|
|
| (3 intermediate revisions by 2 users not shown) |
| Line 1: |
Line 1: |
| '''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
| | __NOTOC__ |
| {{Infobox Disease | | | {{Progeria}} |
| Name = Progeria |
| | {{CMG}}; {{AE}} {{VKG}} |
| Image = |
| |
| Caption = |
| |
| DiseasesDB = 10704 |
| |
| ICD10 = {{ICD10|E|34|8|e|20}} |
| |
| ICD9 = {{ICD9|259.8}} |
| |
| ICDO = |
| |
| OMIM = 176670 |
| |
| MedlinePlus = |
| |
| eMedicineSubj = derm |
| |
| eMedicineTopic = 731 |
| |
| MeshID = D011371 |
| |
| }}
| |
| {{SI}} | |
| {{EH}} | |
|
| |
|
| '''Progeria''' is a condition that resembles premature aging <ref>{{Stedman's|1556196|Progeria}}</ref> which usually refers specifically to '''Hutchinson-Gilford Progeria syndrome'''.
| | {{SK}}Hutchinson-Gilford progeria syndrome, HGPS,Hutchinson-Gilford syndrome, premature aging syndrome, progeria of childhood |
|
| |
|
| Hutchinson-Gilford Progeria syndrome is an extremely rare condition where symptoms resembling some aspects of [[Senescence|aging]] are manifested at an early age, and few affected children live past age 13. About 1 in 8 million babies are born with this condition. It is a [[Genetic disorder|genetic condition]], but occurs sporadically and is usually not inherited in families.
| | ==[[Progeria overview|Overview]]== |
|
| |
|
| Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.<ref name="pmid18060063">{{cite journal |author=McClintock D, Ratner D, Lokuge M, ''et al'' |title=The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin |journal=[[PLoS ONE]] |volume=2 |issue=12 |pages=e1269 |year=2007 |pmid=18060063 |doi=10.1371/journal.pone.0001269 |url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001269}}</ref><ref name=Kork08>{{cite journal |author=Korf B |title=Hutchinson-Gilford progeria syndrome, aging, and the nuclear lamina |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=552–5 |year=2008 |pmid=18256390 |doi=10.1056/NEJMp0800071 |url=http://content.nejm.org/cgi/content/full/358/6/552}}</ref><ref>{{cite journal |author=Merideth MA, Gordon LB, Clauss S, ''et al'' |title=Phenotype and course of Hutchinson-Gilford progeria syndrome |journal=N. Engl. J. Med. |volume=358 |issue=6 |pages=592–604 |year=2008 |pmid=18256394 |doi=10.1056/NEJMoa0706898 |url=http://content.nejm.org/cgi/content/full/358/6/59}}</ref>
| | ==[[Progeria historical perspective|Historical Perspective]]== |
|
| |
|
| ==Symptoms== | | ==[[Progeria classification|Classification]]== |
| The earliest symptoms include [[failure to thrive]] (FTT) and a localized [[scleroderma]]-like skin condition. As the child ages past infancy, additional conditions become apparent. Limited growth, [[alopecia]], and a distinctive appearance with small face and jaw and pinched nose all are characteristic of progeria. The people diagnosed with this disease usually have small, fragile bodies like those of elderly people.
| |
|
| |
|
| Later the condition causes wrinkled skin, [[atherosclerosis]] and [[cardiovascular]] problems.
| | ==[[Progeria pathophysiology|Pathophysiology]]== |
|
| |
|
| ==Cause== | | ==[[Progeria causes|Causes]]== |
| Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by mutations in one of the major architectural proteins of the cell nucleus.
| |
|
| |
| Unlike most other "[[DNA repair-deficiency disorder|accelerated aging diseases]]" (such as [[Werner's syndrome]], [[Cockayne's syndrome]] or [[xeroderma pigmentosum]]), progeria is not caused by defective [[DNA repair]]. Because these "accelerated aging" diseases display different aspects of aging, but never every aspect, they are often called "segmental progerias".
