Progeria is an extremely rare genetic condition wherein symptoms resembling aspects of
agingSenescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
are manifested at an early age. The word
progeria comes from the Greek words "pro" (πρό), meaning "before", and "géras" (γῆρας), meaning "old age". The disorder has very low incidences and occurs in an estimated 1 per 8 million live births. Those born with progeria typically live to their mid teens and early twenties. It is a
genetic conditionA genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that occurs as a new mutation (de novo), and is rarely inherited. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson-Gilford Progeria Syndrome.
Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging. Progeria was first described in 1886 by
Jonathan HutchinsonSir Jonathan Hutchinson , was an English surgeon, ophthalmologist, dermatologist, venereologist and pathologist.-Life:He was born in Selby, Yorkshire, England of Quaker parents and educated in the local school...
. It was also described independently in 1897 by Hastings Gilford. The condition was later named
Hutchinson-Gilford Progeria Syndrome (
HGPS).
Signs and symptoms
Children with progeria usually develop the first symptoms during infancy. The earliest symptoms include
failure to thriveFailure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
and a localized
sclerodermaSystemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
-like skin condition. As a child ages past infancy, additional conditions usually become apparent around 18–24 months. Limited growth, full-body
alopeciaAlopecia means loss of hair from the head or body. Alopecia can mean baldness, a term generally reserved for pattern alopecia or androgenic alopecia. Compulsive pulling of hair can also produce hair loss. Hairstyling routines such as tight ponytails or braids may induce Traction alopecia. Both...
, and a distinctive appearance (small face and jaw, pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to get worse as the child ages. Later, the condition causes wrinkled skin,
atherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, kidney failure, loss of eyesight, hair loss, and cardiovascular problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. The face is usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by hair loss), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Individuals usually retain normal mental and motor development.
Cause
In normal conditions, the LMNA gene encodes a protein called prelamin A, which leads to the lamin A form. There is a farnesyl group attached to the carboxyl-terminus of its structure. Farnesyl molecule allows prelamin A to be anchored to nuclear rim, and then it is removed.
Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a
point mutationA point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
in position 1824 of the
LMNALamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.-Function:...
gene, replacing cytosine with thymine, creating a truncated form,
progerinProgerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a silent point mutation in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino...
, of the prelamin A protein whose further processing is abnormal. Normal lamin A is a major structural protein of the
nuclear laminaThe nuclear lamina is a dense fibrillar network inside the nucleus of a eukaryotic cell. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division...
of the nucleus (along with lamin C);when LMNA is mutated, farnesyl group can not be removed and progerin does not integrate into this structure and accumulates, disrupting it. This is when HGPS appears. Since the nuclear lamina participates in organizing
chromatinChromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
and supporting the
nuclear envelopeA nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
; this disrupts the human cell nucleus as a whole, limiting the ability of the cell to divide. Then, the appearance of affected nuclei is like bubbles or a cluster of grapes. Progerin may also play a role in normal human aging, since its production is activated in senescent wild type cells.
Unlike "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or
xeroderma pigmentosumXeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. In extreme cases, all exposure to sunlight must be forbidden, no matter how small. Multiple basal cell carcinomas and other skin...
), progeria is not caused by defective
DNA repairDNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
. Because these diseases display what are considered different aspects of aging, but never every aspect, they are often called "segmental progerias".
Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. A genetic test for LMNA mutations can confirm the 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
aspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
. Children may also benefit from a high-calorie diet.
Growth hormone treatmentGrowth hormone treatment refers to the use of growth hormone in medical treatment. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. GH is now produced by...
has been attempted.
