View source for Medicine:Progeria

{{Short description|Genetic disorder that causes early aging}}
{{Infobox medical condition (new)
| name          = Progeria
| image         = Hutchinson-Gilford Progeria Syndrome.png
| caption       = A young girl with progeria (left). A healthy [[Biology:Cell nucleus|cell nucleus]] (right, top) and a progeric cell nucleus (right, bottom).
| pronounce     = {{IPAc-en|p|r|oʊ|ˈ|dʒ|ɪər|i|ə}}<ref>'''Dictionary Reference''': [http://dictionary.reference.com/browse/Progeria Progeria] {{Webarchive|url=https://web.archive.org/web/20130410001415/http://dictionary.reference.com/browse/progeria |date=2013-04-10 }}</ref><ref>'''[[Company:TheFreeDictionary.com|The Free Dictionary]]''': [http://www.thefreedictionary.com/Progeria Progeria] {{Webarchive|url=https://web.archive.org/web/20130515093101/http://www.thefreedictionary.com/progeria |date=2013-05-15 }}</ref>
| synonyms      = Hutchinson–Gilford progeria syndrome (HGPS),<ref name="Andrews">{{cite book | vauthors = James W, Berger T, Elston D |year=2005 |title=Andrews' Diseases of the Skin: Clinical Dermatology |url=https://archive.org/details/andrewsdiseasess00mdwi_659 |url-access=limited |edition=10th |page=[https://archive.org/details/andrewsdiseasess00mdwi_659/page/n584 574] |publisher=Saunders |isbn=978-0-7216-2921-6}}</ref><ref name="Bolognia">{{cite book | vauthors = Rapini RP, Bolognia JL, Jorizzo JL |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |isbn=978-1-4160-2999-1}}{{page needed|date=November 2022}}</ref> progeria syndrome,<ref name="Bolognia" /> Joseph Syndrome
| field         = Medical genetics
| symptoms      = Growth delay, short height, small face, [[Medicine:Hair loss|hair loss]]
| complications = Heart disease, [[Medicine:Stroke|stroke]], hip dislocations<ref name=NORD2014/>
| onset         = 9–24 months<ref name=NORD2014/>
| duration      = 
| causes        = [[Biology:Genetics|Genetic]]<ref name=NORD2014>{{cite web|title=Hutchinson–Gilford Progeria – NORD (National Organization for Rare Disorders)|url=https://rarediseases.org/rare-diseases/hutchinson-gilford-progeria/|website=NORD (National Organization for Rare Disorders)|access-date=21 April 2017|date=2014|archive-url=https://web.archive.org/web/20200413052258/https://rarediseases.org/rare-diseases/hutchinson-gilford-progeria/|archive-date=April 13, 2020}}</ref>
| risks         = 
| diagnosis     = Based on symptoms, genetic tests<ref name=NORD2014/>
| differential  = [[Medicine:Hallermann–Streiff syndrome|Hallermann–Streiff syndrome]], [[Medicine:Acrogeria|Gottron's syndrome]], [[Medicine:Wiedemann–Rautenstrauch syndrome|Wiedemann–Rautenstrauch syndrome]]<ref name=NORD2014/>
| prevention    = 
| treatment     = Mostly [[Medicine:Symptomatic treatment|symptomatic]]<ref name=NORD2014/>
| medication    = Lonafarnib<ref name="FDA PR 20201120">{{cite press release | title=FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies | website=U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) | date=20 November 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-hutchinson-gilford-progeria-syndrome-and-some-progeroid-laminopathies | access-date=20 November 2020}} {{PD-notice}}</ref><ref name="FDA snapshot">{{cite web | title=Drug Trials Snapshots: Zokinvy | website=U.S. Food and Drug Administration | date=20 November 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zokinvy | access-date=11 December 2020}} {{PD-notice}}</ref>

| prognosis     = Average age of death is 15 years{{citation needed|date=May 2022}}
| frequency     = Rare: 1 in 18 million<ref name=NORD2014/>
| deaths        = 
| alt           = 
}}
'''Progeria''' is a specific type of [[Biology:Progeroid syndromes|progeroid syndrome]], also known as '''Hutchinson–Gilford syndrome''' or '''Hutchinson–Gilford progeroid syndrome''' (HGPS).<ref name=":3" /> A single gene mutation is responsible for causing progeria. The gene, known as lamin A (LMNA), makes a protein  necessary for holding the nucleus of the cell together. When this gene gets mutated, an abnormal form of lamin A protein called progerin is produced. Progeroid syndromes are a group of diseases that causes individuals to age faster than usual, leading to them appearing older than they actually are. Patients born with progeria typically live to an age of mid-teens to early twenties.<ref name="Roach & Miller">{{cite book |title=Neurocutaneous Disorders |url=https://archive.org/details/neurocutaneousdi00roac |url-access=limited |publisher=Cambridge University Press |year=2004 |page=[https://archive.org/details/neurocutaneousdi00roac/page/n163 150] |isbn=978-0-521-78153-4 | vauthors = Roach ES, Miller VS }}</ref><ref name="Hsiao">{{cite book |title=Advances in Clinical Chemistry | edition = 33rd |publisher=Academic Press |year=1998 |page=10 |isbn=978-0-12-010333-1 | vauthors = Hsiao KJ }}</ref>

Severe cardiovascular complications usually develop by puberty, later on resulting in death.

==Signs and symptoms==
[[File:Orrico Strada 2.jpg|thumb|Progeria in a 19-year-old male, compared to male of same age without.]]
Most children with progeria appear normal at birth and during early infancy.<ref name=":2">{{Cite web |title=Hutchinson-Gilford syndrome (Concept Id: C0033300) |url=https://www.ncbi.nlm.nih.gov/medgen/?term=Hutchinson-Gilford+syndrome |access-date=2023-11-12 |website=www.ncbi.nlm.nih.gov |language=en}}</ref> Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a [[Medicine:Failure to thrive|failure to thrive]] and a localized [[Medicine:Scleroderma|scleroderma]]-like skin condition. As a child ages past infancy, additional conditions become apparent, usually around 18–24 months. Limited growth, full-body alopecia (hair loss), and a distinctive appearance (a small face with a shallow, recessed jaw and a pinched nose) are all characteristics of progeria.<ref name=NORD2014/> Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, the condition causes wrinkled skin, kidney failure, loss of eyesight, and [[Medicine:Atherosclerosis|atherosclerosis]] and other cardiovascular problems.<ref>{{cite journal | vauthors = Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L, Gerhard-Herman M, Machan JT, Kutys R, Virmani R, Collins FS, Wight TN, Nabel EG, Gordon LB | display-authors = 6 | title = Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 30 | issue = 11 | pages = 2301–2309 | date = November 2010 | pmid = 20798379 | pmc = 2965471 | doi = 10.1161/ATVBAHA.110.209460 }}</ref> 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 older adults. The head is usually large relative to the body, with a narrow, wrinkled 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 typical mental and motor function.{{Citation needed|date=August 2020}}

