INTRODUCTION

HISTORY :
Progeria (also known as "Hutchinson±Gilford Progeria Syndrome", "Hutchinson±Gilford syndrome", and "Progeria syndrome") is an extremely rare genetic condition where symptoms resembling aspects of aging are manifested at an early age. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years. This condition does not disrupt intellectual development or the development of motor skills such as sitting, standing, and walking. The word Progeria comes from the Greek words "pro" which means "before" and "géras" which means "old age". The disorder has very low incidences and occurs in an estimated 1 per 8 million live births. Those born with progeria typically live to their mid teens and early twenties. It is a genetic condition that occurs as a new mutation , and is rarely inherited. People with Hutchinson-Gilford progeria syndrome experience severe hardening of the arteries (arteriosclerosis) beginning in childhood. This condition greatly increases the chances having a heart attack or stroke at a young age. These serious complications can worsen over time and are life-threatening for affected individuals. Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception. 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. It was also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS). A 2003 report in Nature said that progeria may be 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.

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CONTENT CONTENT Introduction Table of Content Sign And Symptoms Causes How To Handle Children With Progeria In Home Treatment Conclusion Reference PAGE 1 2 3-4 5-7 8 9 10 11 2 .

A child with this condition show signs of symptoms usually around 18±24 months. As a child ages past infancy. It is not transferred by the offspring. and a distinctive appearance (small face and jaw.SIGN AND SYMPTOMS: The earliest symptoms include failure to thrive and a localized scleroderma-like skin condition. lifelong Weight distinctly low for height Head disproportionately large for face Thin. the condition causes wrinkled skin. with the following sequellae: o o o o o Prominent scalp veins Prominent veins over most of body Irregular small outpouchings of skin over lower abdomen and/or proximal thighs Prominent eyes Lack of ear lobes. their height and weight suddenly fall below average for their age. like those of elderly people. in some but not all cases y Skin/hair/nails o o o o o Taut. hair loss. atherosclerosis. and cardiovascular problems. high-pitched voice Body fat. alopecia. Limited growth. additional conditions become apparent. Diminished subcutaneous fat globally. There are many signs and symptoms of this progressive disease. loss of eyesight. kidney failure. fragile bodies. pinched nose) are all characteristics of progeria. lifelong Weight (<3rd percentile). Later. dry skin that is variably pigmented (spotty) Loss of eyebrows and sometimes eyelashes Dystrophic fingernails and toenails Lagophthalmos (the inability to fully close the eye) Thin lips 3 . Individuals having the silent mutation and most of the following features after age three years are considered to have the classic Hutchinson-Gilford progeria syndrome: y Growth o o o o o y Short stature (<3rd percentile). People diagnosed with this disorder usually have small. and they tend to get worse as the child ages. After being born a healthy looking baby. Individuals generally retain normal mental and motor development.

and secondary tooth eruption behind primary teeth y Skeletal system/joints o o o o o o o o o o o Narrow nasal bridge.y Teeth o o o o Delayed eruption of primary teeth Delayed loss of erupted primary teeth Partial secondary tooth eruption Dental crowding as a result of small mouth. pointed nasal tip Osteolysis of the distal phalanges Delayed closure of the anterior fontanelle Pear-shaped thorax Retrognathia and micrognathia Short. shuffling gait Low bone density Thin limbs Tightened joint ligaments globally but variable in severity y Cardiovascular/neurovascular o Severe progressive atherosclerosis with variable age of clinical manifestation resulting in:   Cardiac manifestations: angina. congestive heart failure. including transient ischemic attacks and silent strokes that are seen on MRI or CT of the head but do not manifest as clinical deficits o Raynaud phenomenon in fingers of some but not all individuals y Endocrine o o o Failure to complete secondary sexual development Low serum leptin concentration Insulin resistance in up to 50% of individuals. Note that frank diabetes mellitus is unusual. 4 . lack of primary tooth loss. dystrophic clavicles Osteoarthritis "Horse-riding" stance and wide-based. myocardial infarction Stroke.

