NORD gratefully acknowledges Tamara Hershey, PhD, Professor of Psychiatry & Radiology, Bess Marshall, MD, Professor of Pediatrics, and Jennifer May, MD, Fellow in Pediatrics, Washington University School of Medicine, for assistance in the preparation of this report.
Wolfram syndrome is an inherited condition that is typically associated with childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy. In addition, many people with Wolfram syndrome also develop diabetes insipidus and sensorineural hearing loss. Another name for the syndrome is DIDMOAD, which refers to diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Most cases of Wolfram syndrome are caused by changes (mutations) in the WFS-1 gene. Less severe mutations in the WFS-1 gene cause WFS1-related disorders, in which the affected person has only some of the features of Wolfram syndrome, such as sensorineural hearing loss without diabetes or other features.
The symptoms and rate of progression of Wolfram syndrome can be quite variable. The primary symptoms of Wolfram syndrome (diabetes mellitus, optic atrophy, diabetes insipidus and hearing loss) can emerge at different ages and change at different rates. If some of these symptoms never appear at all, the patient’s condition would be called a WFS1-related disorder.
Most people affected by Wolfram syndrome develop insulin-dependent diabetes mellitus before the age of 16 (87%). The starches and sugars (carbohydrates) in the foods we eat are normally processed by the digestive system into glucose that circulates in the blood as one energy source for body functions. A hormone produced by the pancreas (insulin) allows muscle and fat cells to take up glucose. In diabetes mellitus, the pancreas does not make enough insulin so the cells cannot take up glucose normally and the blood sugar gets too high. In diabetes mellitus caused by the Wolfram gene, the patient needs daily injections of insulin to control the blood sugar. Symptoms of diabetes may include frequent urination, excessive thirst, increased appetite, weight loss, and blurred vision.
In addition, it is thought that almost all of those affected by Wolfram syndrome have primary optic atrophy (OA) and subsequent vision impairment of varying severity before the age of 16 (80%). The optic nerve conducts visual information to the brain for processing. Loss of the nerve fibers and/or their insulation (myelin) results in color blindness and reduced vision typically beginning in childhood and progressing with age, though some progress quickly and others slowly.
Some people who have Wolfram syndrome also develop diabetes insipidus (42%). This is not related to diabetes or insulin. The only thing it has in common with diabetes is the symptoms of excessive thirst and urination. This condition results in excretion of large quantities of very watery-appearing urine and excessive thirst due to the brain not making enough of a hormone (vasopressin) that causes the kidneys to hold onto water. Patients tend to drink enormous quantities of fluid and urinate very often. Other symptoms may be dehydration, weakness, dryness of the mouth, and sometimes constipation, which may develop rapidly if the loss of fluid is not continuously replaced. Diabetes insipidus can be treated with vasopressin hormone replacement called dDAVP.
Hearing loss is the fourth major symptom of Wolfram syndrome and occurs in approximately 48% of patients. This symptom may occur at any age and may be partial or complete. The hearing loss is due to a loss of sound perception transmitted by nerves (sensorineural). Symptoms may include loss of sound intensity or pitch, or loss of the ability to hear high tones.
Some of the following additional symptoms may develop:
Urinary tract abnormalities (33%) – this is most often a problem with the bladder not emptying properly, so that the person needs to empty often. This symptom may be confused or complicated by diabetes insipidus, so both need to be checked if a person with Wolfram syndrome is having frequent urination.
Neurological symptoms such as poor smell, poor balance, an awkward, unbalanced way of walking (ataxia) and central sleep apnea can occur. In addition, imaging of the brain reveals that people with Wolfram syndrome have smaller brainstem and cerebellum volumes and smaller optic nerves than those without Wolfram syndrome. These differences may increase over time.
Psychiatric and behavioral problems such as depression, anxiety and fatigue can occur in patients with Wolfram syndrome (26%). These symptoms may be related to the changes in the nervous system from Wolfram syndrome itself or to the psychological and quality of life burden caused by the effects of the disease.
Disordered sleep may be a problem and can be due to sleep apnea or to frequent waking to urinate.
Other problems that may occur:
Lowered production of testosterone (hypogonadism) in males (6%)
Gastrointestinal disorders (5%) – including constipation, trouble swallowing, choking, diarrhea.
Bilateral clouding of the lens of the eyes (cataracts) (1%)
Abnormal temperature regulation (e.g. overheating).
Wolfram syndrome is caused by mutations in the WFS1 (most common) or WFS2 (CISD2) gene that are inherited in an autosomal recessive pattern in most affected individuals, although dominant forms exist.
Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a disease. The altered gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) gene mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
Since diabetes mellitus and optic atrophy usually begin before the age of 16, Wolfram syndrome is typically diagnosed in childhood to adolescence. However, onset of key symptoms or the genetic confirmation can come much later in some patients. Wolfram syndrome affects males and females in equal numbers and is equally prevalent worldwide.
Wolfram syndrome is difficult to diagnose. In many instances, people with this disorder and their doctors may be unaware that the various symptoms and complaints are related and indicate a specific disorder. Initially, the focus may be on one symptom, typically diabetes mellitus, and its treatment. Later, the presence of other symptoms may become apparent. Wolfram syndrome should be considered in anyone with diabetes mellitus and optic atrophy; anyone with low frequency sensorineural hearing loss; anyone with either diabetes mellitus or optic atrophy in addition to hearing loss or diabetes insipidus or bladder dysfunction or loss of sense of smell or a family member with Wolfram syndrome.
Molecular genetic testing for mutations in the WFS1 and WFS2 genes is available to confirm the diagnosis.
Treatment of Wolfram syndrome is symptomatic and supportive. It requires a multidisciplinary effort to manage the various aspects of this condition. When diabetes mellitus is present, the patient will need insulin treatment. Diabetes insipidus can be difficult to diagnose and may need to be treated with intranasal or oral dDAVP. Treatment of diabetes insipidus in Wolfram may be very complicated as the person may also have diabetes mellitus and bladder dysfunction. Patients with hearing loss may benefit from hearing aids or cochlear implants as well as accommodations for hearing loss. All patients should be followed closely by an eye doctor (ophthalmologist) and may need glasses or other accommodations for low vision such as large print reading materials, high contrast visuals at school or work, allowances for colorblindness, etc. Occupational therapy may be helpful in some cases. Regular evaluation of the bladder is important to detect poor bladder emptying. Psychological evaluation and care are important for many, particularly with school performance issues. Treatment of constipation, diarrhea, and trouble swallowing may be needed. Sleep should be monitored, and sleep apnea considered. Patients may have trouble tolerating high or low temperatures and may need accommodations for air conditioning or heating.
Genetic counseling is recommended for Wolfram syndrome patients and their families.
Information on current clinical and natural history trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
Individuals and families affected by Wolfram syndrome should check the U.S. government clinical trials web site (www.clinicaltrials.gov) by searching for Wolfram Syndrome related trials.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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