A REVIEW: PROGERIA, THE YOUNG WHO DIE OLD

Chaithanya et al. World Journal of Pharmaceutical Research

www.wjpr.net Vol 9, Issue 8, 2020.

1225

A REVIEW: PROGERIA, THE YOUNG WHO DIE OLD

Chaithanya K.J.*1, Spurthi B.S.

1 and Narayan Sah Sonar

2

14

th Year Pharm D, Dept. of Pharmacy Practice, Mallige College of Pharmacy, Bangalore,

Karnataka, India.

13

rd Year Pharm D, Dept. of Pharmacy Practice, Mallige College of Pharmacy, Bangalore,

Karnataka, India.

22

nd Year M. Pharm, Dept. of Pharmacology, Mallige College of Pharmacy, Bangalore,

Karnataka, India.

ABSTRACT

The premature ageing disorder Hutchinson - Gilford Progeria

syndrome (HGPS) is one of the orphan (rarest) human diseases The

Classic type of Progeria is HGPS. In humans hundreds of mutations in

LMNA gene have been identified which causes several diseases

termed as laminopathies. Products of LMNA gene primarily lamin A

and C are key components of the nuclear lamina, a proteinaceous mesh

work of inner nuclear membrane. Classic HGPS is caused by a de novo

point mutation in exon 11(Residue 1824 C to T) of the LMNA gene

which results in the production of mutant lamin A protein termed as

'Progerin'. In particular, progerin accumulation elicits nuclear

morphological abnormalities. HGPS is characterized by the presence of aging associated

symptoms, including loss of subcutaneous fat, alopecia, cardiovascular Pathology and death

due to myocardial infarction and stroke in childhood. Laboratory findings are unremarkable,

with the exception of an increased urinary excretion of hyaluronic acid. Without progerin -

specific treatment death occurs at an average age of 14.6 years from accelerated

atherosclerosis. Supportive therapy like vitamin supplementation, Nutrini, pro-cal are

recommended. Treatment usually includes low dose aspirin, lonafarnib, zoledronic acid,

pravastatin, gene therapy and RNA therapy.

KEYWORDS: Progeria, Hutchinson -Gilford Progeria Syndrome (HGPS), Orphan disease,

gene LMNA, Laminopathies, gene therapy.

Article Received on

12 June 2020,

Revised on 02 July 2020,

Accepted on 23 July 2020,

DOI: 10.20959/wjpr20208-18313

*Corresponding Author

Mr. Chaithanya K.J.

4th

Year Pharm D, Dept. of

Pharmacy Practice, Mallige

College of Pharmacy,

Bangalore, Karnataka, India.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.084

Volume 9, Issue 8, 1225-1241. Review Article ISSN 2277– 7105



1226

1) INTRODUCTION

Progeria is also known as Hutchinson– Gilford Progeria Syndrome it is a rare, sporadic,

monogenic, autosomal dominant, fatal childhood disease that belongs to a group of ailment

called as laminopathies which affect nuclear lamins.[1,2,3]

Progeria was first portrayed in 1886

by Jonathan Hutchinson.[1]

It was additionally depicted autonomously in 1897 by Hastings

Gilford. The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).[2]

The word progeria comes from the Greek words "pro" meaning "before", and "geras"

meaning "old age".[2]

In this disease the aging process of the body surge much more faster

than what it does in normal individuals. This process of aging gallops to about seven times

the conventional rate. Because of this accelerated aging, a child of ten years would have a

look of 70 years old.[4]

The term progeria applies strictly speaking to all diseases

characterized by premature aging symptoms, and is often used as such, and applied

specifically in reference to Hutchinson-Gilford Progeria Syndrome.[2]

It is a rare human

genetic disease linked with a subset of specific mutations within the LMNA gene, coding for

lamin A and lamin C proteins. The LMNA gene is located at position 1q22 and is not usually

inherited, although there is a uniquely inheritable form.[1,5]

LMNA encodes 4 sorts of laminar

proteins, through alternative cutting and splicing,lamin A and C are comparative up to

nucleotide position 574. Lamin A has parent prelamin A,next to post-translational processing,

and generating the mature protein.[3]

In addition to their structural roles they are implicated in

basic nuclear functions such as chromatin organisation, DNA replication, transcription, DNA

repair, and cell cycle progression.[6]

