Wolfram Syndrome...

a closer look

The frequency of those who carry the ressive genetic trait in the US population is approximately 1% ⁽⁹⁾. Individuals who carry this recessive trait do not show the full range of symptoms of Wolfram Syndrome. They are subject to an increased rate of various forms of mental illness. It is only when parents who both carry this trait recessively have children that the WSF1 gene has a dominant affect. In such families the possibility of inheriting the dominant trait is 1 in 4 for each birth. Multiple incidents within a single genetically predesposed family are not uncommon. In the UK it is estimated that one person in seven hundred thousand ⁽¹⁾ have this disorder. A US scientist, Dr. Michael Swift, estimates that the frequency of affected individuals is much more common than previously reported. Notwithstanding the debate on actual frequency, Wolfram Syndrome (WS)⁽²⁾ is a rare genetic disorder. WS is understood presently to be the result of either nuclear or mitochondria gene dysfunction. This autosomal recessive trait affects males and females with the same frequency. The typical symptoms associated with this condition are: diabetes insipidus, diabetes mellitus, low vision and hearing loss. Other complications may include urinary tract and seizure disorders. WS is also commonly known internationally by an acronym of its major complications: DIDMOAD

Treatment of WS symptoms depends upon the symptoms that are present. When treated with thiamin, vitamin B₆, WS patients usually decrease their need for insulin, and blood findings such as anemia can return to normal. ⁽³⁾

Diabetes Mellitus

Diabetes Mellitus (DM) is typically the symptom which requires medical treatment first in the development of Wolfram Syndrome. There is no stereotypical progression of the disease and other complications may precede the introduction of DM. With DM the foods we eat are processed by digestive fluids in the stomach into glucose or blood sugar. Blood sugar is the major energy source used by the cells of the body. In order for the cells to use blood sugar a hormone which is produced naturally by the pancreas, insulin, is required. When the pancreas does not manufacture the correct amount of insulin needed to use blood sugar the excess blood sugar is passed through the kidneys into the urine and voided from the body. Excessive blood sugar is known as diabetic acidosis and may cause loss of consciousness, coma, and loss of life. The complaints a person with DM may have may include: slow healing, frequent thirst and urination, weight loss, ( or lack of weight gain or growth in children) constant hunger, itching and/or dryness of the skin.

The treatment of DM in WS patients is no different than the management of DM in non Wolfram Syndrome patients. This is typically 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 replaced with self blood glucose testing.

Diabetes Insipidus

Patients with Diabetes Insipidus will drink large quantities of fluid, and they void a diluted urine very often. This contributes to weakness, dehydration, dry mouth and skin. Constipation can result when fluid is not replaced. When patients have Diabetes Insipidus the hypothalamus gland ⁽⁴⁾ produces an abnormal amount of anti diuretic hormone. Diabetes Insipidus has nothing to do with the amount of insulin or blood sugar in the body. This condition has also been known to occur in patients with severe head trauma totally unrelated to WS.

DI is treated by Desmopressin Acetate (DDAVP) nasal spray. This drug is also available in tablet and injectable form. This was approved by the FDA as a treatment for Diabetes Insipidus in 1989. This offers enhanced anti diuretic activity with nominal adverse effects on the vascular system or smooth muscles of DI patients.

Blindness/Low Vision

The most visible aspect of WS is dilated iris of the eye. Even in a bright light the iris will remain wide and react slowly. The gradual loss of the optic nerves that connect the eye to the brain is what causes this to occur. This is known as Optic Atrophy. An eye doctor will see a saucer shaped cavity which looks white or grayish (5⁾. Some reports indicate that the optic nerve appears pale pink. This may occur at any age but usually before age 12. There is no known treatment for this condition at this time.

