ABOUT AUTHOR:
Akshay Rajgaria
Kanak Manjari Institute of Pharmaceutical Sciences
akshaykrish2007@gmail.com
ABSTRACT:
Progeria is a rare and peculiar combination of dwarfism and premature ageing. The incidence is one in several million births. It occurs sporadically and is probably an autosomal recessive syndrome. Though the clinical presentation is usually typical, conventional radiological and biochemical investigations help in confirming the diagnosis.
Reference Id: PHARMATUTOR-ART-1987
INTRODUCTION:.
HGPS (Hutchinson-Gilford Progeria Syndrome) or Progeria is an extremely rare, fatal genetic condition. The word Progeria comes from the Greek progeros meaning 'prematurely old'. The Greek word pro means 'before', while the word geras means 'old age'. It is genetic condition that occurs as a new mutation, 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.
CAUSES:
In normal conditions, the LMNA gene codes for a structural protein called prelamin A. There is a farnesyl functional group attached to the carboxyl-terminus of its structure. The farnesyl group allows prelamin A to attach temporarily to the nuclear rim. Once the protein is attached, the farnesyl group is removed. Failure to remove this farnesyl group, permanently affixes the protein to the nuclear rim. Without its farnesyl group, prelamin A is referred to as. Lamin A, along with lamin B and lamin C, make up the nuclear lamina, which provides structural support to the nucleus.
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 apoint mutation in position 1824 of the LMNA gene, in which cytosine is replaced with thymine. This mutation causes transcription of the LMNA gene to stop too early, which results in the creation of an abnormally short mRNA transcript. This mRNA strand, when translated, yields an abnormal variant of the prelaminA protein whose farnesyl group cannot be removed. Because its farnesyl group cannot be removed, this abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim, and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear lamina is unable to provide the nuclear envelope with adequate structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide.
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Progerin may also play a role in normal human aging, since its production is activated in senescent wild type cells.
Unlike "accelerated aging diseases" (such as Werner's syndrome, Cockeyes’ syndrome, or xeroderma pigment sum), progeria is not caused by defective DNA repair. Because these diseases cause changes in different aspects of aging, but never in every aspect, they are often called "segmental progerias".
SIGN AND SYMPTOM:
Children with progeria usually develop the first symptoms during their first few months. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent usually around 18–24 months. Limited growth, full-bodyalopecia, and a distinctive appearance (a small face with a shallow recessed jaw, and a 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 alopecia), 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 do usually retain normal mental and motor development.
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. Children may also benefit from a high-energy diet.
Growth hormone treatment has been attempted. The use of morpholinos has also been attempted in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used.
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. In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through autophagy. It has been proved that pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl group production. However, it is important to remember that no treatment is able to cure progeria.
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 cannot remain attached to the nucleus rim and it now has 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.
Pravastatin, traded as Pravachol or Selektine, 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 and zoledronate 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”. 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.
A 2012 study showed that the cancer drug Lonafarnib can be used to treat progeria
It should always be taken in account that no treatment is delivered in order to cure Hutchinson-Gilford progeria syndrome; all potential drugs are in pre-clinical stages.
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RESEARCH:
Several discoveries have been made that have led to greater understandings and perhaps eventual treatment for this disease.
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 asprogerin. 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 Bern’s, founded the Progeria Research Foundation.
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.
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.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 his tone, 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 are associated with normal aging.
Mouse model
A mouse model of progeria exists, though in the mouse, the LMNAprelamin 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. 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). 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.
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 stains 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, lip dystrophy, hair loss, and bone defects".
WERNER SYNDROME: Werner syndrome also known as "adult progeria" is a rare, autosomal recessive progeroid syndrome (PS), which is characterized by the appearance of premature aging.
Werner syndrome is named after the German scientist Otto Werner. He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.
It has a global incidence rate of less than 1 in 100,000 per live birth (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000-40,000 and 1 in 50,000, respectively), there have been 1,300 reported cases. Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed. The youngest person diagnosed was six years old. The median and mean age of death is 47-48 and 54 years, respectively, the main cause of death is cardiovascular disease or cancer.
CAUSES OF WERNER SYNDROME: Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the eponymous gene, WRN; the only gene currently attributed to cause Werner syndrome. WRN, which lies on chromosome 8 in humans, encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication. Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.
Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein leading to the loss of its nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair. Furthermore, mutated proteins are more likely to be degraded than normal WRNp. Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increase the survival of these dysfunctional cells.
Cells of affected individuals have reduced lifespan in culture, have more chromosome breaks and translocations and extensive deletions. These mutations may in turn cause more RecQ-independent aging phenotypes.
TREATMENT OF WERNER SYNDROME:
In 2010, vitamin C supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factorNF-κB. Vitamin C decreases activity of genes activated in human Werner syndrome, and increases gene activity involved in tissue repair. Vitamin C supplementation is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice.
CONCLUSION:
Progeria is a disease that causes rapid aging and is caused by a base-pair substitution in the LMNA gene. Effects include abnormally projecting eyes and other growth defects. Treatments include FTI’s that inhibit the progerin from reaching nucleus, increased supplements of GH and calcium, and medication to reduce effects ofatherosclerosis.Werner’s syndrome is a rare form of progeria with an autosomal recessive mode of inheritance mimicking the symptoms of accelerated aging. The reduced life expectancy is caused by the increased incidence and early onset of atherosclerosis and malignant tumors.
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