| |
|
| |
|
| ==Diagnosis== | | ==[[Progeria differential diagnosis|Differentiating Progeria from other Diseases]]== |
| [[Image:Hutchinson-Gilford Progeria Syndrome.png|200px|thumb|left| | |
| In HGPS patients, the cell nucleus has dramatically aberrant morphology (bottom, right) rather than the uniform shape typically found in healthy individuals (top, right)]]
| |
|
| |
|
| 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.<ref name="titlegenome.gov | Learning About Progeria">{{cite web |url=http://www.genome.gov/11007255#isthere |title=genome.gov | Learning About Progeria |accessdate=2008-03-17 |format= |work=}}</ref>
| | ==[[Progeria epidemiology and demographics|Epidemiology and Demographics]]== |
|
| |
|
| | ==[[Progeria risk factors|Risk Factors]]== |
|
| |
|
| ==Treatment== | | ==[[Progeria screening|Screening]]== |
| No treatments have been proven effective. Most treatment focuses on reducing complications such as cardiovascular disease, such as [[heart bypass]] surgery or low-dose [[aspirin]].<ref name="titleProgeria: Treatment - MayoClinic.com">{{cite web |url=http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=7 |title=Progeria: Treatment - MayoClinic.com |accessdate=2008-03-17 |format= |work=}}</ref> Children may also benefit from a high-calorie diet.
| |
|
| |
|
| [[Growth hormone treatment]] has been attempted.<ref name="pmid17642424">{{cite journal |author=Sadeghi-Nejad A, Demmer L |title=Growth hormone therapy in progeria |journal=[[J. Pediatr. Endocrinol. Metab.]] |volume=20 |issue=5 |pages=633–7 |year=2007 |pmid=17642424 |doi=}}</ref> | | ==[[Progeria natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
|
| |
|
| A type of anti-cancer drug, the [[farnesyltransferase inhibitor]]s (FTIs), have been proposed, but their use has been mostly limited to animal models.<ref name="pmid16942914">{{cite journal |author=Meta M, Yang SH, Bergo MO, Fong LG, Young SG |title=Protein farnesyltransferase inhibitors and progeria |journal=[[Trends Mol Med]] |volume=12 |issue=10 |pages=480–7 |year=2006 |pmid=16942914 |doi=10.1016/j.molmed.2006.08.006 |url=http://linkinghub.elsevier.com/retrieve/pii/S1471-4914(06)00175-4}}</ref> A phase II clinical trial using the FTI [[Lonafarnib]] began in May 2007.<ref name="ls1">{{cite web | url=http://clinicaltrials.gov/ct2/show/NCT00425607?term=progeria&rank=2 | title=Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria | pmid=ls1 |doi=}}</ref>
| | ==Diagnosis== |
| | [[Progeria diagnostic study of choice|Diagnostic study of choice]] | [[Progeriahistory and symptoms|History and Symptoms]] | [[Progeria physical examination|Physical Examination]] | [[Progeria laboratory findings|Laboratory Findings]] | [[Progeria electrocardiogram|Electrocardiogram]] | [[Progeria x ray|X-Ray Findings]] | [[Progeria echocardiography and ultrasound|Echocardiography and Ultrasound]] | [[Progeria CT scan|CT-Scan Findings]] | [[Progeria MRI|MRI Findings]] | [[Progeria other imaging findings|Other Imaging Findings]] | [[Progeria other diagnostic studies|Other Diagnostic Studies]] |
|
| |
|
| ==Prognosis== | | ==Treatment== |
| There is no known cure. Few people with progeria exceed 13 years of age.<ref name="USA T">{{cite web | url=http://www.usatoday.com/news/science/2003-04-16-agin-gene_x.htm | title=Gene found for rapid aging disease in children | author=Steve Sternberg | date=April 16, 2003 | publisher=USA Today | accessdate=2006-12-13 }}</ref> At least 90% of patients die from complications of [[atherosclerosis]], such as heart attacks or strokes.<ref name="titleProgeria - MayoClinic.com">{{cite web |url=http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=1 |title=Progeria - MayoClinic.com |accessdate=2008-03-17 |format= |work=}}</ref>
| | [[Progeria medical therapy|Medical Therapy]] | [[Progeria interventions|Interventions]] | [[Progeria surgery|Surgery]] | [[Progeria primary prevention|Primary Prevention]] | [[Progeria secondary prevention|Secondary Prevention]] | [[Progeria cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Progeria future or investigational therapies|Future or Investigational Therapies]] |
