Wolfram syndrome is a rare but serious genetic disorder that progressively destroys the nervous system and leads to other abnormalities in the body. It occurs when a genetic mutation interferes with the production of wolframin, a protein required for nerve cells to function normally.

Wolfram syndrome is also called DIDMOAD, an acronym for its primary symptoms:

• Diabetes insipidus (a hormonal disorder causing excess urination)
  
  
• Onset of insulin-dependent diabetes mellitus (an impaired ability to use glucose) before age 15
  
  
• Optic atrophy (nerve damage causing vision problems)
  
  
• Deafness

Urinary tract, respiratory and seizure disorders and psychiatric problems, such as depression, are some of the secondary symptoms that often complicate the syndrome and its treatment. These symptoms are usually first detected in childhood beginning with insulin-dependent diabetes mellitus, although the sequence of symptoms varies among individuals. Eventually, the symptoms can become life-threatening.

Physicians first look for other possible explanations for symptoms. However, Wolfram syndrome is suggested if insulin-dependent diabetes mellitus and optic nerve damage leading to blindness occur by the age of 15. Genetic testing can confirm the presence of the gene mutation but not the condition.

There is no known prevention or cure for Wolfram syndrome. Treatment revolves around relieving symptoms and may include:

• Insulin therapy for diabetes mellitus
• Antidiuretic medication for diabetes insipidus
• Antidepressants for depression
• Anticonvulsant medication for seizures

The gene for Wolfram syndrome is recessive, which means a child with this disorder received the gene from each parent. The parents of patients have a 25 percent chance of having another child with Wolfram syndrome with each consecutive pregnancy. Wolfram syndrome affects males and females equally.

Wolfram syndrome is a rare genetic disease that progressively causes the nervous system to break down. Several systems in the body are affected, causing a variety of symptoms that begin in childhood and develop through adolescence and early adulthood. This condition leads to premature death.

Wolfram syndrome is also known as DIDMOAD, an acronym for the primary components of this condition:

• Diabetes insipidus (DI, also called water diabetes). A disease in which excessive urination (polyuria) and excessive thirst (polydipsia) result from the pituitary gland’s inadequate release of the anti-diuretic hormone vasopressin. DI is not reported in all cases of Wolfram syndrome.
  
  
• Diabetes mellitus (DM, sometimes called sugar diabetes). For Wolfram syndrome patients, DM is a rare form of insulin-dependent diabetes that starts in childhood and has an unclear origin. Diabetes is a disorder of the body’s ability to use glucose (blood sugar). Wolfram syndrome is generally categorized separately from type 1 and type 2 diabetes, although it features two hallmarks of type 1: destruction of the pancreas’ insulin-producing beta cells and need for insulin by injection or other means.
  
  

  

• Optic atrophy (OA). Damage to both optic nerves that impairs vision and eventually causes blindness.
  
  
• Deafness (D). Partial or complete loss of hearing, affecting the perception of tone, pitch, intensity or frequency. Deafness is not reported in all cases of Wolfram syndrome.

Urinary tract and seizure disorders, and behavioral and psychiatric episodes sometimes leading to hospitalization, are common additional complications of the disease.

Wolfram syndrome is usually caused by a mutation or defect in the DNA of a gene called WFS1.  It is an autosomal gene, meaning that it affects males and females equally and is not related to sex traits. The genetic defect causes changes in the chemical structure of the protein wolframin, making it inactive. Nerve cells require wolframin to function. A lack of wolframin eventually damages the nervous system.

The gene is recessive, meaning both parents must contribute the gene for a child to develop Wolfram syndrome. About 1 percent of the population carries the recessive genetic trait for Wolfram syndrome, according to the National Center for Biotechnology Information. This means that the gene was inherited from only one parent and that the full range of symptoms is not present.

Studies have shown that carriers of the gene tend to develop diabetes mellitus and mental disorders at a higher rate than the general population. However, they do not develop the other conditions associated with Wolfram syndrome.

Wolfram syndrome is genetically mixed. This means that several forms of the syndrome exist with different genetic causes.

The most common form of Wolfram syndrome affects a gene called WFS1. The WFS1 genetic defect occurs within the DNA of a chromosome.

Another form of Wolfram syndrome occurs within a different type of DNA – that of the mitochondria (the part of a cell that uses glucose to create energy).

Mitochondria and chromosomes have different DNA structures. Defects in mitochondrial DNA inherited from the mother are sometimes found in Wolfram syndrome patients. However, the relationship between mitochondrial and chromosomal defects is unknown. Studies are being conducted to identify differences in the mechanics of these diseases based on their origin and to identify treatment and prevention for each.

Another form of Wolfram syndrome is mapped to the WFS1 gene on a different chromosome. This form usually does not involve diabetes insipidus and includes brainstem atrophy (brain cell damage) and eventual central respiratory failure.