==Pathophysiology==
Hutchinson-Gilford progeroid syndrome (HGPS) is an extremely rare autosomal dominant [[Medicine:Genetic disorder|genetic disorder]] in which symptoms resembling aspects of [[Biology:Senescence|aging]] are manifested at an early age.<ref name=":3">{{cite journal | vauthors = Sinha JK, Ghosh S, Raghunath M | title = Progeria: a rare genetic premature ageing disorder | journal = The Indian Journal of Medical Research | volume = 139 | issue = 5 | pages = 667–674 | date = May 2014 | pmid = 25027075 | pmc = 4140030 }}</ref> Its occurrence is usually the result of a sporadic [[Biology:Germline mutation|germline mutation]]; although HGPS is genetically dominant, people rarely live long enough to have children, preventing them from passing the disorder on in a [[Biology:Heredity|hereditary]] manner.<ref name="SBM">{{cite web | vauthors = Hall H |title=Progeria |url=https://sciencebasedmedicine.org/progeria/ |url-status=live |archive-url= https://web.archive.org/web/20210423175901/https://sciencebasedmedicine.org/progeria/ |archive-date=23 April 2021 |access-date=23 April 2021 |website=Science-Based Medicine |date=8 December 2020}}</ref>

[[File:Ultrastructural analysis of the nuclear envelope in fibroblasts from the subject with HGPS (progeria).jpg|thumb|320px|Ultrastructural analysis of the nuclear envelope in fibroblasts from a subject with HGPS. Low magnification transmission electron microscopic image of a passage 10 PT001 nucleus showed several herniations (a). Two higher-magnification images of the same nucleus at sites of blebs (b and c) showed a close apposition of the chromatin to the nuclear envelope. In a, b, and c, the nucleus is to the left. Scale bars correspond to 2 μm in panel a, and 500 nm in panels b and c.]]

HPGS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The [[Biology:Histone|histone]] mark H4K20me3 is involved and caused by ''de novo'' mutations that occur in a gene that encodes lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized [[Biology:Heterochromatin|heterochromatin]]. Patients also do not have appropriate DNA repair, and they also have increased genomic instability.<ref name="aging">{{cite journal | vauthors = Arancio W, Pizzolanti G, Genovese SI, Pitrone M, Giordano C | title = Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review | journal = Gerontology | volume = 60 | issue = 3 | pages = 197–203 | year = 2014 | pmid = 24603298 | doi = 10.1159/000357206 | hdl-access = free | s2cid = 2459118 | hdl = 10447/93705 }}</ref>

In normal conditions, the ''[[Biology:LMNA|LMNA]]'' gene codes for a structural protein called prelamin A, which undergoes a series of processing steps before attaining its final form, called lamin A.<ref name="ghr">[http://ghr.nlm.nih.gov/gene/LMNA LMNA] {{Webarchive |url=https://web.archive.org/web/20151228123006/http://ghr.nlm.nih.gov/gene/LMNA |date=2015-12-28 }} {{color|green|At}} [http://ghr.nlm.nih.gov/BrowseGenes Genes] {{Webarchive |url=https://web.archive.org/web/20151222154709/http://ghr.nlm.nih.gov/BrowseGenes |date=2015-12-22 }} {{color|green|At}} [http://ghr.nlm.nih.gov/ Genetics Home Reference] {{Webarchive |url=https://web.archive.org/web/20190204211229/http://ghr.nlm.nih.gov/ |date=2019-02-04 }}</ref> Prelamin A contains a "CAAX" where C is a cysteine, A an aliphatic amino acid, and X any amino acid. This motif at the carboxyl-termini of proteins triggers three sequential enzymatic modifications. First, protein [[Biology:Farnesyltransferase|farnesyltransferase]] [[Chemistry:Catalysis|catalyzes]] the addition of a farnesyl moiety to the cysteine. Second, an endoprotease that recognizes the farnesylated protein catalyzes the peptide bond's cleavage between the cysteine and -aaX. In the third step, isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the carboxyl-terminal farnesyl cysteine. The farnesylated and methylated protein is transported through a [[Biology:Nuclear pore|nuclear pore]] to the [[Biology:Nucleoplasm|interior of the nucleus]]. Once in the nucleus, the protein is [[Biology:Proteolysis|cleaved]] by a [[Biology:Protease|protease]] called zinc metallopeptidase STE24 (ZMPSTE24), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2, and lamin C, makes up the [[Biology:Nuclear lamina|nuclear lamina]], which provides shape and stability to the inner nuclear envelope.{{Citation needed|date=May 2020}}
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 [[Biology:Point mutation|point mutation]] in position 1824 of the ''LMNA'' gene, which replaces a cytosine with thymine.<ref>{{cite journal | vauthors = De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Lévy N | display-authors = 6 | title = Lamin a truncation in Hutchinson-Gilford progeria | journal = Science | volume = 300 | issue = 5628 | pages = 2055 | date = June 2003 | pmid = 12702809 | doi = 10.1126/science.1084125 | s2cid = 33927803 }}</ref> This mutation creates a 5' cryptic splice site within [[Biology:Exon|exon]] 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is [[Biology:Translation|translated]] into protein, it produces an abnormal variant of the prelamin A protein, referred to as [[Biology:Progerin|progerin]]. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the [[Biology:Nuclear envelope|nuclear envelope]] with enough structural support, causing it to take on an abnormal shape.<ref name="Cao">{{cite journal | vauthors = Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS | title = Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells | journal = Science Translational Medicine | volume = 3 | issue = 89 | pages = 89ra58 | date = June 2011 | pmid = 21715679 | doi = 10.1126/scitranslmed.3002346 | s2cid = 206678031 }}</ref> Since the support that the nuclear lamina normally provides is necessary for the organizing of [[Biology:Chromatin|chromatin]] during [[Biology:Mitosis|mitosis]], weakening of the nuclear lamina limits the ability of the cell to divide.<ref name="UCSF">{{cite web | vauthors = Norris J |title = Aging Disease in Children Sheds Light on Normal Aging |work = UCSF web site |publisher = UCSF |date = 2011-10-21 |url = http://www.ucsf.edu/news/2011/10/10766/aging-disease-children-sheds-light-normal-aging |access-date = 2011-10-25 |archive-date = 2011-10-25 |archive-url = https://web.archive.org/web/20111025094756/http://www.ucsf.edu/news/2011/10/10766/aging-disease-children-sheds-light-normal-aging |url-status = live}}</ref> However, defective cell division is unlikely to be the main defect leading to progeria, particularly because children develop normally without any signs of disease until about one year of age. Farnesylated prelamin A variants also lead to defective DNA repair, which may play a role in the development of progeria.<ref name="pmid15980864">{{cite journal | vauthors = Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z | display-authors = 6 | title = Genomic instability in laminopathy-based premature aging | journal = Nature Medicine | volume = 11 | issue = 7 | pages = 780–785 | date = July 2005 | pmid = 15980864 | doi = 10.1038/nm1266 | s2cid = 11798376 }}</ref> Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging.<ref>{{cite journal | vauthors = Chang W, Wang Y, Luxton GW, Östlund C, Worman HJ, Gundersen GG | title = Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 9 | pages = 3578–3583 | date = February 2019 | pmid = 30808750 | pmc = 6397528 | doi = 10.1073/pnas.1809683116 | doi-access = free | bibcode = 2019PNAS..116.3578C }}</ref>

