Download A Review on Hutchinson-gilford Syndrome “PROGERIA”

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International Journal of Pharmagenesis
2(1), January-June 2011, pp. 115-120
A Review on
Hutchinson-gilford Syndrome
“PROGERIA”
Kinja K. and Gupta N.
NIMS Institute of Pharmacy, Shobha Nagar, Jaipur-303121, Rajasthan, India
Abstract: Progeria (also known as “Hutchinson-Gilford Progeria Syndrome “) is an extremely rare genetic condition
wherein symptoms resembling aspects of aging are manifested at an early age. Progeria is a rare condition that
is remarkable because its symptoms strongly resemble normal human aging, but occur in young children. It is
never transmitted from parent to child since the individuals with Progeria do not live long enough to reproduce.
Currently, there are about 50 known cases of HGPS in the world and most Progeria patients die at around 13
years of age. HGPS is caused by a mutation in the Lamin A gene (LMNA) that results in the synthesis of a
mutant prelamin A (also called progerin). Progerin undergoes farnesylation but cannot be further processed to
mature lamin A, a key structural component of the cell nucleus. In HGPS cells, progerin accumulates at the rim
of the nucleus, causing misshapen nuclei. There is no cure for Progeria but we can treat some of the symptoms.
Key Words: Premature aging, Progeria of childhood, Progerin.
Introduction
Progeria is also known as Hutchinson-Gilford
Progeria Syndrome, Werner Syndrome (adult
form), Cockayne Syndrome, and RothmundThomson Syndrome. The name stems from the
Latin and Greek words of pro and geriaos which
mean, in the simplest terms, ‘prematurely old’.
Progeria occurs in two forms; Hutchinson Gilford syndrome and Werner Syndrome. It was
first described by DR. Jonathan Hutchinson in
1886 and Dr. Hastings Gilford in 1904
(Hutchinson-Gilford) and by Otto Werner in 1904
(Werner)[1,2].
Progeria is an extremely rare genetic disease
that accelerates the aging process to
approximately 7 times the normal rate. Children
with this disease will experience similar
conditions, respiratory, cardiovascular, and
arthritic, that a 70 year old person would[3].
Corresponding Author: Kuldeep Kinja
E-mail: [email protected]
Children with progeria look normal during
their first years of life, but soon symptoms begin
to appear. By the age of 1 or 2, their hair turns
lighter in colour, and eventually begins to fall out.
By 3 or 4, they are almost completely bald, thin
skinned, wrinkled and spotted in various parts
of their body, with a stooped appearance and
large veiny heads, a pinched nose, delayed tooth
formation, stiffness of joints, hip dislocations,
cardiovascular problems, arteriosclerosis,
wrinkled/aged-looking skin, dwarfism [4]. The
children develop early arteriosclerosis, high blood
pressure heart disease, and stroke. They do not,
however, typically show other characteristics of
aging such as Alzheimer’s disease, and arthritis
of the hips unless caused by prior hip dislocations.
They very rarely reach a height of 107cm or a
weight of 18 kg. People with progeria seldom
make it to the approximate age of 30, and for most
the lifespan is the early teens. They all bear a
remarkable resemblance to each other. They both
look alike and are affected by very similar
symptoms. Although their physical appearance
116
is beyond their years their mental development
and intelligence is at the normal place for their
actual age[5,6].
History of Progeria
Dr. Jonathan Hutchinson recorded the first
Progeria case in 1886 and in 1904; Dr. Hastings
Gilford recorded another case. Progeria is a rare
genetic condition that affects one in eight million
new-borns worldwide. It can occur without any
cause and can be seen in a family with no history
of progeria. In very rare cases, more than one child
from the same family can be affected by the
disease.
In the nearly 120 years since it was first
identified, more than 130 cases have been
reported in the scientific literature., 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 new-borns. Both boys and girls run
an equal risk of having Progeria.
Progeria appears to affect children of all races
equally. Over the last 15 years the following
countries have had reported cases - Algeria,
Argentina, Australia, Austria, Canada, China,
Cuba, England, France, Germany, Israel, Italy,
Mexico, the Netherlands, Poland, Puerto Rico,
South Africa, South America, South Korea,
Switzerland, Turkey, the US, Venezuela, Vietnam
and Yugoslavia.
It is estimated that 97% of all children with
Progeria are Caucasian and males outnumber
females by a 1.5:1 ratio. Sadly, death can occur
between the ages of 7-28, but the average age is
13.4 years. It is estimated that 80% of Progeria
deaths are caused by congestive heart failure or
heart attacks.
While the average life expectancy of a child
with Progeria is less than 14 years, it is believed
that the oldest case ever recorded 26 years of age.