A defect in a similar gene (WFS2) can cause symptoms that include severe upper gastrointestinal bleeding and ulceration, and an absence of diabetes insipidus. However, this is an uncommon form of Wolfram syndrome.

Wolfram syndrome is caused by an inherited genetic defect or mutation to DNA, most commonly the WFS1 gene. More than 100 such mutations have been identified to date.

The defect affects the production and function of wolframin, a protein found and used in the cells of the nervous system affecting the heart, brain, lungs, kidneys, bladder and pancreas. People with Wolfram syndrome are unable to use and produce this protein normally, which is believed to damage the nervous system and cause problems throughout the body.

Wolfram syndrome is inherited as a recessive genetic defect. The patient must inherit the recessive gene from both parents to develop Wolfram syndrome, and the parents have a 25 percent chance of having another child with Wolfram syndrome with each consecutive pregnancy. That means each child has one chance in four of inheriting Wolfram syndrome.

It is not uncommon for a family to have more than one member diagnosed with Wolfram syndrome. Also, some cases of consanguineous (related by blood) parents have been reported, which also increase the chances of inheritance.

DIDMOAD is an acronym for the primary and most prominent symptoms of Wolfram syndrome:

• Diabetes insipidus (DI). Inability to concentrate urine because of insufficient production of vasopressin (antidiuretic hormone). Diabetes insipidus is not related to diabetes mellitus (impaired ability to use glucose for energy). It occurs in a majority of Wolfram syndrome patients. Symptoms of diabetes insipidus include:
  
  
• • Frequent thirst  (polydipsia)
  • Frequent urination of diluted urine (polyuria)
  • Dehydration
  • Fatigue
  • Dry mouth and skin
    
    
• Diabetes mellitus (DM). An inability to convert glucose (blood sugar) into energy the body can use. Insulin-dependent diabetes that starts in childhood is usually the first component of Wolfram syndrome requiring medical treatment. This form of diabetes is not typical, and the exact developmental cause is unclear. Symptoms of diabetes mellitus include:
  
  
• • Slow healing of wounds
  • Frequent thirst
  • Frequent and large volume of urination
  • Unexplained weight loss
  • Weight gain or growth less than appropriate for patient’s age
  • Persistent hunger (polyphagia)
  • Dry and itchy skin (pruritus)
    
    
• Optic atrophy (OA). Nerve damage in the eyes. The most common sign of optic nerve damage is a dilated (enlarged) iris – the colored part of the eye that regulates the amount of light entering the eye – and a contracted (narrowed) pupil. The iris typically contracts when exposed to light and the pupil (opening in the iris) dilates. Atrophy of the optic nerve interferes with the communication between the iris and the brain. This results in less of a change in pupil size when exposed to light. This may cause difficulty seeing or related problems, such as a general “graying” of vision.

Optic atrophy is diagnosed with an eye examination when the physician sees a white or grayish cavity in the pupil. In Wolfram syndrome, this component generally occurs before age 12 along with diabetes mellitus. Optic atrophy most often worsens, and the patient is rendered blind within eight years of diagnosis.

• Deafness (D). Loss of hearing with a weakening of sound frequency, intensity, tone and pitch. It may be caused by damage to the otic nerve connecting each ear to the brain. Two-thirds of people with Wolfram syndrome experience loss of hearing, although this is usually not as severe as damage to the two optic nerves.

Other signs and symptoms that are sometimes present in Wolfram syndrome include:

• Chronic fatigue. Persistent low levels of energy. Decline in physical stamina leads to a need for increased amounts of sleep.
  
  
• Loss of vision due to diabetic retinopathy. Disorder of the retina (light-sensitive tissue in the back of the eye that projects images as nerve impulses to the brain) due to diabetes complications. This is an additional cause of vision loss that may lead to blindness. High blood glucose levels (hyperglycemia) can damage the retina.
  
  
• Seizure disorder. Sudden convulsive attacks. Seizures may begin as petite mal (without convulsions) and progress to grand mal (with convulsions and loss of consciousness). Not all Wolfram syndrome patients experience seizures.
  
  
• Urinary tract disorders. Damage to the kidneys and/or the urinary bladder will lead to urinary tract disorders. Two-thirds of Wolfram patients suffer from frequent urination, frequent kidney and bladder infections, incontinence (loss of bladder control) and bed-wetting due to dilated ureters (tubes connecting the kidneys with the urinary bladder). The excessive production of urine stretches the ureters, causing incontinence. Kidney damage may occur because of urinary retention.
  
  
• Blood disorders, such as anemia. Symptoms may include:
  
  
• • Diarrhea
  • Weight loss
  • Vomiting
  • Lack of appetite
  • Increased likelihood of fungal and bacterial infections
  • Nosebleeds
  • Easy bruising
    
    
• Color blindness. The inability to detect and identify colors accurately. Ordinarily a male sex trait that is rare in girls, color blindness has a high rate of occurrence in female and male Wolfram syndrome patients.
  
