Progeria

From Wikipedia, the free encyclopedia

Progeria (also known as "Hutchinson-Gilford syndrome"^[1]:574) is an extremely rare genetic condition where symptoms resembling aspects of aging are manifested at an early age. About 1 in 8 million babies are born with this condition, and most affected children usually die at around age 13, although many have been known to live into their late teens and early twenties. It is a genetic condition, but occurs as a new mutation (sporadically) and is not usually inherited, although there is one unique form of the condition identified in only one family in the world that is inherited from parents who carry the protein genetically. In this case, five children in the family had the condition.

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.^[2][3][4]

[edit] Symptoms

The earliest symptoms include failure to thrive and a localized scleroderma-like skin condition. As the 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. 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.

[edit] Cause

Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by a point mutation in position 1824 Replacing Thymine with Cytosine creating an unusable type of protein called 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 "accelerated aging" diseases display different aspects of aging but never every aspect, they are often called "segmental progerias."

[edit] Diagnosis

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.^[5]

[edit] 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.^[6] Children may also benefit from a high-calorie diet.

Growth hormone treatment has been attempted.^[7]

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), have been proposed, but their use has been mostly limited to animal models.^[8] A Phase II clinical trial using the FTI Lonafarnib began in May 2007.^[9]

[edit] Prognosis

There is no known cure. Few people with progeria exceed 13 years of age.^[10] At least 90% of patients die from complications of atherosclerosis, such as heart attacks or strokes.^[11]

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.^[12]

[edit] Epidemiology

One study from the Netherlands has shown an incidence of 1 in 4 million births.^[13] Currently, there are between 35 and 45 known cases in the world.^[14] Approximately 100 cases have been formally identified in medical history.^[15][10]

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 it became evident that a healthy parent can carry the LMNA mutation that causes progeria in her or his egg or sperm cells. In this case, five siblings were born with HGPS. But Hutchinson-Gilford Progeria syndrome is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children.^[3] Affected children do not live long enough to have children themselves.

A family from India had five Progeria children, two of which are now deceased. They were the subject of a 2005 Bodyshock documentary entitled 'The 80 Year Old Children'.

[edit] Research areas

Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.^[16]

A 2003 report in Nature^[17] 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.^[18]

[edit] Lamina

Nuclear lamina 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 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.^[19] 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.^[20] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.^[21] These studies suggest that lamin A defects contribute to normal aging.

[edit] Mouse model of progeria

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.^[22]

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.

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 deficient in the metalloproteinase ZMPSTE24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects."^[23]

[edit] History

Progeria was first described in 1886 by Jonathan Hutchinson^[24] and also described independently in 1897 by Hastings Gilford.^[25] The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS).

[edit] See also

• Biogerontology
• Degenerative disease
• Farnsyltransferase
• Genetic disorder
• Laminopathies
• Werner syndrome
• When Bad Things Happen to Good People

[edit] References

[edit] External links

This article's external links may not follow Wikipedia's content policies or guidelines. Please improve this article by removing excessive or inappropriate 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.
• 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
• Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI)