Hutchinson-Gilford progeria syndrome (HGPS), or more commonly known as progeria, is an extraordinary uncommon fatal genetic illness that causes accelerated aging in young people (Jitendra Kumar Sinha, 2014). There are many forms of progeria (progeroid syndromes) were symptoms can onset later on in life and/or are not as drastic in physical and/or internal changes. For simplicity sake, this research paper will focus primarily on HGPS, the most commonly known form of progeria, (but will briefly touch on progeriod syndromes). Progeria is a mutation in the lamin A protein, that is encoded by the LMNA gene. The mutated version of this protein is called progerin and it causes the nucleus of cells to not be able to maintain its appropriate shape, thus disrupting the original function of such cells. Mutations in this gene can cause a variety of side effects, such as disrupting proper development of muscles, nerves, and premature aging (Howard J. Worman, 2004). Young individuals with progeria age rapidly, eight times faster than a normal human, because of the gargantuan amount of progerin they produce. Healthy individuals can naturally produce a little bit of progerin, but never to the quantity that an individual suffering with progeria produces (Health, 2011). Progeria thus causes rapid aging, a shorten life span, and numerous physical symptoms as a result. Studying the effects of progeria (and the disease itself) might be able to better explain the ageing process and how and why aging accelerates dramatically to those with genetic mutations—as well as finding a cure to alleviate these ageing accelerations caused by such genetic mutations.
Progeria is caused by a mutation in the gene called LMNA. The LMNA gene, when healthy, produces a lamin A protein that holds the shape of the nucleus. The nucleus is the storage of DNA information, so once altered, adverse side effects can arise. The atypical form of lamin A, progerin, causes the nucleus of such protein to become unstable and therefore disrupting proper development (Syndrome, 2003). (See figure 1.)
Figure 1: A cell with the normal lamin A protein (left) and a cell with the mutated version of the lamin protein: progerin (right) (Nissan, 2012).
The chances of receiving the progerin LMNA mutation of the lamin A protein is very rare and occurs through a de novo mutation of DNA. This means that during meiosis the germ cell was mutated and as a result the child that is born with progeria is the first individual in the family pedigree to be inflicted by the new disease.
The mutation of the LMNA gene is new to a family and there is usually no other individual in the family tree with such disorder. Progeria affects genes, but is not necessarily hereditary. Progeria is an autosomal dominant disorder. For an offspring to express the mutation, both parents have to carry the gene, but not necessarily express it in order for it to be passed on.
Disorders such as Tay’s syndrome, Cockayne syndrome, and Werner syndrome are all grouped in with progeria as progeriod syndromes. All these diseases are related to progeria and are all caused by mutations in different genes but display very similar physical and internal symptoms. For example, Werner syndrome, or “adult progeria”, is caused by a mutation in the WRN gene that controls DNA helicase. Werner syndrome is autosomal recessive and has the exact same symptoms as progeria, but interestingly enough the disorder doesn’t onset until the age of ten. It is fascinating that mutations that are on completely different genes can cause very similar symptoms, but just delay or prolong the process (Jitendra Kumar Sinha, 2014).
Table 1: Synoposis of progeriod syndromes, their mutations, and symptoms (Jitendra Kumar Sinha, 2014).
Progeria is not demographically or geographically biased, as it is distributed universally. There are roughly 200-250 humans with progeria around the whole world (GARD, n.d.). Progeria occurs one in 4-8 million births (Foundation, n.d.).
Most children with progeria look perfectly healthy and typical until about the ages of one to two. Individuals with the mutated version of the gene LMNA display acute physical and internal symptoms as a result of the mutation. The most common symptoms of progeria consist of a permanent short, baby-like stature with an enlarged head (when compared to the body) and beaked nose, accompanied by prominent veins and wrinkles on the face and body. Other side effects include a high-pitched voice, absence of facial and body hair, and atypical teeth. Restricted movement due to hardening of connective tissues is common as well (Nordqvist, 2017).
