Progeria - a genetic disorder

Only 80 children worldwide, including 18 in the United States, have been identified with progeria, making it an incredibly rare genetic illness (Swahari & Nakamura, 2016). The condition was initially identified in 1886 by Dr. Jonathan Hutchinson and is thought to affect one in every eight million live births. The fundamental characteristic of progeria is premature aging, which ultimately results in mortality. This essay's goal is to examine the two forms of progeria, Werner's syndrome and Hutchinson-Gilford syndrome. Each type has a unique genetic mutation mechanism, and the diagnosis of this condition is made by finding that mutation. The symptoms can arise from different body organs to physical characteristics such as facial features and musculoskeletal disorders. Although progeria remains incurable, there are various medications and therapeutic therapy can aid in alleviating the symptoms and delay regression. The acquisition of the medical attention and preventive measures is essential for the victims. Regular medical checkups are important for the vulnerable population.













Introduction

The first case of progeria dates back to 1886 and it was described by Dr. Jonathon

Hutchinson from the United Kingdom. The most extensively studied type of progeria is the Hutchinson–Gilford progeria syndrome named after the two scientists (Jonathan Hutchinson in 1886 and Hastings Gilford in 1897) who independently studied the syndrome (Walsh, McClellan, McCarthy, Addington, Pierce, Cooper & Stray, 2008). Another form of progeria condition is known as the Werner’s syndrome that is also called adult progeria (Liu, Barkho, Ruiz, Diep, Qu, Yang & Thompson, 2011). Progeria is an exceptionally rare and deadly genetic condition characterized by the manifestation of accelerated aging in young people. The word progeria is actually derived from the Greek word meaning “prematurely old” (Walsh, McClellan, McCarthy, Addington, Pierce, Cooper & Stray, 2008). Progeria occurs infrequently with a reported incidence of one in eight million. According to reports in the medical literature, children as young as 9 months can develop this disease and begin to experience growth delays resulting in short physique and low weight. The average life expectancy of a person diagnosed with progeria is about 13 years but there have been cases where patients lived up to 20 years. Recent revelations indicate that mutations that occur in the genes responsible for these untimely aging diseases result from the progressive DNA damage (Walsh, McClellan, McCarthy, Addington, Pierce, Cooper & Stray, 2008). These mutations occur in the LMNA gene which produces the structural proteins lamin A and lamin C. These proteins are essential components of the nuclear envelope that surround the nucleus of cells (Liu, Barkho, Ruiz, Diep, Qu, Yang & Thompson, 2011). ​Progeria is currently incurable and for a large part untreatable, researchers are now beginning to understand the genetics behind this mysterious disease. This paper will discuss the differences between the Hutchinson-Gilford syndrome and Werner's syndrome.



The 2 types of Progeria

A comparison between the Hutchinson-Gilford and the Werner syndromes could be useful to provide an insight into the nature of the genetic mutations underlying these conditions. The abnormalities and growth delay associated with childhood progeria are not usually apparent at birth but progressively develop in the first year of life. Likewise, the recognizable phenotype of the Werner syndrome is not often apparent until the individuals are in their mid-teens to early twenties, and diagnosis is not made until their thirties. This is the reason they are known as childhood progeria and adulthood progeria respectively. However, there are similar characteristics involving the two syndromes other than growth failure which includes developing a receding chin, narrow nasal bridge and a pointed nasal tip (Brown, 2003). After the first year of diagnosis, partial alopecia which progresses to total alopecia also becomes apparent. Alopecia is an autoimmune skin disease which causes the sudden loss of hair follicles from the scalp, face and sometimes on other areas of the body. The patients diagnosed with progeria will also begin to experience loss of subcutaneous fat and muscle loss which explains the small framed physical appearance that they possess. Further characteristics include the shortening and hardening of joints, bone changes, and nail dystrophy. ​Later findings include dental crowding, partial lack of secondary tooth eruption, and low-frequency and conductive hearing loss.

Genetic Mechanism

In the past, progeria used to be diagnosed solely on the physical symptoms that were previously mentioned such as the skin changes and failure to gain weight. However, progeria can now be diagnosed with a genetic test as it is a disorder resulting from mutations in the genes. The Hutchinson-Gilford syndrome and the Werner syndrome both have different mutation mechanisms that will be discussed in the next section. The building block of every cell in a human body is the nucleus which contains the DNA that makes up the genetic material. The genes are responsible for the make-map that can lead to the phenotypic and genotypic characteristics of a human. The genes that are the key components of the nuclear lamina are Lamin A and C which are essential for nuclear architecture. Therefore, when there are alterations in these genes, it disrupts the integrity and function of the nucleus. This results in different mutations of the LMNA gene that is correlated to many disorders and one being the Hutchinson-Gilford syndrome (Gonzalo, Kreienkamp & Askjaer, 2017). As for Werner's syndrome, it is caused by a mutation in the WRN gene which provides instructions for producing the Werner protein and plays a crucial role in repairing damaged DNA. The ​WRN gene is also known to serve a critical role in homology-dependent recombination (HDR) repair thereby preventing genomic instability and controlling proper DNA duplication and restoration to ensure the capability of the cell (Swahari & Nakamura, 2016). Almost all mutations in WRN lead to the production of an abnormally short, nonfunctional Werner protein (Swahari & Nakamura, 2016). According to research, it is suggested that this shortened protein is not transported to the cell’s nucleus, where it would interact with DNA (Gonzalo, Kreienkamp & Askjaer, 2017). The following figure shows the pathway of a normal splicing versus mutant splicing of the gene of the Hutchinson-Gilford syndrome that leads to the production of progerin.











