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Other names :– Hutchinson–Gilford progeria syndrome, Hutchinson–Gilford syndrome
Progeria is a disease that produces rapid aging, beginning in childhood. It is an extremely rare, severe, genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The disorder has a very low incidence and occurs in one per eight million live births. Those born with progeria typically live about thirteen years, although many have been known to live into their late teens and early twenties and rare individuals may even reach their forties. It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.
Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging. Progeria was first described in 1886 by Jonathan Hutchinson and also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS).
Heart problems or stroke is the eventual cause of death in most children with progeria. There’s no cure for this condition, but ongoing research shows some promise for treatment.
Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.
The symptoms of this progressive disorder include:
*Slowed growth, with below-average height and weight
*A narrowed face and beaked nose, which makes the child look old
*Hair loss (alopecia), including eyelashes and eyebrows
*Hardening and tightening of skin on trunk and extremities (scleroderma)
*Loose, aged-looking skin
*Head too large for face
*Prominent scalp veins
*Small lower jaw (micrognathia)
*Delayed and abnormal tooth formation
*Loss of body fat and muscle
*Growth failure during the first year of life
*Narrow, shrunken or wrinkled face
*Loss of eyebrows and eyelashes
*Large head for size of face (macrocephaly)
*Open soft spot (fontanelle)
*Small jaw (micrognathia)
*Dry, scaly, thin skin
*Limited range of motion
*Teeth – delayed or absent formation
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.
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 “accelerated aging” diseases display different aspects of aging but never every aspect, they are often called “segmental progerias.
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.
Exams and Tests:-
The signs include:
*Insulin-resistant diabetes (diabetes that does not respond readily to insulin injections)
*Skin changes similar to that seen in scleroderma (the connective tissue becomes tough and hardened)
Cardiac stress testing may reveal signs of early atherosclerosis of blood vessels.
Genetic testing can detect mutations in lamin A that cause progeria.
No treatments have been proven effective. Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. Children may also benefit from a high-calorie diet.
Growth hormone treatment has been attempted.
A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI Lonafarnib began in May 2007.
There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.
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).
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.
A study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are between 35 and 45 known cases in the world.Approximately 100 cases have been formally identified in medical history.
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. 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; 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.
Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.
A 2003 report in Nature 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.
Support Groups: ->Progeria Research Foundation, Inc.
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 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. 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. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin A defects contribute to normal aging.
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.
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”.
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.
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 rapidly ages backwards.
The Indian film Paa, released in December 2009, has its story line around progeria (starring Amitabh Bachchan playing a twelve year old boy Auro).
Progeria is also a central theme in the animated film Renaisance in which one of the characters finds the much sought cure.
Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.