What is Werner syndrome?
The Werner syndrome (WRN) gene is transmitted as an autosomal recessive trait. The risk for Werner syndrome is related to the level of consanguinity (close relation) in a population.
In the United States, Werner syndrome occurs in approximately 1 in 200,000 births. However, it is more common in the Japanese population (approximately 1 in 20,000 to 1 in 40,000; based on the frequencies of detectable heterozygous mutations). This is likely the result of a founder mutation in the Japanese population.
The WRN gene is located on chromosome 8 (cytogenetic location: 8p12-p11.2) and codes for a DNA helicase belonging to the RecQ family. This DNA helicase normally plays an important role in cell division, maintenance, and repair of DNA, and the regulation of telomeres. DNA helicases are critical for preserving genome integrity. The molecular role of the WRN gene in Werner syndrome is not yet known. Mutations in the WRN gene (also called RECQL2 or REQ3) lead to the production of an abnormally short, nonfunctional Werner protein. This mutated form of WRN cannot interact with DNA, probably because of defective transport of the WRN protein to the nucleus. It is thought that cells with the mutated form of WRN may divide more slowly or stop dividing earlier than normal, thus causing growth problems. Additionally, without a functional WRN protein, DNA damage may accumulate that could prevent normal cell functions and cause the health problems seen in Werner syndrome. The genome of Werner syndrome cells is highly unstable, with large, spontaneous DNA deletions. Telomere length dynamics are abnormal—that is, as cells divide, telomeres shorten more rapidly than normal. The unstable genome of Werner syndrome cells may play a key role in the pathogenesis of Werner syndrome.
So far, fifty distinct mutations have been discovered since the WRN gene was first cloned in 1996. All these mutations result in the elimination of the nuclear localization signal, thus impeding any functional interactions in the nucleus.
The age of onset of Werner syndrome is variable, but patients develop normally until they reach puberty. One of the first signs of Werner syndrome is the lack of a growth spurt in the early teen years, which results in short stature. After puberty, patients begin to age rapidly, and by age forty, they appear several decades older than they are.
The cardinal signs and symptoms (onset after age ten years) of Werner syndrome include cataracts in both eyes; characteristic skin patterns (tight skin, atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, regional subcutaneous atrophy); characteristic birdlike faces (nasal bridge appears pinched and subcutaneous tissue is diminished); short stature; premature graying and/or thinning of scalp hair; and parental consanguinity (third cousin or closer) or affected sibling.
Additional signs and symptoms include Type II diabetes mellitus; hypogonadism (secondary sexual underdevelopment, diminished fertility, testicular or ovarian atrophy); osteoporosis; osteosclerosis of distal phalanges of fingers and/or toes; soft-tissue calcification; premature atherosclerosis (history of myocardial infarction); neoplasms; abnormal voice (high-pitched, squeaky, or hoarse); and flat feet.
In families in which the disease-causing mutations have been identified in an affected family member, prenatal screening (genetic testing) is available and family members may be tested. Diagnosis is based on the presence of the cardinal signs and symptoms of Werner syndrome.
There is no cure for Werner syndrome. Therapy is based on the treatment of symptoms: aggressive treatment of skin ulcers with standard therapies; control of Type II diabetes mellitus (promising results have been reported with the use of pioglitazone); cholesterol-lowering drugs if the lipid profile is abnormal; surgical treatment of ocular cataracts; treatment of malignancies in a standard fashion (except that radiation therapy is not used, as it may do more harm than good to those with Werner syndrome). Current clinical trials are studying the treatment of symptoms. Preliminary laboratory findings suggest restoring normal WRN function in cells from a patient with Werner syndrome may correct the molecular defects.
Early diagnosis is useful so that screening for cancer and associated diseases such as diabetes can then be performed on a regular basis. Genetic counseling for patients and their family is advised.
Patients usually live to their late forties or early fifties, the most common cause of death being cancer or atherosclerosis.
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"Werner Syndrome." Genetics Home Reference. Natl. Lib. of Medicine, Dec. 2012. Web. 2 Sept. 2014.