Figure 1- Abnormal processing of lamin A in HGPS

The progeria disorder is not a hereditary disorder; it cannot be passed down to other family members. The changes in the gene usually occur by chance and it is usually rare in most populations across the world. Children with other forms of the progeroid disorders which are not HGPS may not be infected by the diseases that are inherited from one family generation to the other. The occurrence of the HGPS is because of the sporadic autosomal dominant mutation. It is termed as sporadic because it is unique or new in the family generation. It is dominant because only one copy of the gene needs to be changed in order to obtain the syndrome. For the parents with no children having the progeria disorder, the chances of getting the child with disorder is usually minimal with the ratio of 1 to 8 million (Swahari & Nakamura, 2016). For the parents who have had children with the progeria disorder, the chances of obtaining the kid with the same condition are usually high with the ratio of 2% to 3%. The above scenario happens as a result of the condition referred to as mosaicism, a situation where one of the parents has the genetic mutation for the progeria disorder in their cells. The genetic mutation usually occurs as a result of the small mutations that occurs inside the cells, but which are not characterized by the progeria condition.

The genetic mutations inside the cell are usually characterized by different factors. Changes in the environmental condition are one factor that greatly affects the genetic composition and arrangement inside the cell. An individual can develop the progeria condition in the course of development due to the changes in the environmental conditions that affect the activities of the cell. In most cases, the DNA structures usually change to conform to a given environmental condition, a situation that leads to the changes in the RNA contents. The above scenario causes situations where children are tested positive while parents remain negative to the progeria condition. The changes in the structure and the components of the DNA are also characterized by the disorders and diseases that an individual acquire in the course of development.



The experience of too many disorders may possibly cause the change in the immune system, a situation that is characterized by the absolute changes in the DNA. Another condition that characterizes the formation of the progeria is the exposure to the harmful radiations that may destroy the cell structure and the DNA contents. In most cases, when the DNA is exposed to the radiations like the gamma ray or the ultraviolet radiations, the orientation of the DNA together with the RNA components may be damaged, a situation that leads to the destruction of the genes that defines a given characteristic, this case, the normal aging (Nordqvist, 2010). There are certain genes that define the procedural steps in the development of human body parts, and when these genes are destroyed, individuals may experience the premature development or aging. The above condition may be characterized by the appearance of the beads in children or any other characteristic that should only appear in the adult. The exact cause of the stimulated aging associated with HGPS has not been established. Many scientists stipulate that the abnormal aging is due to the cumulative cell damage that is caused by the continuous metabolic processes that take place within the body cells. The above theory suggests that the free radicals produced as a result of chemical reactions accumulate in the body cells, a situation that may cause the chemical mutation.

The accumulation of the radical chemicals within the body results in the destruction of the cells and tissues and may cause the loss of some genetic characteristics thereby causing aging. There are enzymes called the antioxidant that play the roles in keeping the aging process by enhancing the processes of free radical elimination. Enzymes are chemical proteins that are produced by the cell organelles; when the cells responsible for their productions are damaged, the production of the enzymes is limited thereby leading to the condition of prognosis. The reduction in the activity of some enzymes may also cause the process of accelerated aging among the individuals with HGPS.

The genetic mutation may also interfere with the crossover, a situation which usually results in the sharing of the genetic components between different gene structures. The above scenario may lead to the expression of certain genes in a way that may influence the development of a given characteristic (Nordqvist, 2010). The mutations that take place in the LMNA results into the Hutchinson-Gilford progeria syndrome. Inside the LMNA, there is a gene that provides the instructions for the formation of the lamin A proteins, the protein that determines the shape of the nucleus inside the cells, it is an important scaffolding component of the nuclear membrane (Lee, Harrigan, Opresko & Bohr, 2005). The mutations that cause progeria condition result in the production of the abnormal form of lamin A. When the protein is altered, the nuclear membrane becomes unstable, a situation that subsequently results in the destruction of the nucleus thereby making the cells to die prematurely. There is progressive research that tries to determine how the changes or destructions of the nucleus result in the progeria condition. The progeria syndrome is an autosomal dominant condition, meaning that the alteration of one copy of the gene is sufficient to cause the disorder; the condition is initiated by the mutations in the LMNA gene and it occurs to people with no history of such disorders in their families.

