Progeria

Progeria
Classification and external resources
ICD-10 E34.8 (ILDS E34.840)
ICD-9 259.8
OMIM 176670
DiseasesDB 10704
eMedicine derm/731
MeSH D011371

Progeria (also known as "Hutchinson–Gilford progeria syndrome"[1], "Hutchinson–Gilford syndrome"[2], and "Progeria syndrome"[2]) is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word Progeria comes from the Greek progeros meaning 'prematurely old'. The Greek word pro means 'before', while the word geras means 'old age' . The disorder has very low incidences and occurs in one per 8 million live births.[3] Those born with progeria typically live to thirteen years, although many have been known to live into their late teens and early twenties and rare individuals may even reach their forties[4][5]. It is a genetic condition that occurs as a new mutation (de novo),and is not usually inherited, although there is a uniquely heritable form. This is in contrast to another rare but similar syndrome, dyskeratosis congenita (DKC), which is heritable and will often be expressed multiple times in a family line.[6]

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.[7][8][9] Progeria was first described in 1886 by Jonathan Hutchinson[10] and also described independently in 1897 by Hastings Gilford.[11] The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS).

Contents

Signs and symptoms

The earliest symptoms include failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent. Limited growth, alopecia, and a distinctive appearance (small face and jaw, pinched nose) are all characteristic of progeria. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. Later, the condition causes wrinkled skin, atherosclerosis, and cardiovascular problems.

Cause

Hutchinson-Gilford progeria syndrome (HGPS) is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene, replacing cytosine with thymine, creating an unusable form of the protein Lamin A. Lamin A is part of the building blocks of the nuclear envelope.

Unlike most other "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases display different aspects of aging but never every aspect, they are often called "segmental progerias".

Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.[12]

Treatment

No treatments have been proven effective. Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin.[13] Children may also benefit from a high-calorie diet.

Growth hormone treatment has been attempted.[14]

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.[15] A Phase II clinical trial using the FTI Lonafarnib began in May 2007.[16]

Prognosis

There is no known cure. Few people with progeria exceed 13 years of age.[17] At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.[18]

Mental development is not affected. The development of symptoms is comparable to aging at a rate eight to ten times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They do not develop physically mediated "wear and tear" conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).[12]

Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems

Epidemiology

A study from the Netherlands has shown an incidence of 1 in 4 million births.[19] Currently, there are between 35 and 45 known cases in the world.[20] Approximately 100 cases have been formally identified in medical history.[17][21]

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. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children.[8] Affected children rarely live long enough to have children themselves.

There have been only two known cases in which it became evident that a healthy parent can carry the LMNA mutation that causes progeria. A family from India has five children with progeria;[22] they were the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children. In the other case, a family from Belgium has two children with progeria.[23]

Research

Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.[24]

A 2003 report in Nature[25] 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 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.[26]

Lamin A

Nuclear lamin A is a protein scaffold on the inner edge of the 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 amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.

In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing.[27] This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.

A study that compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading to reduced heterochromatin.[28] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[29] These studies suggest that lamin A defects contribute to normal aging.

A range of putative disease-causing mechanisms for the case of HGPS, in which lamin A is permanently farnesylated in the form of progerin. We predict that progerin becomes entrapped in the nuclear membrane as a result of permanent farnesylation, resulting in a multitude of downstream effects. Disruption of the normal lamina architecture leads to fragility, vulnerability to mechanical stresses and nuclear blebbing. Other consequences include disrupted interactions with other nuclear envelope proteins – such as nesprin, emerin and laminaassociated protein 2 (LAP2) – which leads to their mislocalization (that is, emerin is relocalized to the cytoplasm in Lmna -/- mice)74 and clustering of nuclear pores. Disorganization and loss of peripheral heterochromatin is also seen, with heterochromatin becoming detached from the nuclear envelope, and disrupted interactions with RNA polymerase II, RNA splicing factors and transcription factors such as the retinoblastoma transcriptional regulator (RB) and sterol response element binding protein (SREBP1), which leads to misregulation of gene expression. GCL, germ cell-less. Capell and Collins, Nature Reviews Genetics 2006.[30]

Mouse model of progeria

Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with farnesyltransferase inhibitors (FTIs). In the test tube, FTIs reverse the nuclear damage caused by the disease.

A mouse model of progeria exists, though in the mouse, the LMNA prelamin A is not mutated. Instead, ZMPSTE24, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al. use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of prelamin A. Treated mice had greater grip strength and lower likelihood of rib fracture and may live longer than untreated mice.[31]

This method does not directly "cure" the underlying cause of progeria. This method prevents prelamin A from going to the nucleus in the first place so that no prelamin A can build up on the nuclear membrane, but equally, there is no production of normal lamin A in the nucleus. Luckily, lamin A does not appear to be essential; indeed, mouse models in which the genes for prelamin A and C are knocked out show no symptoms. This also shows that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal function of lamin A, that causes the disease.

Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice, one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Staining was smooth muscle alpha-actin (green), lamins A/C (red) and DAPI (blue). (Original magnification, x 40)

It was hypothesized that part of the reason that treatment with an FFI such as alendronate is inefficient is 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 in the metalloproteinase ZMPSTE24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects".[32]

Popular culture

Charles Dickens has been suggested in Bleak House to have described a case of progeria in the family of Smallweed in the grandfather and his grandchildren Judy and twin brother Bart.[33]

The 1922 short story "The Curious Case of Benjamin Button" by F. Scott Fitzgerald (and later released as a feature film in 2008) may have been inspired by progeria. The main character, Benjamin Button, is born as a seventy-year-old man and ages backwards.[34]

The Hindi film Paa, released in December 2009, has its story line around progeria (starring Amitabh Bachchan playing a thirteen year old boy Auro).[35]

Progeria is also a central theme in the animated film Renaissance in which one of the characters finds the much sought cure.

Orlando Gardiner of the science fiction book series Otherland suffers from this disease.

On the episode "Designate This" from the series "Dark Angel", Max's "younger version" has the disease.

Rabbi Harold Kushner, author of the well known book, "When Bad Things Happen to Good People", had a son who suffered from this disease, and likely his son's tragic illness was the impetus for this book on suffering.

Progeria was featured in the X-Files episode "Young at Heart," where a scientist studying the disease found a way to reverse the aging process.

A disease similar to progeria, called Werner syndrome, was featured in the movie Jack, starring Robin Williams, in which his character aged 4 times faster than normal.

Leon Botha, a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group Die Antwoord, is one of the oldest people in the world living with Progeria Syndrome.[36]

The Chuck Palahniuk novel Haunted includes one character, Brandon Whittier, who is dying of progeria at 13.

