$Unique_ID{BRK04338} $Pretitle{} $Title{Wolfram Syndrome} $Subject{Wolfram Syndrome Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness DIDMOAD Pernicious Anemia Chronic Granulomatous Disease Myelofibrosis-Osteosclerosis Vitamin B-12 Deficiency} $Volume{} $Log{} Copyright (C) 1990 National Organization for Rare Disorders, Inc. 850: Wolfram Syndrome ** IMPORTANT ** It is possible that the main title of the article (Wolfram Syndrome) is not the name you expected. Please check the SYNONYM listing to find the alternate name and disorder subdivisions covered by this article. Synonyms Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness DIDMOAD Information on the following diseases can be found in the Related Disorders section of this report: Pernicious Anemia Chronic Granulomatous Disease Myelofibrosis-Osteosclerosis Vitamin B-12 Deficiency General Discussion ** REMINDER ** The Information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Wolfram Syndrome is a rare, congenital, multi-system disorder caused by an abnormality of thiamine (a form of vitamin B) metabolism. Diabetes insipidus, diabetes mellitus, vision and hearing defects are the main symptoms associated with this syndrome. Disorders of the urinary tract are also often present. Wolfram Syndrome affects males and females equally and is inherited as a autosomal recessive trait. Symptoms Symptoms of Wolfram Syndrome are: 1. Insulin-Dependent Diabetes Mellitus usually occurs as the first symptom of Wolfram Syndrome. This type of diabetes generally starts during childhood or adolescence. The starches and sugars (carbohydrates) in the foods we eat are normally processed by digestive juices into glucose. The glucose 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). 2. Primary Optic Atrophy is vision failure caused by wasting away of the nerves that conduct visual stimuli to the brain (optic nerve). The part of the eye devoid of light receptors has sharp edges, a saucer shaped cavity and appears white or grayish to an eye doctor. Patients with Wolfram Syndrome may develop primary optic atrophy at any age. 3. Diabetes Insipidus is not related to diabetes or insulin. The only thing it has in common with diabetes is the symptoms of excessive thirst and urination. In Diabetes Insipidus there is an abnormality of anti-diuretic hormone (vasopressin or ADH) in the pituitary gland. The effect of this abnormal hormone on the kidney causes excessive excretion of large quantities of very dilute urine. Excessive thirst is the 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 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). 4. Deafness is the fourth major symptom of Wolfram Syndrome. 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: 5. Dilatation (widening) of the urinary tract. 6. 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). 7. 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). 8. 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). 9. Thrombocytopenia is a disorder in which there is 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). 10. 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). 11. Other symptoms of Wolfram Syndrome may be severe depression, and impulsive verbal and physical aggression. Causes Wolfram Syndrome is inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene from the same trait from each parent. If one 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent, and will be genetically normal. The inherited abnormality of thiamine metabolism is responsible for the symptoms of Wolfram Syndrome. Thiamine is a vitamin of the B complex that is found in tissue and is essential for conversion of carbohydrates to fat, as well as nervous system functioning. When there is an abnormally low amount of thiamine in the body, fat metabolism (which produces and maintains changes in cells and provides the body with energy) does not function properly. Affected Population Wolfram Syndrome affects males and females in equal numbers. The symptoms of this disorder may appear at any age from infancy to early adulthood. Related Disorders Symptoms of the following disorders can occur as part of Wolfram Syndrome or be similar to symptoms of Wolfram Syndrome: Pernicious Anemia (Vitamin B-12 Deficiency Anemia) is a blood disorder resulting from an impaired absorption of vitamin B-12. This vitamin is used in the production of red blood cells. Healthy individuals absorb sufficient amounts of vitamin B-12 in their normal diet with the help of a substance secreted by the stomach called intrinsic factor. Patients