We're celebrating
40 years!
Last updated:
3/27/2024
Years published: 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: prpl@cc.nih.gov
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/
REVIEW ARTICLES
Lee EM, Verma M, Palaniappan N, et al. Genotype and Clinical Characteristics of Patients with Wolfram Syndrome and WFS1-related Disorders. Preprint. medRxiv. 2023;2023.02.15.23284904. Published 2023 Feb 16. doi:10.1101/2023.02.15.23284904
Rigoli L, Caruso V, Salzano G, Lombardo F. Wolfram Syndrome 1: From Genetics to Therapy. Int J Environ Res Public Health. 2022;19(6):3225. Published 2022 Mar 9. doi:10.3390/ijerph19063225
Rosanio FM, Di Candia F, Occhiati L, et al. Wolfram Syndrome Type 2: A Systematic Review of a Not Easily Identifiable Clinical Spectrum. Int J Environ Res Public Health. 2022;19(2):835. Published 2022 Jan 12. doi:10.3390/ijerph19020835
Samara A, Rahn R, Neyman O, Park KY, Samara A, Marshall B, Dougherty J, Hershey T. Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses. Orphanet J Rare Dis. 2019 Dec 3;14(1):279. doi: 10.1186/s13023-019-1260-9.PMID: 31796109
Urano F. Wolfram syndrome: diagnosis, management, and treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6. PMID: 26742931
Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. 2012 Aug;24(4):512-7. doi: 10.1097/MOP.0b013e328354ccdf. PMID: 22790102
Boutzios G, Livadas S, Marinakis E, Opie N, Economou F, Diamanti-Kandarakis E. Endocrine and metabolic aspects of the Wolfram syndrome. Endocrine. 2011 Aug;40(1):10-3. doi: 10.1007/s12020-011-9505-y. PMID: 21725703
Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet. 2011 Feb;79(2):103-17. doi: 10.1111/j.1399-0004.2010.01522.x. PMID: 20738327
Kumar S. Wolfram syndrome: important implications for pediatricians and pediatric endocrinologists. Pediatr Diabetes. 2010 Feb;11(1):28-37. doi: 10.1111/j.1399-5448.2009.00518.x. PMID: 20015125
Ganie MA, Bhat D. Current developments in Wolfram syndrome. J Pediatr Endocrinol Metab. 2009 Jan;22(1):3-10. PMID: 19344068
Ari S, Keklíkçí U, Caça I, Unlü K, Kayabaşi H. Wolfram syndrome: case report and review of the literature. Compr Ther. 2007 Spring;33(1):18-20. PMID: 17984488
Barrett TG. Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered? Pediatr Diabetes. 2007 Oct;8 Suppl 6:15-23. PMID: 17727381
Domenech E, Gomez-Zaera M, Nunes V. Wolfram/DIDMOAD syndrome, a heterogenic and molecularly complex neurodegenerative disease. Pediatr Endocrinol Rev. 2006 Mar;3(3):249-57. PMID: 16639390
Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med. 2004 Aug;82:510-29. PMID: 15175861
Cryns K, Sivakumaran TA, Van den Ouweland JM, et al. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat. 2003 Oct;22:275-87. PMID: 12955714
Minton JA, Rainbow LA, Ricketts C, Barrett TG. Wolfram syndrome. Rev Endocr Metab Disord. 2003 Mar;4(1):53-9. PMID: 12618560
Barrett TG. Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract Res Clin Endocrinol Metab. 2001 Sept;15:325-43. PMID: 11554774
Khanim F, Kirk J, Latif F, Barrett TG. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Hum Mutat. 2001 May;17:357-67. PMID: 11317350
JOURNAL ARTICLES
Licis A, Davis G, Eisenstein SA, Lugar HM, Hershey T. Sleep disturbances in Wolfram syndrome. Orphanet J Rare Dis. 2019 Aug 2;14(1):188. doi: 10.1186/s13023-019-1160-z.PMID: 31375124
Lugar HM, Koller JM, Rutlin J, Eisenstein SA, Neyman O, Narayanan A, Chen L, Shimony JS, Hershey T. Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry. Sci Rep. 2019 Apr 12;9(1):6010. doi: 10.1038/s41598-019-42447-9.PMID: 30979932
Hoekel J, Narayanan A, Rutlin J, Lugar H, Al-Lozi A, Hershey T, Tychsen L. Visual pathway function and structure in Wolfram syndrome: patient age, variation and progression. BMJ Open Ophthalmol. 2018 Jan 18;3(1):e000081. doi: 10.1136/bmjophth-2017-000081. eCollection 2018.PMID: 29657975
Karzon R, Narayanan A, Chen L, Lieu JEC, Hershey T. Longitudinal hearing loss in Wolfram syndrome. Orphanet J Rare Dis. 2018 Jun 27;13(1):102. doi: 10.1186/s13023-018-0852-0.PMID: 29945639
Rove KO, Vricella GJ, Hershey T, et al. Lower Urinary Tract Dysfunction and Associated Pons Volume in Patients with Wolfram Syndrome. J Urol. 2018;200(5):1107-1113. doi:10.1016/j.juro.2018.06.002