A type of anticancer drug, the
farnesyltransferase inhibitorThe farnesyltransferase inhibitors are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras , which is commonly abnormally active in cancer....
s (FTIs), has been proposed, but their use has been mostly limited to
animal modelAn animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s. A Phase II clinical trial using the FTI
lonafarnibLonafarnib is a farnesyl-OH-transferase inhibitor that is being investigated in a human clinical trial as a potential treatment for progeria....
began in May 2007. In studies on the cells another anti-cancer drug, rapamycin, caused removal of
progerinProgerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a silent point mutation in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino...
from the nuclear membrane through
autophagyIn cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
. It has been proved that
pravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
and
zoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...
are effective drugs when it comes to the blocking of farnesyl group production. However, it is important to bear in mind that no treatment is able to cure progeria nowadays.
- Farnesyltransferase inhibitors (FTIs) are drugs which inhibit the activity of an enzyme needed in order to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can be appreciated because that attachment takes place and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim and it has now a more normal state.
The delivery of Lonafarnib is not approved by the US
Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA). Therefore, it can only be used in certain clinical trials. Until the treatment of FTIs is implemented in progeria children we will not know its effects -- which are positive in mice.
-
PravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
is traded as Pravachol or Selektine and it is included in the family of statins. As well as zelodronate (also known as Zometa and Reclast, which is a bisphosphonate), its utility in Hutchinson-Gilford progeria syndrome (HGPS) is the prevention of farnesyl groups formation, which progerin needs to provoke the disease.
Some animal trials have been realized using FTIs or a combination of
pravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
and
zoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...
so as to observe whether they are capable of reversing abnormal nuclei.
The results, obtained by blinded electron microscopic analysis and immunofluorescence microscopy, showed that nucleus abnormalities could be reversed in transgenic mice expressing progerin. The reversion was also observed in vivo -- cultured cells from human subjects with progeria -- due to the action of the pharmacs, which block protein prenylation (transfer of a farnesyl polypeptide to C-terminal cysteine). The authors of that trial add, when it comes to the results, that: “They further suggest that skin biopsy may be useful to determine if protein farnesylation inhibitors are exerting effects in subjects with HGPS in clinical trials”.
Unlike FTIs,
pravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
and
zoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...
were approved by the U.S. FDA (in 2006 and 2001 respectively), although they are not sold as a treatment for progeria.
PravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
is used to decrease cholesterol levels and
zoledronateZoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis...
to prevent
hypercalcaemiaHypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a workup should be undertaken if it persists...
.
- Rapamycin, also known as
SirolimusSirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
, is a
macrolideThe macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
. There are recent studies concerning rapamycin which conclude that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are: abolishment of nuclear blebbing, degradation of progerin in affected cells and reduction of insoluble progerin aggregates formation. All these results do not come from any clinical trial, although it is believed that the treatment might benefit HGPS kids.
It should always be taken in account that no treatment is delivered in order to cure Hutchinson-Gilford progeria syndrome, for all of them are in pre-clinical stages.
Prognosis
As there is no known cure, few people with progeria exceed 13 years of age. At least 90% of patients die from complications of
atherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, such as heart attack or stroke.
Mental development is not adversely affected; in fact, intelligence tends to be above average. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to features of aging that progeria does not exhibit, patients show no
neurodegenerationNeurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
or
cancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
predisposition. They also do not develop the so-called "wear and tear" conditions commonly associated with aging, such as cataracts (caused by UV exposure) and
osteoarthritisOsteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
(caused by mechanical wear).
Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems.
Epidemiology
A study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are between 35 and 45 known cases in the world. Approximately 100 cases have been formally identified in medical history.
Classical Hutchinson-Gilford Progeria Syndrome is usually caused by a sporadic mutation taking place during the early stages of embryo development. It is almost never passed on from affected parent to child, as affected children rarely live long enough to have children themselves (very few children with progeria even live past the teen years to be 21).
There have been only two known cases in which it became evident that a healthy person can carry the LMNA mutation that causes progeria. These carriers were identified because they passed it on to their children. One family from India has five children with progeria, although this is not a classical HGPS ; they were the subject of a 2005
BodyshockBodyShock is a sensationalistic documentary series about the conditions or lives of extraordinary people. It was originally produced by redback for Channel 4 in the UK, but since September 2006, it has been carried by ArkMedia....
documentary entitled
The 80 Year Old Children, while another from Belgium has two.
