Title: Leigh Syndrome: One disorder, more than 75 monogenic causes Running head: Leigh Syndrome: One disorder, many genes Author list: Nicole J. Lake, MSc,1,2 Alison G. Compton, PhD,1,2 Shamima Rahman, MD, PhD,3 and David R. Thorburn, PhD1,2,4 Affiliations: From the 1Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; 2Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia; 3Mitochondrial Research Group, Genetics and Genomic Medicine, Institute of Child Health, University College London and Metabolic Unit, Great Ormond Street Hospital, London, United Kingdom; 4Victorian Clinical Genetic Services, Royal Children's Hospital, Melbourne, Victoria, Australia. Corresponding author: Prof. David Thorburn Email
[email protected] Telephone +61 3 8341 6235 Fax +61 3 8341 6212 Address Murdoch Childrens Research Institute, The Royal Children’s Hospital, 50 Flemington Rd, Parkville, Victoria, 3052, Australia Number of characters in the title and running head: 51 and 35, respectively Number of words in the abstract (107), and the body of manuscript not including abstract (4877) Number of figures (3), colour figures (1/3), and tables (3) 1 Abstract Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in more than 75 genes have been identified, encoded by two genomes (mitochondrial and nuclear). More than a third of these disease genes have been characterized in the last 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological and metabolic features that can provide clues for diagnosis.