It causes aberrant mRNA splicing, which results in the

assembly of a truncated and partially processed pre-lamin A protein called “progerin”.[7]

Children with Progeria appear normal at birth while the symptoms manifests in first or

second year of life, these patients present stunted growth, muscular atrophy, and skin atrophy,

loss of subcutaneous fat, osteoporosis, arthritis, alopecia, cataracts, diabetes.[1,3]

Death

normally occurs due to complications like atherosclerosis, myocardial infarction, congestive

cardiac failure or coronary thrombosis.[1]

2) EPIDEMOLOGY

HGPS is a lethal, congenital, segemental, premature aging disorder.[7,8,9]

A disease is

considered to be rare(orphan) when it affects one person out of 2000 or less.They are about

5000 to 8000 rare disease most of them are genetic which are chronic disease and are often

fatal .Among these Hutchinson Gilford Progeria is one of the world's rarest disease.[10]

The

estimated prevalence of HGPS is 1 in 20 million people.[11]

The observed male to female ratio



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of incidence in HGPS is 1.2 :1 and there has been no report on ethnic-specific recurrence.[7]

In 2017 Progeria Research Foundation found that there are 144 cases in 45 countries, of

which 112 children have classic Hutchinson Gilford progeria, and 32 have some progeroid

laminopathy.[3]

In the past 15 years, children with Progeria turn up everywhere around the

world The disease is present in India too.[4]

Generally the disease does not pass from parents

to child as the victim dies before the age of reproduction. It is usually caused by a

replacement (sporadic) mutation during the first division of the cells within the child and

usually genetically dominant; therefore, parents who are healthy will normally not pass it on

to their children.[1]

Death occurs at an average age of 14.6 years.[11]

3) CLINICAL MANIFESTATION

No clinical features present at birth, but within one to two years they begin to display the

effect of accelerated aging means severe growth retardation is usually observed Within the

first year, patients have short stature growth, and weight is more affected than height(median

final height of 100-110cms, median final weight of 10 – 15 kg).[7,12]

Some of the typical physical characteristics of HGPS includes

Alopecia (loss of hair and eyebrows)[7]

Lower weight and loss of subcutaneous fat.[13]

Cranium which appears to be large in comparison with the face.[13]

Thin skin[3,14]

Prominent scalp veins[2,7]

Scleroderma is a transient feature[14]

Micro-ganthia(small jaw)[12]

Narrow face and beaked nose[1]

Protruding ears with absent lobes[13]

Excessive folding on forehead and cheeks[14]

Hip dislocation[4]

Body hair is completely absent[14]

Pyriform thorax.[15]



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Figure 1: Prominent scalp veins.[16]

4) PHENOTYPES

Osteolysis

There are reports of osteolysis involving the primary ribs.

All these bones are formed by membranous ossification including the center a part of the

distal phalanges.

Osteolysis of the distal phalanges usually starts between 1 and 2 years of age, but can be seen

early as the first months of life or later than 5 years.

The process starts in the index and little fingers, and gradually extends.[14]

Clavicle

The osteolysis starts at the acromial ends of the clavicles, and is merely slowly progressive.At

the early stage it may cause just mild tapering of the distal clavicle.[14]

Skin and hair

Skin changes at the time of birth could also be present. The significant deformity include

glossy and elastic skin. The skin may appear wrinkled with low cutaneous fat.[1]

The loss of subcutaneous fat produces Hypothermia.[3]

The patient is physically weak, when in touch with bright sunlight, hyper pigmentation of

skin may occur with irritation.

Complete loss of hair of all the body parts including scalp, eye lash and skin.[1]



1229

Figure 2: Child with Progeria presenting different phenotypes.[17]

5) ETIOLOGY

The only gene associated with HGPS is LMNA gene, in which point mutations are found in

90% of individuals.[13]

HGPS is related to a mutation in ZMPSTE24 that codes for a

metalloproteinase specifically involved in the post-translational proteolytic processing of

prelamin A to mature lamin A, which is responsible for scaffolding and organizing the

nuclear envelope surface.[15]

6) GENERAL MECHANISM OF LAMIN REGULATED EXPRESSION

HGPS belongs to a set of disorders called laminopathies which affect nuclear lamins and

build up a number of mutations within the gene LMNA, which are recognizised within the

major cases of HGPS. The gene LMNA encodes nuclear lamin A, with the predominant

vegetative cell isoforms lamin A and C arising by alternative RNA splicing, which underlies

and organizes the inner surface of the nuclear envelope. There are at least 11 distinct diseases

associated with >300 different mutations in LMNA.[15]

