Progeria (also known as "Hutchinson–Gilford Progeria Syndrome",[1] "Hutchinson–Gilford syndrome",[2] and "Progeria syndrome"[2]) is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word Progeria comes from the Greek words "pro" (πρό) means "before" and "géras" (γῆρας) means "old age". The disorder has very low incidences and occurs in an estimated 1 per 8 million live births.[3] Those born with progeria typically live to their mid teens and early twenties.[4][5] It is a genetic condition that occurs as a new mutation (de novo), and is not inherited. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson-Gilford Progeria Syndrome.
Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.[6][7][8] Progeria was first described in 1886 by Jonathan Hutchinson.[9] It was also described independently in 1897 by Hastings Gilford.[10] The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).
A child with this condition show signs of symptoms usually around 18–24 months. After being born a healthy looking baby, their height and weight suddenly fall below average for their age. Individuals generally retain normal mental and motor development. There are many signs and symptoms of this progressive disease, and they tend to get worse as the child ages. The facial appearance is usually wrinkled, with a larger head in relation to their body, with a narrow face and a beak nose. The child experiences full-body alopecia. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is also prevalent. Since they experience hair loss, prominent scalp veins are noticeable, as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population.
Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered. The LMNA gene is responsible for producing lamin proteins, which provide strength and stability in cells. Lamin A and Lamin C support the nuclear envelope. When Lamin A is altered, it affects the shape and the function of the nuclear envelope. These changes cause other cells to die prematurely.
Unlike "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases display what are considered different aspects of aging, but never every aspect, they are often called "segmental progerias".[11]
Growth hormone treatment has been attempted.[14]
A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.[15] A Phase II clinical trial using the FTI Lonafarnib began in May 2007.[16] In studies on the cells another anti-cancer drug—rapamycin caused removal of progerin from the nuclear membrane.[17]
Mental development is not affected. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to features of aging that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop the so-called "wear and tear" conditions commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).[12]
Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems.
Classical Hutchinson-Gilford Progeria Syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves.
There have been only two known cases in which it became evident that a healthy person can carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children.[7] One family from India has five children with progeria, although this is not a classical HGPS ;[23] they were the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children, while another from Belgium has two.[24]
A 2003 report in Nature[26] said that progeria may be a de novo dominant trait. It develops during cell division in a newly conceived zygote or in the gametes of one of the parents. It is caused by mutations in the LMNA (lamin A protein) gene on chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.[27]
Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.
In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing.[28] This results in the symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.
A study that compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading to reduced heterochromatin.[29] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[30] These studies suggest that lamin A defects are associated with normal aging.
Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with farnesyltransferase inhibitors (FTIs). In the test tube, FTIs reverse the nuclear damage caused by the disease.A mouse model of progeria exists, though in the mouse, the LMNA prelamin A is not mutated. Instead, ZMPSTE24, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al. use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of prelamin A. Treated mice had greater grip strength and lower likelihood of rib fracture and may live longer than untreated mice.[32]
This method does not directly "cure" the underlying cause of progeria. This method prevents prelamin A from going to the nucleus in the first place so that no prelamin A can build up on the nuclear membrane, but equally, there is no production of normal lamin A in the nucleus. Luckily, lamin A does not appear to be essential; indeed, mouse models in which the genes for prelamin A and C are knocked out show no symptoms.[33] This also shows that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal function of lamin A, that causes the disease.
Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Staining was smooth muscle alpha-actin (green), lamins A/C (red) and DAPI (blue). (Original magnification, x 40)It was hypothesized that part of the reason that treatment with an FTI such as alendronate is inefficient is due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FTI and statins was tried, and markedly improved "the aging-like phenotypes of mice in the metalloproteinase ZMPSTE24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects".[34]
In other literary references, Charles Dickens has been suggested in Bleak House to have described a case of progeria in the family of Smallweed in the grandfather and his grandchildren Judy and twin brother Bart.[36] Orlando Gardiner of the science fiction book series Otherland suffers from this disease. The Chuck Palahniuk novel Haunted includes one character, Brandon Whittier, who is dying of progeria at 13.