To date over 1,400 [[Biology:Single-nucleotide polymorphism|SNPs]] in the ''LMNA'' gene are known.<ref>[https://www.genecards.org/cgi-bin/carddisp.pl?gene=LMNA&#snp "LMNA Gene"] {{Webarchive|url=https://web.archive.org/web/20171012201754/http://www.genecards.org/cgi-bin/carddisp.pl?gene=LMNA&#snp |date=2017-10-12 }}. [[Biology:GeneCards|GeneCards]]. Retrieved June 6, 2015.</ref> They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys,<ref>{{cite journal | vauthors = Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B, Kuchelmeister K, Müller U, Hahn A | display-authors = 6 | title = Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 8 | pages = 1049–1054 | date = April 2008 | pmid = 18348272 | doi = 10.1002/ajmg.a.32259 | s2cid = 205309256 }}</ref> Arg482Gln,<ref>{{cite journal | vauthors = Cao H, Hegele RA | title = Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy | journal = Human Molecular Genetics | volume = 9 | issue = 1 | pages = 109–112 | date = January 2000 | pmid = 10587585 | doi = 10.1093/hmg/9.1.109 | doi-access = free }}</ref> Arg527Leu,<ref>{{cite journal | vauthors = Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M | display-authors = 6 | title = A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome | journal = European Journal of Human Genetics | volume = 20 | issue = 11 | pages = 1134–1140 | date = November 2012 | pmid = 22549407 | pmc = 3476705 | doi = 10.1038/ejhg.2012.77 }}</ref> Arg527Cys,<ref>{{cite journal | vauthors = Agarwal AK, Kazachkova I, Ten S, Garg A | title = Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 12 | pages = 4617–4623 | date = December 2008 | pmid = 18796515 | pmc = 2626450 | doi = 10.1210/jc.2008-0123 }}</ref> Ala529Val<ref>{{cite journal | vauthors = Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal AK | title = A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 90 | issue = 9 | pages = 5259–5264 | date = September 2005 | pmid = 15998779 | doi = 10.1210/jc.2004-2560 | doi-access =  }}</ref>).

Progerin may also play a role in normal human aging, since its production is activated in typical [[Biology:Senescence|senescent]] cells.<ref name = "UCSF"/>

Unlike other "[[Biology:Progeroid syndromes|accelerated aging diseases]]" (such as [[Medicine:Werner syndrome|Werner syndrome]], [[Medicine:Cockayne syndrome|Cockayne syndrome]] or [[Medicine:Xeroderma pigmentosum|xeroderma pigmentosum]]), progeria may not be directly caused by defective [[Biology:DNA repair|DNA repair]]. These diseases each cause changes in a few specific aspects of aging, but never in every aspect at once, so they are often called "segmental progerias".<ref>{{cite journal | vauthors = Best BP | title = Nuclear DNA damage as a direct cause of aging | journal = Rejuvenation Research | volume = 12 | issue = 3 | pages = 199–208 | date = June 2009 | pmid = 19594328 | doi = 10.1089/rej.2009.0847 | citeseerx = 10.1.1.318.738 }}</ref>

A 2003 report in ''Nature''<ref>{{cite journal | vauthors = Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS | display-authors = 6 | title = Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome | journal = Nature | volume = 423 | issue = 6937 | pages = 293–298 | date = May 2003 | pmid = 12714972 | doi = 10.1038/nature01629 | pmc = 10540076 | bibcode = 2003Natur.423..293E | hdl-access = free | s2cid = 4420150 | hdl = 2027.42/62684 }}</ref> said that progeria may be a [[Biology:De novo mutation|de novo]] dominant trait. It develops during [[Biology:Cell division|cell division]] in a newly conceived zygote or in the [[Biology:Gamete|gamete]]s of one of the parents. It is caused by [[Biology:Mutation|mutation]]s in the ''LMNA'' (lamin A [[Biology:Protein|protein]]) [[Biology:Gene|gene]] on [[Biology:Chromosome 1|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 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.<ref>{{cite journal |title=Family Crisis Becomes Scientific Quest |journal=Science |date=9 May 2003 |volume=300 |issue=5621 |pages=899 |doi=10.1126/science.300.5621.899a |s2cid=220095842 }}</ref>
{{multiple image
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 | image1 = Hastings Gilford 58.jpg
 | alt1 = Male patient age 22
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 | alt2 = Female patient age 40
 | footer = A male patient age 22 (top) and a female patient age 40 (bottom) with atypical progeria
}}
A subset of progeria patients with [[Biology:Zygosity|heterozygous]] mutations of ''LMNA'' have presented an atypical form of the condition, with initial symptoms not developing until late childhood or early adolesence. These patients have had longer lifespans than those with typical-onset progeria.<ref name=":2" /> This atypical form is extremely rare, with presentations of the condition varying between patients with even the same mutation.<ref>{{Cite journal |last1=Yukina |first1=Marina |last2=Nuralieva |first2=Nurana |last3=Sorkina |first3=Ekaterina |last4=Troshina |first4=Ekaterina |last5=Tiulpakov |first5=Anatoly |last6=Belaya |first6=Zhanna |last7=Melnichenko |first7=Galina |date=2021-03-15 |title=Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis |journal=Endocrinology, Diabetes & Metabolism Case Reports |volume=2021 |pages=20–0188 |doi=10.1530/EDM-20-0188 |issn=2052-0573 |pmc=8052577 |pmid=33859056}}</ref> The general phenotype of atypical cases is consistent with typical progeria, but other factors (severity, onset, and lifespan) vary in presentation.<ref>{{Cite web |title=UpToDate |url=https://www.uptodate.com/contents/hutchinson-gilford-progeria-syndrome/print |access-date=2023-11-12 |website=www.uptodate.com}}</ref>

===Lamin A===

Lamin A is a major component of a protein scaffold on the inner edge of the [[Biology:Cell nucleus|nucleus]] called the nuclear lamina that helps organize nuclear processes such as [[Biology:RNA|RNA]] and [[Biology:DNA|DNA]] synthesis.{{citation needed|date=May 2020}}

Prelamin A contains a CAAX box at the [[Biology:C-terminus|C-terminus]] of the protein (where C is a [[Chemistry:Cysteine|cysteine]] and A is any aliphatic amino acids). This ensures that the cysteine is [[Biology:Prenylation|farnesylated]] and allows prelamin A to bind [[Biology: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, now lamin A, is no longer membrane-bound and carries out functions inside the nucleus.{{citation needed|date=May 2020}}

