PROGERIA

Progeria

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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 progeriacomes from the Greek words "pro" (πρό), meaning "before", and "géras" (γῆρας), meaning "old age". The disorder has very low incidences and occurs in an estimated 1 per 8 million live births.^[3] Those born with progeria typically live to their mid teens and early twenties.^[4][5] It is agenetic condition that occurs as a new mutation (de novo), and is rarely inherited. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson-Gilford Progeria Syndrome.

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.^[6][7][8] Progeria was first described in 1886 by Jonathan Hutchinson.^[9] It was also described independently in 1897 by Hastings Gilford.^[10] The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).

Contents   [hide]  1 Signs and symptoms 2 Cause 3 Diagnosis 4 Treatment 5 Prognosis 6 Epidemiology 7 Research 7.1 Lamin A 7.2 Mouse model of progeria 8 Popular culture 9 See also 10 References 11 External links

[edit]Signs and symptoms

Children with progeria usually develop the first symptoms during infancy. The earliest symptoms include failure to thrive and a localizedscleroderma-like skin condition. As a child ages past infancy, additional conditions usually become apparent around 18–24 months. Limited growth, full-body alopecia, and a distinctive appearance (small face and jaw, pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to get worse as the child ages. Later, the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, hair loss, and cardiovascular problems. 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 elderly people. The face is usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by hair loss), 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 normal mental and motor development.

[edit]Cause

Comparison between a normal cell and a progeria cell.

In normal conditions, the LMNA gene encodes a protein called prelamin A, which leads to the lamin A form. There is a farnesyl group attached to the carboxyl-terminus of its structure. Farnesyl molecule allows prelamin A to be anchored to nuclear rim, and then it is removed. 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 point mutation in position 1824 of the LMNA gene, replacing cytosine with thymine, creating a truncated form, progerin, of the prelamin A protein whose further processing is abnormal. Normal lamin A is a major structural protein of the nuclear lamina of the nucleus (along with lamin C);when LMNA is mutated, farnesyl group can not be removed and progerin does not integrate into this structure and accumulates, disrupting it.^[11] This is when HGPS appears. Since the nuclear lamina participates in organizing chromatin and supporting the nuclear envelope; this disrupts the human cell nucleus as a whole, limiting the ability of the cell to divide.^[12] Then, the appearance of affected nuclei is like bubbles or a cluster of grapes. Progerin may also play a role in normal human aging, since its production is activated in senescent wild type cells.^[12]

Unlike "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 what are considered different aspects of aging, but never every aspect, they are often called "segmental progerias".^[13]

[edit]Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. A genetic test for LMNA mutations can confirm the diagnosis of progeria.^[14][15]

[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.^[16] Children may also benefit from a high-calorie diet.

Growth hormone treatment has been attempted.^[17]

A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models.^[18] A Phase II clinical trial using the FTI lonafarnib began in May 2007.^[19] In studies on the cells another anti-cancer drug,rapamycin, caused removal of progerin from the nuclear membrane through autophagy.^[11][20] It has been proved that pravastatin andzoledronate are effective drugs when it comes to the blocking of farnesyl group production. However, it is important to bear in mind that no treatment is able to cure progeria nowadays.

- Farnesyltransferase inhibitors (FTIs) are drugs which inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can be appreciated because that attachment takes place 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 has now a more normal state. The delivery of Lonafarnib is not approved by the US Food and Drug Administration (FDA). Therefore, it can only be used in certain clinical trials. Until the treatment of FTIs is implemented in progeria children we will not know its effects—which are positive in mice.^[21]

- Pravastatin is traded as Pravachol or Selektine and it is included in the family of statins. As well as zoledronate (also known as Zometa and Reclast, which is a bisphosphonate), its utility in Hutchinson-Gilford progeria syndrome (HGPS) is the prevention of farnesyl groups formation, which progerin needs to provoke the disease. Some animal trials have been realized using FTIs or a combination of pravastatin andzoledronate so as to observe whether they are capable of reversing abnormal nuclei. The results, obtained by blinded electron microscopic analysis and immunofluorescence microscopy, showed that nucleus abnormalities could be reversed in transgenic mice expressing progerin. The reversion was also observed in vivo—cultured cells from human subjects with progeria—due to the action of the pharmacs, which block protein prenylation (transfer of a farnesyl polypeptide to C-terminal cysteine). The authors of that trial add, when it comes to the results, that: “They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials”.^[22] Unlike FTIs, pravastatin and zoledronate were approved by the U.S. FDA (in 2006 and 2001 respectively), although they are not sold as a treatment for progeria. Pravastatin is used to decrease cholesterol levels and zoledronate to prevent hypercalcaemia.

