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). Wolfram syndrome is caused by pathogenic variants (mutations) in one of two genes — WFS1 or CISD2 — with the majority of patients carrying mutations in the WFS1 gene. The first causative gene for Wolfram syndrome, WFS1, was discovered by Dr. M. Alan Permutt, M.D. at Washington University in St. Louis. Wolfram syndrome was subsequently established as a prototype endoplasmic reticulum disorder caused by dysregulated unfolded protein response by Dr. Fumihiko Urano, M.D., Ph.D. at Washington University in St. Louis. Fewer than 5,000 people in the US have this disease, with WFS1-Wolfram Syndrome being more common than CISD2-Wolfram Syndrome.
Signs and symptoms 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 cranial diabetes insipidus, which the kidneys are less able to retain water due to a decrease in the hormonal signalling from the hypothalamic pituitary axis. This condition affects around 70% of people with WSF1 mutations (CISD2 mutations do 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, optic nerve shrinkage 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. Urinary tract disorders are also found in more than 90% patient with Wolfram Syndrome, in which neurogenic bladder is the main manifestation of neurological disorder that can lead to urinary incontinence, hydroureter and recurrent infections. Recurrent UTIs are one of the most prevalent clinical challenges associated with Wolfram syndrome. These urological abnormalities usually onset at the age of 20 and can peak at 13, 21 and 33 years of age. Furthermore, bladder dysfunction can progress over time. Endocrine dysfunction is another clinical manifestation of Wolfram syndrome, which include hypogonadism. More specifically, hypogonadism presents more frequent in male than female. Male patients are more likely to experience fertility impairment and erectile dysfunction, while female patients may encounter menstrual abnormalities. Additionally, due to the decrease in function of the anterior pituitary gland, patients with Wolfram syndrome can also have short statue, growth hormone deficiency and corticotrophin secretion deficiency. Since patients with Wolfram syndrome can experience diabetes mellitus, diabetes insipidus and urinary tract disorder, they are treated with desmopressin, which can lead to the development of hyponatremia. Other abnormalities associated with Wolfram syndrome include gastrointestinal disorders (gastroparesis and bowel incontinence) and heart disease. These disorders have been reported in rare cases of WFS1 mutation.
Causes Wolfram syndrome was initially thought to be caused by mitochondrial dysfunction due to several reports of mitochondrial DNA mutations. However, it has now been established that Wolfram syndrome is caused by a congenital endoplasmic reticulum (ER) dysfunction.
Two forms have been described: WFS1-Wolfram syndrome and CISD2-Wolfram syndrome.
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