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Wolfram syndrome

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Other Names:
WFS; Diabetes insipidus and mellitus with optic atrophy and deafness; DIDMOAD; WFS; Diabetes insipidus and mellitus with optic atrophy and deafness; DIDMOAD; DIDMOAD syndrome See More
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Wolfram syndrome, which is also known by the acronym DIDMOAD, is an inherited condition characterized by diabetes insipidus (DI), childhood-onset diabetes mellitus (DM), a gradual loss of vision caused by optic atrophy (OA), and deafness (D).[1] Other symptoms may include bladder and bowel dysfunction, problems with the parts of the inner ear and brain that help control balance and eye movements (vestibular deficits), temperature regulation problems, decreased balance, uncoordinated (ataxic) gait and olfactory deficits. Also, psychiatric symptoms such as anxiety and depression have also been noted in some cases.[2][3] There are two types of Wolfram syndrome (type 1 and type 2) which are primarily differentiated by their genetic cause. Type 1 is caused by changes (mutations) in the WFS1 gene, while type 2 is caused by mutations in the CISD2 gene. Both forms are inherited in an autosomal recessive manner.[2][4] However, some cases of  Wolfram syndrome type 1 have an autosomal dominant inheritance and are more severe.[5] Diagnosis is suspected in cases of childhood-onset diabetes mellitus and optic atrophy, and this visual impairment is not due to the diabetes.[6] Treatment is symptomatic and supportive.[2]
Last updated: 5/19/2018
The two types of Wolfram syndrome (type 1 and type 2) have many overlapping features. Wolfram syndrome type 1, which is also known by the acronym DIDMOAD, is characterized by diabetes insipidus (DI), childhood-onset diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA), and deafness (D).[1] About 65% of affected people will develop all four of these symptoms, while others will only have some of the associated health problems.[7]

Other signs and symptoms of Wolfram syndrome type 1 may include:[7][1][8]
  • Urinary tract abnormalities
  • Ataxia (problems with coordination and balance)
  • Loss of sense of smell
  • Loss of gag reflex
  • Myoclonus (muscle spasms)
  • Decreased sensation in some parts of the body (peripheral neuropathy)
  • Seizures
  • Depression
  • Impulsive and/or aggressive behavior
  • Psychosis
  • Gastrointestinal problems
  • Intellectual disability
  • Irregular breathing due to lack of brain's inability to control breathing (central apnea) and central respiratory failure
  • Hypogonadism in males (reduced amounts of the sex hormone testosterone)

In addition to the signs and symptoms found in Wolfram syndrome type 1, people with Wolfram syndrome type 2 may also have stomach and/or intestinal ulcers; and a tendency to bleed excessively after injuries.[1]  

