1443
A rare genetic condition that produces rapid aging in children.
Werner syndrome (WS) or Werner’s syndrome, also known as progeria is a rare, autosomal recessive disorder which is characterized by the appearance of premature aging.
It has a global incidence rate of less than 1 in 100,000 live births.
The incidence in Japan and Sardinia is higher, affecting 1 in 20,000–40,000 and 1 in 50,000, respectively.
Affected individuals typically grow and develop normally until puberty.
Symptoms strongly resemble normal human aging, but occur in young children.
The mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed.
The youngest person diagnosed was six years old.
The median and mean ages of death are 47–48 and 54 years, respectively.
The main causes of death are cardiovascular disease and cancer.
It usually is not passed down through families.
In more than 90% of cases a mutation of a cytosine with thymine at position 1824 in LMNA, which encodes lamin A.
Rarely seen in more than one child in a family.
Symptoms:
Growth failure during the first year of life
Narrow, shrunken or wrinkled face
Baldness
Severe failure to thrive
Loss of eyebrows and eyelashes, and scalp hair
Short stature
Macrocephaly
Open fontanelle
Micrognathia
Dry, scaly, thin skin
Limited range of motion
Joint contracture, skeletal dysplasia
Teeth – delayed or absent
Patients exhibit growth retardation, short stature, premature graying, alopecia. wrinkling prematurely aged faces with beaked noses, skin atrophy with scleroderma-like lesions, lipodystrophy, abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli.
Other symptoms include voice weakness, hoarseness, high-pitch, atrophy of gonads leading to reduced fertility, bilateral cataracts, premature arteriosclerosis, calcinosis, atherosclerosis, type 2 diabetes, osteoporosis, telangiectasia, and malignancies.
Laboratory tests may show insulin resistance
Skin changes similar to that seen in scleroderma
Loss of subcutaneous fat, and vascular smooth muscle cells
Generally normal cholesterol and triglyceride levels
Cardiac stress testing may reveal signs of early atherosclerosis of blood vessels.
Genetic testing reveals changes in the gene (LMNA) that causes progeria.
A genetic condition that occurs as a new mutation, and is rarely inherited, as carriers usually do not live to reproduce.
No specific treatment for progeria, but aspirin and statin medications may be used to protect against a heart attack or stroke.
Causes early death with average lifespan 13 years.
The cause of death is usually related to the heart or a stroke.
The prevalence of rare cancers are increased in individuals with Werner syndrome.
Gene transcription changes found in WS cells are strikingly similar to those observed in normal aging.
The mutation in the WRN gene that causes Werner syndrome is autosomal and recessive.
Rapid premature aging begins in young adulthood, usually in their early twenties.
There is no cure.
Diagnosis is based on six cardinal symptoms: premature graying of the hair or hair loss, presence of bilateral cataracts, atrophied or tight skin, soft tissue calcification, sharp facial features, and an abnormal, high-pitched voice.
Short-stature is due to absence of the adolescent growth spurt.
Patients display decreased fertility.
The most common symptom of the six is premature graying and loss of hair.
Loss of hair is the earliest observed symptom, with hair loss occurring first on the scalp and the eyebrows.
Werner syndrome patients often have skin that appears shiny and tight, and may also be thin or hardened, and is due to atrophy of the subcutaneous tissue and dermal fibrosis.
These characteristic facial features may be more apparent due to these skin conditions.
Skin conditions include ulcers are very difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.
WS cataracts are distinctly different from those of normal aging, and are associated with problems in the lens posterior cortex and subcapsular regions.
These cataracts are generally treatable with cataract surgery.
Symptoms become apparent in the late teens and early twenties and continue to progress.
Most patients live to about fifty years of age, with most common causes of death associated with atherosclerosis and cancer.
Atherosclerosis, the thickening of artery walls due to cholesterol buildup, is one common complication.
While normal atherosclerosis generally involves the major arteries, smaller arterioles are more likely to be affected.
Brain atrophy is present in 40% of patients.
Osteoporosis is a common finding.
In contrast with the normal population, the rate of osteoporosis is especially high for male patients.
Diabetes mellitus is another common accompaniment.
Skin ulcers occur in about 75% of patients, and often require amputation.
Patients are also at an increased risk of cancer, especially malignant melanoma.
Soft-tissue sarcomas are the most common cancer types.
Other types of skin cancer, thyroid and liver cancers, myelodysplastic syndrome, and malignant fibrous histiocytoma are also prevalent among.
Mutations in the WRN gene, especially single-nucleotide polymorphisms (SNPs), are associated with many of the cancers and other associated diseases.
WRN SNPs correlate with cancers such as sarcomas and non-Hodgkin lymphomas, diabetes and cardiovascular problems.
Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, WRN, the only gene currently attributed to cause Werner syndrome.
WRN, which lies on chromosome 8 in humans, encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases.
RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled stranded breaks, which are a form of DNA damage that results in a break of both strands of DNA.
Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of Werner syndrome.
Normally functioning WRN gene and its associated protein (WRNp) are important for maintaining genome stability.
WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication.
WRNp has an important role in responding to replication malfunctions, particularly double-stranded breaks, and stalled replication machinery.
WRNp may reactivate replication by preventing unwanted recombination processes from occurring or by promoting recombination, depending on the type of DNA damage.
WRNp physically interacts with or binds to several other proteins that are involved in processing DNA.
WRNp also physically interacts with p53, a tumor suppressor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the WRNp.
WRN protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.
WRN protein plays a direct role in the repair of methylation induced DNA damage.
Mutations which cause Werner syndrome all occur at the regions of the gene which encode for the protein.
There are 35 different known mutations of WRN, which correspond to stop codons, insertions, or deletions that result in a frameshift mutation.
Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increasing the survival of these dysfunctional cells.
Patients with Werner syndrome lose the RecQ helicase activity in the WRN protein because of the loss of its C-terminus region.
It is thought that the WRN helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability.
WRN helicase is important for preventing catastrophic telomere loss during DNA replication.
In a normal cell, the telomeres undergo repeated shortening during the cell cycle, which can prevent the cell from dividing and multiplying.
Telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome.
Patients with Werner syndrome often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the WRN helicase activity and telomere and cell instability.
Without the WRN protein, the interwoven pathways of DNA repair and telomere maintenance fail to suppress cancer and the aging symptoms seen in patients with Werner syndrome.
Events such as rapid telomere shortening cause WS cells to exhibit low responses to overall cellular stress.
In addition to telomere dysfunction, over-expression of oncogenes and oxidation can induce this type of response.
High stress causes a synergistic effect, where WS cells become even more sensitive to agents that increase cell stress and agents that damage DNA.
WS cells show a drastic reduction in replicative lifespan and enter into a stage of aging prematurely.
The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why WS symptoms only appear after an individual is about twenty years old.
WRN protein was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress, particularly in slowly replicating cells.
A cure for Werner syndrome has not yet been discovered. It is often treated by managing the associated diseases and relieving symptoms to improve quality of life.
Management:
Symptomatic Management
Cardiovascular Disease Standard cardiac medications (ACE inhibitors, beta-blockers, statins) Surgical interventions when appropriate (angioplasty, bypass surgery) Regular cardiac monitoring and risk factor management
Diabetes Management Insulin therapy is often required due to insulin resistance Blood glucose monitoring and diabetic complications screening Dietary management with diabetic nutrition counseling Cancer Surveillance and Treatment Regular screening for common malignancies (sarcomas, meningiomas, thyroid cancer) Standard oncological treatments when cancer develops Genetic counseling regarding cancer risks
Wound management due to poor healing Protection from sun exposure and trauma Treatment of chronic ulcers with specialized wound care
Fall prevention strategies
Management of weight loss and muscle wasting Nutritional supplementation as needed Swallowing evaluation if dysphagia develops
Cataract surgery when indicated
The focus remains on managing symptoms, preventing complications, and maintaining quality of life while research continues into potential disease-modifying treatments.
The skin ulcers that accompany WS can be treated with topical treatments for minor ulcers, but are not effective in preventing new ulcers from occurring.
In the most severe cases, surgery may be required to implant a skin graft or amputate a limb if necessary.
Diseases commonly associated with WS such as diabetes and cancer are treated in generally the same ways as they would be for a non-Werner syndrome individual.
Diet and exercise can help prevent and control arteriosclerosis, and regular cancer screenings can allow for early detection of cancer.
Supplementation of vitamin C is suspected to be beneficial in the treatment of WS.
The premature aging displayed in WS is not the same, on a cellular level, as normal aging.