- Rapamycin, also known as Sirolimus, is a macrolide. There are recent studies concerning rapamycin which conclude that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are: abolishment of nuclear blebbing, degradation of progerin in affected cells and reduction of insoluble progerin aggregates formation. All these results do not come from any clinical trial, although it is believed that the treatment might benefit HGPS kids.^[11]

It should always be taken in account that no treatment is delivered in order to cure Hutchinson-Gilford progeria syndrome, for all of them are in pre-clinical stages.

Points where pharmacs used to inhibit progerin farnesylation act.

[edit]Prognosis

As there is no known cure, few people with progeria exceed 13 years of age.^[23] At least 90% of patients die from complications ofatherosclerosis, such as heart attack or stroke.^[24]

Mental development is not adversely affected; in fact, intelligence tends to be above average.^[25] 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 features of aging that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop the so-called "wear and tear" conditions commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).^[14]

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.

[edit]Epidemiology

A study from the Netherlands has shown an incidence of 1 in 4 million births.^[26] Currently, there are between 35 and 45 known cases in the world.^[27] Approximately 100 cases have been formally identified in medical history.^[23][28]

Classical Hutchinson-Gilford Progeria Syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves (very few children with progeria even live past the teen years to be 21).

There have been only two known cases in which it became evident that a healthy person can carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children.^[7] One family from India has five children with progeria, although this is not a classical HGPS ;^[29] they were the subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children, while another from Belgium has two.^[30]

In September 2011, the first reported case of a black African child with progeria was reported, 12-year-old South African Ontlametse Phalatse.^[31] The Progeria Research Foundation at Children's Hospital Boston, affiliated with the Harvard University Medical School, is treating her and monitoring her case.

[edit]Research

Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.^[32]

A 2003 report in Nature^[33] 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 did not 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.^[34]

[edit]Lamin A

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.^{[35][caption too long]}

Lamin A is a major component of a protein scaffold on the inner edge of the nucleus called thenuclear lamina 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.^[36] 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 demethylation of histone, leading to reducedheterochromatin.^[37] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.^[38] These studies suggest that lamin A defects are associated with normal aging.

[edit]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 fractureand may live longer than untreated mice.^[39]

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. Lamin A does not appear to be necessary for life; mice in which the Lmna gene is knocked out show no embryological symptoms (they develop an Emery–Dreifuss muscular dystrophy-like condition postnatally).^[40] This implies 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)^{[caption too long]}

It was hypothesized that part of the reason that treatment with an FTI such as alendronate is inefficient is due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FTI 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".^[41]

[edit]Popular culture

Perhaps one of the earliest influences of progeria on popular culture occurred in the 1922 short story The Curious Case of Benjamin Buttonby F. Scott Fitzgerald (and later released as a feature film in 2008). The main character, Benjamin Button, is born as a seventy-year-old man and ages backwards; it has been suggested that this was inspired by progeria.^[42]

In other literary references, 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.^[43] Orlando Gardiner of the science fiction book seriesOtherland suffers from this disease. The Chuck Palahniuk novel Haunted includes one character, Brandon Whittier, who is dying of progeria at 13.

In film, a number of well-known films have featured progeria or progeria-like diseases. The 2009 Bollywood film Paa, released in December 2009, has its storyline around progeria (starring Amitabh Bachchan, playing a 13-year old boy Auro).^[44] Progeria is also a central theme in the animated film Renaissance in which one of the characters finds the much sought cure.^{[citation needed]} The 1996 film Jack, starring Robin Williams, portrays a character who has a condition which causes him to age at 4 times the normal rate. This was possibly based on progeria though is otherwise not an accurate portrayal of the syndrome. The 1983 lesbian vampire film, The Hunger, starred Susan Sarandon as a physician researching progeria, and showed a vampire (played by David Bowie) undergoing rapid progeria-like aging. In the film Blade Runnerthe character J.F.Sebastian is a genetic designer who is not allowed to emigrate off-world because of his progeria.

The extraterrestrial space traveler in the 1986 film The Aurora Encounter was played by Mickey Hays, a teenage boy who suffered from progeria.

In the episode of the series Dark Angel titled "Designate This", Max's "younger version" has the disease. 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.

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 his son's illness was probably the impetus for this book on suffering. Leon Botha, a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group Die Antwoord, was one of the oldest people in the world who lived with progeria, dying one day after his 26th birthday on June 5, 2011.

QUESTIONS

 Question: The following are typical of progeria (the HUTCHINSON-GILFORD SYNDROME) a) rarely affects females b) erosion of the medial aspect of the clavicle c) hyperpigmentation d) tight skin e) agenesis of the corpus callosum ???????????