Hutchinson-Gilford Progeria Syndrome

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Table of Contents

Introduction
Cellular Cause of Disease
Basic Information
Treatment and Research
Conclusion
References

Introduction

The functionality of the body’s cell systems can be impaired for a variety of reasons, including mutagenic and autoimmune factors, physical and chemical damage. The consequence of such disturbances is often the development of disease states, and each type of such disease depends on which organelle and how it has been damaged. This essay will examine the case of Hutchinson-Gilford progeria syndrome, a clinical disease in which there is abnormal development of the cell nucleus, resulting in the impaired division.

Cellular Cause of Disease

Every somatic cell in the human body, with the exception of the mature red blood cell, has a formed nucleus, which is a repository of genetic information. The nucleus is the primary cell organelle responsible, among other things, for the mechanisms of cell division leading to the formation of new daughter cells. Usually, the cell nucleus consists of two membranes sent by laminin proteins (NORD, 2021). A mutation in the LMNA gene, usually occurring by replacing cytosine with thymine at nucleotide 1824, results in the formation of an abnormal form of nuclear proteins characterized by an irregular, wrinkled shape (NIH, 2022; Wang et al., 2020). It should be emphasized that nucleotide substitution does not lead to the coding of a new amino acid, but it initiates splicing mechanisms, which are caused by the removal of up to 50 nucleotides from the genetic code. The consequence of this anomaly is the impossibility of cell division because the nucleus literally becomes dysfunctional: dying cells can no longer be replaced by new cells, leading to premature aging. Studies also show that accelerated aging may have a metabolic mechanism related to the function of a mutated protein (NORD, 2021). In particular, significantly reduced activity of antioxidant enzymes that inhibit aging processes was observed in the cells of people with progeria.

Basic Information

Premature aging caused by progeria generally begins to make itself felt around the second year of life. This is when the first symptoms begin: a comparably large head, short stature, underdeveloped jaw bones, bulging eyes, and lopsided ears. In addition, the child has muscle atrophy and poor physical activity, dystrophy of the teeth and tooth enamel, and clouding of the lens. Of the visually non-detectable signs of disease, the child has decreased subcutaneous fat production, hair loss, hyperpigmentation, and thinning of the skin; veins are often seen through the skin (NORD, 2021). Biochemical blood tests of patients show decreased cholesterol and lipoprotein concentrations (Sharma & Shukla, 2020). A consequence of this metabolic failure is also delayed puberty in the child, along with accelerated aging of the body.

This disorder is rarely classified as inherited, and in most cases, it occurs sporadically. However, in some cases, autosomal recessive inheritance, in which the disease occurs only when two recessive alleles of the LMNA gene coincide (NORD, 2021), has been ascribed to the disease. Due to the low life expectancy of such patients (as a rule, they die before the age of 13-15 years), progeria patients do not have time to have offspring, which is a restraining mechanism for the spread of the abnormal mutation (Hayashi et al., 2021). Thus, most patients die in childhood or adolescence, although it is fair to note that the clinical condition itself is rare.

Treatment and Research

No universal cure has yet been created for such a rare genetic disease, so the current clinical discipline offers a number of restraining mechanisms to improve patients’ quality of life. These include taking antioxidant medications and vitamins, as well as using physical activity to improve muscle tone. Critical recommendations for treatment suggest that patients should avoid any activity that might traumatize thinning skin, including prolonged exposure to direct sunlight. The academic discourse continues to attempt to develop new drugs, as has already been reported by several authors (Voelker, 2021). In most cases, such developments do not reach mass clinical trials and are based on theoretical concepts. However, the drug Lonafarnib (brand name Zokinvy) may be a promising treatment for this condition. Lonafarnib works as a farnesyltransferase inhibitor to reduce the production of abnormal proteins mutated in LMNA. The FDA-approved drug is reported to be able to extend the life expectancy of patients: in clinical trials, the maximum extension reached 2.5 years compared to patients not taking the drug (Kahn, 2020). Notably, Lonafarnib was initially developed as an antitumor drug, so it was used primarily to treat various types of cancer; however, the drug was later discovered to be beneficial for the treatment of progeria as well.

Since the disease is caused by a gene mutation, a reasonable strategy for treating it is gene therapy, which allows the recovery of the lost nucleotide. This procedure requires early detection of the risk of developing the disease while the patient is still in the embryonic stages of development. Nevertheless, it should be understood that the rarity of this clinical condition, combined with the technical difficulty of replacing a specific nucleotide in the entire DNA, are deterrents to the mass distribution of gene therapy for the treatment of progeria. Meanwhile, this does not mean that efforts to find new forms of treatment should be stimulated since, to date, there is still no universal and affordable cure, which means that patients continue to live with a low quality of life and an expectation of early death.

Conclusion

Thus, Hutchinson-Gilford progeria syndrome is a rare genetic disease caused by mutations in the genes encoding the cell nuclear membrane protein. The result of this mutation is a partial or complete inability of cell division, which leads to metabolic malfunction and premature aging. Most patients with progeria do not survive until the age of 15 and have many clinical limitations in their lives. The medical community is trying to develop a mass drug product for patients with this diagnosis, and a recently FDA-approved drug may qualify for this role.

References

Hayashi, K., Yamamoto, N., Takeuchi, A., Miwa, S., Igarashi, K., Araki, Y., & Tsuchiya, H. (2021). Long-term survival in a patient with Hutchinson-Gilford progeria syndrome and osteosarcoma: A case report. World Journal of Clinical Cases, 9(4), 854-863. Web.

Kahn, J. (2020). FDA approves first treatment for Hutchinson-Gilford Progeria Syndrome and some progeroid laminopathies. US FDA. Web.

NIH. (2022). LMNA lamin A/C [Homo sapiens (human)]. National Library of Medicine. Web.

NORD. (2021, May 03). Hutchinson-Gilford Progeria syndrome. National Organization for Rare Disorders. Web.

Sharma, V., & Shukla, R. (2020). Progeria: A rare genetic syndrome. Indian Journal of Clinical Biochemistry, 35(1), 3-7. Web.

Voelker, R. (2021). First progeria drug is approved. JAMA, 325(1), 20-21. Web.

Wang, F., Zhang, W., Yang, Q., Kang, Y., Fan, Y., Wei, J., & Niu, Y. (2020). Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing. Protein & Cell, 11(11), 809-824. Web.

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