Xeroderma pigmentosa, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient. This disorder leads to multiple basaliomas and other skin malignancies at a young age. In severe cases, it is necessary to avoid sunlight completely. The two most common causes of death for XP victims are metastatic malignant melanoma and squamous cell carcinoma[1]. XP is about six times more common in Japanese people[1] than in other groups.
Fictional characters with severe cases of XP sometimes play prominent roles in books and movies. Some of the most notable characters include Christopher Snow, the protagonist and narrator of Dean Koontz' Moonlight Bay Trilogy of novels, and the children of the protagonist of Alejandro Amenábar's 2001 film, The Others.
The most common defect in xeroderma pigmentosum is an autosomal recessive genetic defect whereby nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER.[2] Unrepaired damage can lead to mutations, altering the information of the DNA in individual cells. If mutations affect important genes, like tumour suppressor genes (e.g. p53) or proto oncogenes then this disorder may lead to cancer. Patients exhibit elevated risk of developing cancer, such as basal cell carcinoma.
Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high energy light leads to the formation of pyrimidine dimers, namely CPD's (cyclobutane-pyrimidine-dimers) and 6-4PP's (pyrimidine-6-4-pyrimidone photoproducts). The normal repair process entails nucleotide excision. The damage is excised by endonucleases, then the gap is filled by a DNA polymerase and "sealed" by a ligase.
[edit] Types
luni, 26 ianuarie 2009
Werner syndrome
Werner Syndrome (WRN) is a very rare, autosomal recessive[1] disorder characterized by the appearance of premature aging.[2]
Werner's syndrome more closely resembles accelerated aging than any other segmental progeria. For this reason, Werner syndrome is often referred to as a progeroid syndrome, as it partly mimics the symptoms of Progeria.
Pathophysiology
The defect is on a gene that codes DNA helicase and it is located on the short arm of the 8th chromosome. The disorder is directly caused by shorter-than-normal length telomere maintenance. As a result DNA replication is impaired.
[edit] Symptoms
Individuals with this syndrome typically develop normally until they reach puberty. Following puberty they age rapidly, so that by age 40 they often appear several decades older. The age of onset of Werner syndrome is variable, but an early sign is the lack of a teenage growth spurt, which results in short stature. Other signs and symptoms appear when affected individuals are in their twenties or thirties and include loss and graying of hair, hoarseness of the voice, thickening of the skin, and cloudy lenses (cataracts) in both eyes. Overall, people affected by Werner syndrome have thin arms and legs and a thick torso.
Affected individuals typically have a characteristic facial appearance described as "bird-like" by the time they reach their thirties. Patients with Werner syndrome also exhibit genomic instability, hypogonadism, and various age-associated disorders; these include cancer, heart disease, atherosclerosis, diabetes mellitus, and cataracts. However, not all characteristics of old-age are present in Werner patients; for instance, senility is not seen in individuals with Werner syndrome. People affected by Werner syndrome usually do not live past their late forties or early fifties, often dying from the results of cancer or heart disease.
Werner's syndrome more closely resembles accelerated aging than any other segmental progeria. For this reason, Werner syndrome is often referred to as a progeroid syndrome, as it partly mimics the symptoms of Progeria.
Pathophysiology
The defect is on a gene that codes DNA helicase and it is located on the short arm of the 8th chromosome. The disorder is directly caused by shorter-than-normal length telomere maintenance. As a result DNA replication is impaired.
[edit] Symptoms
Individuals with this syndrome typically develop normally until they reach puberty. Following puberty they age rapidly, so that by age 40 they often appear several decades older. The age of onset of Werner syndrome is variable, but an early sign is the lack of a teenage growth spurt, which results in short stature. Other signs and symptoms appear when affected individuals are in their twenties or thirties and include loss and graying of hair, hoarseness of the voice, thickening of the skin, and cloudy lenses (cataracts) in both eyes. Overall, people affected by Werner syndrome have thin arms and legs and a thick torso.
Affected individuals typically have a characteristic facial appearance described as "bird-like" by the time they reach their thirties. Patients with Werner syndrome also exhibit genomic instability, hypogonadism, and various age-associated disorders; these include cancer, heart disease, atherosclerosis, diabetes mellitus, and cataracts. However, not all characteristics of old-age are present in Werner patients; for instance, senility is not seen in individuals with Werner syndrome. People affected by Werner syndrome usually do not live past their late forties or early fifties, often dying from the results of cancer or heart disease.
Trichothiodystrophy
Trichothiodystrophy is a rare genetic condition caused by mutations in either of the ERCC2/XPD and ERCC3/XPB genes. The symptoms of the disease result from a loss of nucleotide excision repair (NER) mechanisms, resulting in high sensitivity to UV light. Patients suffer from brittle hair and nails, ichthyotic or dry and scaly skin as well as physical and mental retardation. Skin cancers have been reported in several cases, associated with Trichothiodystrophy, which is also known as Tay syndrome.[1]
In some cases, it can be diagnosed prenatally.[2]
In some cases, it can be diagnosed prenatally.[2]
Cockayne syndrome
Cockayne syndrome (also called Weber-Cockayne syndrome, or Neill-Dingwall Syndrome) is a rare autosomal recessive[1] congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), and premature aging. Hearing loss and eye abnormalities (pigmentary retinopathy) are other common features, but problems with any or all of the internal organs are possible.
It is named after English physician Edward Alfred Cockayne (1880-1956).
Forms of Cockayne syndrome
* CS Type I, the classic form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Impairment of vision, hearing, and the central and peripheral nervous system progressively degenerate until death in the first or second decade of life.
* CS Type II, otherwise known as connatal CS, involves very little neurological development after birth. Death usually occurs by age 7.
* CS Type III is rare and is characterized by late onset. It is milder than Type I and II.
* Xeroderma-pigmentosum-Cockayne syndrome (XP-CS) occurs when an individual also suffers from Xeroderma pigmentosum, another DNA repair disease. Some symptoms of each disease are expressed.
It is named after English physician Edward Alfred Cockayne (1880-1956).
Forms of Cockayne syndrome
* CS Type I, the classic form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Impairment of vision, hearing, and the central and peripheral nervous system progressively degenerate until death in the first or second decade of life.
* CS Type II, otherwise known as connatal CS, involves very little neurological development after birth. Death usually occurs by age 7.
* CS Type III is rare and is characterized by late onset. It is milder than Type I and II.
* Xeroderma-pigmentosum-Cockayne syndrome (XP-CS) occurs when an individual also suffers from Xeroderma pigmentosum, another DNA repair disease. Some symptoms of each disease are expressed.
Ataxia telangiectasia
Ataxia-telangiectasia (AT) (Boder-Sedgwick syndrome[1] or Louis-Bar syndrome) is a rare, neurodegenerative, inherited disease which affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.
AT affects the cerebellum (the body's motor control center) and also weakens the immune system in about 70% of the cases, leading to respiratory disorders and increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as lack of balance, slurred speech, and increased infections. Because all children at this age take time to develop good walking skills, coherent speech, and an effective immune system, it may be some years before AT is properly diagnosed.
AT affects the cerebellum (the body's motor control center) and also weakens the immune system in about 70% of the cases, leading to respiratory disorders and increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as lack of balance, slurred speech, and increased infections. Because all children at this age take time to develop good walking skills, coherent speech, and an effective immune system, it may be some years before AT is properly diagnosed.
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