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 | vauthors = Lans H, Hoeijmakers JH | title = Cell biology: ageing nucleus gets out of shape | journal = Nature | volume = 440 | issue = 7080 | pages = 32–34 | date = March 2006 | pmid = 16511477 | doi = 10.1038/440032a | bibcode = 2006Natur.440...32L | s2cid = 4387289 }}</ref> 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 [[Biology:Demethylation|demethylation]] of [[Biology:Histone|histone]], leading to reduced [[Biology:Heterochromatin|heterochromatin]].<ref name="pmid16645051">{{cite journal | vauthors = Scaffidi P, Misteli T | title = Lamin A-dependent nuclear defects in human aging | journal = Science | volume = 312 | issue = 5776 | pages = 1059–1063 | date = May 2006 | pmid = 16645051 | pmc = 1855250 | doi = 10.1126/science.1127168 | bibcode = 2006Sci...312.1059S }}</ref> [[Biology:Nematode|Nematode]]s over their lifespan show progressive lamin changes comparable to HGPS in all cells but [[Biology:Neuron|neuron]]s and [[Biology:Gamete|gamete]]s.<ref name="pmid16269543">{{cite journal | vauthors = Haithcock E, Dayani Y, Neufeld E, Zahand AJ, Feinstein N, Mattout A, Gruenbaum Y, Liu J | display-authors = 6 | title = Age-related changes of nuclear architecture in Caenorhabditis elegans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 46 | pages = 16690–16695 | date = November 2005 | pmid = 16269543 | pmc = 1283819 | doi = 10.1073/pnas.0506955102 | doi-access = free | bibcode = 2005PNAS..10216690H }}</ref> These studies suggest that lamin A defects are associated with normal [[Biology:Senescence|aging]].<ref name="pmid16645051" /><ref>{{cite web| vauthors = Zagorski N |date=November 2006|title=A Comeback for the Ages: Lamin's connection with aging has reinvigorated research |url= https://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/aging/200611_a_comeback_for_the_ages.html|work=Johns Hopkins University|access-date=2020-05-22|archive-date=2017-03-28|archive-url=https://web.archive.org/web/20170328205041/http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/aging/200611_a_comeback_for_the_ages.html }}</ref>

=== Mitochondria ===
The presence of progerin also leads to the accumulation of dysfunctional [[Biology:Mitochondrion|mitochondria]] within the cell. These mitochondria are characterized by a swollen morphology, caused by a condensation of mtDNA and TFAM into the mitochondria, which is driven by a severe mitochondrial dysfunction (low mitochondrial membrane potential, low [[Chemistry:Adenosine triphosphate|ATP]] production, low respiration capacity and high [[Biology:Reactive oxygen species|ROS]] production).<ref name=":1">{{cite journal | vauthors = Monterrubio-Ledezma F, Navarro-García F, Massieu L, Mondragón-Flores R, Soto-Ponce LA, Magaña JJ, Cisneros B | title = Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 | journal = Cells | volume = 12 | issue = 2 | pages = 275 | date = January 2023 | pmid = 36672210 | doi = 10.3390/cells12020275 | pmc = 9856861 | doi-access = free }}</ref><ref name="Xiong_2016">{{cite journal | vauthors = Xiong ZM, Choi JY, Wang K, Zhang H, Tariq Z, Wu D, Ko E, LaDana C, Sesaki H, Cao K | display-authors = 6 | title = Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria | journal = Aging Cell | volume = 15 | issue = 2 | pages = 279–290 | date = April 2016 | pmid = 26663466 | pmc = 4783354 | doi = 10.1111/acel.12434 }}</ref><ref>{{cite journal | vauthors = Feric M, Demarest TG, Tian J, Croteau DL, Bohr VA, Misteli T | title = Self-assembly of multi-component mitochondrial nucleoids via phase separation | journal = The EMBO Journal | volume = 40 | issue = 6 | pages = e107165 | date = March 2021 | pmid = 33619770 | pmc = 7957436 | doi = 10.15252/embj.2020107165 }}</ref> Therefore, contributing substantially to the senescence phenotype. Although, the explanation for this defective-mitochondria accumulation in progeria is about to be elucidated, it has been proposed that low PGC1-α expression<ref name=":1" /><ref name="Xiong_2016"/><ref>{{cite journal | vauthors = Maynard S, Hall A, Galanos P, Rizza S, Yamamoto T, Gram HH, Munk SH, Shoaib M, Sørensen CS, Bohr VA, Lerdrup M, Maya-Mendoza A, Bartek J | display-authors = 6 | title = Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1α and the NAMPT-NAD+ pathway | journal = Nucleic Acids Research | volume = 50 | issue = 17 | pages = 9948–9965 | date = September 2022 | pmid = 36099415 | pmc = 9508839 | doi = 10.1093/nar/gkac741 }}</ref> (important for [[Biology:Mitochondrial biogenesis|mitochondrial biogenesis]], maintenance and function) along with low [[Biology:LAMP2|LAMP2]] protein level and [[Biology:Lysosome|lysosome]] number  (both important for [[Biology:Mitophagy|mitophagy]]: the degradation of defective mitochondria pathway),<ref name=":1" /> could be implicated.

==Diagnosis==
Skin changes, abnormal growth, and loss of hair occur. These symptoms normally start appearing by one year of age. A genetic test for LMNA mutations can confirm the diagnosis of progeria.<ref name="titlegenome.gov1 | Learning About Progeria">{{cite web |url=http://www.genome.gov/11007255#isthere |publisher=genome.gov |title=Learning About Progeria |access-date=17 March 2008 |archive-date=16 April 2008 |archive-url=https://web.archive.org/web/20080416065357/http://www.genome.gov/11007255#isthere |url-status=live }}</ref><ref name="pr">{{cite web |url= http://www.progeriaresearch.org/diagnostic_testing.html |title= Progeria Research Foundation &#124; The PRF Diagnostic Testing Program |access-date= 16 November 2011 |archive-url= https://web.archive.org/web/20160828010535/http://www.progeriaresearch.org/diagnostic_testing.html |archive-date=28 August 2016|url-status= dead }}</ref> Prior to the advent of the genetic test, misdiagnosis was common.<ref name="pr"/>

=== Differential diagnosis ===
Other syndromes with similar symptoms (non-[[Medicine:Laminopathy|laminopathy]] progeroid syndromes) include:<ref>{{Citation |last1=Gordon |first1=Leslie B. |title=Hutchinson-Gilford Progeria Syndrome |date=1993 |url=http://www.ncbi.nlm.nih.gov/books/NBK1121/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |access-date=2023-11-12 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301300 |last2=Brown |first2=W. Ted |last3=Collins |first3=Francis S. |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref>

* [[Medicine:Acrogeria|Acrogeria]]
* Berardinelli-Seip congenital lipodystrophy ([[Medicine:Congenital generalized lipodystrophy|congenital generalized lipodystrophy]])
* [[Medicine:Cockayne syndrome|Cockayne syndrome]]
* [[Medicine:Ehlers–Danlos syndromes|Ehlers-Danlos syndrome]], progeroid form
* [[Medicine:Gerodermia osteodysplastica|Gerodermia osteodysplastica]]
* [[Medicine:Hallermann–Streiff syndrome|Hallermann-Streiff syndrome]]
* [[Medicine:Mandibuloacral dysplasia|Mandibuloacral dysplasia]]
* Neonatal progeroid syndrome ([[Medicine:Wiedemann–Rautenstrauch syndrome|Wiedemann-Rautenstrauch syndrome]])
* Nestor-Guillermo syndrome
* Penttinen syndrome
* Petty-Laxova-Weidemann progeroid syndrome
* POLR3A-related Wiedemann-Rautenstrauch syndrome
* [[Biology:PYCR1|PYCR1]]-related Wiedemann-Rautenstrauch-like syndrome
* [[Medicine:Werner syndrome|Werner syndrome]]

