Progeria is a rare
disease, fatal genetic condition that produces
rapid aging, beginning in childhood also known as "Hutchinson–Gilford
progeria syndrome" or "HGPS" and "Hutchinson–Gilford syndrome" wherein
symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan
Hutchinson in 1886, and Dr. Hastings Gilford in 1897 - both in England.
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Its name is derived from the Greek and means "prematurely old."
Approximately 1 in 4000000 people are diagnosed with this condition.
Those born with progeria typically live about 13-20 years, It is a
genetic condition that occurs as a new mutation and is not usually
inherited, although there is a uniquely inheritable form. This is in
contrast to another rare but similar premature aging
syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be
expressed multiple times in a family line.
Although they are born looking healthy, children with
Progeria begin
to display many characteristics of accelerated aging at around 18-24
months of age. Progeria signs include growth failure, loss of body fat
and hair, aged-looking skin, stiffness of joints, hip dislocation,
generalized atherosclerosis, cardiovascular
(heart) disease and stroke.
The children have a remarkably similar appearance, despite differing
ethnic background. Children with Progeria die of atherosclerosis (heart
disease) at an average age of thirteen years (with a range of about 8 -
21 years). According to Hayley's Page "At present there are 53 known
cases of Progeria around the world and only 2 in the UK". There is a
reported incidence of Progeria of approximately 1 in every 4 to 8
million newborns. Both boys and girls run an equal risk of having
Progeria.
Progeria Symptoms
Progeria is a progressive genetic disorder that causes children to
age rapidly, beginning in their first two years of life. The condition
is rare; since 1886, only about 130 cases of progeria have been
documented in the scientific literature. Usually within the first year
of life, growth of a child with progeria slows markedly so that height
and weight fall below average for his or her age, and weight falls low
for height. Motor development and mental development remain normal.
Signs and symptoms of this progressive disorder include:
Limited growth or Growth failure during the
first year of life
Narrow, shrunken or wrinkled face
failure to thrive
Baldness (alopecia)
Insulin-resistant diabetes (diabetes that does
not respond readily to insulin injections)
Skin changes similar to that seen in
scleroderma (the connective tissue becomes tough and hardened)
Loss of eyebrows and eyelashes
a distinctive appearance (small face and jaw,
pinched nose)
Short stature and small, fragile bodies, like
those of elderly people
Large head for size of face (macrocephaly)
Open soft spot (fontanelle)
Small jaw (micrognathia)
Dry, scaly, thin skin
Limited range of motion
Teeth - delayed or absent formation
Later, the condition causes wrinkled skin,
atherosclerosis, and cardiovascular problems.
Slowed growth, with below-average height and
weight
A narrowed face and beaked nose, which makes
the child look old
Head too large for face
Prominent scalp veins
Prominent eyes
Small lower jaw (micrognathia)
High-pitched voice
Delayed and abnormal tooth formation
Loss of body fat and muscle
Stiff joints
Hip dislocation
Progeria Causes
Progeria usually occurs without cause - it is not seen in siblings of
affected children. In extremely rare cases more than one child in the
same family may have the condition.
It is only very rarely seen in more than one child in a family.
Progeria is a childhood disorder caused by a point mutation in position
1824 of the LMNA gene (Lamin A), replacing cytosine with thymine,
creating an unusable form of the protein Lamin A. Lamin A is part of the
building blocks of the nuclear envelope. 90% of children with progeria
have a mutation on the gene that encodes the protein lamin A. a protein
that holds the nucleus of the cell together. It is believed that the
defective Lamin A protein makes the nucleus unstable. This instability
seems to lead to the process of premature aging among Progeria patients.
Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin
changes, abnormal growth, and loss of hair. It can be confirmed through
a genetic test. The health care professional will possibly suspect
Progeria if the signs and symptoms are there - aging skin, loss of hair,
stiffness of joints, etc. This can then be confirmed through a genetic
test. The Progeria Research Foundation has created a Diagnostic Testing
Program.
No diagnostic test confirms progeria. Doctors typically make a
diagnosis based on signs and symptoms, such as failure to grow and hair
loss, which typically aren't fully evident until your child is nearly 2.
However, with the discovery of the genetic mutation that causes progeria,
it's possible to use genetic testing for LMNA mutations at the first
suspicion of progeria. The sooner you know your child has progeria, the
sooner your doctor can recommend treatments that may help ease the signs
and symptoms of the disorder.
A blood test may reveal that your child has a low level of
high-density lipoprotein (HDL) cholesterol, the so-called good
cholesterol that helps keep arteries open. This laboratory finding isn't
diagnostic by itself, but may lend support to a diagnosis of progeria.
