Progeria: A Rare, Time-Defying Disease

Imagine being a 10-year-old with a body of a 70-year-old—a life just beginning to bloom yet already facing autumn and its consequences. It may sound surreal, a straight out-of-the-book scenario, but this is the reality of children with progeria—a rare genetic condition that hastens aging at an alarming rate, robbing their childhood freedom.

Progeria, also known as the Hutchinson–Gilford Progeria Syndrome (HGPS), is a rare, fatal genetic condition characterized by premature aging in children [1, 3, 6]. It is a progressive disease that affects approximately one (1) in four (4) million live births worldwide. Among laminopathies, it is also considered the most severe disorder and serves as a prominent model for all progeroid syndromes (e.g., Werner Syndrome) [2, 6, 7]. But what exactly causes this condition?

The underlying cause of progeria is a mutation in the LMNA gene, which is responsible for coding proteins called lamins. This primarily gives rise to alternating splice transcripts of lamins A and C, which are essential components of the nuclear lamina [2, 4, 5]. Basically, LMNA gene - related progeria occurs when alterations in these two proteins disrupt the integrity and function of the nuclear lamina. This results to abnormal protein expression, producing a mutant product called progerin—a specific mutant form of lamin A. [4, 5, 8]. Replication of this expression further leads to genomic instability, triggering cellular dysfunctions and accelerating the aging process in progeria patients [5, 6].

Despite their young age, patients diagnosed with progeria display distinct features of accelerated aging, including age spots, alopecia, and swollen veins. They also experience growth retardation, osteoporosis, cardiovascular complications, and other conditions commonly associated with old age. All of these symptoms result from the LMNA gene mutation, leading to the production of progerin. Notably, progerin is also produced in senescent cells of elderly individuals. Its abnormal accumulation causes affected children to suffer at an early age, limiting their life span to just 10-15 years [2, 5, 6].

There is no specific cure for progeria, but medical advancements continue to alleviate symptoms and improve patient outcomes. Lonafarnib, a farnesyltransferase inhibitor, is gaining clinical significance as a potential drug for progeria by enhancing weight gain, cardiovascular, and skeletal health concerns. Additionally, clinical trial reports exhibit the advantage of CRISPR-Cas9, a genetic intervention potent for mitigating progerin-associated symptoms. Moreover, MG132, Rapamycin, and Sulforaphane have also shown therapeutic efficacy against progeria [1, 6].

Progeria was first described by Jonathan Hutchinson in 1886 and Hasting Gilford in 1897. Although discovered in the 1880s, the genetic defect causing progeria remained undiscovered until 2003 [3, 4]. Subsequently, ongoing research and clinical trials continue to understand the complexity of the disease, with the aim of developing more effective treatments for diagnosed patients [6].

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References

1. Suzuki, M., Jeng, L., Chefo, S., Wang, Y., Price, D., Li, X., Wang, J., Li, R., Ma, L., Yang, Y., Zhang, X., Zheng, N., Zhang, K., Joseph, D., Shroff, H., Doan, J., Pacanowski, M., Smpokou, P., Donohue, K., & Joffe, H. (2023). FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies. Genet Med. doi: 10.1016/j.gim.2022.11.00

2. Piekarowicz, K., Machowska, M., Dzianisava, V., & Rzepecki, R. (2019). Hutchinson-Gilford progeria syndrome-current status and prospects for gene therapy treatment. Cells. doi: 10.3390/cells8020088

3. Pitrez, P.R., Rosa, S.C., Praca, C., & Ferreira, L. (2016). Vascular disease modeling using induced pluripotent stem cells: Focus in Hutchinson-Gilford progeria syndrome. Biochemical and Biophysical Research Communications. doi: 10.1016/j.bbrc.2015.10.014

4. Ghosh, S., & Zhou, Z. (2014). Genetic of aging, progeria and lamin disorders. Current Opinions in Genetics and Development. 26: 41-46. doi: 10.1016/j.gde.2014.05.003

5. Gonzalo, S., Kreienkamp, R., & Askjaer, P. (2018). Hutchinson-Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res Rev. 33:18-29. doi: 10.1016/j.arr.2016.06.007

6. Arun, A., Nath, A., Thankachan, B., & Unnikrishnan, M. (2024). Hutchinson-Gilford progeria syndrome: unraveling the genetic basis, symptoms, and advancement in therapeutic approaches. Therapeutic Advances in Rare Disease. doi: 10.1177/26330040241305144

7. Chen, L., & Oshima, J. (2002). Werner syndrome. Journal of Biomedicine & Biotechnology. 2(2): 46-54. doi: 10.1155/S1110724302201011

8. Noda, A., Mishima, S., Hirai, Y., Hamasaki, K., Landes, R., Mitani, H., Hada, K., Kiyono, T., Nakamura, N., & Kodama, Y. (2015) Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposing to ionizing radiation. Genes Environ. doi: 10.1186/s41021-015-0018-4

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