Discovery highlights new way to identify and diagnose serious genetic disease

The findings, which are published today in Cell Metabolism, were made after researchers used next generation DNA sequencing technologies to test over 1,000 genes encoding proteins active in the mitochondria in two individuals with Leigh syndrome.

The discovery points to the value of next-generation sequencing technologies for diagnosing rare diseases and learning more about the underlying biology.
In Leigh syndrome, infants are born apparently healthy only to develop movement and breathing disorders that worsen over time often leading to death by the age of three. The problem is that the mitochondria responsible for powering their cells can't keep up with the demand for energy in their developing brains.

Leigh syndrome is the most common recognised mitochondrial disease of childhood, affecting 1 in 30,000 people (≤10 Australian children born each year). The new genetic discovery adds to a growing list of about 40 genes known to cause Leigh syndrome when mutated.

Professor David Thorburn from Murdoch Childrens Research Institute says the discovery highlights the huge potential of new technology.

"These findings demonstrate the ability of sequencing technologies to improve diagnosis. It's an all comers approach that can be applied to individuals, even with no family history of the disease," he said.

Although it isn't clear in the case of Leigh syndrome whether a precise molecular diagnosis will necessarily lead to therapies, the current findings represent a meaningful advance.

"It can be very reassuring for families to have a definitive answer. They are often referred around from one doctor to another. A diagnosis at least provides some closure to the diagnostic odyssey, even without a treatment."

"Diagnosis of the disease along with its specific genetic cause can also be informative about the risk a couple has of having another affected child. The diagnostic information can help in decisions about whether and how to pursue alternative means of having children, for instance through the use of donor sperm or eggs."

The gene they uncovered encodes an enzyme in mitochondria known as MTFMT. Mitochondria carry DNA of their own and their operation depends on a combination of proteins encoded locally and others encoded in the nuclear genome of a cell and imported. The MTFMT enzyme encoded in the mitochondrial DNA is responsible for converting the transfer RNA (tRNA) carrying the amino acid methionine into a form used by mitochondria to initiate protein translation. Without that enzyme, the mitochondria fail to translate proteins efficiently leading to the symptoms recognised as Leigh syndrome. Studies in patient skin cells showed that the defects in translation could be corrected by replacing the MTFMT gene.

In addition to their clinical implications, the new findings also offer insight into the biology of human mitochondria. Previously, mutations in more than 10 different nuclear genes had been shown to cause defects in human mitochondrial translation. It's now clear that MTFMT, too, is required for efficient mitochondrial translation. That's in contrast to earlier studies in yeast suggesting that mitochondrial translation could continue without the enzyme.