Progeria is an extremely rare genetic disorder wherein symptoms resembling aspects of aging
are manifested at a very early age. Progeria is one of several progeroid syndromes. The
word progeria comes from the Greek words "pro", meaning "before" or "premature", and "gēras",
meaning "old age". The disorder has a very low incidence rate, occurring in an estimated
1 per 8 million live births. Those born with progeria typically live to their mid teens
to early twenties. It is a genetic condition that occurs as a new mutation, and is rarely
inherited, as patients usually do not live to reproduce. Although the term progeria applies
strictly speaking to all diseases characterized by premature aging symptoms, and is often
used as such, it is often applied specifically in reference to Hutchinson–Gilford progeria
syndrome. Scientists are particularly interested in
progeria because it might reveal clues about the normal process of aging. Progeria was
first described in 1886 by Jonathan Hutchinson. It was also described independently in 1897
by Hastings Gilford. The condition was later named Hutchinson–Gilford progeria syndrome.
Signs and symptoms Children with progeria usually develop the
first symptoms during their first few months of life. The earliest symptoms may include
a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy,
additional conditions become apparent usually around 18–24 months. Limited growth, full-body
alopecia, and a distinctive appearance are all characteristics of progeria. Signs and
symptoms of this progressive disease tend to become more marked as the child ages. Later,
the condition causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, and cardiovascular
problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the
body, is prevalent. People diagnosed with this disorder usually have small, fragile
bodies, like those of elderly people. The face is usually wrinkled, with a larger head
in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable,
as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle,
stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly
population. Individuals usually retain normal mental and motor development.
Cause In normal conditions, the LMNA gene codes
for a structural protein called prelamin A. There is a farnesyl functional group attached
to the carboxyl-terminus of its structure. The farnesyl group allows prelamin A to attach
temporarily to the nuclear rim. Once the protein is attached, the farnesyl group is removed.
Failure to remove this farnesyl group permanently affixes the protein to the nuclear rim. Without
its farnesyl group, prelamin A is referred to as lamin A. Lamin A, along with lamin B
and lamin C, makes up the nuclear lamina, which provides structural support to the nucleus.
Before the late 20th century, research on progeria yielded very little information about
the syndrome. In 2003, the cause of progeria was discovered to be a point mutation in position
1824 of the LMNA gene, in which cytosine is replaced with thymine. This mutation creates
a 5' cryptic splice site within exon 11, resulting in an abnormally short mature mRNA transcript.
This mRNA strand, when translated, yields an abnormal variant of the prelamin A protein
whose farnesyl group cannot be removed. Because its farnesyl group cannot be removed, this
abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim,
and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear
lamina is unable to provide the nuclear envelope with adequate structural support, causing
it to take on an abnormal shape. Since the support that the nuclear lamina normally provides
is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina
limits the ability of the cell to divide. Progerin may also play a role in normal human
aging, since its production is activated in senescent wildtype cells.
Unlike "accelerated aging diseases", progeria is not caused by defective DNA repair. Because
these diseases cause changes in different aspects of aging, but never in every aspect,
they are often called "segmental progerias." Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal
growth, and loss of hair. A genetic test for LMNA mutations can confirm the diagnosis of
progeria. Treatment
No treatment has proven effective. Most treatment focuses on reducing complications with coronary
artery bypass surgery or low-dose aspirin. Children may also benefit from a high-energy
diet. Growth hormone treatment has been attempted.
The use of Morpholinos has also been attempted in order to reduce progerin production. Antisense
Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction
in the mutated pre-mRNAs were used.
A type of anticancer drug, the farnesyltransferase inhibitors, has been proposed, but their use
has been mostly limited to animal models. A Phase II clinical trial using the FTI lonafarnib
began in May 2007. In studies on the cells another anti-cancer drug, rapamycin, caused
removal of progerin from the nuclear membrane through autophagy. It has been proved that
pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl
group production. However, it is important to remember that no treatment is able to cure
progeria. Farnesyltransferase inhibitors are drugs that
inhibit the activity of an enzyme needed in order to make a link between progerin proteins
and farnesyl groups. This link generates the permanent attachment of the progerin to the
nuclear rim. In progeria, cellular damage can be appreciated because that attachment
takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it
can avoid this link, so progerin can not remain attached to the nucleus rim and it now has
a more normal state. The delivery of lonafarnib is not approved
by the US Food and Drug Administration. Therefore, it can only be used in certain clinical trials.