| | |
| Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no [[neurodegeneration]] or [[cancer]] predisposition. They do not develop "wear and tear" conditions commonly associated with aging, like [[cataracts]] and [[osteoarthritis]].<ref name="titlegenome.gov1 | Learning About Progeria">{{cite web |url=http://www.genome.gov/11007255#isthere |title=genome.gov | Learning About Progeria |accessdate=2008-03-17 |format= |work=}}</ref>
| |
| | |
| ==Epidemiology==
| |
| One study from the Netherlands has shown an incidence of 1 in 4 million births.<ref name="pmid16838330">{{cite journal |author=Hennekam RC |title=Hutchinson-Gilford progeria syndrome: review of the phenotype |journal=[[Am. J. Med. Genet. A]] |volume=140 |issue=23 |pages=2603–24 |year=2006 |pmid=16838330 |doi=10.1002/ajmg.a.31346 |doi=10.1002/ajmg.a.31346}}</ref> Currently, there are 48 known cases in the world. Approximately 100 cases have been formally identified in medical history.<ref>{{cite web |url=http://www.mayoclinic.com/health/progeria/DS00936 |title=Progeria - MayoClinic.com |accessdate=2008-02-06 |format= |work=}}</ref><ref name="USA T"/>
| |
| | |
| Classical Hutchinson–Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. There has been one case in which became evident that a healthy parent can carry the LMNA-mutation that causes progeria in her or his egg- or spermcells. In this case two siblings were born with HGPS.
| |
| But Hutchinson–Gilford Progeria Syndrome is usually [[genetic dominance|genetically dominant]], therefore parents who are healthy will normally not pass it on to their children. <ref name=Kork08/> Affected children do not live long enough to have children themselves.
| |
| | |
| However, there are milder cases in which either the gene is not expressed in parents, or a different gene is responsible for a different form of progeria, and healthy parents can pass on their children.
| |
| | |
| Four families have been identified as having more than one child with the disease.<ref>[http://www.progeria.be/index_EN.php Progeria.be - Home]</ref>
| |
| | |
| == Research areas ==
| |
| Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.<ref name="pmid17615378">{{cite journal |author=Capell BC, Collins FS, Nabel EG |title=Mechanisms of cardiovascular disease in accelerated aging syndromes |journal=[[Circ. Res.]] |volume=101 |issue=1 |pages=13–26 |year=2007 |pmid=17615378 |doi=10.1161/CIRCRESAHA.107.153692 |url=http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=17615378}}</ref>
| |
| | |
| A 2003 report in Nature<ref>{{cite journal |author=M. Eriksson et al. |title= Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome |journal=[[Nature]] |volume=423 |pages=293–298 |year=2003 |url=http://www.nature.com/nature/journal/v423/n6937/pdf/nature01629.pdf}}</ref> said progeria may be a [[De novo mutation|de novo]] [[dominant trait]]. It develops during [[cell division]] in a newly conceived zygote or in the [[gamete]]s of one of the parents. It is caused by [[mutation]]s in 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 didn't 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.<ref>[http://www.sciencemag.org/content/vol300/issue5621/r-samples.dtl Family Crisis Becomes Scientific Quest, Science, 300(5621), 9 May 2003]</ref>
| |
| | |
| ===Lamin A===
| |
| [[Nuclear lamina]] is a protein [[scaffold]] on the inner edge of the [[cell nucleus|nucleus]] 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]] [[list of standard amino acids|amino acids]]). This ensures that the cysteine is [[prenylation|farnesylated]], and this allows preLamin A to bind [[Cell membrane|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 is 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]].<ref>{{cite journal |author=Lans H, Hoeijmakers JH |title=Cell biology: ageing nucleus gets out of shape |journal=Nature |volume=440 |issue=7080 |pages=32–4 |year=2006 |pmid=16511477 |doi=10.1038/440032a |url=}}</ref> This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.