In September 2011, the first reported case of a black African child with progeria was reported, 12-year-old South African Ontlametse Phalatse . The Progeria Research Foundation at
Children's Hospital BostonChildren's Hospital Boston is a 396-licensed bed children's hospital in the Longwood Medical and Academic Area of Boston, Massachusetts.At 300 Longwood Avenue, Children's is adjacent both to its teaching affiliate, Harvard Medical School, and to Dana-Farber Cancer Institute...
, affiliated with the Harvard University Medical School, is treating her and monitoring her case.
Research
Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.
A 2003 report in
Nature said that progeria may be a de novo dominant trait. It develops during
cell divisionCell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
in a newly conceived zygote or in the
gameteA gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...
s of one of the parents. It is caused by
mutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the LMNA (lamin A
proteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
)
geneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on chromosome 1; the mutated form of lamin A is commonly known as
progerinProgerin is a truncated version of lamin A protein involved in Hutchinson-Gilford progeria syndrome. Progerin is most often generated by a silent point mutation in the lamin A gene, LMNA. This mutation activates a cryptic splice site and gives rise to a form of lamin A with a deletion of 50 amino...
. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.
Lamin A
Lamin A is a major component of a protein scaffold on the inner edge of the
nucleusIn cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
called the
nuclear laminaThe nuclear lamina is a dense fibrillar network inside the nucleus of a eukaryotic cell. It is composed of intermediate filaments and membrane associated proteins. Besides providing mechanical support, the nuclear lamina regulates important cellular events such as DNA replication and cell division...
that helps organize nuclear processes such as
RNARibonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
and
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
synthesis.
Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a
cysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
and A is any aliphatic amino acids). This ensures that the cysteine is
farnesylatedPrenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
and allows prelamin A to bind
membranesThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, 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
proteaseA protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
. The resulting protein, now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.
In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing. This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known.
A study that compared HGPS patient cells with the skin cells from young and elderly normal human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
damage, and
demethylationDemethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
of
histoneIn biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
, leading to reduced
heterochromatinHeterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
.
NematodeThe nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
s over their lifespan show progressive lamin changes comparable to HGPS in all cells but
neuronA neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and
gameteA gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...
s. These studies suggest that lamin A defects are associated with normal
agingSenescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
.
Mouse model of progeria
A mouse
modelAn animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
of progeria exists, though in the mouse, the
LMNALamin A/C also known as LMNA is a protein that in humans is encoded by the LMNA gene. Lamin A/C belongs to the lamin family of proteins.-Function:...
prelamin A is not mutated. Instead,
ZMPSTE24ZMPSTE24 is a human gene. The protein encoded by this gene is a metallopeptidase. It is involved in the processing of Lamin A....
, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al. use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of prelamin A. Treated mice had greater grip strength and lower likelihood of
rib fractureA rib fracture is a break or fracture in one or more of the bones making up the rib cage.The first rib is rarely fractured because of its protected position behind the clavicle . However, if it is broken serious damage can occur to the brachial plexus of nerves and the subclavian vessels...
and may live longer than untreated mice.
This method does not directly "cure" the underlying cause of progeria. This method prevents prelamin A from going to the nucleus in the first place so that no prelamin A can build up on the nuclear membrane, but equally, there is no production of normal lamin A in the nucleus. Lamin A does not appear to be necessary for life; mice in which the
Lmna gene is knocked out show no embryological symptoms (they develop an Emery–Dreifuss muscular dystrophy-like condition postnatally). This implies that it is the buildup of prelamin A in the wrong place, rather than the loss of the normal function of lamin A, that causes the disease.
It was hypothesized that part of the reason that treatment with an FTI such as
alendronateAlendronic acid or alendronate sodium — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...
is inefficient is due to
prenylationPrenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...
by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FTI and statins was tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss, and bone defects".
