Progeria: A
rare Genetic Disorder
Sayed
Saziya F., Khan Afreen, Bushra Fatema, Choudary Sumaiya
J.I.I.U’S Ali-Allana College of Pharmacy Akkalkuwa, Dist-
Nandurbar (425415) Maharashtra, India.
*Correspondence: s.saziya003@gmail.com;
INTRODUCTION
Progeria, or Hutchinson-Gilford
progeria syndrome (HGPS), 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; 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. Individuals with HGPS
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 14.5 years. As with any person
suffering from heart disease, children with progeria can experience high blood
pressure, strokes, angina (chest pain due to poor blood flow to the heart
itself), enlarged heart, and heart failure, all conditions associated with aging.[5]
SIGNS
& SYMPTOMS
Newborns with HGPS may have certain suspicious findings
present at birth, such as unusually taut, shiny, hardened (i.e.,
“scleroderma-like”) skin over the buttocks, upper legs, and lower abdomen;
bluish discoloration of the skin and mucous membranes within the mid-portion of
the face (midfacial cyanosis); and/or a “sculptured” nose and areas of the
dorsal trunk where small ( 1 to 2 cm ) soft bulging skin is present. Profound,
progressive growth delay usually becomes evident by approximately 24 months of
age, resulting in short stature and weight that remains extremely low for height.
Affected children who are 10 years of age typically have a height approximating
that of an average three-year-old child.[5]
During childhood or adolescence,
progressive arteriosclerosis may lead to episodes of chest pain due to
deficient oxygen supply to heart muscle (anginal attacks); obstructed blood
flow within blood vessels of the brain (cerebrovascular occlusion); progressive
inability of the heart to effectively pump blood to the lungs and the rest of
the body (heart failure);and/or localized loss of heart muscle caused by
interruption of its blood supply (myocardial infarction or heart attack).
Progressive arteriosclerosis and associated cardiovascular abnormalities may
result in potentially life-threatening complications during childhood, adolescence,
or young adulthood. Transient ischemic attacks and strokes may ensue as early
as 4 years of age, but more often they occur in the later years. Death results
from sequelae of wide spread arteriosclerosis between the ages of 8 and 21
years almost exclusively from myocardial infraction or strokes. [5]
Eye:
Most patients with Progeria have ocular surface disease secondary to exposure
keratopathy. They can present with photophobia, discomfort, and decreased
vision.Patients with Progeria have also reported significant relief using
umbilical cord serum eyedrops; however, these are not commercially available in
many countries, including the United States. Patients with Progeria have not
been found to develop glaucoma, cataracts, or retinal degenerations that are
typically associated with normal aging. [4]
Fig 01: Lack of eyebrow
hair, Fig 02: Inferior corneal scarring Fig 03:
Aggressive pterygium
from exposure keratopathy
involving the visual axis.
Ear: In the typical
ear, the pinna and lateral 1/3 of the ear canal are comprised of cartilage that
is compliant, and subcutaneous fat allows the transducers (earphones) used in
behavioral and electrophysiological tests of hearing to fit snugly and
comfortably in the ear. The status of the external ear in children with
Progeria poses a special difficulty in conducting hearing assessment, as the
ear canals in children with Progeria are characterized by loss of compliance of
the cartilage and loss of skin flexibility. [4]
Figure 4 : the
right and left ears of children with progeria
Teeth: Delayed eruption of baby teeth is extremely common
in Progeria. Secondary teeth may eventually erupt behind primary teeth, but
some may never erupt. Dental risks includes Crowding of the teeth,Delayed
eruption and/or failure of eruption of baby and adult teeth,Insufficient space
for permanent teeth ,Gum disease ,High rate of cavities Small, underdeveloped
jaws, Attrition (wear) of the primary teeth. [4]
Causes:
HGPS is caused by a single-letter misspelling in a gene on
chromosome 1 that codes for lamin A, a protein that is a key component of the
membrane surrounding the cell’s nucleus. The abnormal lamin A protein produced
in HGPS is called progerin . HGPS is not usually
passed down in families. The gene change is almost always a chance occurrence
that is extremely rare. For parents who have never had a child with progeria,
the chance of having a child with progeria is 1 in 4 – 8 million. [5]
The specific
underlying cause of the accelerated aging associated with HGPS is not yet
known. Many researchers suggest that the abnormal aging process is due to
cumulative cellular damage resulting from ongoing chemical (metabolic)
processes within bodily cells. According to this theory, certain compounds
called free radicals are produced during chemical reactions in the body. The
increasing accumulation of free radicals within bodily tissues is thought to
eventually cause damage to cells and impair functioning of cells, ultimately
resulting in aging. [3]
Some
researchers suspect that reduced activity of certain enzymes may play a role in
causing accelerated aging in individuals with HGPS. In one study, skin cells
(fibroblasts) obtained from individuals with progeria were compared with skin
cells from individuals without the disease. In the fibroblasts of people with
progeria, the activity levels of certain primary antioxidant enzymes (e.g.,
gluthathione peroxidase [GPx], catalase [CAT]) were significantly lower than
the levels present in healthy fibroblasts. Further research is necessary to
determine the implications of these findings [5]
Diagnosis:
HGPS is
usually diagnosed during the second year of life or later, when progeroid
features begin to be noticeable. The diagnosis is based upon a thorough clinical
evaluation, characteristic physical findings, a careful patient history and
diagnostic genetic testing which is available through the Progeria Research
Foundation.[5]
Specialized
imaging tests may be conducted to confirm or characterize certain skeletal abnormalities
potentially associated with the disorder, such as degenerative changes
(osteolysis) of certain bones of the fingers (terminal phalanges) and/or the
hip socket (acetabulum). [5]
Pathophysiology:
HGPS is a
sporadic, autosomal dominant disorder caused almost entirely by de novo point
mutations of the LMNA gene in codon 608 of exon 11 on chromosome 1. The LMNA
gene enciphers three components of the nuclear laminae, which are proteins
called lamin A (LA), lamin C (LC), and lamin 10, a molecular interface within
the inner nuclear membrane. [1]
Clinical Trials:
2.