After prelamin A has been localized to the cell nuclear membrane. the cause of progeria was discovered. The LMNA gene is responsible for producing lamin proteins. Cockayne's syndrome. including the farnesylated cysteine. which provide strength and stability in cells. the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. and carries out functions inside the nucleus. The resulting protein. causing a characteristic nuclear blebbing. but never every aspect. Lamin A cannot be produced. although the mechanism connecting the misshapen nucleus to the symptoms is not known. the C-terminal amino acids. they are often called "segmental progerias". creating a form of the Lamin A protein which cannot be processed properly and accumulates in the cell nucleus. or xeroderma pigmentosum). Lamin A and Lamin C support the nuclear envelope. are cleaved off by a specific protease. Before the late 20th century. specifically the nuclear membrane. it affects the shape and the function of the nuclear envelope. 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 results in the symptoms of progeria. and prelamin A builds up on the nuclear membrane. Lamin A Lamin A is a major component of a protein scaffold on the inner edge of the nucleus called the nuclear lamina that helps organize nuclear processes such as RNA and DNA synthesis. 5 . progeria is not caused by defective DNA repair. Because these diseases display what are considered different aspects of aging. In HGPS.CAUSES: Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene. research on progeria yielded very little information about the syndrome. replacing cytosine with thymine. is no longer membrane-bound. In 2003. Unlike "accelerated aging diseases" (such as Werner's syndrome. This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes. Lamin A is a major structural protein of the human cell nucleus. now lamin A. When Lamin A is altered. These changes cause other cells to die prematurely.

Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. including down-regulation of certain nuclear proteins. Disorganization and loss of peripheral heterochromatin is also seen. In the test tube. RNA splicing factors and transcription factors such as the retinoblastoma transcriptional regulator (RB) and sterol response element binding protein (SREBP1). Capell and Collins. vulnerability to mechanical stresses and nuclear blebbing. increased DNA damage which leading to reduced heterochromatin. We predict that progerin becomes entrapped in the nuclear membrane as a result of permanent farnesylation. in which lamin A is permanently farnesylated in the form of progerin. with heterochromatin becoming detached from the nuclear envelope. resulting in a multitude of downstream effects. and disrupted interactions with RNA polymerase II. Mouse model of progeria Untreated cells from children with the genetic disease progeria (left) compared to similar cells treated with farnesyltransferase inhibitors (FTIs).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. germ cell-less. FTIs reverse the nuclear damage caused by the disease. Disruption of the normal lamina architecture leads to fragility. Nature Reviews Genetics 2006. which leads to misregulation of gene expression. A range of putative disease-causing mechanisms for the case of HGPS. These studies suggest that lamin A defects are associated with normal aging. GCL. 6 .

there is no production of normal lamin A in the nucleus. the combination of an FTI and statins was tried. Staining was smooth muscle alpha-actin (green). Fong et al. The microphotographs show prevention of the vascular smooth muscle cell loss that is otherwise rampant by this age. Confocal microscopy photographs of the descending aortas of two 15-month-old progeria mice. but equally. that causes the disease. mouse models in which the genes for prelamin A and C are knocked out show no symptoms. (Original magnification. indeed. This method does not directly "cure" the underlying cause of progeria. rather than the loss of the normal function of lamin A. loss of weight. and bone defects". 7 . one untreated (left picture) and the other treated with the farnsyltransferase inhibitor drug tipifarnib (right picture). though in the mouse. Luckily. lipodystrophy. ZMPSTE24. including growth retardation. the specific protease that is required to remove the C-terminus of prelamin A. x 40) It was hypothesized that part of the reason that treatment with an FTI such as alendronate is inefficient is due to prenylation by geranylgeranyltransferase. and markedly improved "the aging-like phenotypes of mice in the metalloproteinase ZMPSTE24. is missing. hair loss. Since statins inhibit geranylgeranyltransferase. use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of prelamin A. lamins A/C (red) and DAPI (blue). Both cases result in the build up of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Instead. the LMNA prelamin A is not mutated. This also shows that it is the buildup of prelamin A in the wrong place. 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. Treated mice had greater grip strength and lower likelihood of rib fracture and may live longer than untreated mice.A mouse model of progeria exists. lamin A does not appear to be essential.

