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Wolfram Syndrome

Synonyms of Wolfram Syndrome

  • Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness
  • DIDMOAD

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Wolfram syndrome is the inherited association of childhood-onset diabetes mellitus and progressive-onset optic atrophy. All people affected by Wolfram syndrome have juvenile-onset diabetes mellitus and degeneration of the optic nerve (optic atrophy). In addition, about 70 to 75% of those affected develop diabetes insipidus and about two-thirds develop auditory nerve deafness. Another name for the syndrome is DIDMOAD, which refers to diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

Symptoms

All of those affected by Wolfram syndrome develop insulin-dependent diabetes mellitus. This occurs generally between one month and 16 years of age, with a median age of six years. The starches and sugars (carbohydrates) in the foods we eat are normally processed by digestive juices into glucose that circulates in the blood as a major energy source for body functions. A hormone produced by the pancreas (insulin) regulates the body's use of glucose. In diabetes mellitus, the pancreas does not manufacture the correct amount of insulin needed to metabolize sugar. As a result, the patient needs daily injections of insulin to regulate blood sugar levels. Symptoms of diabetes mellitus may be frequent urination, extreme thirst, constant hunger, weight loss, itching of the skin, changes in vision, slow healing of cuts and bruises, and in children there is a failure to grow and develop normally. (For more information on this disorder choose "diabetes mellitus" as your search term in the Rare Disease Database).

In addition, all of those affected by Wolfram syndrome also develop primary optic atrophy (OA). This is vision failure caused by wasting away of the nerves that conduct visual stimuli to the brain (optic nerve). Optic atrophy typically becomes apparent with loss of color vision and reduced visual acuity at around 10 years, although the range of ages at which this occurs is from one month to 19 years. Over a period of about eigght years, this condition progresses to perception of only light and dark.

Some people (about 70 to 75%) who have Wolfram syndrome also develop diabetes insipidus. This is not related to diabetes or insulin. The only thing it has in common with diabetes are the symptoms of excessive thirst and urination. This condition results in excretion of large quantities of very dilute urine. Excessive thirst is another major symptom of this disorder. Patients tend to drink enormous quantities of fluid, and they urinate very often. Other symptoms may be dehydration, weakness, dryness of the mouth and skin, and constipation that may develop rapidly if the loss of fluid is not continuously replaced. (For more information on this disorder choose "diabetes insipidus" as your search term in the Rare Disease Database).

Deafness is the fourth major symptom of Wolfram syndrome. About 66% of patients with WS will become deaf. The hearing loss may occur at any time, and may be partial or complete. In some patients the hearing loss may be due to a loss of sense perception transmitted by nerves (sensorineural). Other symptoms may be severe hearing loss, loss of sound intensity or pitch, or loss of the ability to hear high tones.

Some (but not all) of the following additional symptoms may be present in patients with Wolfram syndrome:

Urinary tract abnormalities occur in about two-thirds of patients with WS.

Neurological symptoms such as an awkward way of walking (ataxia) and an exaggerated startle response (myoclonus) affect about 60% of those diagnosed with WS.

Megaloblastic anemia is a blood disorder in which there are large, abnormal, immature red blood cells (megaloblasts). The main symptoms of this disorder are diarrhea, vomiting, lack of appetite (anorexia), and weight loss. Lesions in the gastrointestinal tract may cause difficulty with the absorption of food. Enlargement of the liver and spleen may also occur along with yellow discoloration of the skin (jaundice). (For more information on this disorder choose "Megaloblastic Anemia" as your search term in the Rare Disease Database).

Sideroblastic anemia refers to a group of blood disorders that are characterized by an impaired ability of the bone marrow to produce normal red blood cells. Abnormal red blood cells called sideroblasts can be found in the blood. The main symptoms of this disorder are weakness, fatigue and difficulty breathing. (For more information on this disorder choose "Sideroblastic Anemia" as your search tern in the Rare Disease Database).

Neutropenia may also be present in Wolfram syndrome. Neutropenia is a blood disorder in which the bone marrow does not produce white blood cells containing granules called "neutrophils". This disorder often makes the patient more susceptible to infections from fungus and bacteria. Fever, infection and an enlarged spleen may be present. (For more information on this disorder choose "Neutropenia" as your search term in the Rare Disease Database).

Thrombocytopenia is a disorder in which there are an abnormally small number of platelets in the circulating blood. These platelets are the part of the blood that helps in clotting. Major symptoms of thrombocytopenia may be excessive bleeding in the skin or mucous membranes, sudden nosebleeds and easy bruising. (For more information on this disorder choose "Essential Thrombocytopenia" as your search term in the Rare Disease Database).

Diabetic retinopathy is a disorder of the light sensitive tissue of the eye (retina) caused by diabetes. Unchecked it may lead to visual impairment or blindness. (For more information on this disorder choose "Diabetic Retinopathy" as your search term in the Rare Disease Database).

Psychiatric and behavioral problems such as acute depression, psychosis, and impulsive verbal and physical aggression affect over 50% of patients with confirmed WS.

Causes

Wolfram syndrome is caused by mutations in the WFS1 gene and is inherited as an autosomal recessive trait. For some time, it was thought that one form of Wolfram syndrome might be caused by changes in the DNA found in the mitochondria of cells. Now, the syndrome is generally thought to be associated with changes in one or more genes on chromosome 4 (4p16.1).

