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Wolfram syndrome
Wolfram syndrome is a condition that affects many of the body's systems. The hallmark
features of Wolfram syndrome are high blood sugar levels resulting from a shortage of
the hormone insulin (diabetes mellitus) and progressive vision loss due to degeneration
of the nerves that carry information from the eyes to the brain (optic atrophy). People
with Wolfram syndrome often also have pituitary gland dysfunction that results in the
excretion of excessive amounts of urine (diabetes insipidus), hearing loss caused by
changes in the inner ear (sensorineural deafness), urinary tract problems, reduced
amounts of the sex hormone testosterone in males (hypogonadism), or neurological or
psychiatric disorders.
Diabetes mellitus is typically the first symptom of Wolfram syndrome, usually diagnosed
around age 6. Nearly everyone with Wolfram syndrome who develops diabetes mellitus
requires insulin replacement therapy. Optic atrophy is often the next symptom to
appear, usually around age 11. The first signs of optic atrophy are loss of color vision
and side (peripheral) vision. Over time, the vision problems get worse, and people with
optic atrophy are usually blind within approximately 8 years after signs of optic atrophy
first begin.
In diabetes insipidus, the pituitary gland, which is located at the base of the brain,
does not function normally. This abnormality disrupts the release of a hormone called
vasopressin, which helps control the body's water balance and urine production.
Approximately 70 percent of people with Wolfram syndrome have diabetes insipidus.
Pituitary gland dysfunction can also cause hypogonadism in males. The lack of
testosterone that occurs with hypogonadism affects growth and sexual development.
About 65 percent of people with Wolfram syndrome have sensorineural deafness that
can range in severity from deafness beginning at birth to mild hearing loss beginning
in adolescence that worsens over time. Sixty to 90 percent of people with Wolfram
syndrome have a urinary tract problem. Urinary tract problems include obstruction
of the ducts between the kidneys and bladder (ureters), a large bladder that cannot
empty normally (high-capacity atonal bladder), disrupted urination (bladder sphincter
dyssynergia), and difficulty controlling the flow of urine (incontinence).
About 60 percent of people with Wolfram syndrome develop a neurological or
psychiatric disorder, most commonly problems with balance and coordination (ataxia),
typically beginning in early adulthood. Other neurological problems experienced by
people with Wolfram syndrome include irregular breathing caused by the brain's
inability to control breathing (central apnea), loss of the sense of smell, loss of the
gag reflex, muscle spasms (myoclonus), seizures, reduced sensation in the lower
extremities (peripheral neuropathy), and intellectual impairment. Psychiatric disorders
 associated with Wolfram syndrome include psychosis, episodes of severe depression,
and impulsive and aggressive behavior.
There are two types of Wolfram syndrome with many overlapping features. The
two types are differentiated by their genetic cause. In addition to the usual features
of Wolfram syndrome, individuals with Wolfram syndrome type 2 have stomach
or intestinal ulcers and excessive bleeding after an injury. The tendency to bleed
excessively combined with the ulcers typically leads to abnormal bleeding in the
gastrointestinal system. People with Wolfram syndrome type 2 do not develop diabetes
insipidus.
Wolfram syndrome is often fatal by mid-adulthood due to complications from the many
features of the condition, such as health problems related to diabetes mellitus or
neurological problems.

Frequency
The estimated prevalence of Wolfram syndrome type 1 is 1 in 500,000 people
worldwide. Approximately 200 cases have been described in the scientific literature.
Only a few families from Jordan have been found to have Wolfram syndrome type 2.

Genetic Changes
Mutations in the WFS1 gene cause more than 90 percent of Wolfram syndrome type
1 cases. This gene provides instructions for producing a protein called wolframin that
is thought to regulate the amount of calcium in cells. A proper calcium balance is
important for many different cellular functions, including cell-to-cell communication, the
tensing (contraction) of muscles, and protein processing. The wolframin protein is found
in many different tissues, such as the pancreas, brain, heart, bones, muscles, lung,
liver, and kidneys. Within cells, wolframin is located in the membrane of a cell structure
called the endoplasmic reticulum that is involved in protein production, processing,
and transport. Wolframin's function is important in the pancreas, where the protein is
thought to help process a protein called proinsulin into the mature hormone insulin. This
hormone helps control blood sugar levels.
WFS1 gene mutations lead to the production of a wolframin protein that has reduced
or absent function. As a result, calcium levels within cells are not regulated and the
endoplasmic reticulum does not work correctly. When the endoplasmic reticulum does
not have enough functional wolframin, the cell triggers its own cell death (apoptosis).
The death of cells in the pancreas, specifically cells that make insulin (beta cells),
causes diabetes mellitus in people with Wolfram syndrome. The gradual loss of cells
along the optic nerve eventually leads to blindness in affected individuals. The death of
cells in other body systems likely causes the various signs and symptoms of Wolfram
syndrome type 1.
A certain mutation in the CISD2 gene was found to cause Wolfram syndrome type
2. The CISD2 gene provides instructions for making a protein that is located in the
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 outer membrane of cell structures called mitochondria. Mitochondria are the energy-
producing centers of cells. The exact function of the CISD2 protein is unknown, but it is
thought to help keep mitochondria functioning normally.
The CISD2 gene mutation that causes Wolfram syndrome type 2 results in an
abnormally small, nonfunctional CISD2 protein. As a result, mitochondria are not
properly maintained, and they eventually break down. Since the mitochondria provide
energy to cells, the loss of mitochondria results in decreased energy for cells. Cells
that do not have enough energy to function will eventually die. Cells with high energy
demands such as nerve cells in the brain, eye, or gastrointestinal tract are most
susceptible to cell death due to reduced energy. It is unknown why people with CISD2
gene mutations have ulcers and bleeding problems in addition to the usual Wolfram
syndrome features.
Some people with Wolfram syndrome do not have an identified mutation in either the
WFS1 or CISD2 gene. The cause of the condition in these individuals is unknown.

