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55-414: Xeroderma pigmentosum I/II/III/IV/V/VI/VII Xeroderma pigmentosum complementation group A/B/C/D/E/F/G • 1 in 370 (India) • 1 in 22,000 (Japan) • 1 in 250,000 (US) • 1 in 430,000 (Europe) Xeroderma pigmentosum ( XP ) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only

110-443: A hominid was in the fossil species Paranthropus robustus , with over a third of individuals displaying amelogenesis imperfecta . EDAR ( EDAR hypohidrotic ectodermal dysplasia ) XPA 1D4U , 1XPA , 2JNW 7507 22590 ENSG00000136936 ENSMUSG00000028329 P23025 Q64267 NM_000380 NM_011728 NP_000371 NP_001341904 NP_035858 DNA repair protein complementing XP-A cells

165-445: A child affected by the disorder. Examples of this type of disorder are albinism , medium-chain acyl-CoA dehydrogenase deficiency , cystic fibrosis , sickle cell disease , Tay–Sachs disease , Niemann–Pick disease , spinal muscular atrophy , and Roberts syndrome . Certain other phenotypes, such as wet versus dry earwax , are also determined in an autosomal recessive fashion. Some autosomal recessive disorders are common because, in

220-650: A faulty gene ( autosomal recessive inheritance) or from a parent with the disorder ( autosomal dominant inheritance). When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease . Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA (due to their size). There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. More than 600 genetic disorders are treatable. Around 1 in 50 people are affected by

275-577: A female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable. X-linked recessive conditions are also caused by mutations in genes on

330-452: A few minutes in the sun, freckling in sun-exposed areas, dry skin and changes in skin pigmentation. Nervous system problems, such as hearing loss , poor coordination, loss of intellectual function and seizures , may also occur. Complications include a high risk of skin cancer , with about half having skin cancer by age 10 without preventative efforts, and cataracts . There may be a higher risk of other cancers such as brain cancers . XP

385-447: A gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder. Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder . Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to

440-418: A genetic disorder rests on the inheritance of genetic material. With an in depth family history , it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth , or contemplate termination . Prenatal diagnosis can detect

495-619: A hereditary disease is an acquired disease . Most cancers , although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes , however, such as BRCA mutations , are hereditary genetic disorders. A single-gene disorder (or monogenic disorder ) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy , however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although

550-636: A known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder . Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as " rare " (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. Genetic disorders are present before birth, and some genetic disorders produce birth defects , but birth defects can also be developmental rather than hereditary . The opposite of

605-787: A person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance , which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease , neurofibromatosis type 1 , neurofibromatosis type 2 , Marfan syndrome , hereditary nonpolyposis colorectal cancer , hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis , Von Willebrand disease , and acute intermittent porphyria . Birth defects are also called congenital anomalies. Two copies of

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660-470: A reduction in or elimination of NER. If left unchecked, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The causes of the neurological abnormalities are poorly understood and are not connected with exposure to ultraviolet light. The most current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER. Since DNA repair

715-739: A wide variety of damages that thermodynamically destabilize DNA duplexes. The XPD ( ERCC2 ) protein, in combination with the XPB helicase-containing transcription/repair complex TFIIH , is employed in unwinding the DNA duplex after damage is initially recognized. Mutations in the XPD(ERCC2) gene cause a variety of syndromes; XP, trichothiodystrophy (TTD), or a combination of XP and Cockayne syndrome (XPCS). Both trichothiodystrophy and Cockayne syndrome display features of premature aging, suggesting an association between deficient DNA repair and premature aging . XPE

770-465: Is Leber's hereditary optic neuropathy . It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance. Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with

825-407: Is autosomal recessive , with mutations in at least nine specific genes able to result in the condition. Normally, the damage to DNA which occurs in skin cells from exposure to UV light is repaired by nucleotide excision repair . In people with xeroderma pigmentosum, this damage is not repaired. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die. Diagnosis

880-533: Is a protein that in humans is encoded by the XPA gene . Nucleotide excision repair (NER) is a major pathway for repairing a variety of bulky DNA damages including those introduced by UV irradiation. The XPA protein appears to play a key role in NER at sites of damage as a scaffold for other repair proteins in order to ensure that the damages are appropriately excised. Among the repair proteins with which XPA interacts

935-531: Is a health problem caused by one or more abnormalities in the genome . It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality . Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome . The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of

990-458: Is a heterodimeric protein composed of two subunits. The larger subunit DDB1 primarily functions as a core component of CUL4A - and CUL4B -based E3 ubiquitin ligase complexes. Substrates that are ubiquitinnated by these complexes include proteins employed in DNA repair. The XPF ( ERCC4 ) protein together with the ERCC1 protein forms a complex usually designated ERCC1-XPF. This complex separates