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4p16.1" refers to band 16.1 on the short arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Diabetes mellitus (DM), as a part of the DIDMOAD set of symptoms, affects children as young as five or six years old, although onset in some cases may not occur until the middle or late teens. Optical atrophy will usually be obvious by age nine or ten but in some cases may be deferred to the middle or late teens. In Wolfram syndrome, both of these symptoms typically will have appeared by 14-15 years of age.

Wolfram syndrome affects males and females in equal numbers.

Related Disorders

Symptoms of the following disorders can occur as part of Wolfram syndrome or be similar to symptoms of Wolfram syndrome:

Leber's hereditary optic atrophy
Leber hereditary optic atrophy (LHOA) is a rare inherited disorder of the eye that is characterized by the relatively slow, painless, progressive loss of vision. This disorder can initially affect one eye or both, but both eyes are usually affected within six months. In most cases, vision loss is permanent. LHOA is a genetic disorder that occurs as the result of a mutation in the mitochondrial DNA that is inherited from the mother or arises as a new sporadic mitochondrial DNA mutation. (For more information on this disorder, choose "Leber's hereditary optic neuropathy" as your search term in the Rare Disease Database.)

Thiamine responsive anemia with diabetes mellitus and deafness
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, sensorineural deafness and diabetes mellitus, among others. Megaloblastic anemia is a blood disorder characterized by anemia, with red blood cells that are larger than normal, usually resulting from a deficiency of folic acid or of vitamin B-12.

Alstrom syndrome, Friedreich ataxia, Kearns-Sayre syndrome, Lawrence-Moon syndrome, and Refsum disease may in some cases present with diabetes mellitus and optic atrophy. (For more information on these disorders, choose the appropriate name as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Treatment
Treatment of Wolfram syndrome is symptomatic and supportive. It will require a multidisciplinary effort to manage the various aspects of this condition. Almost all patients require replacement insulin. Cranial diabetes insipidus responds to intranasal or oral vasopressin. Approximately 25% of patients with hearing impairment benefit from hearing aids.

Genetic counseling may be of benefit for Wolfram syndrome patients and their families.

Investigational Therapies

Information on current clinical 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 with Wolfram syndrome should check the U.S. government clinical trials web site (www.clinicaltrials.gov) by searching separately for trials involving each of the major symptoms: diabetes insipidus, optical atrophy, diabetes mellitus, and deafness.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Wolfram Syndrome

References

TEXTBOOKS
Behrman RE, Kliegman RM, Arvin AM, eds. Nelson Textbook of Pediatrics. 15th ed. W.B. Saunder Company. Philadelphia, PA; 1996:1574.

Wilson JD, Foster DW, eds. Textbook of Endocrinology. 8th ed. W.B. Saunders Company. Philadelphia, PA; 1992:1563.

Sperling MA, ed. Pediatric Endocrinology. 1st ed. W.B. Saunders Company. Philadelphia, PA; 1996:208; 256.

REVIEW ARTICLES
Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med. 2004;82:510-29.

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;22:275-87.

Barrett TG. Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract Res Clin Endocrinol Metab. 2001;15:325-43.

Khanim F, Kirk J, Latif F, et al. WFS1/wolframin mutations, Wolfram syndrome, and associated diseases. Hum Mutat. 2001;17:357-67.

Swift M, Swift RG. Psychiatric disorders and mutations at the Wolfram syndrome locus. Biol Psychiatry. 2000;47:787-93.

JOURNAL ARTICLES
Domenech E, Kruyer H, Gomez C, et al. First prenatal diagnosis for wolfram syndrome by molecular analysis of the WFS1 gene. Prenat Diagn. 2004;24:787-89.

Smith CJ, Crock PA, King BR, et al. Phenotype-genotype correlations in a series of wolfram syndrome families. Diabetes Care. 2004;27:2003-09.

Sequeira A, Kim C, Seguin M, et al. Wolfram syndrome and suicide: evidence for a role of WFS1 in suicidal and impulsive behavior. Am J Med Genet B Neuropsychiatr Genet. 2003;119:108-13.

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;129:411-20.

Al-Till M, Jarrah NS, Ajlouni KM. Ophthalmologic findings in fifteen patients with wolfram syndrome. Eur J Ophthalmol. 2002;12:84-88.

Torres R, Leroy E, Hu X, et al. Mutation screening of the Wolfram syndrome gene in psychiatric patients. Mol Psychiatry. 2001;6:39-43.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Wolfram Syndrome. Entry Number; 222300: Last Edit Date; 2/22/2005.

Patient Information Leaflet: Wolfram Syndrome. Worldwide Society of Wolfram Syndrome Families. 7th February, 2000. 3pp.
www.wolframsyndrome.org

Wolfram Syndrome. National Coalition for Health Professional Education in Genetics. (NCHPEG). nd. 2pp.
www.nchpeg.org/cdrom/wolfram.htm

Wolfram Syndrome. Clinical Molecular Genetics Society (CMGS). 11.2.99. 2pp.
www.ich.ucl.ac.uk/cmgs/wolfram.htm

Koenig J. DI : Stories and Articles: Wolfram Syndrome. The Diabetes Insipidus Foundation. 2003. 2pp.
www.diabetesinsipidus.org/4di_wolfram.htm

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2008/05/28 00:00:00 GMT+0

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