Última actualización:
3/27/2024
Años publicados: 1990, 1994, 1998, 2005, 2017, 2020, 2024
NORD gratefully acknowledges Tamara Hershey, PhD, Professor of Psychiatry & Radiology, and Bess Marshall, MD, Professor of Pediatrics for assistance in the preparation of this report.
Summary
Wolfram syndrome is an inherited condition that typically includes childhood-onset insulin-dependent diabetes mellitus and progressive optic atrophy. In addition, many people with Wolfram syndrome also develop diabetes insipidus, sensorineural hearing loss and autonomic nervous system degeneration. Another name for the syndrome is DIDMOAD, which is an acronym for diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Most cases of Wolfram syndrome are caused by changes (variants) in the WFS1 gene. Less severe variants in the WFS1 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 vary between affected individuals. The primary symptoms of Wolfram syndrome (diabetes mellitus, optic atrophy, diabetes insipidus, hearing loss and nervous system dysfunction) 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. The starches and sugars (carbohydrates) in the foods we eat are primarily processed by the digestive system into glucose, a sugar 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 WFS1 gene variants, the patient usually needs daily injections of insulin to control the blood sugar. Symptoms of uncontrolled diabetes include frequent urination, excessive thirst, increased appetite, weight loss and blurred vision.
The optic atrophy (OA) and subsequent vision impairment seen in Wolfram syndrome is of varying severity and is usually diagnosed before the age of 16. The optic nerve conducts visual information from the eye 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, with some patients progressing quickly and others slowly.
Some people who have Wolfram syndrome also develop diabetes insipidus (now also called arginine-vasopressin deficiency). Diabetes insipidus is not related to diabetes mellitus or to insulin. The only thing it has in common with diabetes mellitus is that both cause excessive thirst and urination. In diabetes insipidus, a part of the brain called the pituitary gland does not produce enough of a hormone called arginine vasopressin. Arginine vasopressin is a hormone that allows the kidneys to keep water in the body and to make concentrated, yellow urine. A deficiency of arginine vasopressin results in production of large quantities of very watery-appearing urine, which causes dehydration and excessive thirst. Patients tend to drink enormous quantities of fluid and urinate very often. Diabetes insipidus can be treated with vasopressin hormone replacement called dDAVP or desmopressin.
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 from the ear to the brain (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 – 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 with 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 in people with Wolfram syndrome, some parts of the brain are smaller than in typical brain scans. There is a smaller brainstem and cerebellum volume and smaller optic nerve 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. 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.
Dysfunction of the autonomic nervous system is a major symptom of Wolfram syndrome that is also difficult to assess and to treat. The autonomic nervous system is the part of the nervous system that controls internal operations such as heart rate, digestion, bladder emptying and temperature regulation. This system works largely unconsciously. Dysfunction of this system can cause several symptoms in Wolfram syndrome. The bladder dysfunction may be in part due to autonomic dysfunction. Another common problem is gastrointestinal disorders including constipation, trouble swallowing, choking and diarrhea. Others include abnormal temperature regulation (e.g. overheating) and sleep apnea or disordered sleep.
Some people with Wolfram may develop dysfunction of glands including lowered production of testosterone (hypogonadism).
Bilateral clouding of the lens of the eyes (cataracts) can occur in some patients.
Wolfram syndrome is caused by variants 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 a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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.
Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Since diabetes mellitus and optic atrophy usually begin before the age of 16, Wolfram syndrome is often diagnosed in childhood to adolescence. However, onset or recognition of key symptoms or confirmation of the diagnosis with genetic testing 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 variants in the WFS1 and WFS2 genes is available to confirm the diagnosis.
Treatment
Currently, treatment of Wolfram syndrome is symptomatic and supportive, but there are trials of possible treatments in progress. 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 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 patients. Regular evaluation of the bladder is important to detect poor bladder emptying. If bladder dysfunction is identified, physical therapy, catheterization, or occasionally surgical procedures may be used. 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: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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INTERNET
Barrett T, Tranebjærg L, Gupta R, et al. WFS1 Spectrum Disorder. 2009 Feb 24 [Updated 2022 Dec 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK4144/ Accessed March 12, 2024.
Wolfram Syndrome. Genetics Home Reference. Last updated February 14, 2022. https://ghr.nlm.nih.gov/condition/wolfram-syndrome. Accessed March 12, 2024.
Wolfram Syndrome, Genetic and Rare Diseases Information Center. Last updated: 5/19/2018. https://rarediseases.info.nih.gov/diseases/7898/wolfram-syndrome Accessed March 12, 2024.
Wolfram Syndrome. Orphanet Last update: August 2019. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3463 Accessed March 12, 2024.
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