==Treatment==
In November 2020, the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] approved [[Chemistry:Lonafarnib|lonafarnib]], which helps prevent buildup of defective progerin and similar proteins.<ref>{{Cite news |url=https://www.npr.org/2020/11/22/937708600/fda-approves-first-drug-for-rare-rapid-aging-genetic-disorder |title=FDA Approves First Drug For Rare, Rapid-Aging Genetic Disorder |newspaper=NPR.org |access-date=2020-11-22 |archive-date=2020-11-22 |archive-url=https://web.archive.org/web/20201122200048/https://www.npr.org/2020/11/22/937708600/fda-approves-first-drug-for-rare-rapid-aging-genetic-disorder |url-status=live }}</ref> A clinical trial in 2018 points to significantly lower mortality rates – treatment with lonafarnib alone compared with no treatment (3.7% vs. 33.3%) – at a median post-trial follow-up time span of 2.2 years.<ref>{{cite journal | vauthors = Gordon LB, Shappell H, Massaro J, D'Agostino RB, Brazier J, Campbell SE, Kleinman ME, Kieran MW | display-authors = 6 | title = Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome | journal = JAMA | volume = 319 | issue = 16 | pages = 1687–1695 | date = April 2018 | pmid = 29710166 | pmc = 5933395 | doi = 10.1001/jama.2018.3264 }}</ref> The drug, given [[Chemistry:Orphan drug|orphan drug]] status and Pediatric Disease Priority Review Voucher, is taken twice daily in the form of capsules and may cost US$650,000 per year, making it prohibitive for the vast majority of families. It is unclear how it will be covered by health insurance in the United States. Common side effects of the drug include "nausea, vomiting, diarrhea, infections, decreased appetite, and fatigue".<ref name="SBM" />

Other treatment options have focused on reducing complications (such as [[Medicine:Cardiovascular disease|cardiovascular disease]]) with [[Medicine:Coronary artery bypass surgery|coronary artery bypass surgery]] and low-dose [[Chemistry:Aspirin|acetylsalicylic acid]].<ref name="titleProgeria: Treatment - MayoClinic.com">{{cite web |url=http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=7 |title=Progeria: Treatment |publisher=MayoClinic.com |access-date=2008-03-17 |archive-date=2007-12-19 |archive-url=https://web.archive.org/web/20071219022922/http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=7 |url-status=live }}</ref>

Growth hormone treatment has been attempted.<ref name="pmid17642424">{{cite journal | vauthors = Sadeghi-Nejad A, Demmer L | title = Growth hormone therapy in progeria | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 20 | issue = 5 | pages = 633–637 | date = May 2007 | pmid = 17642424 | doi = 10.1515/jpem.2007.20.5.633 | s2cid = 5988572 }}</ref> The use of [[Biology:Morpholino|Morpholino]]s has also been attempted in mice and cell cultures in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used.<ref name="pmid15750600">{{cite journal | vauthors = Scaffidi P, Misteli T | title = Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome | journal = Nature Medicine | volume = 11 | issue = 4 | pages = 440–445 | date = April 2005 | pmid = 15750600 | pmc = 1351119 | doi = 10.1038/nm1204 }}</ref>

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.<ref name="pmid16942914">{{cite journal | vauthors = Meta M, Yang SH, Bergo MO, Fong LG, Young SG | title = Protein farnesyltransferase inhibitors and progeria | journal = Trends in Molecular Medicine | volume = 12 | issue = 10 | pages = 480–487 | date = October 2006 | pmid = 16942914 | doi = 10.1016/j.molmed.2006.08.006 }}</ref> A Phase II clinical trial using the FTI [[Chemistry:Lonafarnib|lonafarnib]] began in May 2007.<ref name="ls1">{{ClinicalTrialsGov|NCT00425607|Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria}}</ref> In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through [[Biology:Autophagy|autophagy]].<ref name = "Cao"/><ref>{{cite journal |title=New Drug Hope for 'Aging' Kids |journal=Science |date=8 July 2011 |volume=333 |issue=6039 |pages=142 |doi=10.1126/science.333.6039.142-b }}</ref> It has been proved that [[Biology:Pravastatin|pravastatin]] and zoledronate are effective drugs when it comes to the blocking of farnesyl group production.{{Citation needed|date=May 2020}}

Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed to make a link between [[Biology:Progerin|progerin]] proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can occur because that attachment occurs, 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.{{Citation needed|date=May 2020}}

Studies of [[Chemistry:Sirolimus|sirolimus]], an [[Biology:MTOR inhibitors|mTOR Inhibitor]], demonstrate that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are abolishing nuclear [[Biology:Bleb (cell biology)|blebbing]], degradation of progerin in affected cells, and reducing insoluble progerin aggregates formation. These results have been observed only ''in vitro'' and are not the results of any clinical trial, although it is believed that the treatment might benefit HGPS patients.<ref name="Cao" />

Recently, it has been demonstrated that the CRM1 protein (a key component of the [[Biology:Nuclear transport|nuclear export]] machinery in mammalian) is upregulated in HGPS cells, which drives to the abnormal localization of [[Biology:Nuclear export signal|NES]] containing proteins from the nucleus to the cytoplasm.<ref name=":0">{{cite journal | vauthors = García-Aguirre I, Alamillo-Iniesta A, Rodríguez-Pérez R, Vélez-Aguilera G, Amaro-Encarnación E, Jiménez-Gutiérrez E, Vásquez-Limeta A, Samuel Laredo-Cisneros M, Morales-Lázaro SL, Tiburcio-Félix R, Ortega A, Magaña JJ, Winder SJ, Cisneros B | display-authors = 6 | title = Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity | journal = Aging Cell | volume = 18 | issue = 5 | pages = e13002 | date = October 2019 | pmid = 31305018 | pmc = 6718587 | doi = 10.1111/acel.13002 }}</ref> Moreover, the inhibition of CRM1 in HGPS alleviates the associated-senescence phenotype<ref name=":0" /> as well as the [[Biology:Mitochondrion|mitochondrial]] function (an important determinant in [[Biology:Senescence|senescence]]) and [[Biology:Lysosome|lysosome]] content.<ref name=":1" /> These results are under ''in vivo'' validation with selinexor (a more suitable CRM1 inhibitor for human use<ref>{{cite journal | vauthors = Ferreira BI, Cautain B, Grenho I, Link W | title = Small Molecule Inhibitors of CRM1 | journal = Frontiers in Pharmacology | volume = 11 | pages = 625 | date = 2020-05-07 | pmid = 32574233 | pmc = 7221118 | doi = 10.3389/fphar.2020.00625 | doi-access = free }}</ref>).

