CD-ROM Today (UK) (Spanish) 15/CDRT.iso/dp/0433/04338.txt

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$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
     [phone]

     American Diabetes Association, National Service Center
     1660 Duke Street
     Alexandria, VA  22314
     [phone]
     [phone]

     Juvenile Diabetes Foundation International
     60 Madison Avenue, 4th Floor
     New York, NY  10010
     [phone]

     National Diabetes Information Clearinghouse
     Box NDIC
     Bethesda, MD  20892
     [phone]

     NIH/National Eye Institute
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

     National Association for the Visually Handicapped
     305 East 24th Street, Room 17-C
     New York, NY  10010
     [phone]

     Vision Foundation, Inc.
     818 Mt. Auburn Street
     Watertown, MA  02172
     [phone]
     [phone] (within Massachusetts

     NIH/National Heart, Lung and Blood Institute
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

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
     [phone]

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.