Progeria Syndrome
Tamara Lansden
East Tennessee State University
Research in Allied Health
Abstract
Progeria syndrome is a rare and fatal genetic condition characterized by an
appearance of rapid aging in children. Progeria syndrome is a disease that
affects only one child in four million live births. These children born with the
disease start out their lives looking and developing as a normal child does.
However, within eighteen to twenty four months, the child begins to develop
characteristics of progressed aging. The purpose of this study of research is to
identify the different ages of children affected with progeria syndrome and how at
that age, can cause stroke and heart disease. In this research I want to be able
to detect an association with age and heart disease. I wish to be able to
determine if manipulation of the Lamin A protein would provide some kind of
depletion of the ageing process in already affected children.
Introduction
Progeria Syndrome is a rare, fatal genetic condition characterized by an
appearance of rapid aging in children. Its name is derived from the Greek and
means "prematurely old." While there are different forms of Progeria, the classic
type is Hutchinson-Gilford Progeria Syndrome or HGPS. HGPS is caused by a
mutation in the gene called LMNA (pronounced, lamin - a). The LMNA gene
produces the Lamin A protein, which is the structural 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.
Although they are born looking healthy, children with progeria begin to
display many characteristics of accelerated aging at around eighteen to twentyfour months of age. Signs of progeria include growth failure, loss of body fat and
hair, aged-looking skin, stiffness of joints, hip dislocation, dry-scaly skin, limited
range of motion, enlarged heart, and high blood pressure. These children have a
remarkably similar appearance, despite differing ethnic background. Children
with progeria usually develop and die from atherosclerosis, cardiovascular (heart)
disease and stroke at an average age of thirteen years (with a range of about
eight to twenty-one years). Although there is presently no treatment or cure for
Progeria syndrome, the Progeria Research Foundation helped in the discovery of
the gene that causes Progeria which is the first important step in finding a cure.
I chose to study this disease because the disease is so rare that many
people are not aware that it does exist. In my research I wish to be able to
provide a better insight on the disease and be able to help individuals who have
an interest in this particular study to understand that age is closely related to
stroke and heart disease in children who are affected with Progeria Syndrome.
Problem Statement
In this research study, I want to look at heart disease and stroke as the
dependent variables and I chose to identify age as the independent variable.
In my research I want to be able to relate or prove that there is an association
between the different ages of patients that have progeria syndrome and relate it
to heart disease and stroke. The second part that I wanted to identify is how the
treatment of this disease would prolong the livelihood of an affected child.
Review of Literature
The progeria syndrome is a rare genetic disorder, first reported in 1886 by
Hutchinson and Guilford in England. The inheritance pattern, paternal age effect,
and lack of consanguinity argue that it is due to a sporadic dominant mutation.
Hutchinson-Guilford progeria syndrome (HGPS) is associated with several
features of premature ageing--for example, growth retardation, characteristic
facies, loss of hair, and subcutaneous fat, restricted joint mobility, prominent
eyes, and severe premature atherosclerosis (Balin, p. 93). In 1886, Jonathan
Hutchinson reported a case of a 3.5 year old boy who had the appearance of an
old man. Later, Hastings Guilford reported a second case with similar features.
The term, "progeria" was taken from the Greek word for old age, "geras",
originally pro posed by Guilford in 1904 (Sarkar, 2001, p. 312).
In 1972, DeBusk presented case reports of four patients and reviewed the
world literature on HGPS. Although these patients develop premature
atherosclerosis and die of cardiac or cerebral vascular disease between 7 and 27
years of age, many other features associated with pathological ageing are
absent. DeBusk observed that patients “with progeria syndrome are typically
considered normal infants at first.” The characteristic facies, posture, stiffness of
joints, and bone, teeth, and skin changes become apparent during the second
year of life (p. 697-700).
Brown suggests that the estimated incidence of HGPS in the USA is one
in eight million births, based on the number of cases. Brown also suggested that
only one half of the affected patients were reported, thereby the estimated
incidence of one in four million live births. Males are affected one and a half
times more often than females (M : F = 1.5 : 1). Ninety seven per cent of affected
patients are white. Several rare conditions exist in human beings that exhibit
certain phenotypic characteristics associated with senescence. Often referred to
as "segmental progeroid syndromes", the most important and widely studied
condition was HGPS. The exact inheritance of HGPS is not known. In the past, it
was thought to be an autosomal recessive (p. 293-294). DeBusk reviewed only
three families where more than one member was affected, consanguinity was
uncommon, and advanced paternal age was noted. These observations made an
autosomal recessive inheritance very unlikely and favour a sporadic, dominant
mutation (p.701). Since most cases are due to isolated mutations of a gamete,
the familial occurrence is rare. Some cases may be due to germ line mutations,
and therefore, parents of one affected child should be counseled that the risk of a
subsequent affected child is one in 500 for each pregnancy" (Brown, p. 293).
