Most patients with mitochondrial disease can be diagnosed via genomic sequencing, study says microbiologystudy

More than half of people with mitochondrial disease can be diagnosed via genomic sequencing, a finding that will revolutionize care for families, according to a new study. And the Melbourne researchers have discovered what boosts and impacts the testing results, especially among children.

The national study, led by Murdoch Children’s Research Institute (MCRI), found genomic sequencing of blood, a lab test that can help identify genetic causes of health and developmental problems, could speed up and simplify the diagnostic journey, sparing those with suspected mitochondrial disease from invasive testing.

MCRI Dr. Alison Compton said the findings were significant for clinical management, allowing families to make informed reproductive decisions and enabling research into new treatments.

The Australian Genomics Mitochondrial Disorders Flagship, involving clinicians and researchers from around the country, conducted the study to determine the diagnostic impact of genomic sequencing using blood samples from those with mitochondrial disease symptoms.

For the study, 140 children and adults were recruited from NSW, Queensland, South Australia, Victoria, Tasmania and Western Australia. Those enrolled had symptoms including muscle weakness, intellectual disability, developmental delay, seizures and hearing impairment.

Published in Genetics in Medicine, the research reported a high diagnostic yield of 55%, with 71% of diagnoses made in genes known to cause mitochondrial disease.

Mitochondria are like the batteries inside our cells, providing the energy our bodies need to operate. When mitochondria are faulty due to genetic variations in key genes, cells begin to die until eventually, organ systems start failing.

Mitochondrial disease can be inherited through mutations in DNA that specifically affect mitochondrial function. About 50 Australian children are born every year with mitochondrial disease.

“When mitochondria don’t work properly our cells don’t get the energy they need, which can lead to various health issues,” Dr. Compton said. “Since every part of the body needs energy to work, problems with mitochondria can affect many different organs and systems, but especially those with high energy needs like the brain, heart, muscles and the nervous system.”

MCRI Professor David Thorburn said families living with mitochondrial disease often endure prolonged diagnostic journeys and invasive testing, yet many remain without a diagnosis.

“A diagnosis is crucial for patients, giving their clinical and allied health teams insights into prognosis and often allowing families to make informed reproductive decisions,” he said. However, the complexity and variability of the underlying causes of mitochondrial disease have made them hard to accurately diagnose.

“Often families with mitochondrial disease have visited multiple specialists, been misdiagnosed several times or required extensive evaluations, including invasive biopsies.”

The study found diagnostic rates were much higher among children than adults, at 71% and 31% respectively. The research noted mitochondrial DNA genetic variations in adult blood can decline with age, even becoming undetectable, which could be a contributing factor to the lower detection rate.

Additionally for children, higher Modified Nijmegen scores, a criteria tool to evaluate the likelihood of a child having mitochondrial disease, correlated with increased diagnostic yield. The testing also showed that almost a third of diagnoses were made in genes not known to cause mitochondrial disease.

“The findings emphasize the clinical variability and overlap of mitochondrial disease with other inherited disorders,” MCRI Professor John Christodoulou said. “It demonstrates the value of genomic testing by providing important health information that can lead to a diagnosis, more appropriate treatment or identify further health risks.”

Leigh and Laura’s son Tyler, 15, was diagnosed with mitochondrial disease four years ago.

“Tyler was perfectly healthy up until his Grade 2 teacher started noticing something wasn’t right,” he said. “She highlighted some issues he was having around not paying attention and following instructions. Tyler is a well-mannered child, so not listening just didn’t fit with his personality.”

To try and pinpoint what was behind the shift, Tyler underwent an assessment, which included a hearing exam.

“Tyler failed the hearing tests and was later diagnosed with retinitis pigmentosa, which causes severe vision loss,” Leigh said. Up until that point, he had learnt to hide it very well through self-taught lip reading.”

After years of further testing, Tyler was eventually diagnosed with mitochondrial disease via genomic sequencing. Tyler now wears hearing aids and specialized glasses, having lost 50% of his hearing and only has a visual field of 10 degrees. He also experiences low energy levels and muscle weakness, which can cause him to miss school.

Leigh said the new MCRI-led research on genomic sequencing for mitochondrial disease would come as a welcome relief to families.

“It was really frustrating not having a diagnosis for so long,” he said. “We were relieved once we knew what we were dealing with so we could zone in on that condition and learn as much as we could. Having a diagnosis means he can get the right medical care and we were able to access metabolic and cardiac clinics and a dietician and pediatrician who treat other children with mitochondrial disease.”

The treatment for mitochondrial disease focuses on managing symptoms and supporting overall health.

However, The mitoHOPE program, established in 2023, is offering hope to hundreds of families affected by some forms of mitochondrial disease. The pilot program, led by Monash University in collaboration with MCRI and other partners, aims to determine the safety, efficacy and feasibility of using mitochondrial donation in Australia.

Under the program, assisted reproductive technology will be harnessed and involves the nuclear DNA, the genetic material found within the nucleus of a cell, from an intending parent’s egg being transferred to a donor egg with healthy mitochondrial DNA. The child would inherit nuclear DNA from the intending parent/s and mitochondrial DNA from the egg donor.

The project aims to assist women to have genetically-related children who may not inherit the predisposition to some forms of mitochondrial disease and will help determine the best way to offer mitochondrial donation to women with the disease.