Treatment strategies

At the mean time, there is no cure to be found that can stop the spread of Progeria in the human body and there is no specific treatment as well. However, it is recommended that the patient should practice therapeutic modalities to delay regression (Swahari & Nakamura, 2016).

These types of modalities include electrical muscle stimulation, ultrasound, heat, ice, and traction.

They can also help to reduce muscle pain, improve circulation and decrease swelling.

The pharmacologic procedures in the treatment of the progeria condition may include the attempts to eliminate the accumulation or expression of the progerin and enhance autophagy. When an individual suffers from the progeria condition, careful monitoring of the cerebrovascular and cardiovascular diseases is important. The application of the low-dose aspirin is usually suggested as prophylaxis against cerebrovascular and cardiovascular atherosclerotic infection. Occupational and physical therapy can assist in increasing or maintaining the active lifestyle and physical activities for the affected individuals. The application of the hydrotherapy may specifically be effective in minimizing symptoms of arthritis and enhancing the mobility of the joints. Children suffering from progeria may develop the tendency of poor feeding. The provision of the sufficient nutrition may call for the establishment of the gastrostomy tube to supplement the enteral feeding. For the older kids, the high intake of the energy giving food is essential and this should be carried out on a daily basis. The energy giving foods include the food materials that have high carbohydrate contents; these foods produce a lot of energy that can be used by the cell during the respiration. In some other cases, the use of growth hormones should be encouraged for it reduces the catabolic demands and increases linear growth and weight gain in some patients with progeria condition.

The application of Sulforaphane can help in mitigating the condition of progeria; it contains antioxidants synthesized from the cruciferous vegetables. It stimulates the activities of the autophagy and proteasome in the cultured progeria fibroblasts. The above scenario enhances the clearance of the progerin by the autophagy, a situation that leads to the restoration of the normal cellular phenotypic conditions. The Vitro studies along with other different researches reveal that the application of the farnesyltransferase inhibitors also reduces that possibility of occurrence in the progeria condition (Regier & Greene, 2017). The farnesyltransferase inhibitors enhance the production of the mutant prelamin A from the nuclear membrane; this enabled it to be rightfully incorporated into the nuclear lamina thereby correcting the functional and structural defects in the nuclear. The above process leads to the formation of the healthy nuclear that enhances the growth of the cell structure, the process that aids in the reduction of the progeria condition. When the cells are actively operating, the occurrence of the progeria condition reduces significantly. The Vivo studies suggest the effective procedural measures that can prevent the occurrence of the progeria condition.

The application of farnesyltransferase inhibitor i.e. FTI-276 or the combination of the lipid lowering agent, pravastatin, and the zoledronic acid reduces the formation of the nuclear abnormalities that may lead to the progeria condition. The zoledronic acid also enhances the bone mineral density which promotes the formation of more red blood cells and subsequent body cells that produce numerous nuclei for growth. In most of the treatment mechanisms, the preservation of the cell structures and components is essential for this aid in the protection of the nucleus of the cells. The nucleus blebbing is also another approach that can be applied to enhance the cellular activities and subsequent prevention of the chemical mutants that may cause changes in the genetic contents. Increasing the daily physical activity is important for the better health conditions; vigorous physical exercise helps in the removal of the excess chemical produced inside the cells during the cellular activities. With the increased physical activities, the rate of excretion activities increases thereby leading to the removal of the excess waste product of metabolic activities.

Conclusion

Although progeria remains incurable, there are various medications and therapeutic therapy that can aid in alleviating the symptoms and delay regression. The most extensively studied type of progeria is the Hutchinson–Gilford progeria syndrome named after the two scientists (Jonathan Hutchinson in 1886 and Hastings Gilford in 1897) who independently studied the syndrome. Progeria occurs infrequently with a reported incidence of one in eight million. The progeria disorder is not a hereditary disorder; it cannot be passed down to other family members. The changes in the gene usually occur by chance and it is usually rare in most populations across the world.

































Works Cited

Brown, W. T. (2003). Hutchinson-Gilford progeria syndrome. Chromosomal Instability and Aging: Basic Science and Clinical Implications, 245-61.

Gonzalo, S., Kreienkamp, R., & Askjaer, P. (2017). Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing research reviews, 33, 18-29.

Lee, J. W., Harrigan, J., Opresko, P. L., & Bohr, V. A. (2005). Pathways and functions of the Werner syndrome protein. Mechanisms of ageing and development, 126(1), 79-86.

Liu, G. H., Barkho, B. Z., Ruiz, S., Diep, D., Qu, J., Yang, S. L., ... & Thompson, J. (2011). Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature, 472(7342), 221-225.

Nordqvist, C. (2010). "Progeria: Causes, Symptoms, and Treatment." ​Medical News

Regier, D. S., & Greene, C. L. (2017). Phenylalanine hydroxylase deficiency.

Swahari, V., & Nakamura, A. (2016). Speeding up the clock: the past, present and future of progeria. Development, growth & differentiation, 58(1), 116-130.

Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., & Stray, S. M. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. science, 320(5875), 539-543.