Inheritance Pattern
When Wolfram syndrome is caused by mutations in the WFS1 gene, it is inherited in an
autosomal recessive pattern, which means both copies of the gene in each cell have
mutations. The parents of an individual with an autosomal recessive condition each
carry one copy of the mutated gene, but they typically do not show signs and symptoms
of the condition. Some studies have shown that people who carry one copy of a WFS1
gene mutation are at increased risk of developing individual features of Wolfram
syndrome or related features, such as type 2 diabetes, hearing loss, or psychiatric
illness. However, other studies have found no increased risk in these individuals.
Wolfram syndrome caused by mutations in the CISD2 gene is also inherited in an
autosomal recessive pattern.

Other Names for This Condition

• diabetes insipidus and mellitus with optic atrophy and deafness
• diabetes insipidus, diabetes mellitus, optic atrophy, and deafness
• DIDMOAD
• DIDMOAD syndrome
• DIDMOADUD

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Diagnosis & Management
Genetic Testing
• Genetic Testing Registry: Diabetes mellitus AND insipidus with optic atrophy AND
deafness
https://www.ncbi.nlm.nih.gov/gtr/conditions/C0043207/
• Genetic Testing Registry: Wolfram syndrome 2
https://www.ncbi.nlm.nih.gov/gtr/conditions/C1858028/

Other Diagnosis and Management Resources

• GeneReview: WFS1-Related Disorders
https://www.ncbi.nlm.nih.gov/books/NBK4144
• Johns Hopkins Medicine: Diabetes Insipidus
http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/
pituitary_center/conditions/diabetes-insipidus.html
• MedlinePlus Encyclopedia: Diabetes Insipidus--Central
https://medlineplus.gov/ency/article/000460.htm
• Washington University, St. Louis: Wolfram Syndrome International Registry
http://wolframsyndrome.dom.wustl.edu/

General Information from MedlinePlus

• Diagnostic Tests
https://medlineplus.gov/diagnostictests.html
• Drug Therapy
https://medlineplus.gov/drugtherapy.html
• Genetic Counseling
https://medlineplus.gov/geneticcounseling.html
• Palliative Care
https://medlineplus.gov/palliativecare.html
• Surgery and Rehabilitation
https://medlineplus.gov/surgeryandrehabilitation.html

Additional Information & Resources

MedlinePlus
• Encyclopedia: Diabetes Insipidus--Central
https://medlineplus.gov/ency/article/000460.htm
• Encyclopedia: Optic Nerve Atrophy
https://medlineplus.gov/ency/article/001622.htm

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• Health Topic: Diabetes
https://medlineplus.gov/diabetes.html
• Health Topic: Diabetes Insipidus
https://medlineplus.gov/diabetesinsipidus.html

Genetic and Rare Diseases Information Center

• Wolfram syndrome
https://rarediseases.info.nih.gov/diseases/7898/wolfram-syndrome

Additional NIH Resources

• National Institute of Diabetes and Digestive and Kidney Diseases: Nerve Disease
and Bladder Control
https://www.niddk.nih.gov/health-information/urologic-diseases/bladder-control-
nerve-disease
• National Institute of Mental Health: Depression
https://www.nimh.nih.gov/health/topics/depression/index.shtml

