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 |
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 11th
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.
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.ncbi.nlm.nih.gov/pmc/articles/PMC3478615/
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].