with Pernicious Anemia generally lack intrinsic factor and cannot absorb sufficient amounts of vitamin B-12. Symptoms of vitamin B-12 Deficiency usually appear years after absorption of the vitamin ceases because B-12 is stored in large quantities in the liver. (For more information on this disorder choose "Pernicious Anemia" as your search term in the Rare Disease Database). Chronic Granulomatous Disease is a rare blood disorder which affects certain white blood cells called lymphocytes. This disorder is characterized by an inability to resist infection and widespread growth of tumor-like lesions. (For more information on this disorder, choose "Chronic Granulomatosis " as your search term in the Rare Disease Database). Myelofibrosis-Osteosclerosis is a disorder characterized by proliferation of fibrous tissue in the bone marrow causing anemia, weakness and fatigue due to low levels of red blood cells. Severe pain in the bones and joints may occur. (For more information on this disorder, choose "Myelofibrosis" as your search term in the Rare Disease Database). Therapies: Standard Treatment of Wolfram Syndrome is symptomatic and supportive. When treated with thiamine (a vitamin of the B complex), patients with Wolfram Syndrome usually decrease their requirements for insulin, and blood findings such as anemia can return to normal. Diabetes Mellitus may be controlled with a daily routine of insulin injections, controlled diet, exercise to burn off glucose, and frequent testing for blood sugar levels. Urine testing for glucose spillage has been a standard recommendation in past years, but has now been replaced with self blood glucose testing. Self monitoring of blood glucose levels uses a single drop of blood which is obtained with a finger stick, and placed on a chemically treated pad on a plastic strip; the color change of the chemically treated pad is compared to a color chart or read by a battery operated portable meter. Hormone therapy may be beneficial to Wolfram Syndrome patients with Diabetes Insipidus. If a lesion is found it may be eradicated in some cases. Otherwise, effective control of Diabetes Insipidus may be obtained with several prescription medications of the vasopressin hormone (ADH) which are commercially available. These include Lypressin (a synthetic vasopressin as a nasal spray) and Desmopressin Acetate (a longer acting synthetic ADH substitute). Both of these drugs may be inhaled or blown high into the nasal passages with a machine known as an insufflator. In some patients nasal irritation may be a limiting factor with this form of treatment. Two types of drugs have been found useful in reducing excessive urination due to Diabetes Insipidus. These include various diuretics (primarily thiazides), and the ADH releasing drugs (including chlorpropamide, carbamazepine and colfibrate). These drugs reduce urine volume by reducing extra cellular fluid volume while increasing use of the natural vasopressin hormone. These drugs may reduce or eliminate the need for vasopressin in some patients. Hypoglycemia may be a significant adverse reaction to Chlorpropamide therapy. If this occurs, partial or total substitution with Clofibrate or Carbamazepine is sometimes suggested. Because the effects of these three drugs differ from those of the thiazides, the use of one of these agents with a diuretic may show additive effects and be of benefit to some patients. Desmopressin Acetate (DDAVP) nasal spray was approved by the FDA as a treatment for Diabetes Insipidus in 1989. This drug appears to offer enhanced antidiuretic activity with minimal adverse effects on the vascular system or smooth muscles of Diabetes Insipidus patients. This drug is also available in injectable form. To remove excess iron from the body of persons with Sideroblastic Anemia, the drug desferrioxamine (D.F.) is infused under the skin or injected into a muscle, often with good results. A combination of desferrioxamine with ascorbate has been even more effective in removing excess iron from the body in many cases. Some forms of Sideroblastic Anemia may respond well to treatment with pyridoxine, while other types do not respond at all. For patients with Chronic Neutropenia, the infections associated with this disorder are usually managed with antibiotics. Some patients may benefit from glucocorticoids, a group of anti-inflammatory drugs that suppress the immune system. Intravenous immunoglobulin, the protein part of the blood that is rich in antibodies, is usually prescribed to control this disorder. The orphan drug Neupogen