==Prognosis==
As there is no known cure, few people with progeria exceed 16 years of age.<ref name="USA T">{{cite web |url=https://www.usatoday.com/news/science/2003-04-16-agin-gene_x.htm |title=Gene found for rapid aging disease in children | vauthors = Sternberg S |date=April 16, 2003 |work=USA Today |access-date=December 12, 2013|archive-url=https://web.archive.org/web/20170712111126/https://usatoday30.usatoday.com/news/science/2003-04-16-agin-gene_x.htm|archive-date=July 12, 2017}}</ref> At least 90 percent of patients die from complications of atherosclerosis, such as heart attack or stroke.<ref name="titleProgeria - MayoClinic.com">{{cite web |url=http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=1 |title=Progeria |publisher=MayoClinic.com |access-date=March 17, 2008 |archive-date=May 11, 2008 |archive-url=https://web.archive.org/web/20080511135212/http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=1 |url-status=live }}</ref>

Mental development is not adversely affected; in fact, intelligence tends to be average to above average.<ref name="Brown">{{cite journal | vauthors = Brown WT | title = Progeria: a human-disease model of accelerated aging | journal = The American Journal of Clinical Nutrition | volume = 55 | issue = 6 Suppl | pages = 1222S–1224S | date = June 1992 | pmid = 1590260 | doi = 10.1093/ajcn/55.6.1222S | doi-access = free }}</ref> 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 those that progeria does not exhibit, patients show no [[Medicine:Neurodegeneration|neurodegeneration]] or [[Medicine:Cancer|cancer]] predisposition. They also do not develop conditions that are commonly associated with accumulation of damage, such as cataracts (caused by UV exposure) and [[Medicine:Osteoarthritis|osteoarthritis]].<ref name="titlegenome.gov1 | Learning About Progeria"/>

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. People with progeria have normal reproductive development, and there are known cases of women with progeria who delivered healthy offspring.<ref>{{cite journal | vauthors = Corcoy R, Aris A, de Leiva A | title = Fertility in a case of progeria | journal = The American Journal of the Medical Sciences | volume = 297 | issue = 6 | pages = 383–384 | date = June 1989 | pmid = 2735343 | doi = 10.1097/00000441-198906000-00010 | s2cid = 72618179 }}</ref>

==Epidemiology==
A study from the Netherlands has shown an incidence of 1 in 20 million births.<ref name="pmid16838330">{{cite journal | vauthors = Hennekam RC | title = Hutchinson-Gilford progeria syndrome: review of the phenotype | journal = American Journal of Medical Genetics. Part A | volume = 140 | issue = 23 | pages = 2603–2624 | date = December 2006 | pmid = 16838330 | doi = 10.1002/ajmg.a.31346 | s2cid = 15692098 | citeseerx = 10.1.1.333.3746 }}</ref> According to the Progeria Research Foundation, as of September 2020, there are 179 known cases in the world, in 53 countries; 18 of the cases were identified in the United States.<ref>{{Cite web|url=https://www.progeriaresearch.org/meet-the-kids/|title=Meet the Kids|date=1 September 2019|website=Progeria Research Foundation|access-date=29 September 2019|archive-date=16 June 2019|archive-url=https://web.archive.org/web/20190616133848/https://www.progeriaresearch.org/meet-the-kids/|url-status=live}}</ref><ref name="SBM" /> Hundreds of cases have been reported in medical history since 1886.<ref>{{cite web|url=http://www.progeria.be/?page_id=165&lang=en|title=Progeria Info|access-date=28 November 2013|archive-url=https://web.archive.org/web/20131202231251/http://www.progeria.be/?page_id=165&lang=en|archive-date=2 December 2013|url-status=dead}}</ref><ref>{{Cite web|url=https://www.progeriaresearch.org/in-memory-of/|title=In loving memory of those children who have passed away since The Progeria Research Foundation was formed in 1999.|date=9 July 2019|website=Progeria Research Foundation|access-date=24 September 2019|archive-date=16 June 2019|archive-url=https://web.archive.org/web/20190616145113/https://www.progeriaresearch.org/in-memory-of/|url-status=live}}</ref><ref>{{Cite web|url=https://www.progeriaresearch.org/progeria-101faq/|title=Progeria 101|date=August 2019|website=Progeria Research Foundation|access-date=29 September 2019|archive-date=16 June 2019|archive-url=https://web.archive.org/web/20190616134851/https://www.progeriaresearch.org/progeria-101faq/|url-status=live}}</ref> However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed cases worldwide.<ref>{{cite web|url=https://markets.businessinsider.com/news/stocks/globalhealthpr-co-founder-and-chair-john-j-seng-receives-award-from-progeria-research-foundation-1022894278|title=GLOBALHealthPR Co-Founder and Chair, John J. Seng, Receives Award from Progeria Research Foundation|work=Business Insider|date=30 April 2018|access-date=20 April 2019|archive-date=20 April 2019|archive-url=https://web.archive.org/web/20190420055048/https://markets.businessinsider.com/news/stocks/globalhealthpr-co-founder-and-chair-john-j-seng-receives-award-from-progeria-research-foundation-1022894278|url-status=live}}</ref>

There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria.<ref name="Kork08">{{cite journal | vauthors = Korf B | title = Hutchinson-Gilford progeria syndrome, aging, and the nuclear lamina | journal = The New England Journal of Medicine | volume = 358 | issue = 6 | pages = 552–555 | date = February 2008 | pmid = 18256390 | doi = 10.1056/NEJMp0800071 | s2cid = 44499453 }}</ref> One family from India had four of six children with progeria.<ref>{{cite news | vauthors = Grant M |title=Family tormented by ageing disease |url=http://news.bbc.co.uk/2/hi/south_asia/4286347.stm |work=BBC News |date=22 February 2005|archive-url= https://web.archive.org/web/20180719174534/http://news.bbc.co.uk/2/hi/south_asia/4286347.stm|archive-date=19 July 2018}}</ref>

==Research==
===Mouse model===
A mouse model of progeria exists, though in the mouse, the [[Biology:LMNA|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.

In 2020 [[Biology:Genome editing#Editing by nucleobase modification (BASE editing)|BASE editing]] was used in a mouse model to target the LMNA gene mutation that causes the progerin protein instead of the healthy Lamin A<ref>{{cite journal | vauthors = Koblan LW, Erdos MR, Wilson C, Cabral WA, Levy JM, Xiong ZM, Tavarez UL, Davison LM, Gete YG, Mao X, Newby GA, Doherty SP, Narisu N, Sheng Q, Krilow C, Lin CY, Gordon LB, Cao K, Collins FS, Brown JD, Liu DR | display-authors = 6 | title = In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice | journal = Nature | volume = 589 | issue = 7843 | pages = 608–614 | date = January 2021 | pmid = 33408413 | pmc = 7872200 | doi = 10.1038/s41586-020-03086-7 | bibcode = 2021Natur.589..608K }}</ref><ref>{{Cite web |date=31 May 2022 |title=Changing our DNA: 'The age of human therapeutic gene editing is here' |url=https://www.cnn.com/2022/05/31/health/reversing-genetic-fate-scn-wellness/index.html |access-date=2022-06-01 |website=CNN |vauthors=LaMotte S}}</ref> while in 2023 a study designed a peptide that prevented progerin from binding to BubR1<ref>{{Cite journal | vauthors = Zhang N, Hu Q, Sui T, Fu L, Zhang X, Wang Y, Zhu X, Huang B, Lu J, Li Z, Zhang Y | display-authors = 6 |date=2023-02-02 |title=Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 |journal=Nature Aging | volume = 3 | issue = 2 |language=en |pages=185–201 |doi=10.1038/s43587-023-00361-w | pmid = 37118121 | pmc = 10154249 | s2cid = 256559744 |issn=2662-8465}}</ref> which is known to regulate aging in mice.<ref>{{cite journal | vauthors = Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A, Kumar R, Jenkins RB, de Groen PC, Roche P, van Deursen JM | display-authors = 6 | title = BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice | journal = Nature Genetics | volume = 36 | issue = 7 | pages = 744–749 | date = July 2004 | pmid = 15208629 | doi = 10.1038/ng1382 | s2cid = 7871496 | url = https://www.nature.com/articles/s41586-020-03086-7.epdf?sharing_token=Yl-GFJVL4NiildBdxd7lnNRgN0jAjWel9jnR3ZoTv0PExIOtmYwADOYajMm-NthN0RhZL-cZfjizCDR0s7roYQkC3dbZuWJkpRZLtqfBjtY3xb6mrECc8pcflyGgBIg_mnMLUvQoBPFGrPG75SVzBbZmEJM2N1i2rI1RM0nkJG1cwI7c92h45sbsYRk4Om-ZtvsUIl-WPESnWZDihJE1mECuP8JBGTOLkKVo4D7Ij-g%3D&tracking_referrer=edition.cnn.com | doi-access = free }}</ref>