  
• Emotional, behavioral and psychiatric disorders and mental retardation. More than half of patients with Wolfram syndrome have severe episodes of depression, psychosis and organic brain disorders. A high incidence of depression and other psychiatric disorders occurs in the parents and siblings of Wolfram patients because of the existence of at least one recessive gene for the disease. Impulsive and aggressive behaviors may require psychiatric hospitalization, and 25 percent of Wolfram patients attempt suicide, according to the National Human Genome Research Institute.
  
  
• Delayed or incomplete sexual development. The gonads (ovaries and testicles) can be underdeveloped, causing a delay in puberty.  For example, females may not menstruate until much later than normal: between 16 and 19 years of age. Not all Wolfram syndrome patients experience this underdevelopment (hypogonadism).
  
  
• Digestive disorders. Recurring constipation or diarrhea are more common in Wolfram patients than the general public. They may be related to dysfunctions in the autonomic nerves that control digestive functions (autonomic neuropathyautonomic neuropathy).
  
  
• Heat stroke. Profuse sweating, dehydration and hyperthermia (high body temperature). Hypersensitivity to temperatures greater than 70 degrees Fahrenheit or 21 degrees Celsius can lead to heat stroke. Autonomic neuropathy may be a cause.
  
  
• Neurological problems. Damage to the nervous system causing a variety of malfunctions and disorders. Symptoms include ataxia (defective voluntary muscle movements), loss of balance, sudden muscle jerks, abnormal eye movements, breathing problems and dizziness.

No tests exist to detect Wolfram syndrome. However, genetic testing will confirm the presence of the Wolfram gene. Wolfram syndrome involves a number of conditions in a patient. Conditions vary among patients and may appear at different stages of the disease. Because there are many variables in the presentation of symptoms, diagnosis of Wolfram syndrome may be difficult.   

In diagnosing the syndrome, insulin-dependent diabetes mellitus and optical atrophy symptoms must occur by 15 years of age. If these two symptoms are present, Wolfram syndrome is presumed to exist.

After age 15, it is unlikely that the presence of diabetes mellitus and damage to the optic nerves are related to Wolfram syndrome. Glaucoma is one example of a condition in which a person with diabetes may experience dysfunction of one or both optic nerves.

There is no known cure for Wolfram syndrome. However, research is being conducted to detect the mechanisms that cause the syndrome. Symptoms are treated as they appear. Common complications and their treatments:

• Insulin is prescribed as necessary.

• Management of diabetes mellitus also includes glucose monitoring,  diet and exercise.
  
  
• Thiamin and vitamin B6 therapy can alleviate the symptoms of anemia and even decrease insulin dosages in some cases.
  
  
• There is no known treatment for optic atrophy. However, maintenance of normal glucose levels can help control diabetic retinopathy. Retinopathy may require treatments such as photocoagulation or vitrectomy.
  
  

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• Hormone therapy such as vasopressin in nasal spray, tablet or injection form may relieve the patient of frequent urination (polyuria) caused by  diabetes insipidus. Other possible options include diuretics, anti-inflammatory drugs or low-sodium diet.
  
  
• Antidepressants and psychotherapy may be used to treat depression.
  
  
• Fluid replacement and cool temperatures are maintained to prevent and remedy dehydration and heat stroke.
  
  
• Anticonvulsant medication is administered to avoid seizures.
  
  
• A hearing aid may be used for hearing loss.
  
  
• A tube or catheter (device used to pass urine from the bladder) may be used several times a day to eliminate urine from the bladder to prevent urine backup and incontinence (loss of bladder control).

There are no prevention methods available. The disease is degenerative and produces symptoms progressively. Nor is there a genetic test available to detect the defective genes in unborn children.

Preparing questions in advance can help patients or parents have more meaningful discussions with their physicians regarding their conditions. Parents may wish to ask their child’s doctor the following questions about Wolfram syndrome:

1. Could my child’s conditions be due to Wolfram syndrome?
   
   
2. What symptoms or signs should we watch for?
   
   
3. Should genetic testing be performed if Wolfram syndrome is suspected?
   
   
4. How is Wolfram syndrome inherited? Can our family members be tested? Should they be?
   
   
5. What are our treatment options for Wolfram syndrome?
   
   
6. What method of insulin administration do you recommend? What is the dosage?
   
   
7. How will you treat the diabetes insipidus?
   
   
8. What complications of Wolfram syndrome should we expect?
   
   
9. What help is available to us for vision loss, hearing loss and emotional problems?
   
   
10. What is my child’s prognosis?
    
    
11. Is there any recent progress on prevention or a cure?