Wolfram syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at November 22, 2016
StartDiseasesWolfram syndrome

Wolfram syndrome is a rare, inherited genetic disorder. It is also called DIDMOAD syndrome and is a childhood-onset disease. It causes damage to the optic nerve, deafness, diabetes mellitus, and sometimes diabetes insipidus in affected children along with a spectrum of other related symptoms. Wolfram syndrome affects roughly 1 in 500,000 children. 

Contents

Definition & Facts

Wolfram syndrome is classified as an autosomal recessive genetic disorder, meaning that both parents must carry the gene to pass it on to a child. The syndrome’s other common name, DIDMOAD is a mnemonic for the conditions it causes: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

These conditions do not present precisely the same way in all children, apart from the universal early-onset of optic nerve damage and diabetes mellitus, so treatment can be very complex. All affected children will require daily injections of insulin and vigilant monitoring of blood sugar levels. 

Symptoms & Complaints

Onset of diabetes can occur anywhere between one month to 16 years of age, but most commonly is diagnosed by about six years of age. Symptoms of diabetes are severe thirst and frequent urination as the body tries to expel excess blood sugar.

Parents will also notice excessive hunger, unexplained weight loss, fatigue, failure to thrive in infants, itching in older children and vision changes. They may also notice slow-healing bruises and cuts.

About 75 percent will also develop diabetes insipidus, which causes dehydration and excessive urination of very dilute urine. Diabetes insipidus is not like diabetes. Rather, it is a disorder that causes the pituitary gland to release insufficient amounts of vasopressin. This prevents the kidneys from regulating urine production and can also cause hypogonadism in males, leading to delayed sexual development and low testosterone levels.

Most patients will develop urinary bladder diseases as well, including obstruction of ducts, an atonic bladder that can’t sufficiently empty, difficulty controlling urine flow, and urinary incontinence.

All children will develop primary optic atrophy which causes wasting of optic nerves, loss of color vision, and near-to-full blindness by adulthood. 65 percent of patients will develop deafness or severe hearing loss as well. Other more common symptoms which can occur are blood disorders including anemia, abnormal gait, muscle spasms, and psychiatric and behavioral problems.

Causes

Wolfram syndrome is caused by abnormalities of the WFS1 gene or the CISD2 gene. These present as Wolfram syndrome type 1 and Wolfram syndrome type 2 respectively.

Genetic mutations of WSF1 can result in the production of wolframin protein that does not function normally. This protein regulates the balance of calcium in the boy and plays an important role in the functioning of the pancreas among other vital organs.

Genetic mutations of CISD2 cause the loss of mitochondria in certain cells of the body. Mitochondria are the power plants of cells, so when they are destroyed, the cells die from lack of energy.

The recessive genes involved in this disorder must be inherited from both parents, which is why it is so rare. If both parents carry the gene, a child has a 25 percent chance of inheriting the disorder and a 50 percent chance of becoming a carrier.

Both male and female children have the same risk of developing Wolfram syndrome. Most children who are carriers will not develop any symptoms of the disorder and will go on to lead normal lives. Therefore, genetic testing of both partners is very important to find the hidden gene and assess the risks that a pregnancy may result in a child being born with this syndrome.

Diagnosis & Tests

Genetic testing is performed through a gene sequencing panel. There are several different types of tests available and most will detect other mitochondrial disorders as well. Results take between four and six weeks. The test can be performed via a blood sample, cultured cells, extracted DNA or an oral rinse. Prenatal tests can also be performed to detect the gene in a developing fetus.

Diagnosis in children usually occurs after the onset of diabetes and loss of vision. The disorder is so rare, however, that most physicians will see only one case in their entire career. If a physician suspects the syndrome after observing early onset diabetes and optic nerve atrophy, they will order a genetic panel. It is important to diagnose the syndrome as early as possible so the symptoms can be controlled and the parents can receive the information and support needed to care for their child.

Treatment & Therapy

There is no cure for Wolfram syndrome, but treatment of symptoms will help the child maintain function into adulthood and provide relief from symptoms. The physician will prescribe insulin and regular testing for blood sugar levels. A controlled diet and exercise to control one's blood sugar will help to reduce the need for insulin.

Those who benefit from hearing aids will also receive frequent hearing tests so that hearing aids can be adjusted to increase their effectiveness. Vasopressin delivered by nasal spray, injection or tablets will help to alleviate diabetes insipidus. Muscle spasms can be treated with anticonvulsants. Thiamin and vitamin B1 can help to counteract anemia. A catheter may improve urine elimination.

Unfortunately, there is no known treatment for the associated vision loss. Most children with Wolfram syndrome will live to middle adulthood. Average life expectancy is 30 years, with one patient in the UK living to 49 years. Many researchers are hopeful that experimental treatments may provide a cure for Wolfram syndrome. Clinical trials are available at major universities.

Prevention & Prophylaxis

The only known current prevention for Wolfram syndrome is genetic counseling for at-risk carriers. If both parents carry the gene, then other reproductive options may be considered. Preimplantation genetic diagnosis can help to identify genetic defects in an embryo before it is implanted into the mother, but the procedure is not perfect.

Parents may also consider egg or sperm donation from a person who does not carry the genetic defect. The child will, however, still have a 25 percent risk of carrying the defective gene from the affected parent.

In vitro fertilization (IVF) may also be performed with both healthy sperm and eggs from unrelated donors. Adoption is also considered by many couples who discover that they both carry the gene. A genetic counselor can provide advice and guidance for couples who must make this decision.