Progeria

From Wikipedia, the free encyclopedia

Progeria (pronunciation: /pro!"d#$%ri%/[1][2]) (HutchinsonGilford progeria syndrome,[3][4] HGPS, progeria syndrome[4]) is an extremely rare genetic disorder wherein symptoms resembling aspects of aging are manifested at a very early age. Progeria is one of several progeroid syndromes. The word progeria comes from the Greek words "pro" (&'(), meaning "before" or "premature", and "g)ras" (*+',-), meaning "old age". The disorder has a very low incidence rate, occurring in an estimated 1 per 8 million live births.[5] Those born with progeria typically live to their mid teens to early twenties.[6][7] It is a genetic condition that occurs as a new mutation, and is rarely inherited, as patients usually do not live to reproduce. 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 HutchinsonGilford progeria syndrome (HGPS).

Progeria
Classification and external resources

A young girl with progeria (left). A progeric cell nucleus (bottom, right) and a healthy cell nucleus (top, right). ICD-10 E34.8 (http://apps.who.int/classifications/icd10/browse/2010/en#/E34.8) (ILDS E34.840) 259.8 (http://www.icd9data.com/getICD9Code.ashx?icd9=259.8) 176670 (http://omim.org/entry/176670) 10704 (http://www.diseasesdatabase.com/ddb10704.htm)

ICD-9 OMIM DiseasesDB

MedlinePlus 001657 (http://www.nlm.nih.gov/medlineplus/ency/article/001657.htm) eMedicine MeSH GeneReviews derm/731 (http://www.emedicine.com/derm/topic731.htm) D011371 (http://www.nlm.nih.gov/cgi/mesh/2014/MB_cgi? field=uid&term=D011371) Hutchinson-Gilford Progeria Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1121/)

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.[8][9][10] Progeria was first described in 1886 by Jonathan Hutchinson.[11] It was also described independently in 1897 by Hastings Gilford.[12] The condition was later named HutchinsonGilford progeria syndrome.

Contents
1 Signs and symptoms 2 Cause 3 Diagnosis 4 Treatment 5 Prognosis 6 Epidemiology 7 Research 7.1 Lamin A

7.2 Mouse model 8 Popular culture 9 See also 10 References 11 External links

Signs and symptoms

Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent usually around 1824 months. Limited growth, full-body alopecia, and a distinctive appearance (a small face with a shallow recessed jaw, and a pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, and cardiovascular problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. The face is usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), 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. Individuals usually retain normal mental and motor development.

Cause
Steps in normal cell Prelamin A has a farnesyl group attached to its end. Farnesyl group is removed from prelamin A. Normal form is called lamin A. Lamin A is not anchored to the nuclear rim. Normal state of the nucleus. Steps in cell with progeria Prelamin A has a farnesyl group attached to its end. Farnesyl group remains attached to prelamin A. Abnormal form of prelamin A is called progerin. Progerin is anchored to the nuclear rim. Abnormally shaped nucleus. The gene LMNA encodes a protein called prelamin A. The gene LMNA encodes a protein called prelamin A.

In normal conditions, the LMNA gene codes for a structural protein called prelamin A. There is a farnesyl functional group attached to the carboxyl-terminus of its structure. The farnesyl group allows prelamin A to attach temporarily to the nuclear rim. Once the protein is attached, the farnesyl group is removed. Failure to remove this farnesyl group permanently affixes the protein to the nuclear rim. Without its farnesyl group, prelamin A is referred to as lamin A. Lamin A, along with lamin B and lamin C, makes up the nuclear lamina, which provides structural support to the nucleus. Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a point mutation in position 1824 of the LMNA gene, in which cytosine is replaced with thymine. This mutation causes transcription of the LMNA gene to stop too early, which results in the creation of an abnormally short mRNA transcript. This mRNA strand, when translated, yields an abnormal variant of the prelamin A protein whose farnesyl group cannot be removed. Because its farnesyl group cannot be removed, this abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim, and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear lamina is unable to provide the nuclear envelope with adequate structural support, causing it to take on an abnormal shape.[13] Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide.[14]

Progerin may also play a role in normal human aging, since its production is activated in senescent wildtype cells.[14] Unlike "accelerated aging diseases" (such as Werner syndrome, Cockayne syndrome or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases cause changes in different aspects of aging, but never in every aspect, they are often called "segmental progerias."[15]

Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. A genetic test for LMNA mutations can confirm the diagnosis of progeria.[16][17]

Treatment
No treatment has proven effective. Most treatment focuses on reducing complications (such as cardiovascular disease) with coronary artery bypass surgery or low-dose aspirin.[18] Children may also benefit from a highenergy diet. Growth hormone treatment has been attempted.[19] The use of Morpholinos has also been attempted in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11exon 12 junction in the mutated pre-mRNAs were used.[20] A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.[21] A Phase II clinical trial using the FTI lonafarnib began in May 2007.[22] In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through autophagy.[13][23] It has been proved that pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl group production. However, it is important to remember that no treatment is able to cure progeria. Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of inhibition of progerin farnesylation an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can be appreciated because that attachment takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim and it now has a more normal state. The delivery of lonafarnib is not approved by the US Food and Drug Administration (FDA). Therefore, it can only be used in certain clinical trials. Until the treatment of FTIs is implemented in progeria children we will not know its effectswhich are positive in mice.[24] Pravastatin, traded as Pravachol or Selektine, is included in the family of statins. As well as zoledronate (also known as Zometa and Reclast, which is a bisphosphonate), its utility in HGPS is the prevention of farnesyl groups formation, which progerin needs to provoke the disease. Some animal trials have been realized using FTIs or a combination of pravastatin and zoledronate so as to observe whether they are capable of reversing abnormal nuclei. The results, obtained by blinded electron microscopic analysis and immunofluorescence microscopy, showed that nucleus abnormalities could be reversed in transgenic mice expressing progerin. The reversion was also observed in vivocultured cells from human subjects with progeriadue to the action of the pharmacs, which
Potential therapeutic targets for the

block protein prenylation (transfer of a farnesyl polypeptide to C-terminal cysteine). The authors of that trial add, when it comes to the results, that: They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials.[25] Unlike FTIs, pravastatin and zoledronate were approved by the U.S. FDA (in 2006 and 2001 respectively), although they are not sold as a treatment for progeria. Pravastatin is used to decrease cholesterol levels and zoledronate to prevent hypercalcaemia. Rapamycin, also known as Sirolimus, is a macrolide. There are recent studies concerning rapamycin which conclude that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are: abolishment of nuclear blebbing, degradation of progerin in affected cells and reduction of insoluble progerin aggregates formation. All these results do not come from any clinical trial, although it is believed that the treatment might benefit HGPS kids.[13] A 2012 clinical trial found that the cancer drug Lonafarnib can improve weight gain and other symptoms of progeria.[26]

Prognosis
As there is no known cure, few people with progeria exceed 13 years of age.[27] At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.[28] Mental development is not adversely affected; in fact, intelligence tends to be normal to above average.[29] 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).[16] 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.

Epidemiology
A study from the Netherlands has shown an incidence of 1 in 4 million births.[30] Currently, there are 100 known cases in the world. Approximately 140 cases have been reported in medical history.[31] However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed cases worldwide. Classical HutchinsonGilford 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 cases in which a healthy person was known to carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children.[9] One family from India has five children with progeria, though not the classical HGPS type.[32] This family was the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children. The Vandeweert family of Belgium has two children, Michiel and Amber, with classic HGPS.[33] The first reported case of a black child with progeria was identified in September 2011. The South African child, named Ontlametse Phalatse, was born in 1999.[34] The Progeria Research Foundation at Children's Hospital Boston, affiliated with the Harvard University Medical School, is treating her and monitoring her case.

Research
Several discoveries have been made that have led to greater understandings and perhaps eventual treatment for this disease.[35] A 2003 report in Nature[36] 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.[37]

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 Cterminal 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.[38] This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known. A study that compared HGPS patient cells with the skin cells from young and elderly normal 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.[39] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[40] These studies suggest that lamin A defects are associated with normal aging.

