Two unrelated patients with Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) in whom MRIs of the brain provide evidence of a diffuse neurodegenerative process are reported from the Departments of Neurology and Ophthalmology, University of California at San Francisco, CA. Patient 1 was mildly mentally retarded and had a 5-year history of ataxia. Diabetes mellitus and diabetes insipidus had developed at age 3, and bilateral optic atrophy was diagnosed at age 13. Deep tendon reflexes were diminished and plantar responses were extensor. An audiogram showed bilateral high frequency hearing loss. Her parents were first cousins. Patient 2 was admitted for treatment of diabetic ketoacidosis at age 21. She had severe bilateral optic atrophy and horizontal nystagmus. Her gait was ataxic. Deep tendon reflexes were diminished and the plantar responses were flexor. MRI showed atrophy of brain stem and cerebellum and ventricles were dilated. 
COMMENT. Wolfram syndrome is inherited as an autosomal recessive disorder or it may be sporadic. Reported neurologic features include ataxia, nystagmus, vertigo, dysarthria, dysphagia, mental retardation, seizures, psychiatric disorders, pigmentary retinopathy, tremor, dystonia, hyporeflexia and neurogenic bladder. Endocrine abnormalities include delayed sexual maturation, growth retardation, hypothyroidism, and testicular atrophy. Recurrent urinary tract infections are associated with bilateral hydronephrosis. The differential diagnoses include olivopontocerebellar atrophy, Friedreich’s ataxia, Refsum’s syndrome, Laurence-Moon-Biedl syndrome, and Alstrom syndrome. The childhood presentation of diabetes mellitus, diabetes insipidus, and optic atrophy together with gait ataxia should suggest the diagnosis of Wolfram syndrome and indicate the need for an MRI, audiogram and renal sonogram.