Progeria comes with lots of internal problems as well; for example, cardiovascular disease, tightening of the skin, hearing loss, fragile bones, and insulin resistance are just a few of the many health issues progeria possesses. The average life expectancy is around the age of fourteen. (Though there are some cases of individuals living to their earlier 20s.) The eventual cause of death is usually catalyzed by the hardening of the arteries. The arteries being drastically solidified—due to the lamin A gene mutation—makes sufferers of progeria very prone to atherosclerosis (Clinic, 2018). Atherosclerosis, when severe, can then cause stroke or heart problems as the blood vessels are unable to supply the heart or brain with blood properly.
Future research/cures of progeria
Progeria is an extremely rare disorder which makes it complex to research. Parents of children with progeria and charities, such as Progeria Research Foundation, have helped by increasing awareness of progeria to the masses. With increased awareness comes more research, as a result more advances in progeria have become possible. For example, recently (in 2010) FTIs have been discovered to be able to help with progeria.
Farnesyltransferase inhibitors (FTI) may help to alleviate the symptoms of progeria. FTIs are drugs that are able to reverse the deformity of the nucleus caused by the mutation of the lamin A gene, progerin. The way that Farnesyltransferases work is by targeting the farnesyls group and causing the group to bind with progerin (Jitendra Kumar Sinha, 2014). There is an issue, however. Most FTIs are new to the medicial field and as a result have not all been tested on humans, but rather on mice. Prgoeroid mice treated with Tipifarnib, a FTI, showed a remarked improvement in age-related syptoms. Hair, bone, weight, bone, and cardiovascular health all showed improvements within the mice (Varela I, 2008).
A FTI that has clinically trialed on humans is Lonafarnib. Lonfarnib linical trial that has been used on individuals with progeria and showed great improvements. A study done with 25 children with progeria showed weight gain/maintenance, increase in skeletal flexibility and cardiovascular health (Gordon LB, 2012). This is an amazing accomplishment for improving the quality of life with those with progeria and makes great stride in the right direction.
As there is no current cure for progeria, lessening the severity of the disease is the only thing current possibility. Besides the helpfulness of medication, there are natural ways to combat the symptoms of progeria. Eating healthfully, sleeping plentifully, and exercising frequently can extend the lifespan of an individual with progeria and make life as comfortable as possible for those with progeria.
Examining the effects of progeria has lead to a slight better understanding of the aging process and ways to combat it to an extent. A simple mutation in the LMNA gene causes disastrous effects. When unaltered the LMNA gene maintains the shape of the nucleus inside a cell. Progeria, is a mutation in this gene. Normally, the lamin A protein does maintains the shape of the nucleus, but when mutated it becomes progerin. Progerin is unable to maintain the structure of the nucleus, thus resulting in the disease progeria. Progeria affects gene but is not inherited. Other diseases, such as Tay’s syndrome and Werner’s syndrome are all grouped with progeria and are known as progeroid syndromes. Progeroid syndromes all act on different mutations, but have similar side effects.
Progeria appears in a family’s gene lineage indiscriminately. Progeria causes rapid premature aging along with numerous external and internal complications. Externally symptoms range from short stature, thin hairless and prominently veiny skin, and a sharp and high voice. Internally, frail bones, hardened connective tissues and arteries, et cetera.; as a result, those with progeria do not have a high life expectancy.
There is no current cure for progeria, but FTIs and having a healhy lifestyle are able to alleviate the pains that come along with progeria.
As progeria seems to be taking hold of the public eye more and more due to the unfortunate and pitiful effects the disease has on an individual, the more information and research will most likely be conducted on progeria. Finding the eventual cure for progeria is a possibility as technology and medicine are rapidly evolving with gene editing becoming more and more prioritized. Not only is the cure a possibility for the sufferers of progeria, but the actual study of progeria itself may lead to more understanding of the aging process and what can be done to alleviate and/or alter such process.
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