Progeria
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| Progeria Classification and external resources | |
| ICD-10 | E34.8 |
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| ICD-9 | 259.8 |
| OMIM | 176670 |
| DiseasesDB | 10704 |
| eMedicine | derm/731 |
| MeSH | D011371 |
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US National Guidelines Clearinghouse on Progeria
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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".
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.[1] 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.[1]
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.[1] 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.[1] 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.[1] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[1] 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.
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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Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