The most overt cellular defects in

HGPS are dramatic changes in nuclear morphology, a phenotype that is not surprising given

the prominent architectural role of lamin A in the nucleus. Whereas the lamin proteins in

healthy cells move dynamically between the nuclear lamina polymer at the nuclear periphery

and the nucleoplasm, they become immobilized in HGPS patient cells, leading to thickening

of the lamina.[18]

The lamins belong to the multiprotein-family of intermediate filaments, and



1230

consist of an N-terminal head domain, an alpha-helical (coiled-coil) rod domain important for

the dimerization, and a usually globular C-terminal tail domain. Lamins are located in the

nuclei at position 1q22 of multicellular eukaryocytes.[5,14]

There are two major types of lamins: the B-type lamins, indispensable for replication and

transcription and expressed in all cells (cells are not viable without Lamin B) and the A-type

lamins, expressed in all differentiated cells. LMNA encodes four A-type lamin isoforms:

Lamin A, AD10, C, and C2, generated by alternative mRNA splicing.[14]

They have many

functions: they provide nuclear envelope its mechanical strength which determine the nuclear

shape, nuclear pore complexes, and form the structure in which many other proteins anchor.

They can be regarded as the main determinants of the nuclear architecture. In addition, lamins

are essential for DNA replication and mRNA transcription and have functions in gene

regulation and many signal transduction pathways, both by themselves has direct interactions

with the DNA or a wide range of protein partners, chromatin organization and cell cycle

progression.[6,14,19,20]

Lamin A and Lamin C are the two abundant structural proteins of the nuclear lamina which

are the products of an equivalent gene, LMNA. Lamin A is twelve exon protein. Prelamin A,

the precursor of Lamin A, involves the splicing from middle of exon 10 to exon 11 then to

exon 12.[1]

Prelamin A has CAAX (where the C is a cysteine, the A residues are aliphatic

amino acids), and the X can be any amino acids.[7,12,15]

This terminal triggers farnesylation of

the carboxy terminal cysteine (the C of the CAAX tetrapeptide) by a cytosolic enzyme,

known as protein farnesyl transferase.[6,21]

The farnesylated Prelamin A attaches with the

Endoplasmic Reticulum.[1]

The farnesylation increases lipophilicity of lamin-A and increases its membrane

association.[12]

Following farnesylation, the ending three amino acids of Prelamin A are

separated by an Endoprotease.[1]

The enzymes accountable for liberation of these amino acids

are: a Zinc metalloproteinase ZMPSTE24[12]

and a prenyl protein endopeptidase RCE1.[1]

After the liberation of the terminal amino acids, farnesyl-cystein residue is methylated by an

enzyme Isoprenylcystein Carboxy Methyl Transferase (ICMT).[22]

In the final step of Prelamin A including farnesyl cysteine methyl ester are released off by

ZMPSTE24 and mature Lamin A is released from endoplasmic reticulum into cytosol. The



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emerging protein, now Lamin A is not any more membrane-bound, and carries out the

outcomes inside the nucleus.[1,12,22]

7) MUTATION IN LAMIN-A CAUSES PROGERIA

The genetic basis for HGPS was not found until it had been found to be autosomal-dominant

which are caused by a repeated, dominant, de novo heterozygous gene mutation in position

1824 of the LMNA gene, replacing cytosine with thymine. Progerin, of the prelamin A

protein whose further processing is abnormal.[2,7]

The mutation G608G of HGPS and

therefore the consequent abnormal splicing produce a prelamin A that also retains the CAAX

box, but is missing a neighbourhood for endoproteolytic cleavage.[7,15]

One mutation in the

gene LMNA that causes HGPS consists of the de novo substitution of exon 11 of LMNA

(c.1824C>T), which produces activation of a cryptic splice site.[3,23,24]

This mutation causes

aberrant splicing in exon 11 and the deletion of 50 residues close to the C terminus of lamin-

A, including the second ZMPSTE24 cleavage site.This deletion prevents complete processing

of prelamin-A, resulting in the accumulation of a farnesylated lamin A,known as

progerin.[3,15]

