Wolfram syndrome is the association of diabetes mellitus and optic atrophy, and is sometimes called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Incomplete characterisation of this autosomal recessive syndrome has relied on case-reports, and there is confusion with mitochondrial genome disorders. We therefore undertook a UK nationwide cross-sectional case-finding study to describe the natural history, complications, prevalence, and inheritance of the syndrome. We identified 45 patients with Wolfram syndrome--a prevalence of one per 770,000. Non-autoimmune, insulin-deficient diabetes mellitus presented at a median age of 6 years, followed by optic atrophy (11 years). Cranial diabetes insipidus occurred in 33 patients (73%) with sensorineural deafness (28, 62%) in the second decade; renal-tract abnormalities (26, 58%) presented in the third decade followed by neurological complications (cerebellar ataxia, myoclonus [28, 62%]) in the fourth decade. Other abnormalities included gastrointestinal dysmotility in 11 (24%), and primary gonadal atrophy in seven of ten males investigated. Median age at death (commonly central respiratory failure with brain-stem atrophy) was 30 years (range 25-49). The natural history of Wolfram syndrome suggests that most patients will eventually develop most complications of this progressive, neurodegenerative disorder. Family studies indicate autosomal recessive inheritance with a carrier frequency of one in 354, an absence of a maternal history of diabetes or deafness, and an absence of the mitochondrial tRNA Leu (3243) mutation. Juvenile-onset diabetes mellitus and optic atrophy are the best available diagnostic criteria for Wolfram syndrome, the differential diagnosis of which includes other causes of neurodegeneration.