Not true. The oldest case ever recorded was a
Japanese man who lived with the disease for 45
years. In this particular case, the child did not
show signs of growth retardation until around 12
years of age. It was noted, however, that his head
was larger than normal at the age of one and he
did experience hair loss in childhood, but enjoyed
International Journal of Pharmagenesis, 2(1) 2011
a rather normal life for 12 years. By age 20, this
particular subject had total Alopecia and aging
began to accelerate. The subject died at the age of
45 from myocardial infarction.
Progeria Syndromes
Following are 2 types of progeria syndromes[7]Hutchinson-Gilford Progeria
•
•
•
Nearly 1 out of 8 million children suffer
from this syndrome.
The child with this syndrome appears
normal at birth, but the symptom begins
to appear at the age of 6 to 12 months.
The baby fails to gain weight and also
there are changes in skin.
Characteristics of Hutchinson-Gilford syndrome
•
•
•
•
•
•
Face and Head – Prominent eyes and scalp
veins, baldness, delayed tooth formation,
small jaw.
Bones – short stature, hip dislocations,
joint stiffness, thin limbs and prominent
joints.
Artery and heart disease.
About 97% affected children are
Caucasian.
All children who have this syndrome
share a similar appearance, whether they
are of same race or ethnic background.
Children with this syndrome generally
survive to an age of 13 years and most of
them succumbing to heart diseases.
Werner Syndrome
•
This syndrome is the most common type
of progeria.
• It occurs in about 1 person out of 1 million
people.
• When a child in adolescence fails to have
a normal growth is the identification of
Werner syndrome.
• Hence, the result is the young person
looks elderly.
Characteristic of Werner Syndrome are –
•
There is a remarkable difference in a
person’s real age and appearance.
A Review on Hutchinson-Gilford Syndrome “PROGERIA”
•
•
•
•
•
Face and head – Face wrinkling, balding
and greying of hair, cataracts, small jaw
and sunken cheek, and voice of high pitch.
Bones – small stature, osteoporosis,
weakness.
Cancer and diabetes are common in this
syndrome.
Werner syndrome mostly occurs in
Sardinian and Japanese people.
People with the syndrome mostly survive
to an age of 46, mostly succumbing to
cancer and heart diseases
Cause of Progeria
Due to the extreme rarity of progeria and the little
research done on it. Scientific research has also
shown that the chemical hyaluronic acid is found
in elevated levels in the urine of both HutchinsonGilford and Werner patients. Another theory
suggests that it is caused by a genetic defect in
the repair of DNA, which with a single change to
only one copy of a gene could be the cause.
According to the Progeria Research
Foundation “a group of leading scientists from
The Progeria Research Foundation’s Genetics
Consortium was able to isolate the Progeria gene
in October 2002, and in April 2003, PRF led the
announcement that Progeria is caused by a
mutation of the gene LMNA, or Lamin A.”
90% of children with Progeria have a mutation
on the gene that encodes Lamin A, a protein that
holds the nucleus of the cell together. It is caused
by a point mutation in position 1824 of the LMNA
gene, 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. 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.
Progeria appears to occur 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[8,9,10].
Symptoms of Progeria
Normal growth of a child slows down
considerably in the initial year, though there is
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normal motor development. The child looks old
with narrowed face, conspicuous scalp veins and
pinched nose. There is high risk of delayed tooth
formation. Generally, the limbs shows fragility
accompanied with joint stiffness.
Listed below are some progeria symptoms:
•
•
•
•
•
•
•
•
•
•
Premature and Rapid Aging
Mental retardation
Balding
Beaked nose
Thin skin
Extreme growth delay begins at 9 months
to 2 years of age
Atherosclerosis
Dwarfism
Dental abnormalities
Hip dislocation
Other symptoms include acro-osteolysis with
its components of hypo plastic facial bones and
sinuses, open cranial structures and fontanelles,
Wormian bones, and coxa valga. They are
extremely short due to the growth failure, have
acrocephaly, micrographic, dry scaly, thin skin,
atrophy of muscles and a limited range of motion.
One may want to seek immediate medical advice
after noticing slow growth, hair loss and skin
change in a child.
Diagnosis of Progeria
Due to a lack of specific laboratory tests at this
current time, a diagnosis of progeria must be
made on the physical appearance of the child.
Diagnosis are usually made in the 1st or 2nd year
of the child life when the characteristic skin
changes and weight gain failure become
apparent. Some of the things that are looked for
upon thought of diagnosis are:
1. Skin changes similar to that seen in
scleroderma (the connective tissue
becomes tough and hardened)
2. Insulin resistant diabetes (diabetes that
does not respond readily to insulin
injections)
3. There may be early atherosclerosis of
blood vessels leading to abnormal stress
tests of the heart.
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At present there are no specific tests that could
be performed to diagnose this condition. There
is only the physical examination diagnosis made
based on the symptoms and signs that are
observed during the examination.
