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What is Progeria?

Risk Factors?

Hutchinson-Gilford Progeria Syndrome, also known simply as Progeria is an extremely rare genetic condition where those who are affected exhibit symptoms of accelerated aging from childhood. Progeria is an autosomal dominant disorder and happens in roughly 1 out of every 4-8 million newborns worldwide. Progeria was first described in 1886 by Dr. Jonathan Hutchinson, and in 1897 by Dr. Hastings Gilford. One of the earliest influences of Progeria in main stream media is in the 2008 movie adaption (the novel was written in 1922) The Curious Case of Benjamin Button. The main character, Benjamin Button is born as a seventy year old man who ages backwards. It is often suggested that this was inspired by progeria [3].

Oddly enough, there are not necessarily any risk factors for Progeria. The mutation is extremely rare, and is almost always occurs in people with no history of the disorder in their family. Additionally, those who are born with progeria often do not live long enough to produce offspring which makes the mutation even harder to come across. 

Signs & Symptoms

What Causes Progeria?

Progeria is caused by a mutation in the gene called LMNA. The LMNA gene encodes the intermediate filament protein Lamin A. Lamin A is a major component of the nuclear lamina, which is a scaffolding like structure in the nuclear envelope which helps give the nucleus some structural integrity. Lamin A is also involved in chromatin organization, epigenetic regulation, and it defines mechanochemical properties of the nucleus. The mutated form of Lamin A, most commonly found in progeria, leads to mis-splicing of the LMNA mRNA which produces a mutant Lamin A protein known as progerin. "Progerin impairs many cellular processes including changes in signaling pathways, altered chromatin organization, impaired genome stability, and changes in mechanosignaling. This leads to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence [1,4]."  

Why Does Progeria Exhibit these Specific Symptoms? 

Signaling Pathway

This question poses a challenge to many researchers. Current knowledge of the specific mechanisms of Progeria is very limited. Researchers believe that Progeria is a true accelerated aging process, rather than a 'pseudoaging' process (resembles aging, but it really is not.) The normal LMNA protein has a farnesyl group on the c-terminal that is cleaved off during proessing which allows it to function normally. The mutated form, progerin, can not undergo the final proteolytic prcessing step and retains the C-terminal farnesyl group. This leads to progerin stability and localization at the nuclear periphery. Expression of progerin induces various  cellular defects in a dominant-negative manner, including highly lobulated nuclei with thickened lamina, loss of peripheral heterochromatin, accumulation of DNA damage, telomere aberrations and mitochondrial dysfunction, leading to differentiation defects, premature cellular senescence  and loss of nucleoplasmic lamins [1]. The mechanisms of these interactions are not fully understood but reearch is currently being conducted on the subject. 

Although children with progeria are born looking healthy, they begin to show signs of accelerated aging within their first two years of life.

Signs/ Symptoms include:

  • Growth Failure

  • Loss of body fat and hair

  • Aged looking skin

  • Stiffness of joints

  • Hip dislocations

  • Generalized atherosclerosis

  • Cardiovascular Disease 

  • Stroke

 

Children with Progeria often die of atherosclerosis around fourteen years old. 

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Normal Pathway: In the normal cellular pathway, the LMNA gene is transcribed and translated into the LMNA protein. Processing of the protein takes place and the farnesyl group is then cleaved and the functional form of the protein is utilized by the cell, specifically in the nucleus, as it is a nuclear lamin [1]. 

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Altered Pathway: The altered pathway begins with a single base substitution in exon 11 of the LMNA gene. The mutation then leads to the activation of a cryptic splice site in the gene, and when it is translated, it is translated into a truncated Lamin-A variant known as progerin. The progerin protein can not undergo the final processing step and the farnesyl group stays attached. This leads to progerin stability and localization on the nuclear periphery, which leads to the altered cellular function of progeric cels [1,4].    

Normal Cell

Progeric Cell

Treatment and Side Effects

Treatments: There is no cure for progeria, but there are things that can be done to better cope or 'reduce' the symptoms. Some of those include:

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  • "Low dose aspirin; may prevent heart attacks

  • Statins to lower cholesterol or drugs to lower blood pressure

  • Physical and Occupational; they may help with joint stiffness and hip problems. 

  • Nutrition; high calorie diet can help to maintain adequete nutrition [5]."

 

There is a treatment that now exists: Lonafarnib. It does not cure progeria, but it does improve some of the symptoms seen in patients with progeria. Such as gaining additional weight. better hearing, improved bone structure, and most importantly increased flexibility of blood vessels. Lonafarnib works as a farnesyltransferase inhibitor. It blocks the farnesylation of prelamin A so that the final form of progerin can not form. The clinical trials have shown improvements in all children treated so the future for this drug is very bright [1,6,7]! 

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Side Effects of Treatment: The two most common side effects seen with FTI treatment in children without progeria is diarrhea and changes in certain blood tests of liver function. The diarrhea can be prevented by taking an anti diarrhea medicine first and the changes in the liver function tests never caused problems and resolved. The side effects will likely be carried over to patients with progeria when further testing is done, with additional possible side effects that are currently unknown [9]. 

A normal ell nucleus

A progeric cell nucleus

picture sourced from [8]

Progeric Cell

References

[1] Progeria. (2018, February 01). Retrieved from https://www.mayoclinic.org/diseases-conditions/progeria/symptoms-causes/syc-20356038

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[2] Vidak, S., & Foisner, R. (2016). Molecular insights into the premature aging disease progeria. Histochemistry and Cell Biology, 145, 401–417. http://doi.org/10.1007/s00418-016-1411-1

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[3] About Progeria. (n.d.). Retrieved April 4, 2018, from https://www.progeriaresearch.org/about-progeria/

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[4] Aliper, A. M., Csoka, A. B., Buzdin, A., Jetka, T., Roumiantsev, S., Moskalev, A., & Zhavoronkov, A. (2015). Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells. Aging, 7(1), 26-37. doi:10.18632/aging.100717

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[5] Progeria. (2018, February 01). Retrieved March 20, 2018, from https://www.mayoclinic.org/diseases-conditions/progeria/diagnosis-treatment/drc-20356043

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[6] First-ever Treatment for Progeria. (n.d.). Retrieved April 24, 2018, from https://www.progeriaresearch.org/first-ever-progeria-treatment/

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[7] Pollex, R., & Hegele, R. (2004). Hutchinson-Gilford progeria syndrome. Clinical Genetics, 66(5), 375-381. doi:10.1111/j.1399-0004.2004.00315.x

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[8] Scaffidi, P., Gordon, L., & Misteli, T. (2005). The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biology, 3(11). doi:10.1371/journal.pbio.0030395

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[9] Gordon, L. B., MD, PHD. (2006, August). Update: Farnesyltransferase Inhibitors (FTIs) as Potential Drug Therapy for Children with Progeria: Recent Research Findings and Frequently Asked Questions [PDF]. The Progeria Research Foundation.

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