| |
| | |
| A study which 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]].<ref>{{cite journal | author=Scaffidi P, Misteli T | title=Lamin A-dependent nuclear defects in human aging | journal= [[Science (journal)|Science]] | year=2006 | date=May 19, 2006 | volume=312 | issue=5776 | pages=1059–63 | pmid=16645051}}</ref> [[Nematode]]s over their lifespan show progressive lamin changes comparable to HGPS in all cells but [[neuron]]s and [[gamete]]s.<ref name="pmid16269543">{{cite journal |author=Haithcock E, Dayani Y, Neufeld E, ''et al'' |title=Age-related changes of nuclear architecture in Caenorhabditis elegans |journal=[[Proc. Natl. Acad. Sci. U.S.A.]] |volume=102 |issue=46 |pages=16690–5 |year=2005 |pmid=16269543 |doi=10.1073/pnas.0506955102 |url=http://www.pnas.org/cgi/content/full/102/46/16690}}</ref> These studies suggest that lamin A defects contribute to normal [[senescence|aging]].
| |
| | |
| ===Mouse model of progeria===
| |
| A mouse model of progeria exists, though in the mouse the LMNA preLamin A is not mutated, but instead [[ZMPSTE24]], the specific protease that is required to remove the C-terminus of preLamin A is missing. Both cases result in the build up 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, lower likelihood of [[rib fracture]] and may live longer than untreated mice.<ref>{{cite journal | author=Loren G. Fong| title=A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria | journal= [[Science (journal)|Science]] | year=2006 | date=March 17, 2006 | volume=311 | issue=5767 | pages=1621–3| url=http://www.sciencemag.org/cgi/content/abstract/1124875v1 |pmid=16484451}}</ref>
| |
| | |
| This method does not directly 'cure' the underlying cause of progeria. This method prevents Prelamin A going to the nucleus in the first place so 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. This also shows that it is the build up 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 FFI such as [[alendronate]] is inefficient due to [[prenylation]] by [[geranylgeranyltransferase]]. Since [[statins]] inhibit geranylgeranyltransferase, the combination of an FFI 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". <ref>{{cite journal |author=Varela I, Pereira S, Ugalde AP, ''et al'' |title=Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging |journal=Nat. Med. |volume=14 |issue=7 |pages=767–72 |year=2008 |pmid=18587406 |doi=10.1038/nm1786 |url=http://www.nature.com/nm/journal/v14/n7/abs/nm1786.html}}</ref>
| |
| | |
| ==History==
| |
| Progeria was first described in 1886 by [[Jonathan Hutchinson]]<ref>{{cite journal |author=Hutchinson J |title=Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six |journal=Lancet |year=1886 |volume=I |issue= |pages=923 |pmid=}}</ref> and also described independently in 1897 by Hastings Gilford.<ref>{{cite journal |author=Gilford H |title=Ateleiosis and progeria: continuous youth and premature old age |journal=Brit. Med. J. |year=1904 |volume=2 |issue= |pages=914–8 |pmid=}}</ref> The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS). | |
| | |
| ==Cultural references==
| |
| * In the TV series Dark Angel some of the transgenics suffer from a condition similar to progeria due to a genetic anomaly.
| |
| * The character Orlando Gardiner in the Otherland series of four books by Tad Williams suffers from progeria.
| |
| * In the play, ''Kimberly Akimbo'', the character Kimberly Levaco has progeria.
| |
| * In the movie ''Renaissance'', a science fiction speculation is made on progeria as the holy grail for the discovery of the genetic key to immortality.