he or she is also likely to experience fear and grief as awareness grows that progeria shortens life span. The Progeria Research Foundation may be able to help you connect with other families coping with progeria. and offer reassurance that's compatible with our belief system. Helping our child cope If our child has progeria. family and friends. and may have a number of difficult but important questions about spirituality and religion. Our child eventually will need our help coping with the concept of death. Our child may also ask questions about what will happen in our family after he or she dies. emotional and financial resources. In a support group. Friends who we meet through support groups also may be able to offer valuable guidance. support groups can be a valuable part of a wider network of social support that includes health care professionals. Our local health department. If a group isn't for us. therapist or clergy member to help us prepare for such conversations with oour child. talking to a therapist or clergy member may be beneficial. we'll be with people who are facing challenges similar to the one that we are. public library. Ask our doctor about self-help groups or therapists in our community. coping with the disorder involves a major commitment of physical. but we may be able to find a group for parents of children with chronic illness. 8 . Ask our doctor. telephone book and the Internet also may be good sources for finding a support group in our area. Our child might also benefit from talking to a therapist or clergy member.HOW TO HANDLE CHILDREN WITH PROGERIA IN HOME Learning our child has progeria can be emotionally devastating. we may not be able to find a progeria-specific support group. Because progeria is so rare. For we and our family. It's critical that we are able to talk openly and honestly with our child. difficult challenges and a shortened life span. In dealing with a disorder such as progeria. Talking to group members can help us cope with our own feelings about our child's condition. Suddenly when we know that our child is facing numerous.

With respect to the features of aging that progeria appears to manifest. y Physical and occupational therapy. Certain therapies may ease or delay some of the signs and symptoms. Extraction may help prevent problems associated with the delayed loss of baby teeth. y Extraction of primary teeth. They also do not develop the so-called "wear and tear" conditions commonly associated with aging. At least 90% of patients die from complications of atherosclerosis. Other medications. has been proposed. such as arthritic. but their use has been mostly limited to animal models. was one of the oldest people in the world who lived with progeria. A daily dose may help prevent heart attacks and stroke. the farnesyltransferase inhibitors (FTIs). Children may also benefit from a high-calorie diet. Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. 9 . Mental development is not affected. Leon Botha. 2011. The use of growth hormone may help increase height and weight. such as statins to lower cholesterol or anticoagulants to help prevent blood clots. These may help with joint stiffness and hip problems and may allow child to remain active. such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear). A Phase II clinical trial using the FTI Lonafarnib began in May 2007.TREATMENT: No treatments have been proven effective. In studies on the cells another anti-cancer drug²rapamycin caused removal of progerin from the nuclear membrane. They include: y y Low-dose aspirin. there are treatments for the problems it causes. A type of anticancer drug. Growth hormone treatment has been attempted. Although there may not be any successful treatments for progeria itself. and cardiovascular problems. a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group Die Antwoord. Depending on child's condition. doctor may prescribe other medications. including overcrowding and developing a second row of teeth when permanent teeth come in. Few people with progeria exceed 13 years of age. such as heart attack or stroke. respiratory. the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. Child's permanent teeth may start coming in before his or her baby teeth fall out. dying one day after his 26th birthday on June 5.

Because nutrition and growth can be an issue for children with progeria. y Make sure child is up to date on childhood immunizations. so he or she can attend school at an age-appropriate level. Progeria won't affect child's intellect. y Get cushioned shoes or shoe inserts for child. y Provide learning opportunities.CONCLUSION: Since progeria cannot be cured and there is no treatment for it. parents or guardians can follow some of the steps at their home that might help their childrens. y Provide opportunities for regular physical activity. 10 . small meals. Check with child's doctor to learn which activities are right for child. y Provide frequent. especially during an illness or in hot weather. but like all children is at risk if exposed to infectious diseases. giving child smaller meals more often may help to increase his or her caloric intake. Some steps can take at home that may help child include: y Make sure child stays well hydrated. Be sure child gets enough to drink. Dehydration can be more serious in children with progeria. A child with progeria isn't at increased risk of infection. The loss of body fat in the feet can cause discomfort.

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