Mouse model
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 Cterminus of prelamin A, is missing. Both cases result in Confocal microscopy photographs of the the buildup of farnesylated descending aortas of two 15-month-old prelamin A on the nuclear progeria mice, one untreated (left) and the membrane and in the other treated with the FTI drug tipifarnib characteristic nuclear LMNA (right) 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.[41]

Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with FTIs

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. Lamin A does not appear to be necessary for life; mice in which the Lmna gene is knocked out show no embryological symptoms (they develop an EmeryDreifuss muscular dystrophy-like condition postnatally).[42] This implies 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. 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 deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects".[43]

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.[44] Charles Dickens may have described a case of progeria in the Smallweed family of Bleak House, specifically in the grandfather and his grandchildren, Judy and twin brother Bart.[45] A Bollywood movie, Paa, was made about the condition; in it, the lead (Amitabh Bachchan) played a 13-yearold child affected by progeria. The 2006 movie Renaissance deals with progeria. The 1996 movie Jack deals with the eponymous character, played by Robin Williams, who has a genetic disorder similar to progeria, and the difficulties he faces fitting into society. The 1983 film The Hunger, starring David Bowie, Catherine Deneuve and Susan Sarandon had progeria as a focus of study by Susan Sarandon's character, Dr. Sarah Roberts. "Young at Heart," the sixteenth episode of the first season of the television show The X-Files, features a violent criminal who has seemingly grown younger due to treatment by a corrupt doctor, who had developed his technique by experimenting on progeria sufferers. In the 4-book series Otherland, by Tad Williams, one of the main characters suffers from progeria. Harold Kushner's 1978 book When Bad Things Happen to Good People, which explores God and the problem of evil, was written in response to his 14-year-old son's death due to progeria. South African artist/hip hop artist Leon Botha was one of the oldest known Progeria sufferers, surviving to the age of 26 before his death in June 2011. In the Star Trek: Voyager episode "Scientific Method", the main character Chakotay begins to rapidly age as a result of an alien science experiment, which the crew are unaware is occurring. Progeria is posited as one possible cause to the rapid aging, but The Doctor notes that there had never been an adult case, and that the disorder had supposedly been eradicated sometime during the 22nd century, approximately 200 years before the events of that episode. Life According to Sam was a 2013 documentary on Foxborough High School (Boston, Massachusetts) student Sam Berns (age 17, when he died of the disease, January 10, 2014, and a fan of the New England Patriots had he lived another day, he would have served as the team's honorary captain in their playoff game versus the

Indianapolis Colts).[46] Produced by Sean Fine and Andrea Nix, it explains progeria and follows the process of finding a cure for it.[47] In an interview, Sam Berns had said that the most important thing people should know about him is that he had a very happy life.[48]

See also
Biogerontology Sam Berns, a Massachusetts boy who suffered from progeria and helped raise awareness of the disease. Degenerative disease Hayley Okines, an English girl with progeria known for spreading awareness Laminopathies Lipodystrophy Lizzie Velsquez, an American motivational speaker whose medical condition approximates neonatal progeroid syndrome