1045-405: Is also a strong environmental component to many of them (e.g., blood pressure ). Other such cases include: A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form of Down syndrome ), in which there

1100-423: Is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether

1155-412: Is an extra copy of chromosome 21 in all cells. Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth , at birth , or during early childhood however some, such as Huntington's disease , can escape detection until the patient begins exhibiting symptoms well into adulthood. The basic aspects of

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1210-421: Is appropriate for the families to discuss probability of occurrence in future pregnancies, feelings of isolation and concern about career prospects. There is no cure for xeroderma pigmentosum. The most common fate for individuals with XP is early death from cancer. The XPA protein acts during NER as a scaffold for assembly of other DNA repair proteins at sites of DNA damage to ensure appropriate excision of

1265-421: Is only possible through the circumvention of infertility by medical intervention. This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA . Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder

1320-416: Is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity , penetrance , and expressivity. On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There

1375-444: Is typically suspected based on symptoms and confirmed by genetic testing . There is no cure for XP. Treatment involves completely avoiding the sun . This includes protective clothing, sunscreen and dark sunglasses when out in the sun. Retinoid creams may help decrease the risk of skin cancer. Vitamin D supplementation is generally required. If skin cancer occurs, it is treated in the usual way. The life expectancy of those with

1430-524: Is under genetic control, it can mutate. Many genetic disorders such as xeroderma pigmentosum (XP; MIM 278700) are caused by mutations in genes that repair damaged DNA. XP affects the mechanism that repairs UV damage in skin cell DNA. Those affected with the autosomal recessive disorder XP are extremely sensitive to UV light produced by the sun and develop pigmented spots, tumors, and skin cancer with minimal exposure. Individuals with XP are about 1,000 times more likely to develop skin cancer than individuals without

1485-403: The DNA helix for a short distance on either side of the site of damage. It then acts as an endonuclease to incise the damaged DNA strand on the 5' side of the damaged site. Mutant cells with deficient ERCC1-XPF are not only defective in NER, but also in the repair of double-strand breaks and inter-strand crosslinks. The XPG protein is an endonuclease that incises DNA during NER at the 3' side of

1540-508: The Dark , was based on the story of the real-life couple Jim and Kim Harrison, whose two daughters have XP. Lurlene McDaniel 's young adult book How I Do Love Thee features the story "Night Vision", in which the protagonist, leukemia survivor Brett, falls in love with a girl named Shayla that has XP. Christopher Snow, the protagonist of novelist Dean Koontz's Moonlight Bay Trilogy , has XP and therefore must live most of his life during

1595-518: The Sun , a 1988 American-Yugoslavian drama film , was directed by Božidar Nikolić and stars Brad Pitt for his first ever leading role as a young man in search of a cure for his disorder. The Others , a 2001 American psychological horror film starring Nicole Kidman , features two children, Anne and Nicholas, who must avoid all sunlight because of a rare disease characterized by photosensitivity . A CBS television movie aired in 1994, Children of

1650-399: The X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of

1705-654: The XP problem on the Navajo Indian Reservation, and links it to the genetic legacy of the Long Walk of the Navajo , when the Navajo people were forced to move to a new location. The 2016 Vietnamese romance drama Khúc hát mặt trời , based on a 2006 Japanese film, A Song to the Sun , tells the story of a girl named Yến Phương with XP and the impact of her sickness on her life and relationships, following

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1760-443: The Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes. Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions

1815-448: The active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy . This includes physical therapy and pain management . The treatment of genetic disorders is an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. Despite this, most treatment options revolve around treating

1870-643: The condition is about 30 years less than normal. The disease affects about 1 in 100,000 worldwide. By region, it affects about 1 in 370 in India, 1 in 20,000 in Japan, 1 in 250,000 people in the United States and 1 in 430,000 in Europe. It occurs equally commonly in males and females. Xeroderma pigmentosum was first described in the 1870s by Moritz Kaposi . In 1882, Kaposi coined the term xeroderma pigmentosum for

1925-401: The condition, referring to its characteristic dry, pigmented skin. Individuals with the disease have been referred to as "children of the night" or "moon children". Signs and symptoms of xeroderma pigmentosum may include: One of the most frequent defects in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to

1980-511: The damage. The XPB (ERCC3) protein is employed in unwinding the DNA double helix after DNA damage is initially recognized. Mutations in the XPB(ERCC3) gene can lead to XP or XP combined with Cockayne syndrome . The XPC protein forms a complex with RAD23B protein to form the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER). This complex recognizes