| |
| * In the TV series Strange a demon called Zoxim is said to cause rapid aging through the progeria.
| |
| * In the novel ''Haunted'', the character Brandon Whittier suffers from progeria.
| |
| * In the television series The X-Files episode Young At Heart the plot involves a doctor working on patients with progeria.
| |
| * The main character in the movie Jack has a fake and exaggerated form of progeria, with Jack aging four times faster than usual, but otherwise normally. That is, he looks exactly like a 40 year old man at age 10.
| |
| * Experiments gone wrong lead to an extremely accelerated form of progeria in the new 2008 TV series FRINGE.
| |
| * In the film ''The Hunger'', Susan Sarandon's character is a scientist who is interested in the disease.
| |
| | |
| ==See also==
| |
| * [[Biogerontology]]
| |
| * [[Degenerative disease]]
| |
| * [[Farnsyltransferase]]
| |
| * [[Genetic disorder]]
| |
| * [[Laminopathies]]
| |
| * [[Werner syndrome]]
| |
| | |
| ==References==
| |
| {{reflist|2}}
| |
| | |
| ==External links==
| |
| * [http://seattlepi.nwsource.com/specials/seth/190908_progeriamain.asp "A Time to Live"] – Seattle Post-Intelligencer feature about Seth Cook, a child with Progeria.
| |
| * [http://seattlepi.nwsource.com/local/321200_seth26.html "Seth Cook, 1993-2007"] – Seattle Post-Intelligencer obituary for Seth Cook.
| |
| * [http://www.channel4.com/health/microsites/0-9/80_year_old_children/index.html Bodyshock: The 80-Year-Old Children]
| |
| * [http://www.mymultiplesclerosis.co.uk/misc/hayleyokines.html The Girl who is older than her Grandmother]
| |
| * [http://news.bbc.co.uk/2/hi/south_asia/4286347.stm "Family tormented by ageing disease"] – BBC News article on a family with Progeria; cites study that progeria is inheritable.
| |
| * [http://www.progeriaresearch.org/ Progeria Research Foundation]
| |
| * [http://www.progeria.ca/ Progeria News and Media Collection]
| |
| * [http://www.benbest.com/lifeext/aging.html#progeria Segmental Progeria]
| |
| * [http://deltaboost.blogspot.com/2006/03/news-farnesyl-transferase-inhibitors.html Farnesyl transferase inhibitors may help children with Hutchinson-Gilford progeria] – Article on the use of FTI inhibitors as potential treatment
| |
| * [http://www.fli-leibniz.de/index_en.php Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI)]
| |
| | |
| {{Endocrine pathology}}
| |
| {{SIB}}
| |
| | |
| [[Category:Aging]]
| |
| [[Category:Gerontology]]
| |
| [[Category:Genetic disorders]]
| |
| [[Category:Rare diseases]]
| |
|
| |
|
| [[be-x-old:Прагерыя]]
| | ==Case Studies== |
| [[da:Progeria]]
| | [[Progeria case study one|Case #1]] |
| [[de:Progerie]]
| |
| [[et:Progeeria]]
| |
| [[es:Progeria]]
| |
| [[fr:Progéria]]
| |
| [[it:Progeria]]
| |
| [[he:פרוגריה]]
| |
| [[nl:Progeria]]
| |
| [[ja:ハッチンソン・ギルフォード・プロジェリア症候群]]
| |
| [[pl:Progeria]]
| |
| [[pt:Progeria]]
| |
| [[ro:Progeria]]
| |
| [[ru:Прогерия]]
| |
| [[sl:Progerija]]
| |
| [[sr:Прогерија]]
| |
| [[fi:Progeria]]
| |
| [[sv:Progeri]]
| |
| [[tr:Progeria]] | |
| [[zh:早年衰老症候群]]
| |
|
| |
|
| {{WH}}
| | [[Category: (name of the system)]] |
| {{WS}}
| |