Hutchinson-Gilford Progeria is an early-aging process disease and is one of the rarest diseases in the world. Research studies show that its global incidence rate is about one case for every four million births. Current health statistics estimate that there are approximately 100 patients who are living with the disease worldwide. However, it is estimated that there may be cases of undiagnosed disease which could be as many as 150. One factor that contributes to the condition's rarity is the high mortality rate. Although the disease is genetically inherited, most of the victims die from complications arising from the syndrome. Additionally, the deaths occur at a very young age, mostly pre-adolescent hence the victims often do not live long enough to pass the rare genetic trait to their offspring. (Coppede, 2013)
Etiology and Pathophysiology
The development of the disease, Hutchinson-Gilford Progeria is mainly due to a genetic mutation. Scientists identified the specific genetic alteration as a point mutation of the LMNA gene at the 1824 position. (Tsiligiri, Fekos, Theodoridou, " Lavdaniti, 2015) The normal gene codes for prelamin A, a structural protein whose final version is lamin A. The latter protein alongside the others like lamin B and C form the nuclear lamina whose function is providing the cell nucleus with the necessary structural support. Following mutation, therefore, the nucleotide, cytosine is replaced with thymine. The development, therefore, results in the alteration of the mature mRNA transcript which becomes shorter than the regular version. The changes, thus, lead to abnormalities in the subsequent steps of DNA synthesis and protein translation. Particularly, translation of the abnormal mRNA leads to the formation of a prelamin A protein known as progerin. The protein is characterized by a non-removable farnesyl group which therefore causes permanent attachment of the progerin to the rim of the nucleus instead of becoming a constituent of the nuclear lamina. The alterations result in a lamin A-deficient nuclear envelop which lacks the necessary structural support that usually confers it with the normal shape. Eventually, there is disorganization of chromatin and the consequent disruption of mitosis and ultimately the process of cell division. (Tsiligiri, Fekos, Theodoridou, " Lavdaniti, 2015) Progeria differs etiologically from other diseases such as xeroderma pigmentosum, and Werner syndrome that also manifest with accelerated aging. Unlike those other related conditions, progeria causes changes in all aspects of aging while the changes caused by the others are partial, leading to their classification as segmental progerias.
Signs and symptoms
Hutchinson-Gilford Progeria is characterized by various signs and symptoms which signify the underlying pathology in different body systems. Th symptoms become increasingly multiple and manifest as the child advances in age from birth, infancy, and childhood. A young child’s failure to thrive, particularly in the initial few as an infant is often the earliest sign of disease. In addition to that, the infant may demonstrate the effect of the disease process on the skin by presenting with dermatological signs and symptoms such as scleroderma or similar conditions. As the child grows towards reaching the second year of life, he develops some of the distinctly characteristic signs and symptoms of the syndrome. Facial features include a pinched-nose appearance and jaws that appear recessed. The general facial outlook depicts a smaller than normal face. (Panigrahi et al., 2013)
How disease impacts body systems
As the child grows and develops further, other larger organ systems become involved as well. Cardiovascular involvement results in symptoms characteristic of atherosclerosis and cardiac compromise. They may include valvular disease, myocardial infarction and features of congestive heart failure such as edema and orthopnea. Involvement of the renal system results in renal failure hence the child could present with kidney symptoms such as hematuria, oliguria, abdominal pain and renal angle tenderness. Signs and symptoms depicting musculoskeletal system involvement may include wasting due to muscle and body fat loss. Additionally, bone development and health are often impaired and manifest in symptoms such as stiffness of joints, frequent bone fractures, and joint dislocations as well as generalized fragility. The most outward signs depict dermatologic pathology with particular skin signs. Scleroderma is prevalent and widespread. It is accompanied by alopecia which often affects the entire body. The loss of skin elasticity results in wrinkling of the face and prominence of the eyes. The loss of hair especially on the head in conjunction with thinner-than-normal skin results in scalp veins that are prominent and obviously visible. (Panigrahi et al., 2013) The characteristic signs and symptoms, therefore, give the affected child not only the appearance of an old person but also the complications that usually occur due to the aging process.