===DNA repair===

Repair of DNA double-strand breaks can occur by either of two processes, [[Biology:Non-homologous end joining|non-homologous end joining]] (NHEJ) or [[Biology:Homologous recombination|homologous recombination]] (HR).  A-type [[Biology:Lamin|lamin]]s promote genetic stability by maintaining levels of proteins that have key roles in NHEJ  and HR.<ref name="pmid21701264">{{cite journal | vauthors = Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S | display-authors = 6 | title = A dual role for A-type lamins in DNA double-strand break repair | journal = Cell Cycle | volume = 10 | issue = 15 | pages = 2549–2560 | date = August 2011 | pmid = 21701264 | pmc = 3180193 | doi = 10.4161/cc.10.15.16531 }}</ref> Mouse cells deficient for maturation of prelamin A show increased DNA damage and [[Biology:Chromosome abnormality|chromosome aberrations]] and have increased sensitivity to DNA damaging agents.<ref name=pmid15980864/> In progeria, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging<ref>{{cite book | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K |year=2008 |chapter=Cancer and aging as consequences of un-repaired DNA damage |title=New Research on DNA Damages | veditors = Kimura H, Suzuki A |publisher=Nova Science Publishers, Inc. |location=New York |pages=1–47 |chapter-url=https://www.novapublishers.com/catalog/product_info.php?products_id=43247 |archive-url=https://web.archive.org/web/20141025091740/https://www.novapublishers.com/catalog/product_info.php?products_id=43247 |archive-date=2014-10-25 |isbn=978-1-60456-581-2 }}</ref> (also see [[Biology:DNA damage theory of aging|DNA damage theory of aging]]).

===Epigenetic clock analysis of human HGPS===
Fibroblast samples from children with progeria syndrome exhibit accelerated epigenetic aging effects according to the [[Biology:Epigenetic clock|epigenetic clock]] for skin and blood samples.<ref name="Horvath2018HGP">{{cite journal | vauthors = Horvath S, Oshima J, Martin GM, Lu AT, Quach A, Cohen H, Felton S, Matsuyama M, Lowe D, Kabacik S, Wilson JG, Reiner AP, Maierhofer A, Flunkert J, Aviv A, Hou L, Baccarelli AA, Li Y, Stewart JD, Whitsel EA, Ferrucci L, Matsuyama S, Raj K | display-authors = 6 | title = Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ''ex vivo'' studies | journal = Aging | volume = 10 | issue = 7 | pages = 1758–1775 | date = July 2018 | pmid = 30048243 | pmc = 6075434 | doi = 10.18632/aging.101508 | doi-access = free }}</ref>

== History ==
Progeria was first described in 1886 by Jonathan Hutchinson.<ref>{{cite journal |journal=The Lancet |date=May 1886 |volume=127 |issue=3272 |pages=922–923 |doi=10.1016/S0140-6736(02)06582-0 |quote-page=923 |quote=Mr. JONATHAN HUTCHINSON contributed a paper on a 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. This paper described the case of a boy three years and a half old, who presented a very withered 'old-manish' appearance. |title=Royal Medical and Chirurgical Society }}</ref> It was also described independently in 1897 by [[Biography:Hastings Gilford|Hastings Gilford]].<ref>{{cite journal | vauthors = Kinmonth JB, Shepherd RC | title = Accidental injection of thiopentone into arteries: studies of pathology and treatment | journal = British Medical Journal | volume = 2 | issue = 5157 | pages = 914–918 | date = November 1959 | pmid = 14409225 | pmc = 1990667 | doi = 10.1136/bmj.2.5157.914 }}</ref> The condition was later named Hutchinson–Gilford progeria syndrome. Scientists are interested in progeria partly because it might reveal clues about the normal process of aging.<ref name="pmid18060063">{{cite journal | vauthors = McClintock D, Ratner D, Lokuge M, Owens DM, Gordon LB, Collins FS, Djabali K | 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 | date = December 2007 | pmid = 18060063 | pmc = 2092390 | doi = 10.1371/journal.pone.0001269 | doi-access = free | bibcode = 2007PLoSO...2.1269M }}</ref><ref name="Kork08" /><ref>{{cite journal | vauthors = Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B, Brooks BP, Gerber LH, Turner ML, Domingo DL, Hart TC, Graf J, Reynolds JC, Gropman A, Yanovski JA, Gerhard-Herman M, Collins FS, Nabel EG, Cannon RO, Gahl WA, Introne WJ | display-authors = 6 | title = Phenotype and course of Hutchinson-Gilford progeria syndrome | journal = The New England Journal of Medicine | volume = 358 | issue = 6 | pages = 592–604 | date = February 2008 | pmid = 18256394 | pmc = 2940940 | doi = 10.1056/NEJMoa0706898 }}</ref>

===Etymology===
The word ''progeria'' comes from the Greek words {{Lang|grc-latn|pro}} (πρό) 'before, premature', and {{Lang|grc-latn|gēras}} (γῆρας), 'old age'.<ref>{{Cite web |title=DICTIONARY |url=http://lexbook.net/en/progeria|url-status=dead |archive-url=https://web.archive.org/web/20160304043500/http://lexbook.net/en/progeria |archive-date=2016-03-04 |access-date=2015-06-22}}</ref>

==Society and culture==
===Notable cases===
[[Biography:Yan Hui|Yan Hui]], a student of [[Biography:Confucius|Confucius]], aged rapidly and died at a young age, appearing as an old man by his late 20s.  He may be one of the earliest potential examples of progeria in history.<ref name=legge>{{harvnb|Confucius|Legge|2009|p=113}}</ref>{{failed verification|date=May 2023}}

In 1987, fifteen-year-old Mickey Hays, who had progeria, appeared along with Jack Elam in the documentary ''I Am Not a Freak''.<ref>{{IMDb title|0345421|"I Am Not a Freak" (1987)}}. Retrieved 2009-11-27.</ref>  Elam and Hays first met during the filming of the 1986 film ''The Aurora Encounter'',<ref>{{IMDb title|0090675|"The Aurora Encounter" (1986)}}. Retrieved 2009-11-27.</ref> in which Hays was cast as an alien.  The friendship that developed lasted until Hays died in 1992, on his 20th birthday. Elam said, "You know I've met a lot of people, but I've never met anybody that got next to me like Mickey."{{cite quote|date=November 2022}}