Until the treatment of FTIs is implemented in progeria children we will not know its
effects—which are positive in mice. Pravastatin, traded as Pravachol or Selektine,
is included in the family of statins. As well as zoledronate, its utility in HGPS is the
prevention of farnesyl groups formation, which progerin needs to provoke the disease. Some
animal trials have been realized using FTIs or a combination of pravastatin and zoledronate
so as to observe whether they are capable of reversing abnormal nuclei.
The results, obtained by blinded electron microscopic analysis and immunofluorescence
microscopy, showed that nucleus abnormalities could be reversed in transgenic mice expressing
progerin. The reversion was also observed in vivo—cultured cells from human subjects
with progeria—due to the action of the pharmacs, which block protein prenylation. The authors
of that trial add, when it comes to the results, that: “They further suggest that skin biopsy
may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects
with HGPS in clinical trials”. Unlike FTIs, pravastatin and zoledronate were
approved by the U.S. FDA, although they are not sold as a treatment for progeria. Pravastatin
is used to decrease cholesterol levels and zoledronate to prevent hypercalcaemia.
Rapamycin, also known as Sirolimus, is a macrolide. There are recent studies concerning rapamycin
which conclude that it can minimize the phenotypic effects of progeria fibroblasts. Other observed
consequences of its use are: abolishment of nuclear blebbing, degradation of progerin
in affected cells and reduction of insoluble progerin aggregates formation. All these results
do not come from any clinical trial, although it is believed that the treatment might benefit
HGPS kids. A 2012 clinical trial found that the cancer
drug Lonafarnib can improve weight gain and other symptoms of progeria.
Prognosis As there is no known cure, few people with
progeria exceed 13 years of age. At least 90% of patients die from complications of
atherosclerosis, such as heart attack or stroke. Mental development is not adversely affected;
in fact, intelligence tends to be normal to above average. With respect to the features
of aging that progeria appears to manifest, the development of symptoms is comparable
to aging at a rate eight to ten times faster than normal. With respect to features of aging
that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition.
They also do not develop the so-called "wear and tear" conditions commonly associated with
aging, such as cataracts and osteoarthritis. Although there may not be any successful treatments
for progeria itself, there are treatments for the problems it causes, such as arthritic,
respiratory, and cardiovascular problems. Epidemiology
A study from the Netherlands has shown an incidence of 1 in 4 million births. Currently,
there are 100 known cases in the world. Approximately 140 cases have been reported in medical history.
However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed
cases worldwide. Classical Hutchinson–Gilford progeria syndrome
is usually caused by a sporadic mutation taking place during the early stages of embryo development.
It is almost never passed on from affected parent to child, as affected children rarely
live long enough to have children themselves. There have been only two cases in which a
healthy person was known to carry the LMNA mutation that causes progeria. These carriers
were identified because they passed it on to their children. One family from India has
five children with progeria, though not the classical HGPS type. This family was the subject
of a 2005 Bodyshock documentary entitled The 80 Year Old Children. The Vandeweert family
of Belgium has two children, Michiel and Amber, with classic HGPS.
The first reported case of a black child with progeria was identified in September 2011.
The South African child, named Ontlametse Phalatse, was born in 1999. The Progeria Research
Foundation at Children's Hospital Boston, affiliated with the Harvard University Medical
School, is treating her and monitoring her case.
Research Several discoveries have been made that have
led to greater understandings and perhaps eventual treatment for this disease.
A 2003 report in Nature said that progeria may be a de novo dominant trait. It develops
during cell division in a newly conceived zygote or in the gametes of one of the parents.
It is caused by mutations in the LMNA gene on chromosome 1; the mutated form of lamin
A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who
did not know anything about progeria until her own son, Sam, was diagnosed at 21 months.
Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.
Lamin A Lamin A is a major component of a protein
scaffold on the inner edge of the nucleus called the nuclear lamina that helps organize
nuclear processes such as RNA and DNA synthesis. Prelamin A contains a CAAX box at the C-terminus
of the protein. This ensures that the cysteine is farnesylated and allows prelamin A to bind
membranes, specifically the nuclear membrane. After prelamin A has been localized to the
cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine,
are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer
membrane-bound, and carries out functions inside the nucleus.
In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin
A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane,
causing a characteristic nuclear blebbing. This results in the symptoms of progeria,
although the relationship between the misshapen nucleus and the symptoms is not known.