References
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36. ^ M. Eriksson et al. (2003). "Recurrent de novo point mutations in lamin A cause HutchinsonGilford progeria syndrome" (http://www.nature.com/nature/journal/v423/n6937/pdf/nature01629.pdf) (PDF). Nature 423 (6937): 293 298. doi:10.1038/nature01629 (http://dx.doi.org/10.1038%2Fnature01629). PMID 12714972 (//www.ncbi.nlm.nih.gov/pubmed/12714972). 37. ^ "Family Crisis Becomes Scientific Quest (http://www.sciencemag.org/content/vol300/issue5621/r-samples.dtl)", Science, 300(5621), 9 May 2003. 38. ^ Lans H, Hoeijmakers JH (2006). "Cell biology: ageing nucleus gets out of shape". Nature 440 (7080): 324. doi:10.1038/440032a (http://dx.doi.org/10.1038%2F440032a). PMID 16511477 (//www.ncbi.nlm.nih.gov/pubmed/16511477). 39. ^ Scaffidi P, Misteli T (May 19, 2006). "Lamin A-dependent nuclear defects in human aging" (//www.ncbi.nlm.nih.gov/pmc/articles/PMC1855250). Science 312 (5776): 105963. doi:10.1126/science.1127168 (http://dx.doi.org/10.1126%2Fscience.1127168). PMC 1855250 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC1855250). PMID 16645051 (//www.ncbi.nlm.nih.gov/pubmed/16645051). 40. ^ Haithcock E, Dayani Y, Neufeld E, et al. (2005). "Age-related changes of nuclear architecture in Caenorhabditis elegans" (http://www.pnas.org/cgi/content/full/102/46/16690). Proc. Natl. Acad. Sci. U.S.A. 102 (46): 166905. doi:10.1073/pnas.0506955102 (http://dx.doi.org/10.1073%2Fpnas.0506955102). PMC 1283819 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC1283819). PMID 16269543 (//www.ncbi.nlm.nih.gov/pubmed/16269543). 41. ^ Fong, L. G. et al. (March 17, 2006). "A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria" (http://www.sciencemag.org/cgi/content/abstract/1124875v1). Science 311 (5767): 16213. doi:10.1126/science.1124875 (http://dx.doi.org/10.1126%2Fscience.1124875). PMID 16484451 (//www.ncbi.nlm.nih.gov/pubmed/16484451). 42. ^ Sullivan et al. (November 29, 1999). "Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy" (//www.ncbi.nlm.nih.gov/pmc/articles/PMC2169344). J Cell Biol. 147 (5): 91320. doi:10.1083/jcb.147.5.913 (http://dx.doi.org/10.1083%2Fjcb.147.5.913). PMC 2169344 (//www.ncbi.nlm.nih.gov/pmc/articles/PMC2169344). PMID 10579712 (//www.ncbi.nlm.nih.gov/pubmed/10579712). 43. ^ Varela I, Pereira S, Ugalde AP, et al. (2008). "Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging" (http://www.nature.com/nm/journal/v14/n7/abs/nm1786.html). Nat. Med. 14 (7): 76772. doi:10.1038/nm1786 (http://dx.doi.org/10.1038%2Fnm1786). PMID 18587406 (//www.ncbi.nlm.nih.gov/pubmed/18587406). 44. ^ Maloney WJ (October 2009). "Hutchinson-Gilford Progeria syndrome: its presentation in F. Scott Fitzgerald's short story 'The Curious Case of Benjamin Button' and its oral manifestations" (http://jdr.sagepub.com/content/88/10/873.full). J. Dent. Res. 88 (10): 8736. doi:10.1177/0022034509348765 (http://dx.doi.org/10.1177%2F0022034509348765). PMID 19783794 (//www.ncbi.nlm.nih.gov/pubmed/19783794). 45. ^ Singh V (2010). "Reflections: neurology and the humanities. Description of a family with progeria by Charles Dickens". Neurology 75 (6): 571. doi:10.1212/WNL.0b013e3181ec7f6c (http://dx.doi.org/10.1212%2FWNL.0b013e3181ec7f6c). PMID 20697111 (//www.ncbi.nlm.nih.gov/pubmed/20697111). 46. ^ Greg Botelho: "Beloved teen Sam Berns dies at 17 after suffering from rare disease (http://edition.cnn.com/2014/01/11/us/progeria-sam-berns-dies/index.html)", CNN, 12 January 2014. 47. ^ HBO Documentaries: Life According to Sam (http://www.hbo.com/documentaries/life-according-to-sam). 48. ^ Sam Berns: My philosophy for a happy life (http://www.youtube.com/watch?v=36m1o-tM05g). TEDxMidAtlantic 2013.

External links
Progeria : Aging starts in childhood (http://medchrome.com/major/paediatrics/progeria/) Progeria Research Foundation (http://www.progeriaresearch.org/) Progeria News and Media Collection (http://www.progeria.ca/) GeneReview/NIH/UW entry on HutchinsonGilford progeria syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1121/) Segmental progeria (http://www.benbest.com/lifeext/aging.html#progeria) "ABC 20/20 special news program about Progeria, with Barbara Walters" (http://abcnews.go.com/2020/barbara-walters-progeria-special-young-girls-living-progeria/story? id=11586041) Retrieved from "http://en.wikipedia.org/w/index.php?title=Progeria&oldid=600316841"

Categories: Ageing Genodermatoses Gerontology Progeroid syndromes Rare diseases Senescence This page was last modified on 19 March 2014 at 15:25. Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.

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Researchers have discovered a single gene mutation responsible for Hutchinson-Gilford progeria syndrome. The gene is known as lamin A (LMNA), which makes a protein necessary for holding the center (nucleus) of a cell together. Researchers believe the genetic mutation renders cells unstable, which appears to lead to progeria's characteristic aging process. Unlike many genetic mutations, Hutchinson-Gilford progeria isn't passed down in families. Rather, the gene change is a chance occurrence that researchers believe affects a single sperm or egg just before conception. Neither parent is a carrier, so the mutations in the children's genes are new (de novo).

