Last updated:
7/28/2025
Years published: 1990, 1994, 1998, 2005, 2017, 2020, 2024, 2025
NORD gratefully acknowledges Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine, Director of Wolfram Syndrome and Related Disorders Clinic and Research, Washington University School of Medicine/Barnes-Jewish Hospital, BJC HealthCare and the Wolfram Syndrome International Clinical Guidelines Team, for assistance in the preparation of this report.
Summary
Wolfram syndrome is a rare genetic disease characterized by an atypical form of diabetes along with other serious health problems. 1,2
People with Wolfram syndrome often develop diabetes, vision loss from damage to the optic nerve and progressive brain and nerve problems. Many people also have hearing loss, bladder issues, hormone problems affecting water balance and anxiety.
Wolfram syndrome is subdivided into two types. Type 1 is the most common type and it is caused by changes (variants) in a gene called WFS1. 3 Type 2 is caused by variants in a gene called CISD2. 4 Inheritance is autosomal recessive in most cases.
Since there are currently no treatments that can slow down or stop the condition, early diagnosis and care from a team of different medical specialists is very important.
Introduction
The term “WFS1 spectrum disorder” has been used to refer to Wolfram syndrome type 1, including the autosomal recessive “classic WFS1 spectrum disorder” caused by pathogenic variants in two copies of the WFS1 gene and “Wolfram syndrome-like disease” (autosomal dominant Wolfram syndrome type 1), caused by a pathogenic variant in only one copy of the WFS1 gene.
However, during the International Wolfram Clinical Guidelines Committee meeting and the most recent international conference in 2025, a consensus was reached to use the term “Wolfram syndrome type 1” for people with pathogenic variants in two copies of the WFS1 gene and “Wolfram syndrome type 2” for people with pathogenic variants in two copies of the CISD2 gene (autosomal recessive forms of Wolfram syndrome). The term “Wolfram related disorders” will be used for people with dominantly inherited WFS1 variants (formerly Wolfram syndrome-like disease).
Wolfram syndrome type 1
Wolfram syndrome type 2
Wolfram related disorders (dominantly inherited WFS1 variants), formerly Wolfram syndrome-like disease
Wolfram syndrome mitochondrial form (as suggested in some reports)
The earliest sign is usually childhood-onset diabetes mellitus, typically around age six. This type of diabetes is different from the more common type 1 diabetes.1,2,5,6
At around age 11, the nerve of the eyes (optic nerve) becomes weak and shrinks (optic nerve atrophy) which causes progressive vision loss. As the affected children grow older, into their teens or early adulthood, other signs and symptoms may appear, such as:1,2,5,6
As the disease progresses, neurologic problems become more serious. These can include:
The autonomic nervous system dysfunction, which disrupts the body’s automatic controls (heart rate, digestion, bladder emptying and temperature regulation) can contribute to bladder problems as well as cause gastrointestinal issues, constipation, diarrhea and abnormal temperature responses (for example, overheating).
Brain imaging shows that the brainstem, cerebellum, thalamus and optic nerves are smaller than average, and these differences tend to worsen over time.
These complications greatly affect quality of life and typically shorten life expectancy to between the late 20s and early 40s.1
Other signs and symptoms that have been reported more rarely include:
People with Wolfram syndrome type 2 often develop stomach ulcers and bleeding problems in addition to the usual features of the disorder.
Wolfram syndrome type 1, the most common type, is caused by variants in the WFS1 gene and Wolfram syndrome type 2 is caused by variants in the WFS2 (CISD2) gene.3,4
The WFS1 gene produces a protein called wolframin, which helps keep calcium levels in balance inside cells. The protein wolframin sits in the membrane of an organelle called the endoplasmic reticulum (ER). The ER is like a factory and shipping center, folding and shaping new proteins so they work properly, and then send them to where they’re needed. By helping to control calcium levels in the ER, wolframin supports this protein-folding machinery. In the pancreas, for example, wolframin helps convert proinsulin (the inactive precursor) into mature insulin. Wolfram syndrome is widely recognized as a model disease of “endoplasmic reticulum (ER) dysfunction”. 7,8
Research has shown that problems in the ER also lead to secondary mitochondrial dysfunction. The interaction between these two cellular stress pathways, ER and mitochondria, plays a key role in driving the disease process. 9-12
The CISD2 gene leads to production of a CISD2 protein that is too short and cannot do its normal job. Without functional CISD2, the cell’s mitochondria are not maintained correctly and gradually break down. When mitochondria fail, cells lose the energy they need to survive and eventually die. This energy loss hits hardest in cells with the highest demands, like nerve cells in the brain, the optic nerves in the eye and the nerves that control the digestive tract, so these tissues are most vulnerable. 13,14
People with CISD2 gene variants often develop stomach ulcers and bleeding problems in addition to the usual features of the disorder. 15 At this time, researchers don’t know exactly why these gastrointestinal complications occur.
