NEURODEGENERATION AND DIABETES - UK NATIONWIDE STUDY OF WOLFRAM (DIDMOAD) SYNDROME

Wolfram syndrome is the association of diabetes mellitus and optic atr ophy, and is sometimes called DIDMOAD (diabetes insipidus, diabetes me llitus, optic atrophy, and deafness). Incomplete characterisation of t his autosomal recessive syndrome has relied on case-reports, and there is confusion with mitochondrial genome disorders. We therefore undert ook a UK nationwide cross-sectional case-finding study to describe the natural history, complications, prevalence, and inheritance of the sy ndrome. We identified 45 patients with Wolfram syndrome-a prevalence o f one per 770000. Non-autoimmune, insulin-deficient diabetes mellitus presented at a median age of 6 years, followed by optic atrophy (11 ye ars). Cranial diabetes insipidus occurred in 33 patients (73%) with se nsorineural deafness (28, 62%) in the second decade; renal;tract abnor malities (26, 58%) presented in the third decade followed by neurologi cal complications (cerebellar ataxia, myoclonus [28, 62%]) in the four th decade. Other abnormalities included gastrointestinal dysmotility i n 11 (24%), and primary gonadal atrophy in seven of ten males investig ated. Median age at death (commonly central respiratory failure with b rain-stem atrophy) was 30 years (range 25-49). The natural history of Wolfram syndrome suggests that most patients will eventually develop m ost complications of this progressive, neurodegenerative disorder. Fam ily studies indicate autosomal recessive inheritance with a carrier fr equency of one in 354, an absence of a maternal history of diabetes or deafness, and an absence of the mitochondrial tRNA Leu (3243) mutatio n. Juvenile-onset diabetes mellitus and optic atrophy are the best ava ilable diagnostic criteria for Wolfram syndrome, the differential diag nosis of which includes other causes of neurodegeneration.