Lugar HM, Koller JM, Rutlin J, et al. Neuroimaging evidence of deficient axon myelination in Wolfram syndrome. Sci Rep. 2016;6:21167. Published 2016 Feb 18. doi:10.1038/srep21167
Moosajee M, Yu-Wai-Man P, Rouzier C, Bitner-Glindzicz M, Bowman R. Clinical utility gene card for: Wolfram syndrome. Eur J Hum Genet. 2016 Nov;24(11). doi: 10.1038/ejhg.2016.49. PMID: 27222289; PMCID: PMC5110049
Bischoff AN, Reiersen AM, Buttlaire A, Al-lozi A, Doty T, Marshall BA, Hershey T. Selective cognitive and psychiatric manifestations in Wolfram Syndrome. Orphanet J Rare Dis. 2015 May:10(1):66. PMID: 26025012; PMCID: PMC4450481
Chaussenot A, Rouzier C, Quere M, Plutino M, Ait-El-Mkadem S, Bannwarth S, Barth M, Dollfus H, Charles P, Nicolino M, Chabrol B, Vialettes B, Paquis-Flucklinger V. Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clin Genet. 2015 May;87(5):430-9. doi: 10.1111/cge.12437. PMID: 24890733
Hoekel J, Chisholm SA, Al-Lozi A, Hershey T, Tychsen L, Washington University Wolfram Study Group. Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome. JAAPOS. 2014 Oct;18(5):461-5. PMID: 25439303; PMCID: PMC4476046
Karzon R, Hullar T and the Washington University Wolfram Study Group. Audiologic and vestibular findings in Wolfram syndrome. Ear Hear. 2013 Nov-Dec;34(6):809-12. PMID: 23698626; PMCID: PMC4142763
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. doi: 10.1038/gim.2012.180. PMID: 23429432
Marshall BA, Permutt MA, Paciorkowski AR, et al. Phenotypic characteristics of early Wolfram syndrome. Orphanet J Rare Dis. 2013;8:64. Published 2013 Apr 27. doi:10.1186/1750-1172-8-64
Nguyen C, Foster E, Paciorkowski AR, Viehoever A, Considine C, Bondurant A, Marshall B, Hershey T, the Washington University Wolfram Study Group. Reliability and validity of the Wolfram Unified Rating Scale (WURS). Orphanet J Rare Dis. 2012 Nov;7:89. PMID: 23148655; PMCID: PMC3552944
Pickett K, Duncan RP, Paciorkowski AR, Permutt MA, Marshall B, Hershey T, Earhart GM, the Washington University Wolfram Study Group. Balance impairment in individuals with Wolfram syndrome. Gait Posture. 2012 Jul;36(3):619-24. PMID: 22771154; PMCID: PMC3417287
Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Mkadem SA, Chabrol B, Cano A, Labauge P, Paquis-Flucklinger V. Neurologic features and genotype-phenotype correlation in Wolfram syndrome. Ann Neurol. 2011 Mar;69(3):501-8. doi: 10.1002/ana.22160. PMID: 21446023
Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexle K, Kordonouri O, Salzano G, Meissner T, Burger W, Schober E, Huebner A, Lee-Kirsch MA; Wolfram Syndrome Diabetes Writing Group. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011 Jul;34(7):1503-10. doi: 10.2337/dc10-1937. PMID: 21602428; PMCID: PMC3120194
Zmyslowska A, Borowiec M, Antosik K, Szalecki M, Stefanski A, Iwaniszewska B, Jedrzejczyk M, Pietrzak I, Mlynarski W. Wolfram syndrome in the Polish population: novel mutations and genotype-phenotype correlation. Clin Endocrinol (Oxf). 2011 Nov;75(5):636-41. doi: 10.1111/j.1365-2265.2011.04102.x. PMID: 21564155
Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, Hayashi E, Ishihara H, Oka Y, Permutt MA, Urano F. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010 Mar;120(3):744-55. doi: 10.1172/JCI39678. PMID: 20160352; PMCID: PMC2827948
Domenech E, Kruyer H, Gomez C, et al. First prenatal diagnosis for wolfram syndrome by molecular analysis of the WFS1 gene. Prenat Diagn. 2004 Oct;24:787-89. PMID: 15503287
Smith CJ, Crock PA, King BR, et al. Phenotype-genotype correlations in a series of wolfram syndrome families. Diabetes Care. 2004 Aug;27:2003-09. PMID: 15277431
Lesperance MM, Hall JW 3rd, San Agustin TB et al. Mutations in the wolfram syndrome type 1 gene (WSF1) define a clinical entity of dominant low-frequency sensorineural hearing loss. Arch Otolaryngol Head Neck Surg. 2003 Apr;129:411-20. PMID: 12707187
Al-Till M, Jarrah NS, Ajlouni KM. Ophthalmologic findings in fifteen patients with wolfram syndrome. Eur J Ophthalmol. 2002 Mar-Apr;12:84-88. PMID: 12022290
Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K,
Sobue G, Oka Y, Permutt MA. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8. PMID: 9771706
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.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/