Improved diagnosis for mitochondrial disease

Scientists at the Murdoch Childrens Research Institute (MCRI) have shown how a new approach to genetic analysis could greatly improve diagnostic rates for children with often fatal mitochondrial diseases.

Mitochondria are the power plants of cells, breaking down molecules from sugars, fats and proteins to generate energy for the human body. Mitochondrial diseases are caused when these mitochondria are not functioning properly, typically as a result of mutations (acquired or inherited) in mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial components.

Mitochondrial diseases take on unique characteristics, both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. This is one of the reasons why mitochondrial disease has until now been very difficult to diagnose, with only about a quarter of patients receiving a genetic diagnosis. And while new diagnostic methods like whole exome sequencing — which can quickly and cheaply sequence a person’s entire genetic blueprint — means up to two-thirds of affected children can now be diagnosed, other approaches are needed to identify more difficult cases.

Now, researchers led by MCRI PhD student Nicole Lake have found a new cause of mitochondrial disease, identifying mutations in a gene called MRPS34 in six patients with the most common form of childhood mitochondrial disease, Leigh Syndrome, from Australia, France and the USA. The MRPS34 gene is one of 80 components of the mitochondrial protein synthesis machinery, known as the ‘mitoribosome’.

“A key approach was using quantitative proteomics,” said Lake. “This process involves sampling all the proteins in a cell at once to identify any problems with the cellular machinery.

“Using this technique, you get a snapshot of what’s happening in cells.”

Co-lead author Dr David Stroud, from Monash University, carried out the quantitative proteomics technique, examining cellular proteins in the patient’s cultured skin cells versus healthy skin cells. This showed one half of the mitoribosome fell apart, meaning cells could not make the key proteins encoded by mitochondrial DNA. It also showed that this led to two of the five major components of the ‘power plants’ falling apart, causing the machinery that fuels the body’s energy to break down.

MCRI Chief Investigator Professor David Thorburn said MRPS34 is one of the first mitochondrial disease genes in the world to show that quantitative proteomics could play a key role in improving diagnostic rates to closer to 100%. “This approach will therefore help to end the diagnostic odyssey for families with children suspected of mitochondrial and other inherited diseases,” he said.

“Early diagnosis improves the chance for early intervention. It can also provide the opportunity to enrol patients with mitochondrial diseases into clinical trials to test many new promising therapies that are in the pipeline but not yet proven.”

The research has been published in the American Journal of Human Genetics.