2035-886: The damaged nucleotide. Mutations in the XPG ( ERCC5 ) gene can lead to XP alone, or in combination with Cockayne syndrome (CS), or in combination with infantile lethal cerebro-oculo-facio-skeletal syndrome. There are seven complementation groups, plus one variant form: There is no cure for the disorder; all treatment is symptomatic or preventive. Symptoms can be avoided or controlled by completely avoiding exposure to sunlight, either by staying indoors or wearing protective clothing and using sunscreen when outdoors. Keratosis can also be treated by using cryotherapy or fluorouracil . In more severe cases of XP, even minuscule amounts of UV light, for example, from covered windows or fluorescent bulbs, can be very dangerous and trigger symptoms. On September 10, 2020, Clinuvel Pharmaceuticals announced that it

2090-449: The dark , children of the night , and vampire children . These terms can be considered derogatory. XP has been a plot element in several fictional works. One of the common themes in films about XP is whether teens with XP will risk sun exposure in pursuit of a romantic partner. Film series like Children of Darkness , a German silent-drama film which was released in two parts in the year of 1921 and 1922 respectively, were among some of

2145-474: The disease itself, and also better understanding the normal biological mechanisms involved in DNA repair. Research into XP has produced insights that have been translated into treatments and prevention for cancer. see also Template:Congenital malformations and deformations of skin appendages , Template:Phakomatoses , Template:Pigmentation disorders , Template:DNA replication and repair-deficiency disorder Genetic disorder A genetic disorder

2200-472: The disorder. The molecular defects in XP cells result in a greatly elevated induction of mutations in sun-exposed skin of affected individuals. This increased mutation frequency probably accounts for the pigmentation changes and the skin cancers. Examination of mutations in the p53 gene in tumors from XP patients reveal p53 mutations characteristic of UV exposure in the majority of tumors As with all genetic disorders, genetic counseling and psychological support

2255-440: The divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism , achondroplasia , is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics could be considered carriers for. Sickle cell anemia

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2310-421: The effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes . Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because

2365-426: The embryo has the genetic disorder. Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations. Only one mutated copy of the gene will be necessary for

2420-408: The gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers . Each parent with a defective gene normally do not have symptoms. Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having

2475-407: The initially popular movies that were made about XP. Other films, like the 1964 American drama film Della , starring Joan Crawford , Paul Burke , Charles Bickford and Diane Baker , directed by Robert Gist , which was originally produced by Four Star Television as a television pilot for a proposed NBC series named Royal Bay , was also based on this skin disease . The Dark Side of

2530-643: The mutated gene. A woman who is a carrier of an X-linked recessive disorder (X X ) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A , Duchenne muscular dystrophy , and Lesch–Nyhan syndrome , as well as common and less serious conditions such as male pattern baldness and red–green color blindness . X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X ( Turner syndrome ). Y-linked disorders are caused by mutations on

2585-527: The night. The first two entries of the trilogy, Fear Nothing and Seize the Night , were both published in 1998. The final entry in the trilogy, tentatively titled Ride the Storm , has yet to be published as of August 2020. The 2011 French drama film The Moon Child is based on a 13-year-old child with XP, which prevents him from exposing himself to daylight. The 2012 documentary Sun Kissed explores

2640-1003: The past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria . Such disorders include cystic fibrosis, sickle cell disease, phenylketonuria and thalassaemia . X-linked dominant disorders are caused by mutations in genes on the X chromosome . Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets . Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome , incontinentia pigmenti type 2, and Aicardi syndrome , are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of

2695-606: The presence of characteristic abnormalities in fetal development through ultrasound , or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis . Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome , while others result in purely physical symptoms such as muscular dystrophy . Other disorders, such as Huntington's disease , show no signs until adulthood. During

2750-423: The significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as " rare " (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. The earliest known genetic condition in

2805-401: The specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype – phenotype associations. One method, the genotype-first approach , starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This

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2860-412: The story of Phương's accidental exposure to sunlight and subsequent neurological degeneration. Midnight Sun (2018 film) is a 2018 American romantic drama film based on the 2006 Japanese film A Song to the Sun. The film was directed by Scott Speer and written by Eric Kirsten, and stars Bella Thorne, Patrick Schwarzenegger, and Rob Riggle. Research into XP has had two main results: better understanding

2915-442: The symptoms of the disorders in an attempt to improve patient quality of life . Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce

2970-431: Was first described in 1874 by Hebra and Moritz Kaposi . In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin. The 1968 paper about XP by James Cleaver demonstrated the link between UV-induced DNA damage, faulty DNA repair and cancer. Because people with XP need to strictly avoid sunlight, but can go outside at night, they have been called children of

3025-665: Was investigating the use of its FDA-approved flagship drug Scenesse as a potential treatment to increase pain-free light exposure for patients with xeroderma pigmentosum. In the United States , the probability for individuals with the disorder to survive until 40 years of age may be as high as 70% if they have never been exposed to sunlight in their life. If a person is diagnosed early, does not have severe neurological symptoms, and takes precautionary measures to completely avoid any exposure to UV light and sunlight, they may be able to survive until middle age. Xeroderma pigmentosum

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