In film, a number of well-known films have featured progeria or progeria-like diseases. The Hindi film Paa, released in December 2009, has its storyline around progeria (starring Amitabh Bachchan playing a thirteen year old boy Auro).[37] Progeria is also a central theme in the animated film Renaissance in which one of the characters finds the much sought cure.[citation needed] The 1996 film Jack, starring Robin Williams, portrays a character who has a condition which causes him to age at 4 times the normal rate. This was possibly based on progeria though is otherwise not an accurate portrayal of the syndrome. The 1983 lesbian vampire film, The Hunger, starred Susan Sarandon as a physician researching progeria, and showed a vampire (played by David Bowie) undergoing rapid progeria-like aging. In the film Blade Runner the character J.F.Sebastian is a genetic designer who is not allowed to emigrate off-world because of his progeria.
The extraterrestrial space traveler in the 1986 film The Aurora Encounter was played by Mickey Hays, a teenage boy who suffered from progeria.
In the episode of the series Dark Angel titled "Designate This", Max's "younger version" has the disease. Progeria was featured in the X-Files episode "Young at Heart," where a scientist studying the disease found a way to reverse the aging process.
In the episode of the series Bones titled "Stargazer in a Puddle", the victim suffered from progeria.
Rabbi Harold Kushner, author of the well known book, When Bad Things Happen to Good People, had a son who suffered from this disease, and his son's illness was probably the impetus for this book on suffering. Leon Botha, a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group Die Antwoord, was one of the oldest people in the world who lived with progeria, dying one day after his 26th birthday on June 5, 2011.
source :
http://en.wikipedia.org/wiki/Progeria
Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.[6][7][8] Progeria was first described in 1886 by Jonathan Hutchinson.[9] It was also described independently in 1897 by Hastings Gilford.[10] The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).
Signs and symptoms
The earliest symptoms include failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent. Limited growth, alopecia, and a distinctive appearance (small face and jaw, pinched nose) are all characteristics of progeria. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. Later, the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, hair loss, and cardiovascular problems. It is not transferred by the offspring.A child with this condition show signs of symptoms usually around 18–24 months. After being born a healthy looking baby, their height and weight suddenly fall below average for their age. Individuals generally retain normal mental and motor development. There are many signs and symptoms of this progressive disease, and they tend to get worse as the child ages. The facial appearance is usually wrinkled, with a larger head in relation to their body, with a narrow face and a beak nose. The child experiences full-body alopecia. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is also prevalent. Since they experience hair loss, prominent scalp veins are noticeable, as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population.
[edit] Cause
Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene, replacing cytosine with thymine, creating a form of the Lamin A protein which cannot be processed properly and accumulates in the cell nucleus. Lamin A is a major structural protein of the human cell nucleus.Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered. The LMNA gene is responsible for producing lamin proteins, which provide strength and stability in cells. Lamin A and Lamin C support the nuclear envelope. When Lamin A is altered, it affects the shape and the function of the nuclear envelope. These changes cause other cells to die prematurely.
Unlike "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases display what are considered different aspects of aging, but never every aspect, they are often called "segmental progerias".[11]
[edit] Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.[12][edit] Treatment
No treatments have been proven effective. Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin.[13] Children may also benefit from a high-calorie diet.Growth hormone treatment has been attempted.[14]
A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.[15] A Phase II clinical trial using the FTI Lonafarnib began in May 2007.[16] In studies on the cells another anti-cancer drug—rapamycin caused removal of progerin from the nuclear membrane.[17]
[edit] Prognosis
There is no known cure. Few people with progeria exceed 13 years of age.[18] At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.[19]Mental development is not affected. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to features of aging that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop the so-called "wear and tear" conditions commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).[12]
Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems.
[edit] Epidemiology
A study from the Netherlands has shown an incidence of 1 in 4 million births.[20] Currently, there are between 35 and 45 known cases in the world.[21] Approximately 100 cases have been formally identified in medical history.[18][22]Classical Hutchinson-Gilford Progeria Syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves.
There have been only two known cases in which it became evident that a healthy person can carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children.[7] One family from India has five children with progeria, although this is not a classical HGPS ;[23] they were the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children, while another from Belgium has two.[24]
[edit] Research
Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.[25]A 2003 report in Nature[26] said that progeria may be a de novo dominant trait. It develops during cell division in a newly conceived zygote or in the gametes of one of the parents. It is caused by mutations in the LMNA (lamin A protein) gene on chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.[27]
[edit] Lamin A
Lamin A is a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina that helps organize nuclear processes such as RNA and DNA synthesis.Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.