A study that compared HGPS patient cells with the skin cells from young and elderly normal
human subjects found similar defects in the HGPS and elderly cells, including down-regulation
of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading
to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes
comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin
A defects are associated with normal aging. Mouse model
A mouse model of progeria exists, though in the mouse, the LMNA prelamin A is not mutated.
Instead, ZMPSTE24, the specific protease that is required to remove the C-terminus of prelamin
A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear
membrane and in the characteristic nuclear LMNA blebbing. Fong et al. use a farnesyl
transferase inhibitor in this mouse model to inhibit protein farnesylation of prelamin
A. Treated mice had greater grip strength and lower likelihood of rib fracture and may
live longer than untreated mice. This method does not directly "cure" the underlying
cause of progeria. This method prevents prelamin A from going to the nucleus in the first place
so that no prelamin A can build up on the nuclear membrane, but equally, there is no
production of normal lamin A in the nucleus. Lamin A does not appear to be necessary for
life; mice in which the Lmna gene is knocked out show no embryological symptoms. This implies
that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal
function of lamin A, that causes the disease. It was hypothesized that part of the reason
that treatment with an FTI such as alendronate is inefficient is due to prenylation by geranylgeranyltransferase.
Since statins inhibit geranylgeranyltransferase, the combination of an FTI and statins was
tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase
Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone
defects". Popular culture
Perhaps one of the earliest influences of progeria on popular culture occurred in the
1922 short story The Curious Case of Benjamin Button by F. Scott Fitzgerald. The main character,
Benjamin Button, is born as a seventy-year-old man and ages backwards; it has been suggested
that this was inspired by progeria. Charles Dickens may have described a case
of progeria in the Smallweed family of Bleak House, specifically in the grandfather and
his grandchildren, Judy and twin brother Bart. A Bollywood movie, Paa, was made about the
condition; in it, the lead played a 13-year-old child affected by progeria.
The 2006 movie Renaissance deals with progeria. The 1996 movie Jack deals with the eponymous
character, played by Robin Williams, who has a genetic disorder similar to progeria, and
the difficulties he faces fitting into society. The 1983 film The Hunger, starring David Bowie,
Catherine Deneuve and Susan Sarandon had progeria as a focus of study by Susan Sarandon's character,
Dr. Sarah Roberts. "Young at Heart," the sixteenth episode of
the first season of the television show The X-Files, features a violent criminal who has
seemingly grown younger due to treatment by a corrupt doctor, who had developed his technique
by experimenting on progeria sufferers. In the 4-book series Otherland, by Tad Williams,
one of the main characters suffers from progeria. Harold Kushner's 1978 book When Bad Things
Happen to Good People, which explores God and the problem of evil, was written in response
to his 14-year-old son's death due to progeria. South African artist/hip hop artist Leon Botha
was one of the oldest known Progeria sufferers, surviving to the age of 26 before his death
in June 2011. Meg Casey, a Milford, CT artist and spokesperson
for the handicapped, was born October 1, 1955 and died May 26, 1985. She survived for 29
years with progeria. In the Star Trek: Voyager episode "Scientific
Method", the main character Chakotay begins to rapidly age as a result of an alien science
experiment, which the crew are unaware is occurring. Progeria is posited as one possible
cause to the rapid aging, but The Doctor notes that there had never been an adult case, and
that the disorder had supposedly been eradicated sometime during the 22nd century, approximately
200 years before the events of that episode. Life According to Sam was a 2013 documentary
on Foxborough High School student Sam Berns. Produced by Sean Fine and Andrea Nix, it explains
progeria and follows the process of finding a cure for it. In an interview, Sam Berns
had said that the most important thing people should know about him is that he had a very
happy life. See also
Biogerontology Sam Berns, a Massachusetts boy who suffered
from progeria and helped raise awareness of the disease.
Degenerative disease Hayley Okines, an English girl with progeria
known for spreading awareness Laminopathies
Lipodystrophy Lizzie Velásquez, an American motivational
speaker whose medical condition approximates neonatal progeroid syndrome
References
External links Progeria : Aging starts in childhood
Progeria Research Foundation Progeria News and Media Collection
GeneReviewUW entry on Hutchinson–Gilford progeria syndrome
Segmental progeria "ABC 20/20 special news program about Progeria,
with Barbara Walters"