Harold Kushner, who among other things wrote the book ''[[Philosophy:When Bad Things Happen to Good People|When Bad Things Happen to Good People]]'', had a son, Aaron, who died at the age of 14 in 1977 of progeria.<ref>{{cite news |author=Patricia Montemurri |date=August 3, 2008  |title='One of a kind': Little girl with progeria makes a big impact on loved ones |newspaper=Detroit Free Press |url=http://www.freep.com/apps/pbcs.dll/article?AID=/20080803/TWIST01/808030320/1128/twist |url-status=dead |archive-url=https://web.archive.org/web/20090426090632/http://www.freep.com/apps/pbcs.dll/article?AID=/20080803/TWIST01/808030320/1128/twist |archive-date=April 26, 2009}}</ref>

Margaret Casey, a 29-year-old woman with progeria who was then believed to be the oldest survivor of the premature aging disease, died on Sunday, May 26, 1985. Casey, a freelance artist, was admitted to Yale-New Haven Hospital on the night of May 25 with respiratory problems, which caused her death.<ref>{{cite news|date=May 26, 1985|title=Woman, Believe to be World's Oldest Progeriac, Dead At Age 29|work=The Associated Press|url=https://apnews.com/8fb062e3fdd112cc58ab815c53ad2be7|access-date=November 5, 2019|archive-date=November 5, 2019|archive-url=https://web.archive.org/web/20191105104714/https://apnews.com/8fb062e3fdd112cc58ab815c53ad2be7|url-status=live}}</ref>

Sam Berns was an American activist with the disease. He was the subject of the HBO documentary ''Life According to Sam''. Berns also gave a TEDx talk titled My Philosophy for a Happy Life on December 13, 2013.<ref>{{Cite web |url=https://www.youtube.com/watch?v=36m1o-tM05g |title=My philosophy for a happy life - Sam Berns - TEDxMidAtlantic - YouTube |website=[[Company:YouTube|YouTube]] |access-date=2016-11-26 |archive-date=2019-07-14 |archive-url=https://web.archive.org/web/20190714233651/https://www.youtube.com/watch?v=36m1o-tM05g |url-status=live }}</ref>

Hayley Okines was an English progeria patient who spread awareness of the condition.<ref>{{Cite news |url=https://www.washingtonpost.com/news/morning-mix/wp/2015/04/03/hayley-okines-a-teen-trapped-in-a-104-year-old-persons-body-dies-at-17/ |title=Hayley Okines, a teen trapped in a 104-year-old's body, dies at 17 - The Washington Post |newspaper={{wipe|The Washington Post}} |access-date=2020-05-22 |archive-date=2019-12-04 |archive-url=https://web.archive.org/web/20191204103741/https://www.washingtonpost.com/news/morning-mix/wp/2015/04/03/hayley-okines-a-teen-trapped-in-a-104-year-old-persons-body-dies-at-17/ |url-status=live }}</ref>

Leon Botha, the South African painter and DJ who was known, among other things, for his work with the hip-hop duo Die Antwoord, lived with progeria.<ref>{{Citation |url = https://mg.co.za/article/2011-06-06-die-antwoord-collaborator-leon-botha-dies-age-26/ |title = Die Antwoord collaborator Leon Botha dies, age 26 |work = Mail and Guardian |date = 6 June 2011 |access-date = February 4, 2021 |archive-url = https://web.archive.org/web/20210204110747/https://mg.co.za/article/2011-06-06-die-antwoord-collaborator-leon-botha-dies-age-26/ |archive-date = February 4, 2021 }}</ref> He died in 2011, aged 26.

Tiffany Wedekind of Columbus, Ohio, is believed to be the oldest survivor of progeria at 44 years old as of September 2022.<ref>{{cite news | vauthors = Diaz A |title=One of the oldest living survivors of rapid aging disease at 44: 'Right now is all we have' |url=https://nypost.com/2022/09/12/44-year-old-woman-is-oldest-living-survivor-of-rapid-aging-disease/ |work=New York Post |date=12 September 2022 }}</ref>

Alexandra Peraut is a Catalan girl with progeria; she has inspired the book ''Una nena entre vint milions'' ('A girl in 20 million'), a children's book to explain progeria to youngsters.<ref>{{Cite web |last=324cat |date=2021-02-28|title="Has vist mai una nena de 10 anys que és com una iaia?", el conte que explica la progèria |url=https://www.ccma.cat/324/has-vist-mai-una-nena-de-10-anys-que-es-com-una-iaiaa-el-conte-que-explica-la-progeria/noticia/3080273/ |access-date=2021-03-06 |website=CCMA |language=ca}}</ref><ref>{{Cite web |title=Asociación Progeria ALEXANDRA PERAUT |url=https://www.asociacionprogeria.com/ |access-date=2021-07-28 |language=es}}</ref>

Adalia Rose Williams, born December 10, 2006, was an American girl with progeria, who was a notable YouTuber and vlogger who shared her everyday life on social media. She died on January 12, 2022, at the age of 15.<ref>{{cite web | vauthors = King C |title=Texas YouTuber Adalia Rose dies at 15 after battle with rare genetic condition, family confirms |url=https://www.ksat.com/news/local/2022/01/13/texas-youtuber-adalia-rose-dies-at-15-after-battle-with-rare-genetic-condition-family-confirms/ |website=KSAT |date=13 January 2022 |access-date=13 January 2022}}</ref>

Amy Foose, born September 12, 1969, was an American girl with progeria, who died at the age of 16 on December 19, 1985. <ref>{{Cite web |title=The Progeria Research Foundation |url=https://www.progeriaresearch.org/assets/files/pdf/PRF%20-%20Amy's%20Story.pdf |website=The Progeria Research Foundation}}</ref> Sister of American automobile designer, artist, and TV star, Chip Foose, who started a foundation in her name called [http://www.amysdepot.org/ Amy's Depot]. <ref>{{Cite web |title=Instagram Page for Amy's Depot |url=https://www.instagram.com/amysdepot/}}</ref> The Progeria Research Foundation gives out The Amy Award every few years, in honor of Amy. <ref>{{Cite web |title=The Amy Awards |url=https://www.progeriaresearch.org/amy-award-winners/ |website=The Progeria Research Foundation}}</ref>

== References ==
{{Reflist}}

===Sources===
* {{cite book | vauthors = Legge J | publisher=Cosimo, Inc. |year=2009 |isbn=978-1-60520-643-1 |title=The Confucian Analects, the Great Learning & the Doctrine of the Mean |url= https://books.google.com/books?id=JiALtt67xicC&pg=PA113 |page=113}}

{{Medical condition classification and resources | DiseasesDB      = 10704
 | ICD10           = {{ICD10|E|34|8|e|20}} (ILDS E34.840)
 | ICD9            = {{ICD9|259.8}}
 | ICDO            =
 | OMIM            = 176670
 | MedlinePlus     = 001657
 | eMedicineSubj   = derm
 | eMedicineTopic  = 731
 | MeshID          = D011371
 | GeneReviewsNBK  = NBK1121
 | GeneReviewsName = Hutchinson–Gilford Progeria Syndrome
|Orphanet=740}}



{{Progeroid syndromes}}

[[Category:Genodermatoses]]
[[Category:Rare diseases]]
[[Category:Senescence]]

{{Sourceattribution|Progeria}}