Treatment (medication " procedure)
Although there have been efforts of research on ways of treating the syndrome, there is no definitive cure for the condition yet. Therefore, the therapeutic options that are often explored currently aim to treat and lessen the symptoms of the disease rather than dealing with the underlying cause. The patients, especially the very young infants, are often given a variety of nutritional supplements to lessen the incidence of malnutrition and nutritional deficiency diseases. Musculoskeletal complications are addressed by various measures such as physiotherapy which may aid in slowing down the development of musculoskeletal complications such as joint stiffness as well as reducing the relative severity of those symptoms. Treatment options targeting the cardiovascular system include measures such as administering aspirin in low dose as prophylaxis for atherosclerosis. Additionally, surgical procedures such as the cardiac bypass surgery may be performed to correct some potentially life-threatening heart conditions. Growth hormone has also been used in some instances to stimulate growth and musculoskeletal development. (Gordon, Rothman, Lopez-Otin, " Misteli, 2014)
Despite the apparent lack of effective and definitive treatment options, much research on possible treatment options that bear higher efficacy is ongoing. The research is particularly genetic-oriented with its target being the reduction of progerin and other proteins that characterize the disease. An example of drugs that research has yielded are Farnesyltransferase inhibitors (FTIs) which function by impeding the linkage been farnesyl groups which are necessary for the permanent progerin attachment to the rim of the nucleus. Examples of FTI drugs that have been explored on trial include Ionafarnib which reached phase II of the clinical trial, and another is Lonafarnib. Other examples of trial drugs include Morpholinos, Sirolimus, and mTOR inhibitors. Despite the drugs showing promise for better efficacy and health outcomes none has received FDA approval for all the trials have mostly been made on mice. (Gordon, Rothman, Lopez-Otin, " Misteli, 2014) Thorough clinical trials on human subjects are necessary to establish the drugs’ efficiency and effectiveness, thus providing a rationale for their use to routinely treat progeria.
Prognosis
Hutchinson-Gilford Progeria has a relatively poor prognosis for 13 years is the average life expectancy for persons who suffer the condition. However, some may live relatively long lives of up to 27 years or more. Various factors influence the prognosis for the disease. Atherosclerosis is the main contributor to the morbidity and the mortality that is associated with the disease. As much as 90% of the fatalities that arise from the condition occur due to atherosclerotic lesions of which the cerebrovascular and the coronary arteries are the most commonly affected vessels. Where mortality does not occur or is delayed, many of the patients suffer various associated life-limiting illnesses. Some of the cardiovascular ailments include valvular disease, fibrotic diseases of the heart, myocardial infarctions and heart failure. The common cerebrovascular conditions arise from infarction of cerebral vessels, and they include conditions such as hematomas, seizures, and hemiplegia. The patients may also suffer nutritional deficiencies such as marasmus and kwashiorkor since the disease can cause impaired feeding
Impact on costs, insurance, and community
The condition usually has a huge impact on the community and other aspects such as insurance and other costs. First, the disease's high mortality rate causes a lot of emotional and psychological pain especially to the patient's family and community of friends and loved ones. The problem is compounded by the unavailability of cure which causes despair and hopelessness. In addition to that, having the disease or a family history for it increases the health risk of an individual. Consequently, such individuals face difficulty in accessing insurance and if they do, the premiums to be paid are often quite high and may thus be unaffordable. Management of the disease also results in high expenditure on health due to the multiple and life-long drugs and medical procedures that one has to undergo therapy.
References
Coppede, F. (2013). The epidemiology of premature aging and associated comorbidities. Clinical Interventions in Aging, 1023. doi:10.2147/cia. s37213
Gordon, L. B., Rothman, F. G., Lopez-Otin, C., " Misteli, T. (2014). Progeria: A Paradigm for Translational Medicine. Cell, 156(3), 400-407. doi: 10.1016/j.cell.2013.12.028
Panigrahi, R. G., Panigrahi, A., Vijayakumar, P., Choudhury, P., Bhuyan, S. K., Bhuyan, R., … Pati, A. R. (2013). Hutchinson-Gilford Progeria Syndrome: A Rare Genetic Disorder. Case Reports in Dentistry, 2013, 1-4. doi:10.1155/2013/631378
Tsiligiri, M., Fekos, C., Theodoridou, E., " Lavdaniti, M. (2015). An Overview of Hutchinson Gilford Progeria Syndrome (HGPS). British Journal of Medicine and Medical Research, 5(12), 1527-1533. doi:10.9734/bjmmr/2015/13452
