Progeria
Classification & external resources

ICD-10	E34.8
ICD-9	259.8
OMIM	176670
DiseasesDB	10704
eMedicine	derm/731
MeSH	D011371

The term progeria narrowly refers to Hutchinson-Gilford Progeria syndrome, but the term is issued to describe any of the so-called "accelerated aging diseases". The word progeria is derived from the Greek for "old age".

Overview

Because the "accelerated aging" diseases display different aspects of aging, but never every aspect, they are often called "segmental progerias" by biogerontologists. Hutchinson-Gilford Progeria syndrome is an extremely rare genetic condition which causes physical changes that resemble greatly accelerated aging in sufferers. The disease affects between 1 in 4 million (estimated actual) and 1 in 8 million (reported) newborns. Currently, there are 51 known cases in the world. There is no known cure, but several discoveries have been made that have lead to greater understanding and perhaps eventual treatment.^[1] Most people with progeria die around 13 years of age.^[2] Progeria is of interest to scientists because the disease may reveal clues about the process of aging. 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.

The condition was first identified in 1886 by Jonathan Hutchinson and Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS). Around 100 cases have been identified since then.^[2]

A 2003 report in Nature said progeria may be a de novo dominant trait. It develops during cell division in a newly conceived child or in the gametes of one of the parents. It is caused by mutations in a LMNA (Lamin A protein) gene on chromosome 1.

Nuclear lamina is a protein scaffold around the 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 this 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 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 the 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.^[3] This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known. A mouse model of progeria exists, though in the mouse the LMNA prelamin A is not mutated, but instead 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.^[4] Note that 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.

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.^[5] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.^[6] These studies suggest that lamin A defects contribute to normal aging.

Symptoms

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. Later the condition causes wrinkled skin, atherosclerosis and cardiovascular problems. Mental development is not affected. Individuals with the condition rarely live more than 17 years; the longest recorded life-span was 29 years. 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, victims show no neurodegeneration or cancer predisposition. The people diagnosed with this disease usually have fragile elderly-like bodies.

Influences and references on or in popular culture

• The movie Blade Runner featured a character named J.F. Sebastian who suffers from a progeria-like disease which he refers to as "Methuselah Syndrome". Methuselah was known for living to a very great age.
• In the The X-Files episode "Young at Heart", a doctor created a method of reversing progeria and rejuvenating humans.
• In the science-fiction novel Otherland by Tad Williams, a young boy in his teenage years (Orlando Gardiner) is affected by progeria.
• In 1996, the movie Jack tells the story of a ten year old boy (Robin Williams) with an aging disorder much like progeria, although depicted closer to an accelerated version of Werner syndrome.
• In the 1983 movie The Hunger, Dr. Sarah Roberts's work on aging, including a study of progeria, attracts the attention of immortal Miriam Blaylock, who fears her mate John will soon start fatal rapid aging.
• In season two, episode two of The Venture Bros., The Monarch insults Dr. Thaddeus Venture's attire (a short-sleeve jumpsuit) by saying their captors will "...think you're a three-year-old with progeria and take pity on us."
• In season four, episode seven ("") of , the Doctor briefly brings up progeria, stating it was a rare case in children and that it was eradicated centuries ago.
• In the novel Haunted by Chuck Palahniuk, Brandon Whittier, who organizes the retreat, is a progeria sufferer.
• In the 2006 futuristic animated film Renaissance, the character of Claude Muller suffers from progeria. The disease also features as a significant plot point in the movie.
• In the animated series Sealab 2021, numerous references are made about progeria being "nature's cruelest joke".
• In the book The Sigma Protocol by Robert Ludlum, the children imprisoned in the "Clockworks" have progeria.
• In the Filipino TV show I-Witness, they documented two children with a real case of progeria.
• A charity CD to raise money into the research of progeria was released in 2006. Titled "VOICES OF TOMORROW", the song features young UK progeria sufferer Hayley Okines on vocals. There is more information at Song For Progeria.
• In the popular sci-fi series Dark Angel, many of the transgenics suffer from progeria.
• In season two of the popular youth sci-fi series The Tribe cases of a progeria-like disease are depicted. This is caused by the virus that killed all adults in the beginning of the first season.
• The protagonist of the 2000 play Kimberly Akimbo by David Lindsay-Abaire is a sixteen year old girl with progeria.
• In the novel The Magic Kingdom by Stanley Elkin, a British man offers a dream vacation to Disneyland to six kids suffering from terminal diseases. One of the kids, named Charles Mudd-Gaddis, suffers from progeria.
• In the anime Mobile Suit Gundam SEED, the character Rau Le Creuset has shortened telomeres due to genetic engineering that cause him to age at an accelerated rate. Without regular doses of a special medication, this causes him intense pain.
• The season finale of Bones season two portrayed a murder victim afflicted with progeria.
• In the second season of The Fresh Prince of Bel-Air, Will Smith meets a character with progeria.
• In Kage Baker's Company novels, it is repeatedly stated that there was an experiment in human cloning, but the clones developed progeria (apparently in the general sense of accelerated aging). The idea that clones would be subject to accelerated aging appears to have arisen from the reports that Dolly the sheep had shortened telomeres, which appears to be false.
• In John Christopher's novel Empty World, a pandemic described as similar to Hutchinson-Gilford syndrome causes the depopulation of Britain. The effects of the disease affecting small children mirror that of the progression of progeria.

See also

• Accelerated aging disease
• Biogerontology
• Cockayne syndrome
• DNA repair
• Degenerative disease
• Farnsyltransferase
• Genetic disorder
• Laminopathies
• Senescence
• Werner syndrome
• Xeroderma pigmentosum

References

External links

• "A Time to Live" – Seattle Post-Intelligencer feature about Seth Cook, a child with Progeria.
• "Seth Cook, 1993-2007" – Seattle Post-Intelligencer obituary for Seth Cook.
• Bodyshock: The 80-Year-Old Children
• The Girl who is older than her Grandmother
• "Family tormented by ageing disease" – BBC News article on a family with Progeria; cites study that progeria is inheritable.
• Hutchinson-Gilford Progeria syndrome Network
• Media – a list of references in common culture
• Progeria Research Foundation
• Progeria News and Media Collection
• Segmental Progeria
• Farnesyl transferase inhibitors may help children with Hutchinson-Gilford progeria – Article on the use of FTI inhibitors as potential treatment

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