What is progeria?

Progeria, also known as Hutchinson-Gilford progeria syndrome (HGPS), is a very rare and fatal autosomal dominant disease. However, progeria may not be passed down through every generation of a family and it is extremely rare that more than one child suffers from progeria in the same family. Many children affected by progeria do not live past the age of 13. Progeria causes rapid ageing in its victims, causing them to become prematurely old. 

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Dean Andrews', a 21 year old man with a 168 year old body due to progeria

Above, is Dean Andrews, well known as the second oldest survivor of progeria. Dean Andrews is a 21 year old man from the UK, who is one of the four people suffering from progeria within the UK. He is known to be the second oldest living survivor of progeria. He suffers from a case of Hutchinson-Gilford progeria, which causes his body to age 8 times faster, hence his body is 168 years old. He has a small stature for his age, being only 4ft 1in (1.2m) and weighing only 3st 10lbs (23kg). Doctors did not expect him to live past the age of 13, however, he survived. His mother noticed some symptoms which related his condition to progeria. For example, Dean would get tired easily from activities such as walking. Dean’s mother passed it off as laziness on his part but soon realized some things that he was not able to do things such as crossing his legs during assembly and having a small appetite.

Symptoms of progeria:

1. Growth failure during first year of life

2.       Narrow, shrunken or wrinkled face

3.       Baldness

4.       Loss of eyebrows and eyelashes

5.       Short strature

6.       Head of which is too large in proportion as compared to the body

7.       Small jaw

8.       Dry, scaly and thin skin

9.       Limited range of motion

10.   Delayed formation or absence of teeth

Complications:

All children with progeria die of the same heart disease that affects millions of aging adults (arteriosclerosis), but instead of the disease occuring at 60 or 70 years of age, they may suffer from strokes and heart attacks even before the age of 10.

Atherosclerosis (hardening of the arteries):  Children with HGPS typically develop a condition called atherosclerosis, which occurs when the walls of the arteries become hard and thick. Atherosclerosis may limit blood flow to the heart, brain, or other parts of the body. When vital organs do not receive enough blood, they can fail. For instance, if blood flow to the heart is blocked, it causes a heart attack. If blood flow to the brain is blocked, it causes a stroke. Most children with HGPS die from cardiovascular abnormalities, including congestive heart failure, heart attacks, and strokes.

Malnutrition: Malnutrition is another common complication of HGPS because some infants have difficulty feeding.

Osteoperosis: Patients with HGPS have an increased risk of developing osteoporosis, a condition that causes the bones to become weak, brittle, and porous. As a result, children with progeria may have an increased risk of experiencing bone fractures than healthy children.

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Diagnosis: 

Other than the physical examination for symptoms, there are other tests that can diagnose if the child is suffering from progeria. These tests include insulin resistance tests, skin tests and cardiac stress tests. A genetic test for LMNA mutations can confirm the diagnosis of progeria.

Cause of progeria:

·        This disease is mainly caused by the malfunction of the LMNA gene, which codes for a structural protein called prelamin A, also known as the A-type nuclear lamins. HGPS or progeria is caused when the 11^th exon of the LMNA gene is mutated, which results in an in-frame deletion of 50 amino acids near the carboxyl terminus of prelamin A. Normal prelamin A will undergo a series of 4 reactions, namely farnesylation, carboxymethylation, methylation and farnesylation-dependent cleavage catalyzed by ZMPSTE24. The farnesylation-dependent cleavage leads to a 15-amino acid farnesylated polypeptide chain  being removed. Therefore, the mature lamin A would be unfarnesylated. However, mutated prelamin A, known as progerin, will only undergo all the reactions excluding the cleavage, as the ZMPSTE24 site is absent. Hence, the mutated mature lamin A will still remain farnesylated when it incorporates into the nuclear lamina. The incorporation of progerin into the neuclear lamina results in an abnormally shaped nucleus. The abnormal nuclear lamina is unable to organize chromatins during mitosis, which hampers the ability of the cell to undergo cell division, causing the cell to age faster.

Differences between normal prelamin A and progerin

Left: nucleus of cells of progeria patients
Right: nucleus of normal cells

Nucleus of a normal cell

Treatment of progeria:

There is no definite cures for treating progeria and children who are affected by it will rarely live to 13 years of age. However, laboratory studies have shown that there is a possibility of reducing the effects of progeria, but at its own risk. This studies have already succeeded in primary clinical trials. Using a protein farnesyltransferase inhibitor (FTI) would result in the blocking of the production of farnesylated progerin in the mice, causing them to produce only non-farnesylated progerin. FTIs work by reversing the abnormalities of the nuclear shape in progeria affected mice. This would cause the cysteine residue of the CAAX (cysteine-aliphatic-aliphatic-any amino acid) motif present at the carboxyl terminus of prelamin A to be replaced by a serine residue. This resulted in a reduced effect of progeria in the mice as compared to those which produce farnesylated progerin. However, there are two main risks of this experimental treatment. First being that the mice could only produce non-farnesylated proteins, which may result in the blocking of other unrelated proteins with a prenyl or isoprenyl group attached to them. The second being the overall utility of FTIs as a treatment for progeria.

After this study was conducted on mice, it proceeded to clinical trials on children suffering from progeria. Overall, every child who was suffering from progeria showed signs of improvements in their conditions. For example improvements in weight gain, bone structure, cardiovascular condition and audiological status. The results have shown that this treatment is useful and has a huge potential as a treatment for sufferers of progeria.

Farnesyltransferase inhibitors (FTIs) are small molecules which reversibly bind to the farnesyltransferase CAAX binding site, thereby inhibiting progerin farnesylation and intercalation into the nuclear membrane.

Related videos and links:

http://www.progeriaresearch.org/about_progeria/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478615/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478615/

 

References:

Mail Online. 2012. Britain's oldest 20-year-old man has the body of a 160-year-old due to rare condition. [ONLINE] Available at: < http://www.dailymail.co.uk/health/article-2134367/Progeria-Dean-Andrews-20-body-160-year-old-rare-condition.html>. Last accessed [20 January 2014].

Progeria Research Foundation. 2013. PRF By The Numbers. [ONLINE] Available at: <http://foundation.progeriaresearch.org/prf-by-the-numbersprf.html>. Last accessed [20 January 2014].

Sharecare. 2012. What are complications of Hutchinson-Gilford progeria syndrome (HGPS)?. [ONLINE] Available at: <http://www.sharecare.com/health/chromosomal-disorders/what-complications-hgps>. Last accessed [20 January 2014].

medpage TODAY. 2013. Life According To Sam Berns. [ONLINE] Available at: <http://www.medpagetoday.com/CelebrityDiagnosis/42315>. Last accessed [20 January 2014].

Leslie, B. et al (2012). Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome.[Online] Available at:

 < http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478615/> Last accessed [17 January 2014].