Progerin, unlike mature lamin-A, persist farnesylated, it gains lipophilicity with

the nuclear membrane, therefore causing an obtrusion within the integrity of the nuclear

lamina. Indeed, HGPS patient cells show variety of abnormalities in nuclear structure and

performance. Upon fluorescence microscopy labelling with antibodies directed against lamins

A/C, fibroblasts from individuals with HGPS were characterised by the presence of

dysmorphic nuclei with altered size and shape, presence of lobules, wrinkles, herniations of

the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin,

and clustering of nuclear pores.[3,7,15,22]

Small amount of progerin is extremely potent in terms

of causing disease phenotypes in humans and in causing misshaped nuclei in cultured

cells. Supporting the theory that progerin endeavour dominant negative impact HGPS.[7]



1232

Figure 3: mRNA gets transalated into protein Pre-lamin A followed by sequential post

translational events such as farnesylation , methylation and cleavage of terminal amino

acids, after farnesylation the C-terminal of the prelamin-A is cleaved and then

methylation is done at the cysteine residue takes place (A) in normal individual after

methylation an endoprotease cleavage enzyme which is known as Zmpste24 cleaves the

prelamin-A at Zmpste24 site results in the release of Mature lamin-A. (B) In HGPS

individuals the enzyme Zmpste24 cannot cleave the prelamin-A and release mature

lamin-A because the cleavge site of Zmpste24 which lies in the 50 amino acid sequence

has got deleted in the process of mutation ,as result of which farnesyl group remains

attached to the cysteine residue and hence gives mature Progerin that will accumulate

at the inner nuclear membrane and are characterized by multiple nuclear defects which

includes abnormal nuclear morphology, altered histone modification patterns and

increased DNA damage.



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8) DIAGNOSIS

To diagnose progeria, doctors observed phenotypes like symptoms such as, skin changes and

a failure to gain weight, and as well as x-rays of patients and on the basis of the excretion of

the glycosaminoglycan and urinary hyaluronic acid testing and radiography.[12]

a) Urinary hyaluronic acid test

The most frequent sign of HGPS is elevated levels of hyaluronic acid excretion in the urine of

patients with HGPS, but are not diagnostic. After performing the urinary hyaluronic test on

HGPS patient it was found that hyaluronic acid level elevated in urine and decreased level of

primary antioxidant enzymes in the blood as well as certain fatty acid compound. Due to

decreased level of antioxidant enzymes in the blood, it may cause aging which believed to be

a buildup oxidant in the blood.[3,12,15]

Hyaluronic acid is a non-sulfated glycosaminoglycan

maintaining skeletal, muscular, cutaneous, and vascular integrity and texture. These

hyaluronic acid abnormalities may account for hardened collagen, calcification of the arterial

walls, and changes in the skin which look very much like scleroderma.[3]

b) Genetic screening

On a genetic level, the screening of correlated mutations is performed by sequencing of

LMNA gene. The diagnosis for HGPS is clinically performed with the subsequent screening

of gene mutation LMNA, which uncovers point mutations in the patients with HGPS, and the

test for uniparental disomy of chromosome 1 and deletions associated with HGPS.[3,15]

Discovery of mutant lamin A gene, nowadays helpful for detection of the elevated mutant

gene, that mutant gene identify from a blood sample and skin biopsy of the patient, this gives

definite diagnosis report.[12,16]

c) Prenatal testing

Investigation of DNA extraction obtained by aminocentesis from the fetal cell of HGPS

children applied for prebirth diagnosis, mostly performed on about 15-18 weeks gestation.[12]

d) Radiological diagnosis

Radiological finding of the common LMNA truncating mutation could also be helpful in the

diagnosis. The characteristic radiological abnormalities are to be found in the skull, thoracic

cage, long bones.



1234

The cranial bones tend to be hypoplastic, fontanels and sutures remain open longer than

expected.The progressive bone loss from the distal phalanges of the fingers and toes is one

hallmarks of the disease.[12,13]

e) Laboratory studies

There is low levels of blood cholesterol are limited to low high-density lipoprotein levels.[12]

Testing can help in the clinical findings of progeria and to evaluate for the potential for

increasing atherosclerosis during early childhood.

Testing might include a HDL blood test, which can reveal a low level of high-density

lipoprotein (HDL) cholesterol, the "good" cholesterol that helps keep arteries open.[2]

9) HGPS AND NORMAL AGING

The similarities between HGPS and normal aging extend to all levels, from shared molecular

features to similarities in symptoms.