Popular culture
Perhaps one of the earliest influences of progeria on popular culture occurred in the 1922 short story
The Curious Case of Benjamin Button by
F. Scott FitzgeraldFrancis Scott Key Fitzgerald was an American author of novels and short stories, whose works are the paradigm writings of the Jazz Age, a term he coined himself. He is widely regarded as one of the greatest American writers of the 20th century. Fitzgerald is considered a member of the "Lost...
(and later released as a
feature filmThe Curious Case of Benjamin Button is a 2008 American fantasy-drama film directed by David Fincher. The screenplay by Eric Roth and Robin Swicord is loosely based on the 1922 short story of the same name by F. Scott Fitzgerald...
in 2008). The main character, Benjamin Button, is born as a seventy-year-old man and ages backwards; it has been suggested that this was inspired by progeria.
In other literary references,
Charles DickensCharles John Huffam Dickens was an English novelist, generally considered the greatest of the Victorian period. Dickens enjoyed a wider popularity and fame than had any previous author during his lifetime, and he remains popular, having been responsible for some of English literature's most iconic...
has been suggested in
Bleak HouseBleak House is the ninth novel by Charles Dickens, published in twenty monthly installments between March 1852 and September 1853. It is held to be one of Dickens's finest novels, containing one of the most vast, complex and engaging arrays of minor characters and sub-plots in his entire canon...
to have described a case of progeria in the family of Smallweed in the grandfather and his grandchildren Judy and twin brother Bart. Orlando Gardiner of the science fiction book series
OtherlandOtherland is a science fiction tetralogy written by Tad Williams and published between 1996 and 2001. The story is set on Earth near the end of the 21st century, probably between 2082 and 2089 , in a world in which...
suffers from this disease. The
Chuck PalahniukCharles Michael "Chuck" Palahniuk is an American transgressional fiction novelist and freelance journalist. He is best known for the award-winning novel Fight Club, which was later made into a film directed by David Fincher and starring Brad Pitt, Edward Norton, and Helena Bonham Carter...
novel
Haunted includes one character, Brandon Whittier, who is dying of progeria at 13.
In film, a number of well-known films have featured progeria or progeria-like diseases. The 2009
BollywoodBollywood is the informal term popularly used for the Hindi-language film industry based in Mumbai , Maharashtra, India. The term is often incorrectly used to refer to the whole of Indian cinema; it is only a part of the total Indian film industry, which includes other production centers producing...
film
PaaPaa is a 2009 Indian film directed by R. Balakrishnan starring Amitabh Bachchan, Abhishek Bachchan, and Vidya Balan. The film is based on a rare genetic condition known as progeria and places emphasis on a father-son relationship...
, released in December 2009, has its storyline around progeria (starring
Amitabh BachchanAmitabh Bachchan is an Indian film actor. He first gained popularity in the early 1970s as the "angry young man" of Hindi cinema, and has since appeared in over 180 Indian films in a career spanning more than four decades...
, playing a 13-year old boy Auro). Progeria is also a central theme in the animated film
RenaissanceRenaissance is a 2006 French black-and-white animated science fiction film by French director Christian Volckman. It was co-produced in France, United Kingdom and Luxembourg and released on 15 March 2006 in France and 28 July 2006 in the UK by Miramax Films...
in which one of the characters finds the much sought cure. The 1996 film
Jack, starring Robin Williams, portrays a character who has a condition which causes him to age at 4 times the normal rate. This was possibly based on progeria though is otherwise not an accurate portrayal of the syndrome. The 1983
lesbian vampireLesbian vampirism is a trope in 20th century exploitation film that has its roots in Joseph Sheridan le Fanu's novella Carmilla about the predatory love of a female vampire for a young woman :...
film,
The Hunger, starred
Susan SarandonSusan Sarandon is an American actress. She has worked in films and television since 1969, and won an Academy Award for Best Actress for her performance in the 1995 film Dead Man Walking. She had also been nominated for the award for four films before that and has received other recognition for her...
as a physician researching progeria, and showed a vampire (played by
David BowieDavid Bowie is an English musician, actor, record producer and arranger. A major figure for over four decades in the world of popular music, Bowie is widely regarded as an innovator, particularly for his work in the 1970s...
