Mitochondrial diseases are the commonest group of inherited metabolic disorders. Children often present with severe disease that is fatal in two thirds of patients before the age of 16. Adults tend to endure chronic and progressive disease that is often be severely debilitating and precludes them from employment. Mitochondrial diseases are notoriously difficult to diagnose due to the diversity of genetic causes (>300 mutations in mitochondrial DNA and >150 known nuclear disease genes), the extreme variability in clinical presentation (the same mutation in a family can manifest very differently) and a lack of comprehensive and definitive diagnostic tools.
The current diagnostic pathway involves invasive, expensive and inaccurate testing that often results in patients going undiagnosed or being misdiagnosed and spending years trying to access appropriate healthcare. This project will evaluate two new diagnostic tools, metabolomic biomarker profiling and genomic sequencing, in order to define a rapid, cost-effective, comprehensive and accurate diagnostic pathway that will improve the diagnosis of mitochondrial diseases.
Accurate diagnosis enables specialist clinicians to encourage disease modifying lifestyle changes, to administer appropriate treatments, identify and avoid contraindicated pharmacological agents (e.g. the common antiepileptic sodium valproate can cause death in mitochondrial disease patients presenting with seizures) and to provide informed family planning. The accurate diagnosis of mitochondrial diseases would also have a significant impact on the cost to NSW Health associated with undiagnosed or misdiagnosed patients, would enable treatment development through better understanding of disease pathophysiology in defined disease-specific cohorts, would define patient cohorts for genotype-specific clinical trials and enable appropriate treatment administration to those who will benefit most.
As genomic sequencing and bioinformatic analysis costs are still considerable, the first objective of this project is to develop metabolite signatures (combinations of small molecules that can be used to define a disease discriminatory test) of the mitochondrial disease group and individual mitochondrial diseases. This frontline indication of disease will inform clinical decision-making on whether to progress to other diagnostic testing, including comprehensive genomic sequencing.
As a result of recent technological advances, it is now possible to simultaneously and comprehensively sequence both mitochondrial and nuclear genomes. However, the very recent introduction of this technique means that objective research evidence for its applicability to genomic healthcare and how best to integrate it into clinical practice is lacking. Therefore, the second objective of this project is to develop a robust bioinformatic approach for the identification of causative mitochondrial disease mutations.