HGPS, a rare disease that speeds the aging process so much that
children with the disorder die from diseases typically associated with advanced
age, usually in their early teens. Since the 2003 discovery that a mutation in the
LMNA gene causes progeria, scientists have developed several mouse models
for the disorder, amassed a growing body of evidence regarding the disease's
molecular and cellular basis, and devised experimental treatment strategies.
Whether such treatments would be safe and effective for children with progeria
remains to be determined, but scientists and advocates are excited by the swift
pace of progress (Kuehn, 2006, p. 876). In particular, the fact that most patients
with progeria die from severe and accelerated cardiovascular disease has led
some researchers to believe that understanding this disorder could lead to a
better understanding and associate typical cardiovascular disease in aging adults
(p. 877). Age changes theory provided by the research of Bennett in 1995
suggested that age related changes occur throughout the whole lifespan, often
involving deterioration of an anatomical/physiological nature. Many cellular
functions appear to change with increasing age. Random molecular damage
leading to accumulation of defects, for example, lipofuscin, causes age related
changes in organs and systems that we recognise as ageing (p. 3-4). “With
increasing age heart disease and many other organ function decline.” Similarly,
ages from 40 to 70, show ageing brain, heart, lungs, bones, joints, muscles, and
even immune systems all have impaired function. Therefore, progeria syndrome
does support the hypothesis that at a DNA level in part, from an imbalance
between DNA damage and repair. In some of these syndromes, malignant
transformations occur due to severe chromosomal aberrations (p. 6-9).
Arteriosclerosis, nephrosclerosis, myocardial fibrosis, and vascular calcifications
are significant cardiovascular findings. Pesce studies of necropsy studies on
patients with HGPS revealed gross abnormalities in skin, cardiovascular and
cerebrovascular tissues, stroke, (p.162-163). Recently, magnetic resonance
angiography demonstrated bilateral occlusion of internal carotid and vertebral
artery origins. (p. 163). Pathological studies have demonstrated premature
subintimal fibrosis in the blood vessels. As the child becomes more and more old
they become more vulnerable to stroke, and heart disease as well many other
contributing factors in the aging process.
The most serious aspect of the disease, however, and the cause of death
in >90% of cases, is rapid, progressive arterial occlusive disease, with death from
myocardial infarction or stroke occurring at an average age of 13 years (range, 8–
21 years). Specifically, postmortem studies have identified profound loss of
vascular smooth muscle cells (VSMC) in the medial layer of large arteries, such
as the aorta and carotid arteries, with replacement by collagen and extracellular
matrix. Superimposed on these medial changes have been generalized features
of atherosclerosis with focal areas of calcification (Yang, p. 10291-94).
By studying cells from patients with progeria and mice with progeria like
disorders, scientists are beginning to sort out how the mutant LMNA gene causes
damage at the cellular and molecular levels. According to Goldman, in the cells of
progeria patients, the aberrant gene results in defective copies of a protein that is
a precursor of the lamin A protein. The defective protein is called LA 50, or
progerin. Unlike normal lamin A, this protein is unable to carry out its normal
functions in the nucleus. In addition, progerin builds up in the nucleus from one
cell generation to the next. This abnormal accumulation causes the nucleus to
lose its structural integrity and induces a very lobulated shape (p. 8963-8964).
Goldman and others hypothesize that beyond providing structural integrity to the
nucleus, normal lamin A proteins provide a scaffolding within the nucleus that
enables normal gene expression. In a pair of studies presented at the American
Society for Cell Biology in San Francisco, Calif, in December, Goldman and
colleagues provided evidence supporting this hypothesis. The results of one
study suggested that progerin changes the organization of heterochromatic
regions of the chromosome and that over many generations of cells
heterochromatin was lost. In this study, the scientists used the inactive X
chromosome (they used only cells from female progeria patients) as a "reporter"
to track what was happening to heterochromatin in these cells. The team also
has found that the location of the defective proteins in the cell may interfere with
DNA replication during the cell cycle, which might explain the rapid accumulation
of physiological changes associated with aging (p. 8967). In a study conducted
by Vargo and colleagues, using the protein progerin, that contains a 50-aminoacid deletion within the carboxyterminal portion of the protein, suspected that
protein farnesylation might be crucial for the targeting of progerin to the nuclear
rim, and we hypothesized that blocking farnesylation with a farnesyltransferase
inhibitor (FTI) would mislocalize progerin away from the nuclear rim and reduce
the frequency of misshapen nuclei (3250).
