What is Progeria?

Hutchinson Gilford Progeria Syndrome (HGPS), which is more commonly referred to as progeria, is an extremely rare and fatal genetic disorder that causes premature aging in affected individuals. With a prevalence of 1 in 20 million births worldwide, it is estimated that 350-400 children around the world have HGPS.

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The genetics of progeria

In 2003, a group of researchers led by Nicolas Lévy and Francis S. Collins discovered that HGPS is an autosomal dominant disease that results from a de novo mutation in the LMNA gene. The LMNA gene encodes four nuclear lamins, which include A, C, CD10, and C2.

The nuclear lamina is a compartment within the nucleus that primary functions to maintain the architecture and stability of this organelle, as well as regulate the organization and activities of the genome. Aside from HGPS, over 400 other mutations in the LMNA gene have been identified and associated with a disease.

Each of these laminae arises following the alternative splicing of the LMNA gene, in which lamins A and C are most ubiquitously expressed. Under normal conditions, the LMNA gene will splice, facilitate the association of precursor lamin proteins with the nuclear envelope, and eventually produce a mature lamin A protein that is comprised of 646 residues.

Comparatively, the mutation in the LMNA gene that causes HGPS will cause a single-base substitution to arise within the LMNA exon 11. This will then activate a cryptic splice site, leading to the deletion of 50 amino acids. This deletion then results in the production of an abnormal protein that is now commonly referred to as ‘progerin.’

Since progerin lacks a second endoproteolytic cleavage site, this protein will remain permanently farnesylated and carboxymethylated. Taken together, this mutant form of lamin A disrupts a wide variety of nuclear processes, which eventually lead to a decline at both the cellular and organismal level.  

Diagnosis

Researchers believe that the progression of HGPS begins at diagnosis; however, progeria patients often appear normal at birth and have normal birth weight. While this may be true, some HGPS patients may exhibit certain subtle features of the disease such as circumoral pallor; however, such symptoms are already inconspicuously present at birth, thereby limiting the ability of clinicians to accurately diagnose this condition immediately.

Researchers believe that this delay in disease manifestation may be due to the attenuated expression of lamin A/C and progerin in undifferentiated or embryonic cells, which may prevent progerin levels from reaching a disease-provoking threshold until several months after birth.

Clinical features

By 9-12 months of age, HGPS patients will begin to present with skin abnormalities, alopecia, circumoral cyanosis, failure to thrive, prominent scalp veins, and a reduced range of motion. Although cranial hair loss will begin around 10 months of age, HGPS patients will gradually lose body hair and eyebrows until progressing to almost complete alopecia.

Some of the specific craniofacial features of progeria include micrognathia, prominent eyes, beaked nose, and certain dental abnormalities, such as dental crowding. As previously mentioned, some of the earliest manifestations of HGPS are skin alterations, which can include discoloration, stippled pigmentation, sclerodermoid changes, and tightened areas that restrict movement.

As a segmental aging disease, HGPS patients will experience some normal aging effects, whereas other features will be absent. For example, the liver, kidneys, lungs, and gastrointestinal tract of HGPS patients are often normal, whereas various other cell and tissue types, particularly those of mesenchymal origin, are more susceptible to the progerin-induced defects.

Aside from the aforementioned features of HGPS, abnormalities in the bones and joints of these patients are common and can typically progress to skeletal dysplasia. Some of the common bone problems that HGPS patients will experience include reduced bone mineral density with accentuated demineralization at the end of long bones, avascular necrosis, disrupted bone formation in the skull, persistent anterior and posterior fontanels, small clavicles, thin ribs, and acroosteolysis.

The average life span of an HGPS patient is approximately 14.6 years, with many patients dying in their early teenage years from complications of rapidly progressive atherosclerosis, including myocardial ischemia, infarction, or stroke. Other cardiovascular complications of HGPS include increased afterload and angina.

Although progerin is typically not expressed at significant levels within the neuronal cells and tissues, thereby allowing HGPS patients to typically have normal cognitive abilities, vascular abnormalities in these patients can result in neurological disease manifestations.

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Treatment

Several promising treatment strategies for HGPS have emerged over the past several years. For example, various farnesyltransferase inhibitors (FTIs) have been used in both in vitro models of HGPSpatient-derived cells, as well as progeria mouse models.

These compounds, which function by inhibiting the processing of prelamin A to the mutant progerin protein, have been found to extend survival by an estimated 1.6 years by reducing the secondary outcomes of HGPS.

However, new clinical trials involving combination therapies that are aimed towards inhibiting multiple steps in the farnesyl biosynthetic pathway are currently being evaluated for their ability to improve disease phenotype.

Other therapeutic strategies that have been investigated include inhibitors of the enzyme that is responsible for the carboxylation of the farnesylcysteine of progerin, compounds that increase the clearance of progerin through autophagy, N-acetyl cysteine, which is a reactive oxygen species (ROS) scavenger which reduces the amount of unrepairable DNA damage and methylene blue, which is a mitochondrial-targeting antioxidant.

As stem cell-based therapies and regenerative medicine continue to advance, researchers anticipate that these types of treatment approaches have the potential to also be used in the management of HGPS.    

References and Further Reading

• Gonzalo, S., Kreinkamp, R., & Askjaer, P. (2017). Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Research Reviews 33; 18-29. doi:10.1016/j.arr.2016.06.007.
• Foo, M. X. R., Ong, P. F., & Dreesen, O. (2019). Premature aging syndromes: From patients to mechanism. Journal of Dermatological Science 96(2); 58-65. doi:10.1016/j.jdermsci.2019.10.003.
• Guilbert, S. M., Cardoso, D., Levy, N., et al. (2020). Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated aging. Methods. doi:10.1016/j.ymeth.2020.04.005.
• Cheung, H., Pei, D., & Chan, W. (2015). Stem cell aging in adult progeria. Cell Regeneration 4(1). doi:10.1186/s13619-015-0021-z.

Written by

Benedette Cuffari

After completing her Bachelor of Science in Toxicology with two minors in Spanish and Chemistry in 2016, Benedette continued her studies to complete her Master of Science in Toxicology in May of 2018.During graduate school, Benedette investigated the dermatotoxicity of mechlorethamine and bendamustine, which are two nitrogen mustard alkylating agents that are currently used in anticancer therapy.