Notably, progerin is produced in normally aged individuals as well as in HGPS patients. This

is because the classical HGPS mutation is a pre-mRNA splicing mutation.[18]

Cells from healthy aged individuals also express low levels of progerin, resulting in similar

phenotypes.

For instance, the levels of γH2AX, DNA DSBs and abnormal nuclei increase with an

individual’s age. Induced DSBs in the same cells can be repaired efficiently.[23]

Preliminary studies indicate that the level of chromatin-bound XPA is much higher in older

HGPS cells. Interestingly, chromatin-bound XPA also was higher in the cells from normal

older individuals than in cells from younger individuals.

Thus, HGPS or related laminopathies are an excellent model for the study of normal human

aging.[23]

Notably, the atherosclerotic plaques in HGPS are similar to those found in aging

individuals. Additionally, vascular stiffening in progeria is much like that seen over a lifetime

of aging reflected in each population by increased pulse wave velocity.

HGPS is a primary vasculopathy, characterized by early and pervasive accelerated vascular

stiffening followed by hypertension, vessel plaques, angina, cardiomegaly, metabolic



1235

syndrome, and congestive heart failure. Isolated from risk factors such as

hypercholesterolemia and increased C-reactive protein.[18]

10) TREATMENT

Presently, HGPS has no cure, and there has been no success in finding a specific treatment.

However, some options exist that attempt to increase the quality of life in patients.[3]

a) Farnesyl transferase Inhibtors – Lonafarnib

As progerin is permanently farnesylated, researchers initially turned to farnesyltransferase

inhibitors (FTIs) within the look for a pathogenic treatment.

The medication will also get involved in the farnesylation of lamin B1 and B2, perhaps

causing more deface to the nuclear lamina. Finally, there was a concern that prelamin-A

might be geranylgeranylated in the presence of FTI.[7]

The farnesyl group is synthesized through the cholesterol biosynthetic pathway, and

medicines like statins and bisphosphonates are known to scale back its production.

Lonafarnib will be taken orally, twice per day. Every patient will start Lonafarnib therapy at a

dose of 115mg/kg and was escalated to 150mg/kg. FTI treatment caused defects in

centrosome separation leading to donut-shaped nuclei.[4,7,20,22]

b) Statins and Bisphosphonates

Statins and aminobisphosphonates, both inhibit protein prenylation than FTIs and alter

cholesterol biosynthetic pathway.[7]

Pravastatin is traded as Pravachol or Selektine and it is included in the family of statins. As

well as zelodronate (also mentioned as Zometa and Reclast, which is a bisphosphonate), its

utility in Hutchinson-Gilford Progeria Syndrome (HGPS) is that the prevention of farnesyl

groups formation, which leads to cause of disease.[2]

Zoledronic acid is a bisphosphonate, used to reduce osteoporosis.[1,22]

c) Rapamycin

The effect of rapamycin is inhibition of mammalian target of rapamycin (mTOR) pathway by

rapamycin.[7]



1236

Rapamycin, caused removal of progerin from the nuclear membrane through autophagy.[2]

Rapamycin, also referred to as Sirolimus, may be a macrolide.

There are recent studies concerning rapamycin which conclude that it can minimize the

phenotypic effects of progeria fibroblasts.[2,4,7]

d) RNA therapy

Because the HGPS mutation results from the activation of an alternative pre-mRNA splice

site, HGPS may be a prime candidate for an RNA therapy approach via inhibition of this

site.[18]

They used antisense morpholino oligonucleotides specifically directed against the aberrant

exon 11 and exon 12 junction contained in mutated pre-mRNAs to focus the splicing defect

observed in HGPS, and consequently decrease the production of progerin.[7]

This strategy was effectively tested to a knockin HGPS mouse model resulting in improved

body weight, increased life expectancy and rectifying mutant phenotypes and an additional

approach is to get rid of progerin mRNA using siRNA based methods.[18]

e) Gene therapy

As the progerin protein acts in a dominant fashion and its effects cannot be compensated by

introduction of wild-type lamin A, gene therapy for HGPS focuses on targeted gene

correction.