Method
I found my participants for this research study (all 16-21 year old
individuals of mixed ethnicity) at 2 area hospitals, Johnson City Medical Center
and Welmont in Kingsport. I obtained consent (parental where needed) from the
individuals after I had my study and instruments (survey questions) reviewed by
the university IRB and completion of the CiTi training program. All conditions to
protect and adhere to the participants confidentiality based upon HIPPA
guidelines were observed as noted in the ETSU IRB webpage. The study did not
include any invasive procedures and the IRB did not perceive any psychological
manipulation or danger to study participants when they reviewed my methods
and Scales of Measurement.
To find an appropriate model, I replicated another study in my review of
the literature. The data came from National Human Genome Research Institute
to find out what factors can contribute to heart disease and stroke. HGPS is
caused by an LMNA mutation that results in the synthesis of a mutant prelamin
A, commonly called progerin, that contains a 50-amino-acid deletion within the
carboxyterminal portion of the protein. The age group of the children analyzed
was from 7-10 years. The survey followed the health history, lab results, and
symptoms from 4 years to 16 years of age. There were 3 subgroups within the
randomized sample, group 1 included children ages 4- 9 years that received
manipulation on the protein farnesylation, group 2 included children ages 10-16
years that received manipulation on the protein farnesylation, and group 3
included children ages 4-16 years that received no manipulation of the gene
(Varga, 2006). I administered a potent FTI, ABT-100 (17), in the drinking water
(39 mg/kg body weight) to both groups 1and 2 both male and female and the 3
group received no potent. There was one child selected for each mother so
there was no relation between the participants. The outcome variables included
questions such as: how many times has your child suffered from a minor stroke?
How many times have your child suffered from a minor heart attack? Following
the American Association of Pediatrics (AAP) guidelines, we dichotomized the
outcome variable as 0 versus < 1 symptom per year for children 4-9 years of age,
and 0 to 2 versus >3 symptoms per year for children 10 years or older. The
Spearman correlation between year and a lifespan of symptoms was >0.8 for
each age group and the average amount of heart failure in a lifespan was not the
same as in a typical year for all ages. The independent variable I chose to
identify is age. The analysis of the cross-sectional sample used the x2 test and
the t test to analyze the independent variables and heart disease. Any predictors
that were significantly (P<.05) correlated with heart failure in the bivariate
analyses were included in multivariate logistic regression models that examined
the odds of suffering heart disease symptoms <1 symptom for the youngest and
middle groups and the odds of suffering >3 symptoms a year over a lifespan at
age 21. The predictor of interest was heart failure or heart disease as a teen or
young adult, but models also controlled for race, gender, child age and birth
order, and multiple affected siblings (Varga, 2006). In my study I found that,
using a Likert scale response method, teens who suffered more than 1 symptom
related to heart disease or stroke, predictably, suffered from at least 3 symptoms
related to heart disease per year at the age of 21. I suspected that protein
farnesylation might be crucial for the targeting of progerin, and hypothesized that
blocking farnesylation with a farnesyltransferase inhibitor (FTI) would mislocalize
progerin in individuals and slow down or alter profound loss of vascular smooth
muscle cells (VSMC) in the medial layer of large arteries, such as the aorta and
carotid arteries contributing factors associated with the aging process, and heart
disease. Furthermore, I found that these high risk individuals that did not
undergo manipulation of the gene (blocking farnesylation) in their teens
developed heart attacks, and suffered from stoke related illnesses than
individuals affected by the mutation or manipulation of the gene, at the same
age.
Discussion
After completing my research I have been able to prove my theory that
there is an association between age and heart disease of affected individuals;
however, research has not proved that manipulation of the Lamin A protein may
cause a treatment, reverse or even deplete the progeria syndrome. Through
progression of future research we can one day come to this magnificent
discovery.
Conclusion
In this research study, I wanted to look at heart disease and stroke as the
dependent variables and I chose to identify age as the independent variable.
In my research paper I wanted to be able to relate and I did prove that there is
an association between the different ages of patients that have progeria
syndrome that suffers from heart disease and stroke. The second part that I
wanted to identify but was not able to conclude is how manipulation of a progerin
gene may lead to the treatment of this disease and furthermore would prolong
the livelihood of an affected child. I would like to one day further my studies of
this particular topic and I think that others interested in this area would like to
progress with research as it develops as well to one treating Progeria syndrome.
Reference
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