In most cases inheritance is autosomal recessive. 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.
Wolfram syndrome is estimated to affect about 1 in 200,000 to 1 in 700,000 people, depending on the source.1,6 However, the actual number may be higher because milder forms of the condition are often underdiagnosed. A commonly used estimate is 1 in 500,000, which would mean there are approximately 1,000 to 1,500 people with Wolfram syndrome in the United States. Other estimates state that Wolfram syndrome affects about 1/100,000 in North America, which is about 3,000 people in US.
Recent research suggests that a milder form of Wolfram syndrome is more common in the Ashkenazi Jewish population, where the carrier frequency is about 3%.12 This highlights the importance of increasing awareness and improving early diagnosis in at-risk populations.
Wolfram syndrome is often suspected when a child develops early-onset diabetes mellitus that is not autoimmune and later shows signs of optic nerve atrophy or other neurological problems. If both diabetes and vision problems due to optic nerve atrophy appear, a diagnosis of Wolfram syndrome should be strongly considered.
A definitive diagnosis requires genetic testing. Most individuals with Wolfram syndrome have two disease-causing variants in the WFS1 gene, one inherited from each parent. If only one variant is found in a patient with typical symptoms, additional testing, such as testing the parents or analyzing the gene’s RNA transcripts, may be needed. A small number of cases are due to pathogenic variants in the CISD2 gene which are often linked to gastrointestinal bleeding or ulcers, features not typically seen in WFS1-related Wolfram syndrome.
The severity of the disease can vary depending on the type and location of the WFS1 variants. People with two loss-of-function variants (such as nonsense or frameshift changes) usually have an earlier onset and faster progression. Certain in-frame variants located in the protein’s transmembrane domains also tend to result in more severe disease than variants outside these regions. Understanding the genetic makeup can help predict how the disease will progress and guide personalized care strategies.6
Upon diagnosis of Wolfram syndrome, all patients should be offered comprehensive support services. This should include connection with a patient advocacy organization to provide reliable information, access to community resources, and a sense of support and belonging. In addition, patients and their families should be evaluated for social work involvement and caregiver support to help address emotional, logistical and financial challenges associated with managing a complex, progressive condition.
Management
Currently, there are no approved treatments that can halt or reverse the progression of Wolfram syndrome. Management requires a multidisciplinary, team-based approach aimed at relieving symptoms, monitoring disease progression, and providing supportive care while actively working toward therapies that may slow or stop the disease.2
Patients should ideally be evaluated at a specialized Wolfram syndrome multidisciplinary clinic at least every two years or sooner if there is significant clinical decline. A comprehensive care team may include a specialist nurse or nurse coordinator, endocrinologist, neurologist, ophthalmologist (with optometry support), genetic counselor, pediatric clinical psychologist, adult psychiatrist, speech and language therapist (for adults), urologist (with access to urodynamic testing), nephrologist, ENT/audiology specialist, transition coordinator and a family liaison from a patient support group.
It is essential to regularly assess and manage the following body systems:
Endocrine Care
Most people with Wolfram syndrome have diabetes that is C-peptide positive and autoantibody negative, meaning their bodies still produce some insulin and the diabetes is not autoimmune.16 Treatment with an insulin pump and continuous glucose monitoring (CGM) is generally recommended. Some patients may also benefit from a GLP-1 receptor agonist, depending on how much insulin their pancreas still makes.5 When considering starting a GLP-1 receptor agonist, caution is required if the patient has autonomic dysfunction and/or gastroparesis.
Arginine vasopressin deficiency (also called central diabetes insipidus), when present, is usually treated with desmopressin. However, it can be difficult to evaluate symptoms like increased thirst and urination in patients who also have neurogenic bladder and diabetes, so sodium levels should be checked regularly during treatment to prevent low sodium (hyponatremia).
Hypogonadism should be treated using standard hormone replacement approaches. In addition, thyroid function, growth and pubertal development should be monitored regularly.
Ophthalmologic Care
Vision loss in Wolfram syndrome is primarily caused by optic nerve atrophy rather than damage to the retina. To monitor and manage this condition, patients should undergo a comprehensive eye examination at least once a year. This evaluation should include best-corrected visual acuity testing, ideally with cycloplegic refraction in children to ensure accurate correction of any refractive errors. Additional assessments should include color vision testing using Ishihara or Hardy-Rand-Rittler plates, measurement of intraocular pressures and slit-lamp examination of both the anterior and posterior segments of the eye.
When age-appropriate, visual field testing and optical coherence tomography (OCT) imaging of the optic nerve and macula should also be performed to assess structural changes and monitor progression.17-19 Although there are currently no proven treatments to reverse optic nerve atrophy, some doctors may consider the use of idebenone or Coenzyme Q10 (CoQ10) in select patients. However, the evidence supporting their effectiveness remains limited.
