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.