Progeria also referred to as Hutchinson-Gilford syndrome (HGS), is a tremendously rare, progressive heritable condition, which makes children to quickly age, starting in their initial two years of their life. Normally, these children are normal at birth, but signs and symptoms start to appear in their first year of life. Most children with progeria fail to live past 13 years. The disease has an effect on both sexes as well as all races evenly. Approximately 1 in 4 million births globally are affected by this disease. A distinct mistake in a particular gene results in it making an abnormal protein. However, at the time cells utilize progerin protein, they break more easily. The protein increases in many cells of children with progeria, resulting to them growing old fast. Approximated 350-400 kids are affected by HGS at any definite period in the world (Braun & Anderson, 2007).
The causes of HGS has been found to be a defect in a chromosomal gene, which codes for a protein that remains a significant element of the membrane that surrounds the nucleus of the cell. This protein is referred to as lamin A. HGPS produces abnormal lamin A referred to as progerin, which is inherited. The definite primary cause of is unknown. However, studies have indicated that this abnormal aging is as a result of a cumulative cellular injury that stems from continuing metabolic (chemical) processes in body cells. Consistent with this theory, free radicals are generated at some stage in body chemical reactions. The grows building up of free radicals in body tissues that eventually result to damage to as well as impaired working of cells, in the due course leading to early aging (Silbernagl & Lang, 2010).
Progeria fails to take place for the reason that the father or mother has a genetic predisposition for the condition. As an alternative, it results from a novel mutation in conception. However, this is the grounds to which the progeria rate is spread quite evenly between all ethnicities and genders. Ideally, the odds of a child born with this disorder are about 1 in 4 million. Generally, there is no way this disorder is passed along, in view of the fact that the mutation remains spontaneous. On the other hand, a child affected by progeria raises the risk of relapse by 2 to 3 percent.
As said earlier, Progeria is a rare condition, which affects females and males as well as all races equally. Progeria was initially described in a number of medical texts in the 19th century (J. Hutchinson1886 and H. Gilford 1897). By early 2014, about 200 cases were reported. Estimates pointed to the fact that the HGPS prevalence is approximately 1 in 18 million, therefore at any particular time, there are about 350 to 400 kids living with this condition globally. Two groups of affected indistinguishable twins have been documented in the literature.
Pathophysiology of the Disorder
It is said that a de novo heterozygous point mutation is the mainstay of HGPS, altering a sequence of GGC to GGT in the LMNA gene exon-11. This mutation causes a 50 amino acid deletion sequence at the prelamin A carboxyl-terminus, produce a shortened progerin for Lamin A (Neelam et al. 2012). Lamins are transitional filamentous proteins, which polymerize to structure nuclear lamina, a framework outlining the inner membrane of nuclear. Lamin A belongs to the Lamin A and C. The latter varies tremendously the first by the extension of its C-terminal that has 90 less residues (Rakha, et al. 2011).
The nuclear lamina proteins not only play a mere structural role but through many studies, it has to turn out to be clear that they also remain significant in diverse cellular purposes for instance signal transduction as well as gene expression (Scaffidi and Misteli, 2006). Consequently, mutations that affect these proteins are capable of having overwhelming impacts on numerous body systems.
HGPS remains rare diseases under the group of disease that is referred to as laminopathies that the nuclear lamina proteins are affected. However, these diseases entirely are caused by LMNA gene mutations as well as take account of muscular dystrophy, lipodystrophy, Progeria and peripheral neuropathy (Liu, et al. 2010). In lipodystrophy, the clinical features start at the start of puberty. Besides, patients present with high cholesterol, loss of subcutaneous fat and type-II diabetes mellitus. Muscular dystrophy remains comparable in that symptoms emerge near to puberty and result to progressive muscle atrophy. Peripheral Neuropathy, on the other hand, is a laminopathy, which grounds to nerve dysfunction. Progeria remains possibly the most distressing of them all given the fact that symptom starts at some months of age, as well as death from cardiovascular disease, is probably by 13 years (Porth & Porth, 2011).