) undergoing rapid progeria-like aging. In the film
Blade RunnerBlade Runner is a 1982 American science fiction film directed by Ridley Scott and starring Harrison Ford, Rutger Hauer, and Sean Young. The screenplay, written by Hampton Fancher and David Peoples, is loosely based on the novel Do Androids Dream of Electric Sheep? by Philip K...
the character J.F.Sebastian is a genetic designer who is not allowed to emigrate off-world because of his progeria.
The extraterrestrial space traveler in the 1986 film
The Aurora EncounterThe Aurora Encounter is a 1986 American science fiction film directed by the Jim McCullough Sr., written by Melody Brooke and Jim McCullough, Jr., and starring Jack Elam, Peter Brown, Carol Bagdasarian and Dottie West....
was played by Mickey Hays, a teenage boy who suffered from progeria.
In the episode of the series
Dark AngelDark Angel is an American biopunk/cyberpunk science fiction television series created by James Cameron and Charles H. Eglee. The show premiered in the United States on the Fox network on October 3, 2000, and was canceled after two seasons...
titled "Designate This", Max's "younger version" has the disease. Progeria was featured in the X-Files episode "
Young at Heart"Young at Heart" is the sixteenth episode of the first season of the American science fiction television series The X-Files. It premiered on the Fox network on February 11, 1994. It was written by Scott Kaufer and series creator Chris Carter, and directed by Michael Lange. The episode featured...
," where a scientist studying the disease found a way to reverse the aging process.
Rabbi
Harold KushnerRabbi Harold Samuel Kushner is a prominent American rabbi aligned with the progressive wing of Conservative Judaism, and a popular author.- Education :...
, author of the well known book,
When Bad Things Happen to Good PeopleWhen Bad Things Happen to Good People is a 1981 book by Harold Kushner, a Conservative rabbi. Kushner addresses in the book one of the principal problems of theodicy, the conundrum of why, if the universe was created and is governed by a God who is of a good and loving nature, there is...
, had a son who suffered from this disease, and his son's illness was probably the impetus for this book on suffering.
Leon BothaLeon Botha was a South African painter, and musical performer, as well as one of the world's oldest survivors of progeria.-Biography:...
, a South African visual artist and DJ who appeared in a video for the conceptual rave-rap group
Die AntwoordDie Antwoord is a hip hop group from Cape Town, South Africa, consisting of three members: Ninja, Yo-Landi Vi$$er and DJ Hi-Tek.-Background:...
, was one of the oldest people in the world who lived with progeria, dying one day after his 26th birthday on June 5, 2011.
See also
- Werner syndrome
Werner syndrome is a very rare, autosomal recessive disorder characterized by the appearance of premature aging....
, also called Adult progeria
- Biogerontology
- Degenerative disease
A degenerative disease, also called neurodegenerative disease, is a disease in which the function or structure of the affected tissues or organs will progressively deteriorate over time, whether due to normal bodily wear or lifestyle choices such as exercise or eating habits...
- Laminopathies
- Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
- Hayley Okines
Hayley Okines is an English girl with the rare aging disease progeria who is known for spreading awareness of the condition.Diagnosed in 1999, Okines was born with progeria, a genetic disease that causes her to age eight times faster than the average person. This puts her projected lifespan to age...
, an English girl with progeria who is known for spreading progeria awareness
- Brooke Greenberg
Brooke Greenberg , is an American from Reisterstown, Maryland, who has remained physically and cognitively similar to a toddler, despite her increasing age. She is about 30 inches tall, weighs about 16 pounds , and has an estimated mental age of nine months to one year...
, an American girl with the opposite condition (permanently a baby), known as Syndrome X.
- Ashley Hegi
Ashley Hegi was a well-known person with Progeria. She died a month shy of her 18th birthday. She was a Canadian. At age 14 she made a YouTube video ....
External links