Wolfram syndrome

Other Names: WFS; Diabetes insipidus and mellitus with optic atrophy and deafness; DIDMOAD; DIDMOAD syndrome Wolfram syndrome is a condition that affects many of the body's systems. The hallmark features of Wolfram syndrome are high blood sugar levels resulting from a shortage of the hormone insulin (diabetes mellitus) and progressive vision loss due to degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). People with Wolfram syndrome often also have pituitary gland dysfunction that results in the excretion of excessive amounts of urine (diabetes insipidus), hearing loss caused by changes in the inner ear (sensorineural deafness), urinary tract problems, reduced amounts of the sex hormone testosterone in males (hypogonadism), or neurological or psychiatric disorders.

Wolfram syndrome is often fatal by mid-adulthood due to complications from the many features of the condition, such as health problems related to diabetes mellitus or neurological problems.

The estimated prevalence of Wolfram syndrome type 1 is 1 in 500,000 people worldwide. Approximately 200 cases have been described in the scientific literature. Only a few families from Jordan have been found to have Wolfram syndrome type 2.

Types

There are two types of Wolfram syndrome with many overlapping features. The two types are differentiated by their genetic cause. In addition to the usual features of Wolfram syndrome, individuals with Wolfram syndrome type 2 have stomach or intestinal ulcers and excessive bleeding after an injury. The tendency to bleed excessively combined with the ulcers typically leads to abnormal bleeding in the gastrointestinal system. People with Wolfram syndrome type 2 do not develop diabetes insipidus.

Epidemiology

The estimated prevalence of Wolfram syndrome type 1 is 1 in 500,000 people worldwide. Approximately 200 cases have been described in the scientific literature. Only a few families from Jordan have been found to have Wolfram syndrome type 2.

Cause

Mutations in the WFS1 gene cause more than 90 percent of Wolfram syndrome type 1 cases. This gene provides instructions for producing a protein called wolframin that is thought to regulate the amount of calcium in cells. A proper calcium balance is important for many different cellular functions, including cell-to-cell communication, the tensing (contraction) of muscles, and protein processing. The wolframin protein is found in many different tissues, such as the pancreas, brain, heart, bones, muscles, lung, liver, and kidneys. Within cells, wolframin is located in the membrane of a cell structure called the endoplasmic reticulum that is involved in protein production, processing, and transport. Wolframin's function is important in the pancreas, where the protein is thought to help process a protein called proinsulin into the mature hormone insulin. This hormone helps control blood sugar levels.

WFS1 gene mutations lead to the production of a wolframin protein that has reduced or absent function. As a result, calcium levels within cells are not regulated and the endoplasmic reticulum does not work correctly. When the endoplasmic reticulum does not have enough functional wolframin, the cell triggers its own cell death (apoptosis). The death of cells in the pancreas, specifically cells that make insulin (beta cells), causes diabetes mellitus in people with Wolfram syndrome. The gradual loss of cells along the optic nerve eventually leads to blindness in affected individuals. The death of cells in other body systems likely causes the various signs and symptoms of Wolfram syndrome type 1.

A certain mutation in the CISD2 gene was found to cause Wolfram syndrome type 2. The CISD2 gene provides instructions for making a protein that is located in the outer membrane of cell structures called mitochondria. Mitochondria are the energy-producing centers of cells. The exact function of the CISD2 protein is unknown, but it is thought to help keep mitochondria functioning normally.

The CISD2 gene mutation that causes Wolfram syndrome type 2 results in an abnormally small, nonfunctional CISD2 protein. As a result, mitochondria are not properly maintained, and they eventually break down. Since the mitochondria provide energy to cells, the loss of mitochondria results in decreased energy for cells. Cells that do not have enough energy to function will eventually die. Cells with high energy demands such as nerve cells in the brain, eye, or gastrointestinal tract are most susceptible to cell death due to reduced energy. It is unknown why people with CISD2 gene mutations have ulcers and bleeding problems in addition to the usual Wolfram syndrome features.

Some people with Wolfram syndrome do not have an identified mutation in either the WFS1 or CISD2 gene. The cause of the condition in these individuals is unknown.

Inheritance

Autosomal recessive inheritance, a 25% chance

When Wolfram syndrome is caused by mutations in the WFS1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Some studies have shown that people who carry one copy of a WFS1 gene mutation are at increased risk of developing individual features of Wolfram syndrome or related features, such as type 2 diabetes, hearing loss, or psychiatric illness. However, other studies have found no increased risk in these individuals.