For example, zinc-finger, TALEN, or CRISPR-based approaches, in which the LMNA is

repaired ex vivo and corrected cells are re-introduced into patients, is a possibility, albeit a

technically challenging one.[18,22]

As proof of principle for the possibility of this perspective,rectifying of the genetic defect in

HGPS patient derived iPS cells and their following differentiation has been accomplished.[18]

f) Stem cell treatment

In vitro, progerin affects the multipotency and differentiation of human mesenchymal stem

cells and HGPS patient-derived iPS cells exhibit differentiation defects.[18]



1237

Figure 4: Drugs that involve in inhibiting the production of farnesyl group, act on the

biosynthetic pathway of cholesterol (statins and bisphosphonates). Farnesyl tranferase

inhibitors(FTI’s) mainly inhibit the enzyme farnesyl transferase and prevent the

farnesylation reaction on Prelamin-A.

11) SUPPORTIVE THERAPY

Treatment is aimed at controlling the devastating effects caused by premature aging.

Prescribed formulas of antioxidants, vitamins, lipoic acid, and coenzyme-Q are used to

increase antioxidant levels. Low antioxidant levels are common in persons with progeria and

cause cellular destruction.[2]

1) Aspirin: Aspirin is now accepted as a crucial weapon in the prevention of heart condition.

Recent clinical trials have shown that aspirin reduces the danger of transient ischemic attacks

(TIA) strokes and heart attacks by inhibiting platelet aggregation.



1238

Dosage is fixed based on patient weight, and should be given 2-3mg/kg once daily or

alternate day. This is of benefit to people with narrowed coronary arteries which is common

place in children with Progeria.[1,4,12,25]

2) Hydrotherapy: Hydrotherapy results in relaxation, pain reduction and assists mobility. It

also can help prevent arthritis from getting worse.[1,4,25]

3) Vitamin E: Vitamin E is a fat-soluble vitamin that protects Vitamin A and essential

fattyacids from oxidation in the body cells and prevents breakdown of body tissues.[4]

Antioxidants such as Vitamin E act to ensure the cells against the harmful effects of

free radicals.[1,4]

Free radicals will damage the cells and eventually leading to cardiovascular

disease.[1,4,25]

4) Fluoride: All Progeria children have problems with their teeth, under development of the

facial bones and the lower jaw leads to delayed eruption of the teeth, they can be small,

irregularly formed or even missing and tooth decay is common. Fluoride can greatly help

dental health by strengthening the tooth enamel, making it more resistant to tooth decay.[1,4,25]

5) Nutrini: Patients have a very small appetite and don’t really enjoy eating. Nutrini provides

all the nutrients essential for well-being[1,4,25]

and it is a sole source of which contain source

Sodium caseinate

Maltodextrin

Beta-carotene

Vegetable oils (rapeseed oil,sunflower oil) Fish oil,

Cyanocobalamin

Phytomenadione

D-biotin

Calcium D-pantpthenate

Ferrous lactate

Sodium chloride

Potassium chloride and calcium hydroxide.

(https://www.nutriciahcp.com/uploadedFiles/Main/Sub_sites/ONS_Site/ons/shop/Datacard_0

7022019_Nutrini(2).pdf



1239

6) Pro-Cal

Pro-Cal may be a new generation protein and calorie food which will be added to a good sort

of food and drink to complement the energy and protein content of the normal diet with the

minimum effect on taste, volume and texture.[1,4,25]

CONCLUSION

Since HGPS is a rare disease and affects only a small percentage of the population around the

world, the support and resources for the invention of newer sites of disease pathology and

treatment options are less. Progress in the HGPS field is increasing over the past decade

cardiovascular failure, myocardial infarction, stroke are the remarkable causes of death ,

notebly these dysfunctions in cardiovascular system are similar to those found in aging

persons, this aspects of it has gained a lot of attention to study the normal aging process.

Therapies like Gene therapy, RNA therapy and stem cell therapy are quiet promising in the

future times.

Source of funding: None.

Conflict of interest: None.

REFERENCES

1. Rakha P, Gupta A, Dhingra G, Nagpal M. Hutchinson-Gilford progeria syndrome: a

review. Der Pharmacia Sinica, 2011; 2(1): 110-7.

2. Neelam S, Krishna M, Semwal BC, Shravan P, Kuldeep S, Deepak S. Progeria: A

Review. Int J Pharm Sci Rev Res., 2012; 14(1): 4449.

3. Camacho-Cruz J, Dary Gutiérrez-Castañeda L, Pulido D, Echeverri C, Bernal B, Bautista

L, et al. Hutchinson-Gilford Progeria Syndrome. Int J Pediatric, 2019; 7(10): 10283-9.