Signs and Symptoms
Children affected by HGPS develop signs and symptoms of hastened aging that incorporate fast coronary and cerebral arteries’ atherosclerosis. Unlike arteriosclerosis, in progeria, the just lipid anomaly is decreased high-density lipoprotein levels. Interestingly, HGPS patients’ fails to develop other diseases linked to aging, for instance, cataract development, raised tumor formation, or senility. Therefore, HGPS is regarded as a segmental progeria syndrome for the grounds that it fails to run through all of the aging phenomena characteristics (Islam & Roach, 2015).
HGPS patients as well present with loss of muscle and subcutaneous fat, skin atrophy, arthritis, osteoporosis, alopecia, and poor growth. However, there is proof these patients also manifest with skeletal dysplasia features with bone structural geometry and skeletal strength abnormalities. Extensive deposition lipofuscin, an indicator for aging, remains at length spread in HGPS patients. Nevertheless, affected body organs incorporate the brain, kidneys, liver, adrenal glands, heart, and testes (Budson & Solomon, 2011).
These clinical signs take place due to defects in function and processing of lamin A, a transitional filamentous protein element of the nuclear membrane, which controls varied cellular functions that incorporate nuclear integrity and morphology, gene expression regulation, DNA repair, along with telomere stability. The progerin is a shortened type of the lamin A precursor pre-lamina A (Chernoff, 2013).
Clear vascular smooth muscle cells’ loss in the large arteries, vessels, and arterioles linked to fibrosis and sclerosis is a reliable finding in HGPS patients. Preferential progerin accumulation in smooth muscle and vascular endothelial cells has been pragmatic. Clinically, progeria children develop arteriosclerosis, atherosclerosis, as well as major adventitial fibrosis with rising progerin deposition in coronary arteries. The fastened vascular hardness along with PVOD (peripheral vascular occlusive disease), which develops symptoms that look like the cardiovascular characteristics of typical aging and atherosclerosis. In cooperation with the clinical studies of hastened and often serious arteriosclerosis, these results imply that the progerin impacts on the cardiovascular system remain a key contributor to the HGPS pathophysiology (Griffiths et al., 2016).
Interestingly, impulsive progerin accumulation has been seen in refined fibroblasts from typically aged persons along with comparable nuclear shortcomings, further emphasizing the theory in which HGPS effects, as a minimum in part, from hastened accumulation and production of progerin. It remains significant to note, which the HGPS pathophysiology stems from the presence of progerin as well as a dominant negative result on lamin A role and not just from the lack of normal lamin A (Jeanteur, 2006).
Typically, Progeria is diagnosed when the child is at his or her second year of life, the time when the features start to manifest. The diagnosis includes a detailed clinical assessment, a patient history, along with genetic diagnostic evaluation. More seldom, this condition may be supposed at birth basing on the identification of certain wary findings, for instance, mid-facial cyanosis; scleroderma-like skin on the baby’s thighs, buttocks, and lower abdomen; and sculptured nose (Fillit et al., 2010).
Apart from symptomatic diagnosis, the child may be subjected to some imaging tests just to authenticate or typify definite skeletal abnormalities possibly linked to associated this condition, for instance, osteolysis (degenerative changes) of certain bones of the hands (terminal phalanges) or the acetabulum (hip socket). Additionally, detailed cardiac assessments, as well as continuing observing, may as well be done (for instance clinical evaluations, specialized cardiac examinations, and X-ray studies) to evaluate related cardiovascular aberrations and establish definite management of the disease (Weiss & Refetoff, 2010).
There is no known cure of Progeria. However, therapy is initiated on symptoms of the disease. However, certain treatments may alleviate or hinder signs and symptoms. They comprise of low-dose aspirin; statins; growth hormone physiotherapy; primary teeth extraction (Budson & Solomon, 2011).
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