Last updated: 5/19/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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HPO ID
80%-99% of people have these symptoms
Diabetes insipidus 0000873
Polydipsia
Extreme thirst
0001959
30%-79% of people have these symptoms
Abnormality of mesentery morphology 0100016
Ataxia 0001251
Dysarthria
Difficulty articulating speech
0001260
Dysuria
Painful or difficult urination
0100518
Feeding difficulties in infancy 0008872
Nephropathy 0000112
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Recurrent urinary tract infections
Frequent urinary tract infections
Repeated bladder infections
Repeated urinary tract infections
Urinary tract infections
Urinary tract infections, recurrent
[ more ] 		0000010
Seizure 0001250
5%-29% of people have these symptoms
Abnormal autonomic nervous system physiology 0012332
Anemia
Low number of red blood cells or hemoglobin
0001903
Cardiomyopathy
Disease of the heart muscle
0001638
Central apnea 0002871
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Constipation 0002019
Delayed puberty
Delayed pubertal development
Delayed pubertal growth
Pubertal delay
[ more ] 		0000823
Dementia
Dementia, progressive
Progressive dementia
[ more ] 		0000726
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood
[ more ] 		0002376
Gastric ulcer
Stomach ulcer
0002592
Gastrointestinal hemorrhage
Gastrointestinal bleeding
0002239
Glaucoma 0000501
Hallucinations
Hallucination
Sensory hallucination
[ more ] 		0000738
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Joint stiffness
Stiff joint
Stiff joints
[ more ] 		0001387
Malabsorption
Intestinal malabsorption
0002024
Male hypogonadism
Decreased function of male gonad
0000026
Myopathy
Muscle tissue disease
0003198
Ophthalmoplegia
Eye muscle paralysis
0000602
Peripheral neuropathy 0009830
Respiratory insufficiency
Respiratory impairment
0002093
Sleep disturbance
Difficulty sleeping
Trouble sleeping
[ more ] 		0002360
Percent of people who have these symptoms is not available through HPO
Abnormal bleeding
Bleeding tendency
0001892
Abnormality of the skeletal system
Skeletal abnormalities
Skeletal anomalies
[ more ] 		0000924
Autosomal recessive inheritance 0000007
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances
[ more ] 		0000708
Blindness 0000618
Cerebral atrophy
Degeneration of cerebrum
0002059
Decreased circulating antibody level 0004313
Depressivity
Depression
0000716
Diabetes mellitus 0000819
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty
[ more ] 		0002015
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth
[ more ] 		0001510
Hydronephrosis 0000126
Hydroureter 0000072
Hypothyroidism
Underactive thyroid
0000821
Impaired collagen-induced platelet aggregation 0008320
Limited mobility of proximal interphalangeal joint
Limited mobility of innermost hinge joint
0006217
Megaloblastic anemia 0001889
Mitochondrial inheritance 0001427
Neurogenic bladder
Lack of bladder control due to nervous system injury
0000011
Neutropenia
Low blood neutrophil count
Low neutrophil count
[ more ] 		0001875
Oligomenorrhea
Light or infrequent menstrual periods
0000876
Optic atrophy 0000648
Optic neuropathy
Damaged optic nerve
0001138
Pigmentary retinopathy 0000580
Primary amenorrhea 0000786
Ptosis
Drooping upper eyelid
0000508
Sensorineural hearing impairment 0000407
Sideroblastic anemia 0001924
Stroke-like episode 0002401
Testicular atrophy
Testicular degeneration
0000029
Thrombocytopenia
Low platelet count
0001873
Tremor 0001337
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Last updated: 7/1/2020
The two types of Wolfram syndrome (type 1 and type 2) are primarily differentiated by their genetic cause.  Variations (mutations) in the WFS1 gene are responsible for about 90% of Wolfram syndrome type 1 cases. This gene encodes wolframin, a protein that is important for the proper functioning of the endoplasmic reticulum (the part of a cell that is involved in protein production, processing, and transport). Wolframin helps regulate the amount of calcium in cells, which is important for many different cellular functions. Mutations in WFS1 result in a defective form of wolframin that is unable to perform its normal role. This causes cells to trigger their own death (apoptosis). The death of cells in various organs and other parts of the body results in the signs and symptoms of Wolfram syndrome type 1.[1]

A specific mutation in the CISD2 gene causes Wolfram syndrome type 2. Although the exact function of this gene is not known, scientists suspect that it plays an important role in the mitochondria (the part of the cell where energy is produced). Mutations in CISD2 lead to the loss of mitochondria which decreases the amount of energy available to cells. Cells that do not have enough energy die. As in Wolfram syndrome type 1, the death of cells in different parts of the body results in the many health problems associated with Wolfram syndrome type 2.[1]

Mutations in mitochondrial DNA may also be a rare cause of Wolfram syndrome in some families.[9]
Last updated: 5/19/2018
Wolfram syndrome is inherited in an autosomal recessive manner.[1] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.
Last updated: 12/8/2014
A diagnosis of Wolfram syndrome is based on the presence of characteristic signs and symptoms. The identification of a change (mutation) in the WFS1 gene or CISD2 gene confirms the diagnosis.[2][8]

The following are the most important features that help with the diagnosis:[2]
  • Juvenile-onset (age <16 years) diabetes mellitus
  • Juvenile-onset optic atrophy (age <16 years)
  • Autosomal recessive inheritance
Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known.[2] 

The Genetic Testing Registry (GTR) is a centralized online resource for information about genetic tests. It offers information on genetic testing for Wolfram syndrome type 1 and Wolfram syndrome type 2. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional. 

