Hutchinson-Gilford Progeria Syndrome

Aging and death are unavoidable in the human life cycle. The question of why people age and the processes essential to aging has been a topic of debate and studies since the nineteenth century. Since the 1990s, significant developments have been made in determining which physiological processes affect longevity. It has recently been agreed that aging is a result of macromolecular dent brought about by reactive oxygen species, which oxidize proteins and lipids. Particularly, reactive oxygen species also damages DNA, which results in chromosomal abnormalities and mutations (Hasty et al.). These changes result in the malfunction of cellular organelles, specifically mitochondria, leading to tissue and cell degeneration.

One rare congenital disease, progeria, has attracted much interest, mainly because of its similarity to an accelerated aging process. The term progeria (Greek word geras, meaning “old age”) narrowly pertains to the Hutchinson-Gilford progeria syndrome (HGPS), but it generally refers to any “accelerated aging disease”. HGPS is an exceptionally uncommon hereditary disease affecting the vasculature, musculoskeletal system, and skin. Progeria is marked by signs of accelerated premature aging.

Progeria was first identified in 1886 by Jonathan Hutchinson and in the following year by Hastings Gilford. HGPS has a prevalence of 1 in 8 million births; however, the true prevalence has been suggested to be about 1 in 4 million births since a considerable number of cases are usually undiagnosed or are likely to be misdiagnosed. Since 1886, there have been just over 100 reported cases of HGPS. At present, there are about 30 to 40 known incidence of HGPS worldwide.

Significant morbidity and mortality in HGPS are a result of accelerated atherosclerosis of the coronary and carotid arteries, resulting in premature death during the first or second decade of life of the person with progeria. In fact, atherosclerosis of the cerebrovascular and coronary arteries accounts for the death of at least 90% of HGPS patients (Shah, Kaiser, & Hanfland). Cerebrovascular complications due to cerebrovascular infarction include seizures, subdural hematoma, and hemiplegia. On the other hand, cardiovascular complications include congestive heart failure and myocardial infarction. Calcification of the mitral and aortic valves, diffuse myocardial fibrosis, and interstitial fibrosis may also occur. Inanition, marasmus, and loss of mobility are other causes of morbidity and mortality. On the average, the life expectancy for an HGPS patient is 13 years, with an age ranging from 7 to 27 years (Shah, Kaiser, & Hanfland).

In terms of race, HGPS has a predilection for White persons, representing 97% of reported patients. However, the explanation for this disparity in race is currently unknown. In addition, there are more male HGPS patients than females, with a male-to-female ratio of 1.5:1. In terms of age, clinical manifestations of progeria may not be noticeable at birth. Delayed recognition of the distinguishing facial features along with the musculoskeletal and cutaneous manifestations may not come about until age 6 to 12 months or older (Shah, Kaiser, & Hanfland). HGPS patients develop accelerated atherosclerosis of the coronary and cerebral arteries.

However, in contrast with arteriosclerosis in the general population, the only lipid abnormality in HGPS is reduced high-density lipoprotein cholesterol levels. In addition, progeria patients also develop other medical signs of premature aging, such as alopecia, poor growth, arthritis, osteoporosis, skin atrophy, and loss of subcutaneous muscle and fat. It is interesting to note that HGPS patients do not acquire other disease processes related to aging, like senility, cataract development, or increased tumor formation. Here, progeria is considered as a segmental progeroid syndrome because it does not recapitulate every characteristic phenomenon of aging.

Basically, HGPS is caused by mutations in LMNA, the gene encoding the A-type nuclear lamins (Eriksson et al.). More than 10 other diseases, which are collectively called laminopathies have been associated with missense mutations of LMNA (Jacob & Garg). While other LMNA mutations have been linked to progeria, the most often mutation is in the form of a nucleotide change that leads to the activation of a cryptic splice site contained by exon 11 and the consequent loss of 50 amino acids inside the carboxyl terminus of the encoded protein (Eriksson et al.).

A study reports the findings that cells from progeria patients display prematurely a number of features similar with cells from aged donors (Scaffidi & Misteli): an upregulated DNA damage response, nuclear deformation, and relocalization of heterochromatin as visualized by staining for tri-methyl-K9 histone HP1 and H3. These findings were somewhat expected, since mutations in LMNA are frequently linked to nuclear alterations and deformation in large-scale heterochromatin organization. Moreover, it was found that hanging lamin function in Caenorhabditis elegans adults caused both nuclear structural abnormalities and early mortality. Lastly, an age-dependent reorganization of A-type lamins to the nuclear periphery from the nuclear interior was reported (Scaffidi & Misteli).

