Hutchinson-Gilford Progeria Syndrome (HGPS)

Moumita Ghosh, Amity University Kolkata

Introduction

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease that affects 1 in every 4-8 million infants worldwide. It is a disease characterized by accelerated aging in humans. Progeroid syndromes (PSs) can be identified as rare and fatal genetic disorders characterized by various features and symptoms of premature physiological aging. The syndromes include various heterogeneous diseases such as Bloom syndrome (BSyn), Fanconi anemia, Cockayne Syndrome (CS), Xeroderma pigmentosum (XP), Hutchinson-Gilford syndrome (Progeria), and Werner syndrome (also known as adult progeria). The Hutchinson–Gilford progeria syndrome (HGPS) is the most extensively studied type out of all the different progeria, is named after scientists Jonathan Hutchinson in 1886 and Hastings Gilford in 1897, who independently depicted and described the syndrome in great detail. At present, 114 children across 39 countries are diagnosed with HGPS. The average survival rate of these children is 13.5 years (with a maximum life expectancy of about 8 – 21 years), and death usually occurs due to the manifestation of various cardiovascular complications viz. stroke, heart failure, or myocardial infarction.

Clinical Symptoms

Children that are diagnosed with these syndromes have the following symptoms:

• Unique facial characteristics with craniofacial disproportion and micrognathia head, prominent eyes, protruding ears, “sculpted nose or beaked nose” which gives a “plucked bird” look.
• A small jaw with a large head adds to what is perceived as an aged appearance.
• Hair-loss with prominent scalp veins, wrinkled skin, nails dystrophy, and loss of subcutaneous fat.
• Very thin limbs restricting joint mobility often causing acute premature atherosclerosis in severe cases.
• Even though they have normal mental and motor development, they have retarded or stunted growth with underdeveloped secondary sexual features.
• An immoderate amount of hyaluronic acid and glycosaminoglycan production.
• There are no abnormalities in the thyroid-stimulating hormones, growth hormone, adrenal hormone, or parathyroid hormone.
• There is increased resistance in insulin and the appearance of abnormal collagen.

At the time of birth and as newborns, these patients were considered normal. It is only during the second year of their life that these symptoms became evident. 

Genetic Changes in HGPS  

After the gene responsible for HGPS was mapped, it was found that the syndrome was sporadic and its inheritance type autosomal dominant. The syndrome was caused due to a splicing mutation in the pre-mRNA of the LMNA gene, which codes for the Lamin A and Lamins C proteins. The mutation in the LMNA gene gives rise to a wide range of overlapping disorders like accelerated aging, muscular dystrophy, etc. The mutation in LMNA results in the partial deletion of exon 11.

The cysteine residue of the C-terminal was first modified by farnesylation and carboxymethylation. Then the terminal 15 amino acids were enzymatically cleavaged which are responsible for the production of lamin A. Nevertheless due to the mutation, the site of cleavage is absent in the prolamin A in HGPS. This results in the collection of uncleaved, farnesylated lamin A isoform called Progerin. In a healthy individual, the lamin As in the cells moves independently between the nucleoplasm and nuclear-lamina-polymer. But in the case of HGPS, lamin A becomes inactivate leading to the lamina becoming thick. As a result of these alterations, there are changes in the mechanical properties of the nuclei of the cells. And the individual becomes stiffer than usual, which is distinctly different from normal individuals. These changes in cells might lead to the reaction of the cells in tissues responsible for the mechanical forces of bones, joints, and vasculature. The tissues in these three regions show the most distinguished indication of HGPS. 

In normal cases, cells divide for a particular period after which they enter the senescence or non-dividing state. Thus it was concluded that aggregation of senescent cells results in the process of aging. Recent studies have shown that senescent cells are present in the tissues of an aged human. Studies further concluded that regulation of cell cycle mechanism and telomere aging clock theory can put an end to senescence.

A group of the repeated base sequence of TTAGGG where T represents Thymine, A represents Adenine and G represents Guanine is present in the telomere of the chromosome. The length of these telomeres and the integrity of the chromosomes are regulated by the telomerase enzyme. It was observed that inactivity of telomerase results in loss of length in telomere thus causing senescence of the cells and if the telomerase enzyme is again introduced it helps in the prevention of the onset of senescence. Thus it led to the opinion that human aging is controlled by the activity telomerase enzyme. Telomerase knock-out mice were studied and it revealed accelerated aging in them. Thus there is a possibility that telomerase activity and telomere length play an important role in the premature aging in HGPS.

Clinical Trials of HGPS

Mostly rare diseases face obstacles in scheming and implementing clinical trials. Since HGPS patients are in very small numbers with a 100% fatality rate, it requires international and classified communication with the patients, their families, and their physicians through various programs like diagnostics programs and patient registries so that it can reach all patients. The first enrolled clinical trial was accomplished by The Progeria Research Foundation which is a patient advocacy organisation. Each patient was used as his or her own control to approach drug efficacy. During the first clinical trial important vascular defects in HGPS were discovered which helped in the trial drug efficacy and later helped in therapeutic efficacy.

Treatments using lonafarnib have been published but its effects on patient mortality and morbidity are not yet confirmed. Long-term exposure of the patient is required for confirmation. Future trials can be conducted using farnesylation inhibitors using a control arm, but it is not yet confirmed if it is bio-ethically and viable.

The Food and Drug Administration (FDA) has taken the responsibility to spread awareness on rare acute diseases since these diseases are now the fastest area of biotechnological and pharmaceutical development. The Centre for Drug Evaluation and Research was specifically created for Rare Diseases Drug Development. Although it is not possible to increase the number of patients undergoing trials but a regulatory body has been created which works on consulting and recommending clinical trials for rare diseases.

Future Prospects

Although no confirmed treatment is found as of now, the Progeria Research Foundation Workshop has made enormous progress in HGPS and is continuing to do so. The revelation of the various molecular, genetic and cellular mechanisms has paved a way to understand the disease, and hopefully shortly with more advanced technology, the cure will soon be achieved.

Also read: aDDA: High-Coverage Genome Sequencing method

References:

1. Benson, E. K., Lee, S. W., & Aaronson, S. A. (2010). Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. Journal of cell science, 123(15), 2605-2612. https://doi.org/10.1016/j.cell.2013.12.028
2. Hutchinson, J. (1886). Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Medico-chirurgical transactions, 69,473. http://dx.doi.org/10.1136/pmj.77.907.312
3. Image Credit (open access): Gordon, L. B., Rothman, F. G., López-Otín, C., & Misteli, T. (2014). Progeria: A paradigm for translational medicine. Cell, 156(3), 400–407. https://doi.org/10.1016/j.cell.2013.12.028

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