In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing.[28] This results in the symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.
A study that compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading to reduced heterochromatin.[29] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[30] These studies suggest that lamin A defects are associated with normal aging.
A range of putative disease-causingmechanisms for the case of HGPS, in which lamin A is permanently farnesylated in the form of progerin. We predict that progerin becomes entrapped in the nuclear membrane as a result of permanent farnesylation, resulting in a multitude of downstream effects. Disruption of the normal lamina architecture leads to fragility, vulnerability to mechanical stresses and nuclear blebbing. Other consequences include disrupted interactions with other nuclear envelope proteins – such as nesprin, emerin and laminaassociated protein 2 (LAP2) – which leads to their mislocalization (that is, emerin is relocalized to the cytoplasm in Lmna -/- mice)74 and clustering of nuclear pores. Disorganization and loss of peripheral heterochromatin is also seen, with heterochromatin becoming detached from the nuclear envelope, and disrupted interactions with RNA polymerase II, RNA splicing factors and transcription factors such as the retinoblastoma transcriptional regulator (RB) and sterol response element binding protein (SREBP1), which leads to misregulation of gene expression. GCL, germ cell-less. Capell and Collins, Nature Reviews Genetics 2006.[31]
[edit] Mouse model of progeria
This method does not directly "cure" the underlying cause of progeria. This method prevents prelamin A from going to the nucleus in the first place so that no prelamin A can build up on the nuclear membrane, but equally, there is no production of normal lamin A in the nucleus. Luckily, lamin A does not appear to be essential; indeed, mouse models in which the genes for prelamin A and C are knocked out show no symptoms.[33] This also shows that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal function of lamin A, that causes the disease.
[edit] Popular culture
Perhaps one of the earliest influences of progeria on popular culture occurred in the 1922 short story The Curious Case of Benjamin Button by F. Scott Fitzgerald (and later released as a feature film in 2008). The main character, Benjamin Button, is born as a seventy-year-old man and ages backwards; it has been suggested that this was inspired by progeria.[35]In other literary references, Charles Dickens has been suggested in Bleak House to have described a case of progeria in the family of Smallweed in the grandfather and his grandchildren Judy and twin brother Bart.[36] Orlando Gardiner of the science fiction book series Otherland suffers from this disease. The Chuck Palahniuk novel Haunted includes one character, Brandon Whittier, who is dying of progeria at 13.
In film, a number of well-known films have featured progeria or progeria-like diseases. The Hindi film Paa, released in December 2009, has its storyline around progeria (starring Amitabh Bachchan playing a thirteen year old boy Auro).[37] Progeria is also a central theme in the animated film Renaissance in which one of the characters finds the much sought cure.[citation needed] The 1996 film Jack, starring Robin Williams, portrays a character who has a condition which causes him to age at 4 times the normal rate. This was possibly based on progeria though is otherwise not an accurate portrayal of the syndrome. The 1983 lesbian vampire film, The Hunger, starred Susan Sarandon as a physician researching progeria, and showed a vampire (played by David Bowie) undergoing rapid progeria-like aging. In the film Blade Runner the character J.F.Sebastian is a genetic designer who is not allowed to emigrate off-world because of his progeria.
The extraterrestrial space traveler in the 1986 film The Aurora Encounter was played by Mickey Hays, a teenage boy who suffered from progeria.
In the episode of the series Dark Angel titled "Designate This", Max's "younger version" has the disease. Progeria was featured in the X-Files episode "Young at Heart," where a scientist studying the disease found a way to reverse the aging process.
In the episode of the series Bones titled "Stargazer in a Puddle", the victim suffered from progeria.
Rabbi Harold Kushner, author of the well known book, When Bad Things Happen to Good People, had a son who suffered from this disease, and his son's illness was probably the impetus for this book on suffering. Leon Botha, a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group Die Antwoord, was one of the oldest people in the world who lived with progeria, dying one day after his 26th birthday on June 5, 2011.
source :
http://en.wikipedia.org/wiki/Progeria
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