solved cases (positive controls).…”

Genetic basis of mitochondrial diseases

“…The last decade has greatly advanced our understanding of the genetics behind mitochondrial disorders: Of almost 1200 currently described mitochondrial proteins, more than 500 are associated with disease, out of which over 340 as a cause of mitochondrial disease [20]. Following the developments in genetic tools, genetic diagnostics has shifted from candidate gene screens into the unbiased analysis of the complete genetic variation landscape.…”

“…Within the GENOMIT project (http://genomit.eu/), we compiled a list currently encompassing 343 genes, for which pathogenic variants have been associated with a defective OXPHOS, involved in a variety of mitochondrial functions (Fig. 2) [20]. For a better understanding of disease genetics, several distinct properties should be considered.…”

Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives

“…Impaired oxidative phosphorylation is a hallmark of mitochondrial disorders with progressive clinical manifestations that can vary from single organ to multisystem disorders, often affecting organs with high energetic demands [26]. Mitochondrial diseases have an estimated prevalence of one in 4300 adults, making them the most common inherited metabolic disorder [27][28][29][30].…”

“…Analyte testing of blood, urine, or even cerebrospinal fluid (CSF) in specific cases, for pyruvate, lactate, amino acids, creatine kinase, and carnitine, can provide information about alterations in metabolism in these patients and provide a biochemical metabolic signature of mitochondrial disease [34,35]. Additionally, pathogenic variants in over 400 genes, both mitochondrial and nuclear, have been identified as contributors to mitochondrial disorders [26]. Pathogenic mutations in mtDNA and nuclear DNA (nDNA) can be used to confirm primary mitochondrial disease due to abnormal OXPHOS function.…”