JUNE 7, 2004: Accumulation of mutant lamin A causes
progressive changes in nuclear architecture in Hutchinson–Gilford progeria
syndrome
3.
AUGUST 29, 2005: Inhibiting farnesylation of progerin
prevents the characteristic nuclear blebbing of
Hutchinson-Gilford progeria syndrome
4.
FEBRUARY 21, 2006: Progressive vascular smooth muscle
cell defects in a mouse model of
Hutchinson–Gilford progeria syndrome
5.
MARCH 20, 2007: A lamin A protein isoform
overexpressed in Hutchinson–Gilford progeria syndrome interferes with mitosis
in progeria and normal cells
6. OCTOBER 14, 2008: A
farnesyltransferase inhibitor prevents both the onset and late progression of
cardiovascular disease in a progeria mouse model
7. NOVEMBER 10, 2009: A perinuclear actin cap regulates nuclear shape
8. MARCH 7, 2011: Protein
farnesylation inhibitors cause donut-shaped cell nuclei attributable to a
centrosome separation defect
9. SEPTEMBER 24, 2012: Clinical trial of a
farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria
syndrome
10. MAY 13, 2020:Evaluation of
musculoskeletal phenotype of the G608G progeria mouse model with lonafarnib,
pravastatin, and zoledronic acid as treatment groups
Progeria Research Foundation: In the
summer of 1998, Dr. Leslie Gordon and Dr. Scott Berns found out that their son
Sam, who was then 22 months old, had been diagnosed with Hutchinson-Gilford
Progeria Syndrome (“Progeria”), commonly referred to as a “rapid-aging”
syndrome. It quickly became apparent to Sam’s parents that there was an
enormous lack of medical information and resources dedicated to Progeria. They
recognized that there was no place for these children to go for medical help,
no place for parents or doctors to turn for information, and no source of
funding for researchers who wanted to do Progeria research. The lack of
information available to families, combined with the lack of research and
research-funding opportunities inspired Sam’s family, together with their friends
and colleagues, to launch The Progeria Research Foundation, Inc. (“PRF”), the
only non-profit organization in the world dedicated to Progeria research. Sam
passed away on Jan 10, 2014, leaving a legacy of inspiration that now drives
PRF and its supporters to continue the quest for a cure, with tremendous
determination, passion and most of all love. [9]
Affected
populations/Statics
HGPS is a rare disorder that appears to affect males and
females equally, and all races equally. The disorder was originally described
in the medical literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). The
prevalence of HGPS is approximately 1 in 20 million, so at any given time,
there are approximately 400 children living with progeria worldwide. Two sets
of affected identical twins have been reported in the literature. As of
December 2020, the Progeria Research Foundation International Progeria Registry
has identified a total of 131 children and young adults living with progeria
worldwide including 20 living in the US.[9]
ACKNOWLEDGEMENT
We would like to express our heartfelt gratitude
to the Principal and management of JIIU’s Ali Allana College of Pharmacy,
Akkalkuwa for moral support and providing necessary facility during this work.
REFERENCES:
1. Gordon, LB. The Premature Aging Syndrome Hutchinson-Gilford
Progeria : Insights into
Normal Aging in: Brocklehurst’s Textbook of Geriatric Medicine and Gerontology,
Seventh Edition. 2010: page no:66-72.
2. What Is Progeria a.k.a. Hutchinson-Gilford Progeria Syndrome (HGPS)? Dr. Hakim. K. Saboowala. 1 May 2016. Page
no :09-20.
3. Hutchinson-Gilford Progeria Syndrome Frequently Asked Questions.
Progeria Research Foundation. Updated October 2020. Available at https://www.progeriaresearch.org/progeria-101faq/ Accessed December 23, 2020.
4. English-Progeria-Handbook-Edition-2.pdf.
Updated March 2019. Available at https://www.progeriaresearch.org/patient-care-and-handbook/
5.
Hutchinson-Gilford Progeria
Syndrome. NORD Org. Updated 4th January, 2021. Available at https://rarediseases.org/
6. Leslie
B. Gordon, Monica
E. Kleinman, David
T. Miller and Mark
W. Kieran. Clinical
trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford
progeria syndrome. Updated September 24, 2012 . Available at https://doi.org/10.1073/pnas.1202529109
7. https://www.pnas.org/