See also

References

  1. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 574. ISBN 0721629210. 
  2. ↑ 2.0 2.1 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 
  3. ↑ Progeria, Incidence of Progeria and HGPS.
  4. ↑ Ewell Steve Roach & Van S. Miller (2004). Neurocutaneous Disorders. Cambridge University Press. p. 150. ISBN 052178153. 
  5. ↑ Kwang-Jen Hsiao (1998). Advances in Clinical Chemistry:33. Academic Press. p. 10. ISBN 0120103338. 
  6. ↑ Heiss NS, Knight SW, Vulliamy TJ, "et al." (May 1998). "X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions.". Nat Genet. 19 (1): 32–38. doi:10.1038/ng0598-32. PMID 9590285. http://www.nature.com/ng/journal/v19/n1/abs/ng0598-32.html. 
  7. ↑ McClintock D, Ratner D, Lokuge M, et al. (2007). "The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin". PLoS ONE 2 (12): e1269. doi:10.1371/journal.pone.0001269. PMID 18060063. PMC 2092390. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001269. 
  8. ↑ 8.0 8.1 Korf B (2008). "Hutchinson-Gilford progeria syndrome, aging, and the nuclear lamina". N. Engl. J. Med. 358 (6): 552–5. doi:10.1056/NEJMp0800071. PMID 18256390. http://content.nejm.org/cgi/content/full/358/6/552. 
  9. ↑ Merideth MA, Gordon LB, Clauss S, et al. (2008). "Phenotype and course of Hutchinson-Gilford progeria syndrome" (– Scholar search). N. Engl. J. Med. 358 (6): 592–604. doi:10.1056/NEJMoa0706898. PMID 18256394. http://content.nejm.org/cgi/content/full/358/6/59. 
  10. ↑ Hutchinson J (1886). "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". Lancet I: 923. 
  11. ↑ Gilford H; Shepherd, RC (1904). "Ateleiosis and progeria: continuous youth and premature old age". Brit. Med. J. 2 (5157): 914–8. PMID 14409225. 
  12. ↑ 12.0 12.1 "Learning About Progeria". genome.gov. http://www.genome.gov/11007255#isthere. Retrieved 2008-03-17. 
  13. ↑ "Progeria: Treatment". MayoClinic.com. http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=7. Retrieved 2008-03-17. 
  14. ↑ Sadeghi-Nejad A, Demmer L (2007). "Growth hormone therapy in progeria". J. Pediatr. Endocrinol. Metab. 20 (5): 633–7. PMID 17642424. 
  15. ↑ Meta M, Yang SH, Bergo MO, Fong LG, Young SG (2006). "Protein farnesyltransferase inhibitors and progeria". Trends Mol Med 12 (10): 480–7. doi:10.1016/j.molmed.2006.08.006. PMID 16942914. http://linkinghub.elsevier.com/retrieve/pii/S1471-4914(06)00175-4. 
  16. ↑ "Phase II trial of Lonafarnib (a farnesyltransferase inhibitor) for progeria". http://clinicaltrials.gov/ct2/show/NCT00425607?term=progeria&rank=2. 
  17. ↑ 17.0 17.1 Steve Sternberg (April 16, 2003). "Gene found for rapid aging disease in children". USA Today. http://www.usatoday.com/news/science/2003-04-16-agin-gene_x.htm. Retrieved 2006-12-13. 
  18. ↑ "Progeria". MayoClinic.com. http://www.mayoclinic.com/health/progeria/DS00936/DSECTION=1. Retrieved 2008-03-17. 
  19. ↑ Hennekam RC (2006). "Hutchinson-Gilford progeria syndrome: review of the phenotype". Am. J. Med. Genet. A 140 (23): 2603–24. doi:10.1002/ajmg.a.31346. PMID 16838330. 
  20. ↑ "Information Progeria". http://www.progeria.be/informatie_EN.php. Retrieved 2008-12-16. 
  21. ↑ "Progeria". MayoClinic.com. http://www.mayoclinic.com/health/progeria/DS00936. Retrieved 2008-02-06. 
  22. ↑ Grant, Matthew (22 February 2005). "Family tormented by ageing disease". BBC News. Retrieved on 3 May 2009.
  23. ↑ Hope, Alan (3 June 2009). "Face of Flanders: Michiel Vandeweert". Flanders Today. Retrieved on 3 September 2009.
  24. ↑ Capell BC, Collins FS, Nabel EG (2007). "Mechanisms of cardiovascular disease in accelerated aging syndromes". Circ. Res. 101 (1): 13–26. doi:10.1161/CIRCRESAHA.107.153692. PMID 17615378. http://circres.ahajournals.org/cgi/pmidlookup?view=long&pmid=17615378. 
  25. ↑ M. Eriksson et al. (2003). "Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome" (PDF). Nature 423 (6937): 293–298. doi:10.1038/nature01629. PMID 12714972. http://www.nature.com/nature/journal/v423/n6937/pdf/nature01629.pdf. 
  26. ↑ "Family Crisis Becomes Scientific Quest", Science, 300(5621), 9 May 2003.
  27. ↑ Lans H, Hoeijmakers JH (2006). "Cell biology: ageing nucleus gets out of shape". Nature 440 (7080): 32–4. doi:10.1038/440032a. PMID 16511477. 
  28. ↑ Scaffidi P, Misteli T (May 19, 2006). "Lamin A-dependent nuclear defects in human aging". Science 312 (5776): 1059–63. doi:10.1126/science.1127168. PMID 16645051. 
  29. ↑ Haithcock E, Dayani Y, Neufeld E, et al. (2005). "Age-related changes of nuclear architecture in Caenorhabditis elegans". Proc. Natl. Acad. Sci. U.S.A. 102 (46): 16690–5. doi:10.1073/pnas.0506955102. PMID 16269543. PMC 1283819. http://www.pnas.org/cgi/content/full/102/46/16690. 
  30. ↑ Capell BC and Collins FS (2006). "Human laminopathies: nuclei gone genetically awry.". Nat Rev Genet 7 (12): 12. doi:10.1038/nrg1906. PMID 17139325. PMC 2674425. http://www.nature.com/nrg/journal/v7/n12/abs/nrg1906.html. 
  31. ↑ Loren G. Fong (March 17, 2006). "A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria". Science 311 (5767): 1621–3. doi:10.1126/science.1124875. PMID 16484451. http://www.sciencemag.org/cgi/content/abstract/1124875v1. 
  32. ↑ 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". Nat. Med. 14 (7): 767–72. doi:10.1038/nm1786. PMID 18587406. http://www.nature.com/nm/journal/v14/n7/abs/nm1786.html. 
  33. ↑ 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 PMID 20697111
  34. ↑ "Hutchinson-Gilford Progeria Syndrome: Its Presentation in F. Scott Fitzgerald’s Short Story ‘The Curious Case of Benjamin Button’ and Its Oral Manifestations". Sage journals online. W.J. Maloney. http://jdr.sagepub.com/cgi/content/abstract/88/10/873. 
  35. ↑ http://www.paathefilm.com/
  36. ↑ http://www.youtube.com/watch?v=8NZBxwjcwMc&feature=player_embedded

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