Hutchinson-Gilford Progeria Syndrome

Malika Laurence

History of Progeria
First described by Jonathan Hutchinson in 1886: Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages in a boy... from the age of six.
Later (independently) described by Hastings Gilford in 1896: A condition of mixed premature and immature development. Progeria comes from the greek words pro and geras, meaning before and old age, respectively.

Background
Progeria is characterized as premature aging.
Individuals usually die between 8-21 years old. Average age of death is 13. It is extremely rare: 1/8 million births Nearly all patients die of heart conditions.

Symptoms in Infnacy
Symptoms emerge in the first few months of life
Failure to thrive Distinctive physical appearance: small face, shallow jaw, pinched nose, and lack of hair.

Large head for size of face

Loss of body fat Joint stiffness Hip dislocation

Symptoms in later years

As aging progresses, symptoms worsen:
Wrinkled, dry, scaly, thin skin Short stature Limited motion range

Atheroslerosis (hardened arteries)

Kidney failure Blindness Scleroderma (tissue disease) Hypertension Heart failure

Cause of Progeria
Progeria is caused by a random point mutation (cytosine to thymine) on the gene LMNA on Chromosome 1.
LMNA codes for Prelamin A, a protein that provides nuclear support. When the mutation occurs, the nucleus is distorted. The mutation also causes production of progerin, a protein that damages cell function.
Interestingly, Progerin is found in the general population as age increases.

Normal nucleus

Progeria nucleus

Cause of Progeria
Prelamin A has a farnesyl group attached to it, allowing it to temporarily adhere to the cell nucleus. When the farnesyl is cleaved off by a protease, the Prelamin becomes Lamin A and joins the nuclear lamina (providing support for the cell). In Progeria, the farnesyl is never detached, causing permanent adhesion to the nucleus, buildup of Prelamin A, and loss of support.

Treatments
There is no cure or treatment to reduce the effects of Progeria Some treatments, such as heart bypass surgery, are used to cure the symptoms of Progeria.

A 2012 study showed that some cancer drugs (such as Lonafarnib) can be used to cure Progeria.
The study focused on farnesyltransferase inhibitors (FTIs) to restore nuclei back to their normal shape.

It was only tested on mice, so the treatment is not yet confirmed.

Identification of Progeria
Most children generally appear normal at birth. By 12 months, signs and symptoms, such as slow growth and hair loss, begin to appear. A genetic test for HutchinsonGilford progeria syndrome, also called HGPS, was recently made available.

Genetics of Progeria and Bioethical Considerations

The disease is called a sporadic autosomal dominant mutation
It is sporadic because it is a new change in that family
It is dominant because only one copy of the gene needs to be changed in order to have the syndrome.

Some doctors believe the mutation is caused by an inherited recessive gene.

This is supported by the fact that one family in India has five children with the disease. The parents are 1st cousins, supplementing this theory. (This is the only case where Progeria is linked to heredity). Though some believe this, there is no test to check whether the parents carry the gene, so no bioethical considerations need to be taken into account.

Interesting Facts about Progeria

Both boys and girls run an equal risk of having Progeria. As of January 2013, there are 100 children living in 36 different countries who have been diagnosed with Progeria (Including 10 children in the Progeroid Laminopathy category that have a mutation in the Lamin pathway, but do not produce progerin). There are an estimated 200-250 children living with Progeria worldwide at any one time.

LMNA is not expressed by the brain cells, so the gene mutation does not affect intelligence level.

Life with Progeria

Hayley Okines, a 13 year old girl with Progeria, describes her life:
The easiest way to explain it is its like my body is 100 years old when I am actually thirteen... but I dont like it when people call me old because I dont feel like I am...

I am smaller than other kids my age. I have a brother, Louis, who is nine and a sister, Ruby, who is six. Although I am the big sister in the family, they are physically bigger than me.
She frequently travels from England to Boston to receive new treatments in the United States. Airfare is not covered by Progeria Reseearch funds, but several athletes have contributed to Hayleys cause. Londons Chelsea Football club raised thousands of dollars for Hayley

Life with Progeria, cont.

Hayley explains, My life with progeria is full of happiness and good memories. If I didnt have progeria I would not have done most of the cool things I have done or met most of the cool people I have met.
Hayley got to meet Justin Beiber in 2010 because of her syndrome

Deep inside I am no different from anyone. We are all human.

Bibliography
Davis, Kyle. "A Race Against Time: An Overview of Progeria and Its Clinical Symptoms." UC Davis: Prized Writing. UC Davis University of California, n.d. Web. 21 Feb. 2013. <http://prizedwriting.ucdavis.edu/past/2007-2008/a-race-againsttime-an-overview-of-progeria-and-its-clinical-symptoms>. "First-ever Treatment for Progeria Discovered!!" Progeria Research Foundation. N.p., n.d. Web. 21 Feb. 2013. <http://www.progeriaresearch.org/first-ever-progeriatreatment.html>. Grant, Matthew. "Family Tormented by Ageing Disease." BBC News. BBC, 22 Feb. 2005. Web. 21 Feb. 2013. <http://news.bbc.co.uk/2/hi/south_asia/4286347.stm>.

Bibliography cont.
"Hutchinson-Gilford Progeria Syndrome." Genetics Home Reference. N.p., July 2007. Web. 17 Feb. 2013. <http://ghr.nlm.nih.gov/condition/hutchinson-gilford-progeriasyndrome>.
Nordqvist, Christian. "What Is Progeria?" Medical News Today. MediLexicon International, 13 May 2009. Web. 17 Feb. 2013. <http://www.medicalnewstoday.com/articles/146746.php>. "The PRF Diagnostic Testing Program." Progeria Research Foundation. N.p., n.d. Web. 18 Feb. 2013. <http://www.progeriaresearch.org/diagnostic_testing.html>. "Progeria 101/FAQ." Progeria Research Foundation. N.p., n.d. Web. 21 Feb. 2013. <http://www.progeriaresearch.org/progeria_101.html>.

Bibliography cont.
Stovall, Ami, Amanda Dean, and Helen Chen. "Cellular Mechanisms of Progeria." The Progeria Project Foundation. N.p., Apr.-May 2001. Web. 18 Feb. 2013. <http://www.progeriaproject.com/Progeria/Richland6.htm>. United States. National Library of Medicine. Center for Biotechnology Information. National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. 19 Feb. 2013. <http://www.ncbi.nlm.nih.gov/gene/4000>. United States. National Library of Medicine. PubMed. Progeria. U.S. National Library of Medicine, 18 Jan. 2011. Web. 21 Feb. 2013. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002622/>.