WOLFRAM SYNDROME (DIDMOAD)
Researched and Written by Joy Koenig, M.D., M.S.
Board Certified in Preventive Medicine
© 1999 All Rights Reserved
This page is lovingly dedicated to
Megan O'Donnell
(October 27, 1986 - March 28, 2004)
SUMMARY
Wolfram Syndrome is a rare and complex genetic disorder, sometimes referred to as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). It is classified as a progressive neurodegenerative disease. This means the disorder primarily affects the body's nervous system and that the nervous system gradually declines in its ability to work correctly. Wolfram syndrome derives its name from the physician who first reported in four siblings the combination of juvenile-onset diabetes mellitus and optic atrophy. Since then (1938), over 170 people with Wolfram syndrome have been reported in the published medical literature.
PAPER ONE
Published in: Lancet. 1995 Dec 2;346(8988):1458-63.
Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.
Barrett TG, Bundey SE, Macleod AF.
Department of Paediatrics and Child Health, University of Birmingham, UK.
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.
PMID: 7490992
PAPER TWO
Published in: Diabetes Care. 1995 Dec;18(12):1566-70
Morbidity and mortality in the Wolfram syndrome.
Kinsley BT, Swift M, Dumont RH, Swift RG.
OBJECTIVE: To determine the major causes of morbidity and mortality in the autosomal recessive Wolfram syndrome, which is defined by diabetes and bilateral progressive optic atrophy with onset in childhood or adolescence.
RESEARCH DESIGN AND METHODS: We abstracted and reviewed the medical records of 68 confirmed cases of Wolfram syndrome identified through a nationwide survey of endocrinologists, ophthalmologists, institutes, and homes for the blind. We also reviewed all available autopsy records.
RESULTS: The most common causes of morbidity and mortality were the neurological manifestations of this syndrome and the complications of urinary tract atony. There was a lower frequency of diabetic ketoacidosis, no histologically proven diabetic glomerulosclerosis, and less severe, more slowly progressive, diabetic retinopathy than in classic type I diabetic patients. Mortality in Wolfram syndrome is much higher than in type I diabetes; 60% of Wolfram syndrome patients die by age 35. Recognition of these clinical differences from classic type I diabetes is important for the proper management of Wolfram syndrome patients.
CONCLUSIONS: Identification of Wolfram syndrome patients among all diabetic patients presenting in childhood or adolescence is important because the management of patients with this syndrome is different from that of patients with classic type I diabetes.
PMID: 8722052
PAPER THREE
Published in: Int J Pediatr Otorhinolaryngol. 2004 Feb;68(2):243-7.
Wolfram syndrome.
Megighian D, Savastano M.
Dipartimento di Specialità Medico-Chirurgiche, Sezione ORL, Padua University, Via Giustiniani 2, 35128, Padua, Italy.
The Wolfram syndrome is a rare dysmorphogenetic disease of autosomic recessive hereditary nature. The pathogenesis of the disease is still not well known. It is characterised by the presence of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Other anomalies, such as renal outflow tracts and multiple neurological disorders may develop later. In our case report the diabetes mellitus appeared at the age of 4; the hearing loss and renal disturbances at the age of 11; the optic atrophy at the age of 16. No signs of ataxia, diabetes insipidus and neurologic anomalies were found. The diagnosis of Wolfram syndrome is not always easy in the first stages of the disease. The suspect may come from the presence of a juvenile diabetes mellitus asssociated with optic atrophy. For the diagnosis a valid clue can be given from the results of some clinical tests such as the positivity of the visual evoked potentials and the retinogram reliefs and the exclusion of the autoimmune origin of the diabetes mellitus. Other signs such as the progressive sensorineural hearing loss, the presence of nystagmus and of urodynamic disturbances and renal complications makes the diagnosis of this syndrome easier.
PMID: 14725994
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