Adult-onset Leigh syndrome is a rare but important manifestation of mitochondrial disease. We report a 17 year old female who presented with subacute encephalopathy, brainstem and extrapyramidal signs, raised CSF lactate, and symmetrical hyperintensities in the basal ganglia on T2-weighted cerebral MRI. The presence of cytochrome c oxidase deficient fibres in muscle tissue prompted sequencing of the entire mitochondrial genome which revealed the novel stop codon mutation m.6579G>A; p.Gly226X in MT-CO1. Here we present the case and review the clinicopathological and molecular spectrum of previously reported MT-CO1 truncating mutations. • The novel stop codon mutation m.6579G > A; p.Gly226X in MT-CO1 causes adult-onset Leigh syndrome. • MT-CO1 truncating mutations are associated with remarkable phenotypic heterogeneity. • Broad clinical spectrum may arise from inter-individual variations in mutant protein degradation and/or complex IV stability. [ABSTRACT FROM AUTHOR]