Other similar syndromes

There are, however, other progeroid syndromes that run in families. They include WiedemannRautenstrauch syndrome and Werner syndrome. In Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, onset of aging begins in the womb, and signs and symptoms are apparent at birth. Werner syndrome begins in adolescence or early adulthood. These inherited progeroid syndromes also cause rapid aging and shortened life span.

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Appointments at Mayo Clinic

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Diseases and Conditions

Progeria
SECTIONS

Causes
By Mayo Clinic Staff

Researchers have discovered a single gene mutation responsible for Hutchinson-Gilford progeria syndrome. The gene is known as lamin A (LMNA), which makes a protein necessary for holding the center (nucleus) of a cell together. Researchers believe the genetic mutation renders cells unstable, which appears to lead to progeria's characteristic aging process. Unlike many genetic mutations, Hutchinson-Gilford progeria isn't passed down in families. Rather, the gene change is a chance occurrence that researchers believe affects a single sperm or egg just before conception. Neither parent is a carrier, so the mutations in the children's genes are new (de novo).

Other similar syndromes

There are, however, other progeroid syndromes that run in families. They include WiedemannRautenstrauch syndrome and Werner syndrome. In Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, onset of aging begins in the womb, and signs and symptoms are apparent at birth. Werner syndrome begins in adolescence or early adulthood. These inherited progeroid syndromes also cause rapid aging and shortened life span.

Symptoms

Complications

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Apr. 23, 2011

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See also
Coronary bypass surgery Coronary bypass surgery Angioplasty Coronary angioplasty New Route to the Heart Genetic testing Mapping the Genome
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Check out these best-sellers and special offers on books and newsletters from Mayo Clinic. Try Mayo Clinic Health Letter FREE! The best arthritis treatments for a more comfortable and active life Get a better night's sleep with this three-step action plan Living with chronic pain? Mayo Clinic can help The Mayo Clinic Diet Eat well. Enjoy life. Lose weight.

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Indian J Orthop. 2008 Jan-Mar; 42(1): 9799. doi: 10.4103/0019-5413.38591 PMCID: PMC2759591

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Progeria syndrome: A case report

Rajul Rastogi and SM Chander Mohan1
Author information ! Copyright and License information ! This article has been cited by other articles in PMC.

Hutchinson-Gilford progeria syndrome in siblings. Report of three [Skeletal new cases. Radiol. 1990] Hutchinson-Gilford progeria syndrome accompanied by severe [J Med skeletal Case Rep. 2013] abnormalities in two Chinese siblings: two Progeria (Hutchison-Gilford syndrome) in siblings: [Indian in J an Dermatol autosomal Venereol recessive Leprol. pattern 2001] of inheritance. The Hutchinson-Gilford Progeria Syndrome: a case report. [Minerva Anestesiol. 2010] [Gilford progeria. A case report]. [Ann Med Interne (Paris). 1999]
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Abstract

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Progeria is a rare and peculiar combination of dwarfism and premature aging. The incidence is one in several million births. It occurs sporadically and is probably an autosomal recessive syndrome. Though the clinical presentation is usually typical, conventional radiological and biochemical investigations help in confirming the diagnosis. We present a rare case of progeria with most of the radiological features as a pictorial essay. Keywords: Acrogeria, dwarfism, progeria

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Hutchinson-Gilford Progeria Syndrome with G608G [Journal LMNA of Korean Mutation Medical Science. 2011]
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INTRODUCTION

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Progeria is a rare combination of dwarfism and premature aging. The classic form is known as Hutchinson-Gilford syndrome. It occurs sporadically with a reported incidence of one in eight million births and male predominance with M:F ratio of 1.5:1 and a strong racial susceptibility for Caucasians who represent 97% of patients.1

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A 14-year-old girl child presented with progressive history of coarsening of skin, failure to thrive and inability to squat for the past three to four years. The child had also developed global alopecia over the past few years. The perinatal history was uneventful. She was apparently normal till one year of age when the parents started noticing the above features. She had normal intelligence. No family history of similar complaints could be elicited. General examination revealed the child to be of short stature and malnourished. Eyes appeared prominent with hypoplastic chin. Multiple patches of coarse and thickened skin, especially over the dorsum of the hands and shoulders. The terminal ends of the fingers appeared broad and stubby. Based on the history and clinical findings a provisional diagnosis of progeria was made. Biochemical investigations were normal except for increased serum cholesterol and increased urinary excretion of hyaluronic acid. To confirm the diagnosis, the child was subjected to a skeletal survey.