Due to the lack of a specific laboratory test, the diagnosis of HGPS is largely based on the physical appearance of the progeria patient. Often, the diagnosis is made during the first or second year of the child’s life when failure to gain weight and changes in skin become evident. HGPS is well-known for its progeroid symptoms and for the restrictions that it places on lifespan. However, since it also involves a number of symptoms absent in normal aging, HGPS is considered as a segmental progeria instead of a true disease of accelerated aging (Lewis).

Symptoms involving the cartilage and bone systems include abnormal bone development and dysplasia; hypoclastic facial bones; stiff joints with contractures in the phlanges, long bones, thorax, and the skull; and thin cranial bones. Symptoms involving the cardiovascular system include atherosclerosis of the small and large arteries; severe depletion, attenuation, or change of shape in vascular smooth muscles; and myocardial fibrosis, calcification of the mitral valve leaflets and prominent veins often with easy bruising (Lewis).

Symptoms involving the metabolic system include failure to thrive and progressive loss of subcutaneous fat and weight and height below the third percentile. As for the skin symptoms, HGPS patients have thickened, hyalinized skin taut in most places, but loose on fingers and toes; eccrine and sebaceous glands may be severely reduced in numbers; and scleroderma usually beginning on lower abdomen, proximal limbs and buttocks. The nails of the HGPS sufferers are usually thin, small and dystrophic, but may also be thick. Their hairs have a “plucked bird” appearance with scalp hair progressively diminishing to a few remaining blonde or white, fuzzy, fine, and brittle hairs. Their eye brows and lashes are often lost (Lewis).

There is currently no effective therapy available for the treatment of HGPS. However, there are many ways to offset the diseases brought about by HGPS. Vigilant monitoring for cerebrovascular and cardiovascular disease is necessary. Physicians recommend the use of low-dose aspirin as prophylaxis against such disease. Also, occupational and physical therapy can help HGPS patients to sustain an active lifestyle and physical activities. Hydrotherapy may be effective in minimizing arthritis symptoms and in improving joint mobility.

In vitro studies are looking for a possible role of farnesyltransferase inhibitors (FTIs) in progeria. Studies are exploring the role of FTIs in promoting the release of the mutant prelamin A from the nuclear membrane. It appears that FTIs allow it to be properly integrated into the nuclear lamina, hence correcting the functional and structural nuclear defects. Furthermore, initial in vitro investigations that use transfection of modified oligonucleotides targeting the cryptic splice site have yielded positive results. The elimination of the making of the mutant LMNA mRNA restores normal nuclear morphology, resulting in the normalization of gene expression and heterochromatin structure.

Works Cited

• Eriksson, Maria, W. Ted Brown, Leslie B. Gordon, Michael W. Glynn, Joel Singer, Laura Scott, Michael R. Erdos, Christiane M. Robbins, Tracy Y. Moses, Peter Berglund, Amalia Dutra, Evgenia Pak, Sandra Durkin, Antonei B. Csoka, Michael Boehnke, Thomas W. Glover, & Francis S. Collins, ‘Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome’, Nature 423 (2003): 293–298.
• Hasty, Paul, Judith Campisi, Jan Hoeijmakers, Harry van Steeg, & Jan Vijg, ‘Aging and genome maintenance: lessons from the mouse?’, Science 299 (2003): 1355–1359.
• Jacob, Katherine A. & Abhimanyu Garg, ‘Laminopathies: multisystem dystrophy syndromes’, Molecular Genetics and Metabolism 87 (2006): 289–302.
• Lewis, Marc, ‘PRELP, collagen, and a theory of Hutchinson–Gilford progerianext term’, Ageing Research Reviews 2.1 (2003): 95-105.
• Scaffidi, Paola & Tom Misteli, ‘Lamin A-dependent nuclear defects in human aging’, Science 312 (2006): 1059–1063.
• Shah, Kara N., Hans-Wilhelm Kaiser, & Julia Hanfland, “Hutchinson-Gilford Progeria”. January 24, 2007. Retrieved November 21, 2007 from http://www.emedicine.com/derm/TOPIC731.HTM