was approved by the FDA in 1991 for use in the treatment of Chronic Neutropenia. It is manufactured by: Amgem, Inc. 1840 Dehavilland Drive Thousand Oaks, CA 91320-1789 Thrombocytopenia is treated by transfusions of normal blood platelets to control bleeding. Intravenous immunoglobulin may be given to increase platelet production. In rare cases Thrombocytopenia may necessitate the removal of the spleen. For patients with Diabetic Retinopathy, normalization of glucose levels in diabetic patients can help reverse changes in the small blood vessels of the eye. If normal glucose levels can be maintained, this complication of diabetes can be avoided. Treatment with a laser can reduce the risk of visual loss from Diabetic Retinopathy in many cases. During this treatment, called photocoagulation, powerful beams of light from a laser are aimed at many spots on the diseased retina. In most cases, this treatment can interrupt the disease process and prevent the development of additional retinal abnormalities. Some patients may experience unwanted side effects such as decreased central and side vision. Genetic counseling may be of benefit for Wolfram Syndrome patients and their families. Therapies: Investigational In recent years research supported by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), and other components of the National Institutes of Health, and non-profit agencies (see resources) that fund scientific research on diabetes has yielded new and exciting information on the possible causes and improved management of diabetes and its complications. Scientists have now identified genetic factors that appear to make a person vulnerable to Diabetes- a finding that could lead to methods of prevention of the disorder in genetically susceptible persons. In related studies, the discovery that the insulin-producing beta cells can be infected and destroyed by common viruses could eventually result in the development of a vaccine to prevent diabetes. For patients with Neutropenia, colony-stimulating factor therapy (a type of drug that stimulates the production of blood cells that enhance the function of mature leukocytes) is being tested. Granulocyte macrophage colony stimulating factor (GM-CSF) is a protein derived from bacteria, yeast and mammalian cells. It is being developed by Schering Plough and Sandoz Pharmaceuticals under the brand name Leucomax. Plasmapheresis can be of benefit in some cases of Neutropenia. This procedure is a method for removing unwanted substances (toxins, metabolic substances and plasma parts) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patients plasma is then replaced with other human plasma and the blood is retransfused into the patient. This therapy is still under investigation to analyze long-term effectiveness. More research is needed before plasmapheresis can be recommended for use in all but the most severe cases of Neutropenia. This disease entry is based upon medical information available through June 1991. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on this disorder, please contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 203-746-6518 Diabetes Insipidus & Related Disorders Network RT #2, Box 198 Creston, IA 50801 (515) 782-7838 American Diabetes Association, National Service Center 1660 Duke Street Alexandria, VA 22314 (703) 549-1000 (800) 232-3472 Juvenile Diabetes Foundation International 60 Madison Avenue, 4th Floor New York, NY 10010 (212) 889-7575 National Diabetes Information Clearinghouse Box NDIC Bethesda, MD 20892 (301) 468-2162 NIH/National Eye Institute 9000 Rockville Pike Bethesda, MD 20892 (301) 496-5583 National Association for the Visually Handicapped 305 East 24th Street, Room 17-C New York, NY 10010 (212) 889-3141 Vision Foundation, Inc. 818 Mt. Auburn Street Watertown, MA 02172 (617) 926-4232 (800) 852-3029 (within Massachusetts NIH/National Heart, Lung and Blood Institute 9000 Rockville Pike Bethesda, MD 20892 (301) 496-4236 For genetic information and genetic counseling referrals: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 914-428-7100 Alliance of Genetic Support Groups 35 Wisconsin Circle, Suite 440 Chevy Chase, MD 20815 (800) 336-GENE (301) 652-5553 References MENDELIAN INHERITANCE IN MAN, 9th Ed.: Victor A. McKusick, Editor: Johns Hopkins University Press, 1990. Pp. 1140. THIAMINE-RESPONSIVE ANEMIA IN DIDMOAD SYNDROME. B. Pignatti, et al.; J Pediatr (March, 1989, issue 114(3)). Pp. 405-10. DIDMOAD SYNDROME WITH MEGACYSTIS AND MEGAURETER. P. Chu, et al.; Postgrad Med J (Sept, 1986, issue 62(731)). Pp. 859-63.