Wolfram syndrome caused by mutations in the CISD2 gene is also inherited in an autosomal recessive pattern.

Signs and symptoms

The two types of Wolfram syndrome (type 1 and type 2) have many overlapping features. Wolfram syndrome type 1, which is also known by the acronym DIDMOAD, is characterized by diabetes insipidus (DI), childhood-onset diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA), and deafness (D).About 65% of affected people will develop all four of these symptoms, while others will only have some of the associated health problems.

Other signs and symptoms of Wolfram syndrome type 1 may include:

• Urinary tract abnormalities
• Ataxia (problems with coordination and balance)
• Loss of sense of smell
• Loss of gag reflex
• Myoclonus (muscle spasms)
• Decreased sensation in some parts of the body (peripheral neuropathy)
• Seizures
• Depression
• Impulsive and/or aggressive behavior
• Psychosis
• Gastrointestinal problems
• Intellectual disability
• Irregular breathing due to lack of brain's inability to control breathing (central apnea) and central respiratory failure
• Hypogonadism in males (reduced amounts of the sex hormone testosterone)

In addition to the signs and symptoms found in Wolfram syndrome type 1, people with Wolfram syndrome type 2 may also have stomach and/or intestinal ulcers; and a tendency to bleed excessively after injuries.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Polydipsia(Extreme thirst)

• 30%-79% of people have these symptoms
• Abnormality of mesentery morphology
• Ataxia
• Dysarthria(Difficulty articulating speech)
• Dysuria(Painful or difficult urination)
• Feeding difficulties in infancy
• Nephropathy
• Recurrent urinary tract infections(Frequent urinary tract infections)

5%-29% of people have these symptoms

• Abnormal autonomic nervous system physiology
• Anemia(Low number of red blood cells or hemoglobin)
• Cardiomyopathy(Disease of the heart muscle)
• Central apnea
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Constipation
• Delayed puberty(Delayed pubertal development)
• Dementia(Dementia, progressive)
• Developmental regression(Loss of developmental milestones)
• Gastric ulcer(Stomach ulcer)
• Gastrointestinal hemorrhage(Gastrointestinal bleeding)
• Glaucoma
• Hallucinations(Hallucination)
• Joint stiffness(Stiff joint)
• Malabsorption(Intestinal malabsorption)
• Male hypogonadism(Decreased function of male gonad)
• Myopathy(Muscle tissue disease)
• Ophthalmoplegia(Eye muscle paralysis)
• Peripheral neuropathy
• Respiratory insufficiency(Respiratory impairment)
• Sleep disturbance(Difficulty sleeping)

Diagnosis

A diagnosis of Wolfram syndrome is based on the presence of characteristic signs and symptoms. The identification of a change (mutation) in the WFS1 gene or CISD2 gene confirms the diagnosis. The following are the most important features that help with the diagnosis:

• Juvenile-onset (age <16 years) diabetes mellitus
• Juvenile-onset optic atrophy (age <16 years)
• Autosomal recessive inheritance
• Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known.

Treatment

Recommendations (based on detailed clinical guidelines for Wolfram syndrome) include routine management by multidisciplinary specialists for the following: insulin-dependent DM; OA; hearing impairment; mobility and activities of daily living; dysarthria; dysphagia; endocrine disorders; developmental delay/intellectual disability; neurogenic bladder; and psychiatric/behavioral issues.

Prognosis

The long-term outlook (prognosis) for people with Wolfram syndrome varies depending on the signs and symptoms present in each person. All the features that give Wolfram syndrome the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) are observed in 65% of people, while others only have some of the associated health problems. Most affected people develop diabetes mellitus and optic atrophy before age 15 years. Hearing loss is present in 64% of affected people by age 20 years and up to 72% will eventually develop diabetes insipidus. Wolfram syndrome may also be associated with a variety of other symptoms that can affect almost every part of the body. Wolfram syndrome is often fatal by mid-adulthood (average lifespan 30 to 40 years) due to complications from the various health problems associated with the condition.

NIH genetic and rare disease info

• NIH info on Wolfram syndrome

Wolfram syndrome is a rare disease.

Wolfram syndrome Resources
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