Wolfram syndrome, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can begin to appear as early as childhood to adult years (2–65 years old). There is a 25% recurrence risk in children.

It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D. In 1995, diagnostic criteria were created based on the profiles of 45 patients. The disease affects the central nervous system (especially the brainstem). There are two subtypes – Wolfram Syndrome Type 1 (WFS1) and Wolfram Syndrome Type 2 (WFS2), that are distinguished by their causative gene.

Fewer than 5,000 people in the US have this disease, with WFS1 being more common than WFS2.

The first symptom is typically diabetes mellitus, which is usually diagnosed around the age of 6. Insulin-dependent diabetes mellitus associate with Wolfram syndrome is differed from type 1 diabetes mellitus by having earlier diagnosis, rarely having positive auto-antibodies and ketoacidosis, having longer remission, needing less daily insulin, having lower average HbA1c level and more frequent hypoglycemia.

The second most common clinical manifestation of the disease is diabetes insipidus, which the kidney is unable to retain water due to renal outflow tract dilation and leads to high level of urine production. This condition affects around 70% of people with WSF1 mutation (WFS2 mutation does not typically associate with diabetes insipidus). Diabetes insipidus occurs around the age of 14, but the condition is often diagnosed late. Therefore, there is a high variability in the onset age.

The next symptom to appear is often optic atrophy, optical shrinkage that due to retinal ganglion cell axons' degeneration, around the age of 11. Blindness tends to develop a few years after the decrease in visual ability with the loss of color vision. Ophthalmic abnormalities often found in the patient with Wolfram Syndrome are cataract, nystagmus, glaucoma and maculopathy. There is also pigmentary retinopathy due to mitochondrial alteration that associated with Wolfram Syndrome. However, it is very rare and have been found in just a few cases.

Approximately 65% of people with Wolfram syndrome experience sensorineural deafness, which can manifest as deafness at birth or mild hearing loss in adolescent years and progressively worsen. However, the progression of sensorineural deafness is relatively slow and initially influences high-frequency sounds. Patients with WFS1 mutation have degenerative impairment in the central nervous system, as they increased in age they are more likely to suffer a more severe deafness than other patients that have hearing loss.

The majority of people (>60%) with WSF1 mutation develop neurological symptoms around the age of 40; however, some may experience these symptoms earlier in life. Some of the most common neurological abnormalities are cerebellar ataxia, peripheral neuropathy, epilepsy, cognitive impairment, dysphagia, dysarthria and diminished sense of taste and smell. In addition, the patient can also experienced orthostatic hypotension, gastroparesis, hypothermia or hyperthermia, hypohidrosis or hyperhidrosis, constipation and headache. Furthermore, there are also cases in which patients also have severe depression, sleep abnormalities, psychosis and physical aggression. The occurrence of the above conditions can add complexity to the clinical presentation of Wolfram syndrome.