 

 

Last updated: 5/20/2018
Treatment of Wolfram syndrome is supportive and based on the signs and symptoms present in each person. For example, almost all affected people require insulin to treat diabetes mellitus. People with hearing loss may benefit from hearing aids or cochlear implantation.[2][7][8]

For more detailed information please visit the GeneReviews section regarding the treatment and management of Wolfram syndrome. 
Last updated: 5/20/2018
The long-term outlook (prognosis) for people with Wolfram syndrome varies depending on the signs and symptoms present in each person. All the features that give Wolfram syndrome the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) are observed in 65% of people, while others only have some of the associated health problems. Most affected people develop diabetes mellitus and optic atrophy before age 15 years. Hearing loss is present in 64% of affected people by age 20 years and up to 72% will eventually develop diabetes insipidus. Wolfram syndrome may also be associated with a variety of other symptoms that can affect almost every part of the body.[7][2]

Wolfram syndrome is often fatal by mid-adulthood (average lifespan 30 to 40 years) due to complications from the various health problems associated with the condition.[10]
Last updated: 12/8/2014

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes mitochondrial disorders such as Maternally-inherited diabetes and deafness, Leber hereditary optic neuropathy, Mohr-Tranebjaerg syndrome, and Autosomal dominant optic atrophy plus syndrome. Other possible differential diagnoses are X-linked Carcot-Marie-Tooth disease type 5, Friedreich ataxia, Thiamine-responsive megaloblastic anemia, Bardet-Biedl and Alstrom syndromes. An autosomal dominant disorder, referred to as Wolfram-like syndrome, with DM occurring in adulthood, a juvenile onset of OA, and/or associated hearing impairment has also been described.
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Wolfram syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
  • The Research Portfolio Online Reporting Tool (RePORT) provides access to reports, data, and analyses of research activities at the National Institutes of Health (NIH), including information on NIH expenditures and the results of NIH-supported research. Although these projects may not conduct studies on humans, you may want to contact the investigators to learn more. To search for studies, enter the disease name in the "Text Search" box. Then click "Submit Query".

Patient Registry

  • A registry supports research by collecting of information about patients that share something in common, such as being diagnosed with Wolfram syndrome. The type of data collected can vary from registry to registry and is based on the goals and purpose of that registry. Some registries collect contact information while others collect more detailed medical information. Learn more about registries.

    Registries for Wolfram syndrome:
    Wolfram Syndrome International Registry
     

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Wolfram syndrome. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
    Wolfram Syndrome 1
    Wolfram Syndrome 2
    Wolfram Syndrome, Mitochondrial Form
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Wolfram syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Wolfram syndrome. Genetics Home Reference. 2012; http://ghr.nlm.nih.gov/condition/wolfram-syndrome.
  2. Tranebjærg L, Barrett T & Rendtorff ND. WFS1-Related Disorders. Gene Review. 2013; http://www.ncbi.nlm.nih.gov/books/NBK4144/.
  3. Doty T, Foster ER, Marshall B, Ranck S & Hershey T. The effects of disease-related symptoms on daily function in Wolfram Syndrome. Translational Science of Rare Diseases. 2017; 2(1-2):89-100. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677191/.
  4. Wolfram Syndrome 2. OMIM. September 2014; http://omim.org/entry/604928.
  5. Rigoli L, Bramanti P, Di Bella C & De Luca F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr Res. May, 2018; 83(5):921-929. https://www.ncbi.nlm.nih.gov/pubmed/29774890.
  6. Bueno GE, Ruiz-Castañeda D, Martínez JR, Muñoz MR & Alascio PC. Natural history and clinical characteristics of 50 patients with Wolfram syndrome. Endocrine. May 4, 2018; https://www.ncbi.nlm.nih.gov/pubmed/29728875.
  7. Wolfram syndrome. Orphanet. September 2014; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3463.
  8. Wolfram Syndrome. NORD. 2017; http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/850/viewFullReport.
  9. Wolfram Syndrome, Mitochondrial Form. OMIM. September 2013; http://www.omim.org/entry/598500?search=wolfram%20syndrome&;highlight=syndromic%20syndrome%20wolfram.
  10. de Heredia ML, Clèries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013 Jul;15(7):497-506. July 2013; 15(7):497-506.