Wolfram Syndrome

Only 1% of the population in the Unites States carries this recessive genetic characteristic. Carriers do not show all of the common symptoms of Wolfram Syndrome (DIDMOAD), but they are usually more likely to suffer from depression, anxiety or more severe mental illnesses. Only when both parents are carrier of this recessive genetic characteristic the WSF1 gene becomes dominant in their progeny. In this case the probability to inherit this dominant characteristic is 1 out of 4 for each child. The birth of more than one child suffering from this Syndrome in the same genetically disposed family is not uncommon. It’s been studied that in the Unites Kingdom 1 person out of seven hundred suffers from this pathology. An American scientist, Dr. Michael Swift, has stated that the percentage of the population suffering from Wolfram Syndrome is today higher than it’s ever been; however, it is still an uncommon disease. Nowadays it is believed that Wolfram Syndrome comes from a genetic dysfunction concerning cell nucleus and mitochondria. It affects both men and women in the same way.
The typical symptoms are diabetes insipidus, diabetes mellitus, optic atrophy, and partial or total loss of hearing. Other complications can include urinary tract troubles and epileptic crisis. Wolfram Syndrome is also known with the acronym DIDMOAD, coming from the main complications of the pathology. The therapy depends on the symptoms affecting each individual. The treatment with Thiamine vitamine is only able to decrease the need of insulin, and other disorders, like anemia, can regress to normal.

Diabetes mellitus is usually the first symptom to show. However, there isn’t a typical evolution of the disease, and other symptoms can appear before it. With DM the food we eat is transformed in glucose or in blood sugar by digestive fluid in the stomach.
Blood sugars represent the main energetic source used by body cells. In order for them to make use of these sugars the presence of insulin, an hormone naturally-produced by the pancreas, is necessary. When the pancreas does not produce the right ammount of insulin to correctly use sugars within the blood, extra sugars pass through the kidneys, where they are filtered and expelled from the blood circle. An excessive amount of sugar in the blood can cause diabetic acidosis, leading to loss of consciousness, coma and, in some cases, even death. Some of the issues that usually come with diabetes mellitus are: slow injury-healing, frequent need to urinate, loss of weight (or difficulty in gaining weight, or then again excessive increasing of weight in children), constant hunger, itch and/or dry skin.
The treatment for patients affected by Wolfram Syndrome is different from the one utilized for diabetic patients not affected by Wolfram Syndrome. It usually involves the daily administration of subcutaneous injections of insulin, a controlled diet, exercise to burn the extra glucose and assiduous monitoring of blood sugar. The research for the presence of sugar in urine by diagnostic strips has been replaced by autoanalysis of blood sugars.

The patients affected by diabetes insipidus drink a lot, and they empty their bladder very often, with very diluted urine. This contributes in causing a general sense of weakness, dehydration, dry mouth and skin. If the lost fluids are not replaced, the patient can also suffer from constipation.  In people affected by diabetes insipidus, the hypothalamus gland products an abnormal amount of anti-diuretic hormone (vasopressin or ADH), or the produced hormone isn’t correctly detected by the kidneys. Diabetes insipidus has nothing to do with the amount of insulin produced by the pancreas, or with blood sugar. This condition can be also found in patients that have suffered head trauma, independently from Wolfram Syndrome.
DI can be cured with Desmopressin Acetate (DDAVP) in tablets or by inhalation. This drug is also injectable. Desmopressin has been approved  in 1989 by FDA (Food & Drug Administration) for the treatment of diabetes insipidus. Desmopressin ensures an appropriate anti diuretic activity with a few side effects on the vascular system or in the smooth muscle tissue of Wolfram Syndrome patients.

The most evident aspect of Wolfram Syndrome is the dilated pupil, associated to the disease, even at normal light levels ; this is caused by the gradual loss of functionality of the optic nerve that connects the eye to the brain.
This symptom is called optic atrophy. An oculist will notice a disc-shaped cavity, white or gray, sometimes slightly pink. This condition can appear before the age of 12. At the moment there is no treatment. The loss of sight in patients affected by Wolfram Syndrome can also be caused by Diabetic Retinopathy. This is a retina trouble caused by constant hyperglycemia, and it can lead to a severe damage to the retina, or to blindness. Keeping stable blood sugar levels can help avoid this trouble.

Deafness is the main final symptom of Wolfram Syndrome, but it doesn’t always come last . It may just imply the incapacity of hearing high frequency sounds, or it may cause severe loss of hearing. The patients can also suffer from ataxia or dizziness. This happens because the statoacoustic nerve does not send correctly the signals concerning balance from the inner ear to the cerebellum.

Depression in a common symptom  in patients affected by Wolfram Syndrome, in healthy carrier parents, and in parents who suffer from Wolfram Syndrome. It can be more or less severe, and it can imply verbal or physical aggressiveness. This symptom is treatable by using antidepressant drugs.

The patients suffering from Wolfram Syndrome show a progressive deterioration of the body, they become less strong and resistant, even though this doesn’t affect the brain. As the disease gets worse, the patients need more and more hours of sleep. They also become hypersensitive to temperatures higher than 21°C. This is results in  profuse sweating and in the risk of hyperthermia or metabolic shock induced by heat (heat stroke). The constant integration of body fluids and maintaining a cooler environemental temperature helps avoiding this risk.

In some cases the patien can suffer from seizures. They usually start as small crisis (petit mal) and can become real seizures (grand mal). Antiepileptic drugs, like Tegretol, are usually able to keep them under control.

The dilatation of ureteres is another symptom that can affect those who suffer from Wolfram Syndrome. Ureteres are small tubes that connect the kidneys with the bladder and usually they are about as big as a thin cane; when they dilate they can appear stretched and warped as an old sock. It is believed that this is due to the high pressure on the kidneys, caused by the overprodution of urine. The kidneys can also be damaged by the pressure caused by urinary retention.

Depending on which characteristic it has, different kinds of anemy can affect Wolfram Syndrome patients. Those kinds of anemia do not only affect the ones who suffer from this desease, they can come with a wide number of different pathologies, even severe ones.
-Megaloblastic Anemia: red blood cells are big, abnormal and immature (megaloblasts). This can cause vomit, diarrhea, lack of appetite (anorexia) and weight loss.
-Sideroblastic Anemia: anomalies in blood, characterized by the inability of the bone marrow to produce normal red blood cells. This can cause troubles in breathing.
-Neutropenia: it makes the patient more susceptible to fungal and bacterical infections. It causes fever, infections and a swollen spleen.
-Thrombocytopenia: the symptoms can be excessive skin  or mucouse membranes purge, improvise epitaxy and easiness in producing liquids.

Bibliography / footnote:
(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
We thank the didmoad.org website for the text