Progeria syndrome: A case report

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Radiographs of the skull showed diastasis of the sagittal suture with numerous wormian bones [Figure 1]. Radiograph of the mandible showed the hypoplastic mandible with infantile angle [Figure 2]. Radiograph of the chest showed sloping ribbon-like ribs with thinning of both third ribs posteriorly. The lateral half of both the clavicles was absent [Figure 3]. Radiograph of the dorsal spine in the lateral projection showed presence of fish mouth vertebrae [Figure 4 ]. Pelvis radiograph in AP projection presence of bilateral coxa valga deformity [Figure 5]. Radiograph of the hands and feet revealed resorption of terminal phalanges [Figures 6and7]. The bone age however corresponded to the chronological age of the patient. The radiological findings confirmed the clinical diagnosis of progeria. Figure 1 X-ray of the skull, AP (a) and Lateral (b) views showing multiple wormian bones, diastasis of the sagittal suture (a) and prominent vascular markings (b) Figure 2 Lateral radiograph of the mandible shows small mandible with small ascending ramus and infantile obtuse angle Figure 3 Radiograph of the chest shows absence of the lateral half of the clavicle and thin ribbon-like third rib on both sides Figure 4 Focused lateral radiograph of the dorsal spine shows fishmouth vertebra

Figure 5 Radiograph of both hips shows severe coxa valga Figure 6 Radiograph of both hands shows acroosteolysis Figure 7 Radiograph of both feet shows acroosteolysis

Review Progeria: a human-disease model of accelerated aging. [Am J Clin Nutr. 1992] LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria [J syndrome. Med Genet. 2004] Review The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the [J literature. Pediatr. 1972] Review Aging and nuclear organization: lamins and progeria. [Curr Opin Cell Biol. 2004] Urinary hyaluronic acid elevation in HutchinsonGilford progeria syndrome.[Mech Ageing Dev. 1986]

DISCUSSION

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Progeria is a genetic disorder rarely encountered and is characterized by features of premature aging.2 It is also known as Hutchinson-Gilford Progeria syndrome. In this syndrome, the rate of ageing is accelerated up to seven times that of normal. The average life span is 13 years (range 7-27 years) occasional survival till the age of 45 years.3 The death is mainly due to cardiovascular
1

Review Hutchinson-Guilford progeria syndrome. [Postgrad Med J. 2001] Review The Hutchinson-Gilford progeria syndrome.