Educational Resources
• Boston Children's Hospital: Hearing Loss
http://www.childrenshospital.org/conditions-and-treatments/conditions/h/hearing-
loss
• Cleveland Clinic: Diabetes Basics
https://my.clevelandclinic.org/health/articles/diabetes-mellitus-an-overview
• Cleveland Clinic: Optic Atrophy
https://my.clevelandclinic.org/health/articles/optic-atrophy
• CLIMB: Wolfram Syndrome Information Sheet
http://www.climb.org.uk/IMD/Whiskey/WolframSyndrome.pdf
• Disease InfoSearch: Wolfram syndrome
http://www.diseaseinfosearch.org/Wolfram+syndrome/7522
• Disease InfoSearch: Wolfram syndrome 2
http://www.diseaseinfosearch.org/Wolfram+syndrome+2/9479
• Kennedy Krieger Institute: Deafness and Hearing Loss
https://www.kennedykrieger.org/patient-care/diagnoses-disorders/hearing-
impairment
• MalaCards: wolfram syndrome
http://www.malacards.org/card/wolfram_syndrome

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• Merck Manual Consumer Version: Central Diabetes Insipidus
http://www.merckmanuals.com/home/hormonal-and-metabolic-disorders/pituitary-
gland-disorders/central-diabetes-insipidus
• Orphanet: Wolfram syndrome
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=3463
• The EURO-WABB Project (Disease Registry)
http://www.euro-wabb.org/en/diabetes-information-all/wabb/wolfram
• University of Michigan: Kellogg Eye Center
http://www.umkelloggeye.org/conditions-treatments/optic-atrophy

Patient Support and Advocacy Resources

• American Diabetes Association
http://www.diabetes.org/
• American Foundation for the Blind
http://www.afb.org/default.aspx
• CLIMB: Children Living with Inherited Metabolic Diseases
http://www.climb.org.uk/
• Diabetes UK
https://www.diabetes.org.uk/Diabetes-the-basics/Other-types-of-diabetes/
• National Organization for Rare Disorders (NORD)
https://rarediseases.org/rare-diseases/wolfram-syndrome/
• Prevent Blindness America
http://www.preventblindness.org/
• University of Kansas Medical Center Resource List: Diabetes
http://www.kumc.edu/gec/support/diabetes.html
• University of Kansas Medical Center Resource List: Hard of Hearing/Deafness
http://www.kumc.edu/gec/support/hearing.html
• Wolfram Syndrome UK Support Group
http://www.wolframsyndrome.co.uk/

GeneReviews
• WFS1-Related Disorders
https://www.ncbi.nlm.nih.gov/books/NBK4144

ClinicalTrials.gov
• ClinicalTrials.gov
https://clinicaltrials.gov/ct2/results?cond=%22Wolfram+syndrome%22

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 Scientific Articles on PubMed
• PubMed
https://www.ncbi.nlm.nih.gov/pubmed?term=%28Wolfram+Syndrome%5BMAJR
%5D%29+AND+%28Wolfram+syndrome%5BTIAB%5D%29+OR+%28DIDMOAD
%5BTIAB%5D%29+AND+english%5Bla%5D+AND+human%5Bmh%5D+AND+
%22last+1800+days%22%5Bdp%5D

OMIM
• WOLFRAM SYNDROME 1
http://omim.org/entry/222300
• WOLFRAM SYNDROME 2
http://omim.org/entry/604928

Sources for This Summary

• Aloi C, Salina A, Pasquali L, Lugani F, Perri K, Russo C, Tallone R, Ghiggeri GM, Lorini R,
d'Annunzio G. Wolfram syndrome: new mutations, different phenotype. PLoS One. 2012;7(1):
e29150. doi: 10.1371/journal.pone.0029150. Epub 2012 Jan 4.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22238590
Free article on PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251553/
• Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H,
Shiang R. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram
syndrome 2. Am J Hum Genet. 2007 Oct;81(4):673-83. Epub 2007 Aug 20.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17846994
Free article on PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2227919/
• 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. Epub 2010 Dec 28.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21446023
• Kanki T, Klionsky DJ. Mitochondrial abnormalities drive cell death in Wolfram syndrome 2. Cell Res.
2009 Aug;19(8):922-3. doi: 10.1038/cr.2009.94.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19648948
Free article on PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832857/
• Marshall BA, Permutt MA, Paciorkowski AR, Hoekel J, Karzon R, Wasson J, Viehover A, White NH,
Shimony JS, Manwaring L, Austin P, Hullar TE, Hershey T; Washington University Wolfram Study
Group. Phenotypic characteristics of early Wolfram syndrome. Orphanet J Rare Dis. 2013 Apr 27;8:
64. doi: 10.1186/1750-1172-8-64.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23981289
Free article on PubMed Central: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651298/
• 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. Review.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22790102

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 • 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. Epub 2010 Aug 26. Review.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20738327
• 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. Epub 2013 Feb 21.
Citation on PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23429432

Reprinted from Genetics Home Reference:

https://ghr.nlm.nih.gov/condition/wolfram-syndrome

Reviewed: September 2015

Published: June 13, 2017

Lister Hill National Center for Biomedical Communications

U.S. National Library of Medicine
National Institutes of Health
Department of Health & Human Services

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