Treatment
No treatments have been proven effective.
Most treatment focuses on reducing
complications (such as cardiovascular disease) with heart bypass
surgery or low-dose aspirin. A daily dose may help prevent heart
attacks and stroke.
Growth hormone treatment has been attempted.
Drugs known as farnesyltransferase inhibitors
(FTIs), which were developed for treating cancer, have shown promise
in laboratory studies in correcting the cell defects that cause
progeria. FTIs are currently being studied in human clinical trials
for treatment of progeria. it 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.
Physical and occupational therapy. These may
help with joint stiffness and hip problems, and may allow your child
to remain active.
High-calorie dietary supplements. Including
extra calories in your child's daily diet may help prevent weight
loss and ensure adequate nutrition.
Feeding tube. Infants who feed poorly may
benefit from a feeding tube and a syringe. You can use the syringe
to push pumped breast milk or formula through the tube to make it
easier for your child to feed.
Extraction of primary teeth. Your child's
permanent teeth may start coming in before his or her baby teeth
fall out. Extraction may help prevent problems associated with the
delayed loss of baby teeth, including overcrowding and developing a
second row of teeth when permanent teeth come in.
Prognosis
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 affected. The development of symptoms is
comparable to aging at a rate six to eight times faster than normal,
although certain age-related conditions do not occur. Specifically,
patients show no neurodegeneration or cancer predisposition. They do not
develop physically mediated "wear and tear" conditions commonly
associated with aging, like cataracts (caused by UV exposure) and
osteoarthritis (caused by mechanical wear).
Epidemiology
Classical Hutchinson-Gilford Progeria Syndrome is almost never passed
on from parent to child. It is usually caused by a new (sporadic)
mutation during the early division of the cells in the child. It is
usually genetically dominant; therefore, parents who are healthy will
normally not pass it on to their children. Affected children rarely live
long enough to have children themselves.
Research indicates that a chemical (hyaluronic acid) may be found in
greatly elevated levels in the urine of Hutchinson-Gilford Progeria
Syndrome patients. The same abnormality has been found in Werner
Syndrome, which is sometimes called 'progeria of the adult'.
Lamin A
Nuclear lamin A is a protein scaffold on the inner edge of the
nucleus that helps organize nuclear processes such as RNA and DNA
synthesis.
Prelamin A contains a CAAX box at the C-terminus of the protein
(where C is a cysteine and A is any aliphatic amino acids). 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 is now lamin A, is no longer
membrane-bound, and carries out functions inside the nucleus.
In 2003, NHGRI researchers, together with colleagues at the Progeria
Research Foundation, the New York State Institute for Basic Research in
Developmental Disabilities, and the University of Michigan, discovered
that Hutchinson-Gilford progeria is caused by a tiny, point mutation in
a single gene, known as lamin A (LMNA). Parents and siblings of children
with progeria are virtually never affected by the disease. In accordance
with this clinical observation, the genetic mutation appears in nearly
all instances to occur in the sperm prior to conception. It is
remarkable that nearly all cases are found to arise from the
substitution of just one base pair among the approximately 25,000 DNA
base pairs that make up the LMNA gene. The LMNA gene codes for two
proteins, lamin A and lamin C, that are known to play a key role in
stabilizing the inner membrane of the cell's nucleus. In laboratory
tests involving cells taken from progeria patients, researchers have
found that the mutation responsible for Hutchinson-Gilford progeria
causes the LMNA gene to produce an abnormal form of the lamin A protein.
That abnormal protein appears to destabilize the cell's nuclear membrane
in a way that may be particularly harmful to tissues routinely subjected
to intense physical force, such as the cardiovascular and
musculoskeletal systems. Interestingly, different mutations in the same
LMNA gene have been shown to be responsible for at least a half-dozen
other genetic disorders, including two rare forms of muscular dystrophy.
In addition to its implications for diagnosis and possible treatment of
progeria, the discovery of the underlying genetics of this model of
premature aging may help to shed new light on humans' normal aging
process.
Possible Complications
Heart attack (myocardial infarction)
Stroke
How we can help children with Progeria?
Make a financial contribution. Donations are
needed to continue the vital work. No donation is too little or too
big – every penny counts in our fight for a cure!
Donate your time. Volunteers are also
important to success. Hold a special event like a bake sale or
letter writing campaign; translate documents for the families; help
with a mailing – we’ll find something for you to do that fits your
schedule, location and talents!
Donate in-kind services or items. Do you own a
printing or office supply business? Do you have a background in
non-profit development? These are just some of the many types of
talents and connections. The more tasks we can get accomplished on a
pro bono basis, the more we can spend on research!
