[Graphic][1] Like so many complex and incurable neurological disorders, the disease first described in this journal in 1951 by (Archibald) Denis Leigh (1915–1998; figure 1) as ‘Subacute Necrotising Encephalomyelopathy’ (SNE)1 remained for many years a rare and intriguing enigma, of interest mainly to paediatric neurologists and neuropathologists. The more recent history of this disorder, now designated Leigh syndrome (LS) in view of its heterogeneity, exemplifies the revolution in clinical neurosciences, culminating in the understanding of the consequences of multiple mitochondrial defects through fundamental insights derived from molecular genetics, and attributing LS to a tale of two genomes, that is, to mutations in the mitochondrial DNA (mtDNA) or to nuclear DNA.2 Figure 1 Dr A Denis Leigh in his office at the Maudsley Hospital, London, circa 1966. The patient described by Leigh was an infant who had died aged 7 months in King's College Hospital, London, following a brief encephalopathic illness marked by drowsiness, respiratory difficulties, blindness, deafness and bilateral spasticity. The neuropathological features of the condition recognised as distinctive by Leigh included a strikingly symmetrical proliferation of smaller blood vessels, neuronal degeneration and gliosis targeting particularly parts of the thalamus, midbrain, pons, medulla and dorsal spinal cord. There was loss of myelin in the optic nerves and in association with the necrotising lesions in the grey matter. Leigh recognised striking similarities—but also important differences—between the pathological lesions seen in the infant with SNE and in Wernicke's encephalopathy. In the former, the subthalamic nuclei and mammillary bodies were strikingly spared, in contrast to Wernicke's encephalopathy. He speculated that the lesions in SNE might also be attributable to a nutritional deficiency, a theme to which he and others returned some years later, hoping that treatment with thiamine or related agents might lie in that direction. Although most patients with LS do not convincingly respond … [1]: /embed/inline-graphic-1.gif