Along with the diagnosis comes the
prognosis, and unfortunately that is associated
with an extremely short lifespan. This is usually
caused by complications with the heart, stroke,
and myocardial infarction.
International Journal of Pharmagenesis, 2(1) 2011
relaxes muscle fibers in blood vessels causing
them to expand or dilate. This permits proper
blood flow to affected areas, which enables cells
and tissues to receive adequate amounts of the
oxygen necessary for cell maintenance.
Experimental Research Management
Recent evidence suggested the benefit of giving
nutritional therapy and growth hormone
supplementation. The combination treatment of
nutritional therapy and growth hormone
supplementation demonstrated an increase in
growth of Progeria patients, an increase in growth
factors (chemicals which promote formation)
within the blood, and a decrease in the patient’s
basal metabolic rate. Basal metabolic rate is the
minimum amount of energy (calories) that an
individual needs to ingest on a daily basis in order
to execute normal activities and tasks[13].
Growth Hormone Treatment has been
Attempted
In HGPS patients, the cell nucleus has
dramatically aberrant morphology (bottom right)
rather than the uniform shape typically found in
healthy individuals (top right)[11,12].
Is Progeria Hereditary?
Experts do not believe that Progeria is hereditary.
They say it is due to a rare gene change which
happens purely by chance. A non-twin sibling
runs the same risk of having Progeria as any other
child from another family. In about 1 in every 100
cases of HGPS the syndrome is passed down to
the next generation within the same family.
Treatment and Management
There is presently no treatment for progeria.
Support groups are available for the families of
children with progeria. Treatment is symptomatic
and aimed at providing psychological support.
Palliative measures such as wearing a wig may
be beneficial. Relief from chest pain due to
changes in arteries can be accomplished by
nitroglycerin. Nitroglycerin is a medication that
A type of anticancer drug, the farnesyl transferase
inhibitors (FTIs), 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. Farnesyl transferase inhibitors
(FTIs), currently used for treating cancer might
reverse the nuclear structure abnormalities that
are believed to cause Progeria. Studies carried out
on mice with Progeria-like signs and symptoms
showed that FTIs appeared to offer some
improvements. Of the 13 mice treated with
FTI, only one died during the 20-week UCLS
study.[14, 15]
Outlook (Prognosis)
Progeria is associated with a short lifespan. The
average patient survives to the early teens.
However, some patients can live up to 30 years.
The cause of death is usually related to the heart
or a stroke as a result of the progressive
atherosclerosis. 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 “wear and
A Review on Hutchinson-Gilford Syndrome “PROGERIA”
tear” conditions commonly associated with aging,
like cataracts and osteoarthritis years.
Possible Complications[16]
•
•
•
Heart attack (myocardial infarction)
Stroke
Coronary artery blockage
Progeria in India
The disease which infects one in four lakh people
is present in India too. Bisul khan and Razia
Khatooon,’s family in Chhapra, Bihar; has seven
children, of which five are Progeria patients.
Out of the five, three daughters, Guriya,
Rehana and Rubina are dead; having passed away
at the ages of 17, 24 and 13 respectively. Two sons
Ikramul (23) and Ali Hosain (22) are still alive,
but their medical ages are 70 and 66. Two children
Sanjita (21 year old) and Gulab Shah (7 year old)
are normal. . Bisul Khan’s family in India is the
ONLY FAMILY in the world that has more than
one case of progeria.
Conclusion
While there is no treatment for progeria, according
to the Progeria Research Foundation, there are
steps parents and doctors can take to improve a
child’s quality of life. For example, children with
progeria often have poor appetites, and certain
nutritional supplements, such as Pediasure and
Boost, can help them get the nutrition and calories
they need. This, in turn, can improve their mood,
energy levels and skin and hair health.
Likewise, physical or occupational therapy
two to three times a week can help children stay
active. Additionally, daily low-dose aspirin
therapy may be recommended to prevent heart
disease, as it is in at-risk adults.
119
References
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[3] James, William; Berger, Timothy; Elston, Dirk.
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Parents and children with progeria are
hopeful that the future will bring therapies that
treat the underlying genetic abnormalities.
[12] Merideth M. A., Gordon L. B., Clauss S., et al.
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604.
As for the prevention of heart disease in
children with progeria, the next step in research
will be to understand the relationship between
the lamin A protein and HDL cholesterol levels.
Such research, she believes, could have “huge
implications for everybody.”
[13] Varela I., Pereira S., Ugalde A. P., et al. “Combined
Treatment with Statins and Aminobisphosphonates
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[14] Sadeghi-Nejad A., Demmer L. “Growth Hormone
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20 (5): 633–7.
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International Journal of Pharmagenesis, 2(1) 2011
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