Auditory Care
Hearing loss in Wolfram syndrome is usually progressive and typically affects high-frequency sounds first.20 It is recommended to have a hearing evaluation every 6 months for the first 4-5 years of life or after the diagnosis. After the first 5 years of life, doctors aim to review hearing every 3 years, unless there is acute deterioration.
– Auditory brain stem responses to confirm pathology and provide baseline or, if not available, can try evoked otoacoustic emissions
– Audiogram (age-dependant)
– Speech discrimination tests
– Assessment for hearing aids if appropriate; children with profound infancy-onset deafness may require cochlear implant.
Many individuals benefit from hearing aids or, in more severe cases, cochlear implants.
Neurologic Care
Neurological symptoms are often the most challenging aspect of Wolfram syndrome.21 All patients should be evaluated by a neurologist annually or at least every two years. Brain MRI without contrast with thin cuts through the brain stem should be considered in patients with significant neurological impairment or an abnormal neurological examination.22 Broadly, Wolfram syndrome patients show progressive atrophy of the cerebellum, brain stem, thalamus and basal ganglia. In patients who require a brain MRI but who have MRI-incompatible cochlear implants, a high-resolution CT head should be considered.
Common neurological issues include cerebellar ataxia, which causes difficulty with balance and coordination and brainstem dysfunction, which can lead to central sleep apnea and swallowing difficulties (dysphagia).
Patients experiencing balance problems should be referred to a physical therapist or physiotherapist to learn exercises that can help improve stability over time.
Regular evaluation by a neurologist and a speech-language pathologist is recommended, especially when there are concerns about swallowing. If dysphagia is suspected, a swallowing study should be performed. Sleep studies may help detect central sleep apnea, which may require treatment with non-invasive ventilation or, in some cases, tracheostomy.
Migraine/headaches are common in Wolfram syndrome and can be exacerbated by systemic infections. The headaches are resistant to medication and can sometimes require inpatient hospitalization. Typical first line treatments include NSAIDs, paracetamol/acetaminophen, triptans, sodium valproate (but avoid sodium valproate in females of fertile age).
Patients should have their autonomic function vitals/observations (orthostatic blood pressure and heart rate: lying, sitting, standing at least 5 minutes in each position) checked at least once per year.
Chronic fatigue is common and should be assessed with a validated questionnaire (e.g. fatigue severity scale) at their clinic appointments. Management should include treating any underlying psychiatric condition (e.g. anxiety, depression) and exercise.
Cognitive function is usually normal in the early stages of the disease.
Psychiatric Care
All children who are newly diagnosed with Wolfram syndrome should have a psychological or psychiatric evaluation. This can help identify any emotional, developmental, or learning needs and connect families with the right support services. Adults with Wolfram syndrome should also be offered a consultation with a mental health specialist. The first treatments for anxiety and depression are usually therapy and medications called SSRIs (selective serotonin reuptake inhibitors).23
Urologic Care
Neurogenic bladder and other urinary problems are common in patients with Wolfram syndrome. Regular evaluation with urodynamic testing, kidney imaging and bladder function tests are important for early detection and management. If there is evidence of increased bladder stretch on urodynamic testing, prophylactic desmopressin should be considered, in discussion with an endocrinologist.24
Treatment options may include anticholinergic medications, Botox injections into the bladder, intermittent catheterization, neural stimulator implants, or, in some patients, surgery, depending on the severity of symptoms and response to treatment.
Transition from Pediatric to Adult Care
When transitioning patients from pediatric to adult care, the process should begin early in the second decade of life to allow adequate time for preparation. It is important to actively involve the young person, along with their pediatric and adult care providers, in a coordinated and well-planned transfer to adult services to ensure continuity of care and support independence.
Patient Registries and Observational Studies
The Wolfram Syndrome International Registry and Clinical Study, based at Washington University School of Medicine in St. Louis, collects clinical data and biospecimens from individuals with confirmed or suspected Wolfram syndrome. The registry supports natural history studies and helps researchers design better clinical trials. Participation in the registry is voluntary and open to people worldwide.
Several clinical trials and research studies are underway to develop potential therapies and improve our understanding of the disease. Patients and families are encouraged to consult with their physicians and research coordinators before enrolling in any study.
Multiple academic centers and pharmaceutical companies are conducting or have recently completed clinical trials targeting the underlying biology of Wolfram syndrome.
Researchers are also evaluating the use of GLP-1 receptor agonists, such as liraglutide and tirzepatide, for their ability to preserve beta cell function, alleviate ER stress and potentially slow disease progression. These agents are currently being tested in human cellular models and pilot studies in patients.14,15,16
AMX0035 (sodium phenylbutyrate/taurursodiol) is a combination compound that targets endoplasmic reticulum (ER) and mitochondrial stress—two key pathways involved in Wolfram syndrome. A phase 2 clinical trial of AMX0035 in individuals with Wolfram syndrome will be recruiting patients.
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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