Subacute necrotising encephalomyelopathy (Leigh’s disease; Leigh syndrome)

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) 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. 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 to such treatment, biotin and thiamine may dramatically improve the condition of biotin-responsive basal ganglia disease, a disorder that can mimic LS. Nonetheless, the notion that a metabolic defect might be at the heart of the problem, and that metabolic stress might precipitate neuronal damage has been amply borne out. Leigh’s career exemplifies a lost interdisciplinary flexibility. After qualifying in medicine in Manchester in 1938, he trained with the eminent neurosurgeon Sir Jeffrey Jefferson, intending a career in neurology or neurosurgery. However, at the outbreak of war he joined the Royal Army Medical Corps, and after a spell as a regimental medical officer, was posted (through the influence of Jefferson) to the Oxford Head Injuries Unit where he worked with the outstanding neurological leaders and