Loss of vision in WS patients can also be caused by Diabetic Retinopathy. This is a disorder of the light sensitive tissue of the eye (retina) caused by continued high blood sugar levels. It may lead to visual impairment or blindness. Normal blood sugar levels can help reverse changes in the small blood vessels of the eye. If normal blood sugar levels can be maintained, this complication of diabetes can be avoided.

Deafness/hearing impairment

Deafness is final primary symptom of Wolfram Syndrome but not necessarily last to become evident. Hearing loss can range from the loss of high pitch tones to severe loss of sound intensity. There can also be complications with ataxia or dizziness. This may be caused by the failure of the nerves to appropriately transmit information from the ear to the brain.

Depression

Depression is a frequent symptom of WS patients and their parents as well as otherwise unaffected siblings of both the affected patient and the affected patients parents. ^(d) Forms of depression can range from mild to severe depression, and impulsive verbal and physical aggression. This characteristic is treatable by the regular and consistent use of anti-depressant medications.

Chronic Fatigue

Patients with WS have a progressively declining level of physical stamina. It has no relationship with mental acuity. As the condition progresses the WS patient will require progressively greater amounts of sleep. WS patients will also develop a hypersensitivity to environmental temperatures in excess of 70^o
Fahrenheit. This is demonstrated by profuse sweating and potential hyperthermia or heat induced metabolic shock. Fluid replacement and cooler temperature environment is the suggested therapy for heat shock.

Seizure Disorder

In some cases seizures can occur. These usually begin as nominal or petite mal seizures and can progress over time to grand mal seizures. Ant- seizure medications, such as tegretol, are usually successful in managing avoidance of these events.

Dilated ureters

Dilated (widening) ureters can also be present with WS patients (7⁾. The ureters are the small tube connecting the kidneys with the urinary bladder. Normally these would appear about the size of a narrow drinking straw. When dilatation occurs they can appear as though they have been stretched like an old stocking. It is believed that this is caused by excessive pressure placed on the ureters by the excessive production of urine. The kidneys can also be damaged by the pressure of urinary retention.

Anemia

The following forms of anemia are also possible for patients with WS to experience. They are not exclusive to WS and can accompany a large number of serious conditions.

Megaloblastic Anemia
A blood condition characterized by large, abnormal, immature red blood cells (megaloblasts). This can result in diarrhea, vomiting, lack of appetite (anorexia), and weight loss. (8⁾
Sideroblastic Anemia
This is a group of blood abnormalities that are characterized by an impaired ability of the bone marrow to produce normal red blood cells. This may cause difficulty breathing.⁽⁸⁾
Neutropenia.
This condition often makes the WS patient more susceptible to infections from fungus and bacteria. Fever, infection and an enlarged spleen may occur.⁽⁸⁾
Thrombocytopenia.
Symptoms may be excessive bleeding in the skin or mucous membranes, sudden nosebleeds and easy bruising.⁽⁸⁾

Footnotes/References:
⁽¹⁾ Timothy G. Barrett, MD
⁽²⁾ WS is named for the discoverer of the relationship of the symptoms in the condition by Dr. Wolfram a physician, at the Cleveland Clinic in 1938.
⁽³⁾THIAMINE-RESPONSIVE ANEMIA IN DIDMOAD SYNDROME. B. Pignatti, et al.; J Pediatr (March, 1989, issue 114(3)). Pp. 405-10.
⁽⁴⁾ Some papers report that this hormone is produced by the pituitary gland.
⁽⁵⁾ NORD
⁽⁶⁾ Ronnie Goreman Swift MD
⁽⁷⁾DIDMOAD SYNDROME WITH MEGACYSTIS AND MEGAURETER. P. Chu, et al.; Postgrad Med J (Sept, 1986, issue 62(731)). Pp. 859-63.
⁽⁸⁾ For more information on this condition please refer to the NORD Website: http://www.rarediseases.org
References
⁽⁹⁾ Dr. Alan Permutt,Professor of Medicine,Professor of Cell Biology and Physiology
Washington University School of Medicine