4. Kumar P. An Overview: Projeria. Pharmacologyonline, 2011; 3: 176-84.

5. Piekarowicz K, Machowska M, Dzianisava V, Rzepecki R. Hutchinson-Gilford progeria

syndrome current status and prospects for gene therapy treatment. Cells, 2019; 8(2): 88.

6. Prokocimer M, Barkan R, Gruenbaum Y. Hutchinson–Gilford progeria syndrome through

the lens of transcription. Aging Cell., 2013; 12(4): 533-43.

7. Baek JH, McKenna T, Eriksson M. Hutchinson-gilford progeria syndrome. Genetic

Disorders, 2013; 1: 65-87.



1240

8. Gerhard-Herman M, Smoot LB, Wake N, Kieran MW, Kleinman ME, Miller DT, et al.

Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria

syndrome. Hypertension, 2012; 59(1): 92-7.

9. Rodriguez S, Coppedè F, Sagelius H, Eriksson M. Increased expression of the

Hutchinson–Gilford progeria syndrome truncated lamin A transcript during cell aging.

Eur J Hum Genet, 2009; 17(7): 928-37.

10. De Vrueh R, Baekelandt ER, De Haan JM. Background paper 6.19 rare diseases. World

Health Organization, Geneva, 2013 Mar 12.

11. Hamczyk MR, Villa‐Bellosta R, Quesada V, Gonzalo P, Vidak S, Nevado RM, et al.

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular

smooth muscle cells. EMBO Mol Med., 2019; 11(4): 9736.

12. Devi S, Singh K. Risk factors, prevalence and diagnosis of hutchison gilford syndrome

with special reference to case reports. Int J Pharm Pharm Sci., 2003; 9: 1-5.

13. Faivre L, Cormier-Daire V. Progeria. Orphanet encyclopedia, 2005.

14. Hennekam RC. Hutchinson–Gilford progeria syndrome: review of the phenotype. Am Jo

Med Genet Part A., 2006; 140(23): 2603-24.

15. Coutinho HD, Falcão-Silva VS, Gonçalves GF, da Nóbrega RB. Molecular ageing in

progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model. Immun Ageing,

2009; 6(1): 1-7.

16. Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford progeria syndrome.

InGeneReviews®[Internet] 2019 . University of Washington, Seattle.

17. Devi AS, Thokchom S, Devi AM. Children Living with Progeria. Nurse Care Open

Acces J, 2017; 3(4): 77.

18. Gordon LB, Rothman FG, Lopez-Otin C, Misteli T. Progeria: a paradigm for translational

medicine. Cell, 2014; 156(3): 400-7.

19. Datta S, Snow CJ, Paschal BM. A pathway linking oxidative stress and the Ran GTPase

system in progeria. Molecular Bio Cell, 2014; 25(8): 1202-15.

20. Gordon LB, Kleinman ME, Massaro J, D’Agostino Sr RB, Shappell H, Gerhard-Herman

M, et al. Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and

zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation,

2016; 134(2): 114-25.

21. Cao K, Capell BC, Erdos MR, Djabali K, Collins FS. A lamin A protein isoform

overexpressed in Hutchinson–Gilford progeria syndrome interferes with mitosis in

progeria and normal cells. Proc Natl Acad Sci., 2007; 104(12): 4949-54.



1241

22. Gonzalo S, Kreienkamp R, Askjaer P. Hutchinson-Gilford Progeria Syndrome: A

premature aging disease caused by LMNA gene mutations. Ageing Res Rev., 2017; 33:

18-29.

23. Musich PR, Zou Y. DNA-damage accumulation and replicative arrest in Hutchinson–

Gilford progeria syndrome. Biochem Soc Trans, 2011; 39(6): 1764-69.

24. Villa-Bellosta R. New treatments for progeria. Aging, Dec 31, 2019; 11(24): 11801.

25. Kumar BP, Chaturvedi DL, Prasad US, Rajasekhar A, Rama DR. Progeria or Hutchinson-

Gilford Progeria Syndrome (HGPS): A Review. World J Pharma Res., 2019; 8(13):

1226-41. DOI: 10.20959/wjpr201913-16309

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A REVIEW: PROGERIA, THE YOUNG WHO DIE OLD