Determining the genetic basis of Leigh Syndrome, the most common clinical presentation in mitochondrial disorders affecting children

PhD Top-up Scholarships

$5,347 AUD

01/10/2013 → 01/10/2016

Carolyn Sue


Nicole Lake


University of Melbourne


Professor David Thorburn

Project Name

Determining the genetic basis of Leigh Syndrome, the most common clinical presentation in mitochondrial disorders affecting children

Project Details

The most common childhood mitochondrial disease presentation is Leigh syndrome, which is a progressive neurodegenerative disease with an onset that usually begins by 12 months of age. Leigh syndrome can be caused by mutations in over 45 different genes, and there are patients whose clinical diagnosis has been confirmed by a test result showing the presence of a genetic mutation. However a substantial proportion of patients with Leigh syndrome remain without a genetic diagnosis and this suggests that there are still many Leigh syndrome disease genes left to discover.

To increase the proportion of Leigh syndrome patients with a genetic diagnosis, there is a significant need to find those undiscovered disease genes and also develop an efficient patient genetic testing system. To do this, Nicole’s PhD project will collate the largest and best characterised cohort of patients with Leigh syndrome diagnosed in Australasia.

Referring clinicians and mitochondrial disease experts will work to confirm a diagnosis of Leigh syndrome and thus their inclusion in the cohort. Patient DNA will be subjected to Massively Parallel Sequencing (MPS) to find genetic mutations that can cause LS, with the initial focus targeting only the genes involved in mitochondrial assembly, maintenance and function (termed the ‘MitoExome’). This approach is expected to identify mutations in both new and well-known Leigh syndrome disease genes, whereby the new disease genes will be confirmed as disease-causing by using available patient tissues and cells for appropriate experiments.

It is anticipated that this research will identify disease-causing mutations that provide genetic diagnoses for over 50 families, allowing them to access accurate genetic counselling to facilitate family planning. The identification of new disease genes in particular may contribute to advancing the general understanding of mitochondrial disorders and to development of successful therapies, something which is currently lacking.

Furthermore, evaluation of the genetic testing outcomes in this cohort will provide valuable insight into the utility of this MPS-based approach in diagnosing not only Leigh syndrome and other mitochondrial diseases, but also for other rare disorders that are also difficult to diagnose.