Spread the word and tap into your connections.
Do you know anyone who can do any of the above.
Care, Coping and support
Learning your child has progeria can be
emotionally devastating. Suddenly you know that your child is facing
numerous, difficult challenges and a shortened life span. For you
and your family, coping with the disorder involves a major
commitment of physical, emotional and financial effort.
In dealing with a disorder such as progeria,
support groups can be a valuable part of a wider network of social
support that includes health care professionals, family and friends.
In a support group, you'll be with people who are facing challenges
similar to the one that you are. Talking to group members can help
you cope with your own feelings about your child's condition. If a
group isn't for you, talking to a therapist or clergy member may be
beneficial.
Ask your doctor about self-help groups or
therapists in your community. Your local health department, public
library, telephone book and the Internet also may be good sources
for finding a support group in your area.
Helping the child to cope
If your child has progeria, he or she is also
likely to experience fear and grief as awareness grows that progeria
shortens life span. Your child eventually will need your help coping
with the concept of death, and may have a number of difficult but
important questions about God and religion. Your child also may ask
questions about what will happen in your family after he or she
dies.
It's critical that you are able to talk openly
and honestly with your child, and offer reassurance that's
compatible with your belief system. Ask your doctor, therapist or
clergy member to help you prepare for such conversations with your
child. Friends who you meet through support groups also may be able
to offer valuable guidance.
Conclusion and General Discussion
Progeria, or Hutchinson-Gilford progeria syndrome, is a rare, fatal,
genetic condition of childhood with striking features resembling
premature aging. Children with progeria usually have a normal appearance
in early infancy. At approximately nine to 24 months of age, affected
children begin to experience profound growth delays, resulting in short
stature and low weight. They also develop a distinctive facial
appearance characterized by a disproportionately small face in
comparison to the head; an underdeveloped jaw (micrognathia);
malformation and crowding of the teeth; abnormally prominent eyes; a
small, nose; prominent eyes and a subtle blueness around the mouth. In
addition, by the second year of life, the scalp hair, eyebrows, and
eyelashes are lost (alopecia), and the scalp hair may be replaced by
small, downy, white or blond hairs. Additional characteristic features
include generalized atherosclerosis, cardiovascular disease and stroke,
hip dislocations, unusually prominent veins of the scalp, loss of the
layer of fat beneath the skin (subcutaneous adipose tissue), defects of
the nails, joint stiffness, skeletal defects, and/or other
abnormalities. According to reports in the medical literature,
individuals with Hutchinson-Gilford progeria syndrome develop premature,
widespread thickening and loss of elasticity of artery walls
(arteriosclerosis), which result in life-threatening complications
during childhood, adolescence, or early adulthood. Children with
progeria die of heart disease (atherosclerosis) at an average age of 13
years, with a range of about eight to 21 years.
Progeria is caused by a mutation of the gene LMNA, or lamin A. The
lamin A protein is the scaffolding that holds the nucleus of a cell
together. Researchers now believe that the defective lamin A protein
makes the nucleus unstable. That cellular instability appears to lead to
the process of premature aging in progeria. Because neither parent
carries or expresses the mutation, each case is believed to represent a
sporadic, new mutation that happens most notably in a single sperm or
egg immediately prior to conception.
REFERENCES
Ayres, S. C.; Mihan, R. : Progeria: a possible
therapeutic approach. (Letter) JAMA 227: 1381-1382, 1974.
Brown, W. T. : Human mutations affecting
aging--a review. Mech. Aging Dev. 9: 325-336, 1979.
Brown, W. T.; Abdenur, J.; Goonewardena, P.;
Alemzadeh, R.; Smith, M.; Friedman, S.; Cervantes, C.; Bandyopadhyay,
S.; Zaslav, A.; Kunaporn, S.; Serotkin, A.; Lifshitz, F. :
Hutchinson-Gilford progeria syndrome: clinical, chromosomal and
metabolic abnormalities. (Abstract) Am. J. Hum. Genet. 47 (suppl.):
A50 only, 1990.
Brown, W. T.; Darlington, G. J. : Thermolabile
enzymes in progeria and Werner syndrome: evidence contrary to the
protein error hypothesis. Am. J. Hum. Genet. 32: 614-619, 1980.
Brown, W. T.; Darlington, G. J.; Arnold, A.;
Fotino, M. : Detection of HLA antigens on progeria syndrome
fibroblasts. Clin. Genet. 17: 213-219, 1980.
Cao, H.; Hegele, R. A. : LMNA is mutated in
Hutchinson-Gilford progeria (MIM 176670) but not in
Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J. Hum.
Genet. 48: 271-274, 2003.
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