complications like myocardial infarction or congestive heart failure.1 The probable cause is a mutation in the Lamin located in the nuclear matrix.4 Increase in the blood hyaluronic acid levels is responsible for sclerodermatous changes and cardiovascular abnormalities. In progeria, rise in blood and serum levels of low-density lipoprotein and cholesterol and total lipids is commonly seen. Failure to thrive may be seen possibly due to a bioinactive growth hormone and lack of vasculogenesis caused by excessive excretion of hyaluronic acid.5 The affected children are normal at birth and grow normally till about the end of the first year, when both normal growth and gain in weight slow down. At the end of the first decade, the size attained is that of a normal child of three years of age. Loss of hairs and subcutaneous fat along with sclerodermatous changes give rise to characteristic plucked bird appearance at about 6-12 months of age. Scalp hair and eyelashes are progressively lost with increased prominence of scalp veins. The affected child is short statured and underweight with an average height of 100 cm and average weight of 12-15 kg or even less.6 Progressive degenerative changes occur in the skeleton and blood vessels with advancing age. Delayed eruption and abnormal dentition is also common. The typical horse-riding stance described in literature is due to the coxa valga deformity. Bone age is normal but mental age may be higher.1 Skeletal survey of the patients reveals the following radiological features:7 The calvarium is thin and relatively large and the diploic space is absent or very shallow; the face is small with a disproportionate small mandible that retains its infantile obtuse angle. The ascending rami of the mandible are very short. Closure of the anterior fontanelle is delayed. Vascular markings and wormian bones are conspicuous in the large thin calvaria. The clavicles are small in caliber and rarefied at birth; during childhood they may disappear in part or in toto due to progressive osteolysis and fibrosis. The ribs are abnormally gracile and the posterior segments of the upper four ribs on both sides may also disappear in early childhood. The long bones are shortened and overconstricted in their central segments and demonstrate flares at the ends. Coxa valga deformity may be marked, with the neck continuing in the axis of the femoral shafts; the femoral heads are only partially in their acetabular fossae. The greater trochanters are bizarre in shape and position. Some carpal ossification centers are sclerotic, while others participate in the general osteopenia. There may be a marked delay in the healing of fractures and nonunion. Other features include occasional acro-osteolysis and persistence of anterior vascular channels in vertebral bodies. The differential diagnosis includes Werner syndrome (WS), Acrogeria, Rothmund-Thomson syndrome (RTS) and Cockayne syndrome (CS). Werner syndrome is also known as progeria adultorum, progeria of the adult and pangeria. It is the most common of the premature aging disorders. The onset might occur in individuals in their mid-teens or it may be delayed until an individual is as old as 30 years. Both sexes are affected equally. Death usually occurs when patients are aged 30-50 years because of atherosclerosis or malignant tumors. Acrogeria is a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in the Hutchinson-Gilford progeria syndrome. It is seen mainly in females and in the form of sporadic cases.

Review The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the [J literature. Pediatr. 1972]

Skeletal abnormalities of acrogeria, a progeroid syndrome. [Skeletal Radiol. 1987]

Familial cases are also seen (Gottron type). Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses and antegonial notching of the mandible are the predominant skeletal features of the disorder.8 Rothmund-Thomson syndrome is a hereditary and familial disease characterized by short stature, cataracts, pigmentation of skin, baldness, abnormalities of bones, nails and teeth. Cockayne syndrome spans a spectrum that includes CS Type 1, the classic form; CS Type 2, a more severe form with symptoms present at birth (i.e. cerebrooculofacial-skeletal [COFS] syndrome, Pena-Shokeir Type 2 syndrome); CS Type 3, a milder form; and xeroderma pigmentosa-Cockayne syndrome (XP-CS). Cockayne syndrome Type 1 and Type 2 are autosomal recessive disorders that feature growth deficiency, premature aging and pigmentary retinal degeneration along with a complement of other clinical findings. Type 1 presents at birth, whereas Type 2 appears during early childhood. Fatality usually occurs in early adolescence, but some patients survive until early adulthood. Till date, no definitive therapy is available and the patient is generally treated conservatively.

Footnotes
Source of Support: Nil Conflict of Interest: None.

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REFERENCES

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1. DeBusk FL. The Hutchinson-Gilford progeria syndrome: Report of 4 cases and review of the literature. J Pediatr. 1972;80:697724. [PubMed] 2. Brown WT. Progeria: A human disease model of accelerated aging. Am J Clin Nutr. 1992;55:1222S4S. [PubMed] 3. Fukuchi K, Katsuya T, Sugimoto K, Kuremura M, Kim HD, Li L, Ogihara T. LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J Med Genet. 2004;41:e67. [PMC free article] [PubMed] 4. Mounkes LC, Stewart CL. Aging and nuclear organization: Lamins and progeria. Curr Opin Cell Biol. 2004;16:3227. [PubMed] 5. Zebrower M, Kieras FJ, Brown WT. Urinary hyaluronic acid elevation in Hutchinson-Guilford progeria syndrome. Mech Ageing Dev. 1986;35:3946. [PubMed] 6. Sarkar PK, Shinton RA. Hutchinson-Guilford progeria syndrome. Postgrad Med J. 2001;77:3127. [PMC free article] [PubMed] 7. Silverman FN. Miscellaneous forms of short stature. In: Silverman FN, Kuhn JP, editors. Caffey's pediatric X-ray diagnosis: An integrated imaging approach. Mosby; 1993. pp. 17257. 8. Ho A, White SJ, Rasmussen JE. Skeletal abnormalities of acrogeria: A progeroid syndrome. Skeletal Radiol. 1987;16:4638. [PubMed]
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