AN OVERVIEW ON PROGERIA: A RARE DISEASE OF CHILD
Kamal Singh Rathore, Sunita P., Khushboo Sharma, R.K.Nema
Progeria is a rare disease, fatal genetic condition that produces rapid aging, beginning in childhood also known as “Hutchinson–Gilford progeria syndrome” or “HGPS” and “Hutchinson–Gilford syndrome” wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 – both in England.
Its name is derived from the Greek and means “prematurely old.” Approximately 1 in 4000000 people are diagnosed with this condition. Those born with progeria typically live about 13-20 years, It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.
Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic background. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). According to Hayley’s Page “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 newborns. Both boys and girls run an equal risk of having Progeria.
Symptoms
Progeria is a progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life. The condition is rare; since 1886, only about 130 cases of progeria have been documented in the scientific literature. Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.
Signs and symptoms of this progressive disorder include:
Causes
Progeria usually occurs 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.
It is only very rarely seen in more than one child in a family. Progeria is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene (Lamin A), 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. 90% of children with progeria have a mutation on the gene that encodes the protein lamin A. a protein that holds the nucleus of the cell together. 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.
Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test. The health care professional will possibly suspect Progeria if the signs and symptoms are there – aging skin, loss of hair, stiffness of joints, etc. This can then be confirmed through a genetic test. The Progeria Research Foundation has created a Diagnostic Testing Program.
No diagnostic test confirms progeria. Doctors typically make a diagnosis based on signs and symptoms, such as failure to grow and hair loss, which typically aren’t fully evident until your child is nearly 2. However, with the discovery of the genetic mutation that causes progeria, it’s possible to use genetic testing for LMNA mutations at the first suspicion of progeria. The sooner you know your child has progeria, the sooner your doctor can recommend treatments that may help ease the signs and symptoms of the disorder.
A blood test may reveal that your child has a low level of high-density lipoprotein (HDL) cholesterol, the so-called good cholesterol that helps keep arteries open. This laboratory finding isn’t diagnostic by itself, but may lend support to a diagnosis of progeria.
Treatment
No treatments have been proven effective.
Prognosis
There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.
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 physically mediated “wear and tear” conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).
Epidemiology
Classical Hutchinson-Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children. Affected children rarely live long enough to have children themselves.
Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.
Lamin A
Nuclear lamin A is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.
Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, 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 protease. The resulting protein is now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.
In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene. The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems. Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy. In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.
Possible Complications
Heart attack (myocardial infarction)
Stroke
How we can help children with Progeria?
Care, Coping and support
Helping the child to cope
Conclusion and General Discussion
Progeria, or Hutchinson-Gilford progeria syndrome, 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; prominent eyes 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. According to reports in the medical literature, individuals with Hutchinson-Gilford progeria syndrome 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 13 years, with a range of about eight to 21 years.
Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception.
REFERENCES
Support Groups
Progeria Research Foundation, Inc. – www.progeriaresearch.org
Tags: cardiovascular heart disease, dr jonathan, gilford progeria syndrome, growth failure, hgps, hip dislocation, hutchinson gilford progeria, hutchinson gilford progeria syndrome, kamal singh, khushbooKamal Singh Rathore, Sunita P., Khushboo Sharma, R.K.Nema
Progeria is a rare disease, fatal genetic condition that produces rapid aging, beginning in childhood also known as “Hutchinson–Gilford progeria syndrome” or “HGPS” and “Hutchinson–Gilford syndrome” wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 – both in England.
Its name is derived from the Greek and means “prematurely old.” Approximately 1 in 4000000 people are diagnosed with this condition. Those born with progeria typically live about 13-20 years, It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.
Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic background. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). According to Hayley’s Page “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 newborns. Both boys and girls run an equal risk of having Progeria.
Symptoms
Progeria is a progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life. The condition is rare; since 1886, only about 130 cases of progeria have been documented in the scientific literature. Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.
Signs and symptoms of this progressive disorder include:
Causes
Progeria usually occurs 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.
It is only very rarely seen in more than one child in a family. Progeria is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene (Lamin A), 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. 90% of children with progeria have a mutation on the gene that encodes the protein lamin A. a protein that holds the nucleus of the cell together. 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.
Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test. The health care professional will possibly suspect Progeria if the signs and symptoms are there – aging skin, loss of hair, stiffness of joints, etc. This can then be confirmed through a genetic test. The Progeria Research Foundation has created a Diagnostic Testing Program.
No diagnostic test confirms progeria. Doctors typically make a diagnosis based on signs and symptoms, such as failure to grow and hair loss, which typically aren’t fully evident until your child is nearly 2. However, with the discovery of the genetic mutation that causes progeria, it’s possible to use genetic testing for LMNA mutations at the first suspicion of progeria. The sooner you know your child has progeria, the sooner your doctor can recommend treatments that may help ease the signs and symptoms of the disorder.
A blood test may reveal that your child has a low level of high-density lipoprotein (HDL) cholesterol, the so-called good cholesterol that helps keep arteries open. This laboratory finding isn’t diagnostic by itself, but may lend support to a diagnosis of progeria.
Treatment
No treatments have been proven effective.
Prognosis
There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.
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 physically mediated “wear and tear” conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).
Epidemiology
Classical Hutchinson-Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children. Affected children rarely live long enough to have children themselves.
Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.
Lamin A
Nuclear lamin A is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.
Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, 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 protease. The resulting protein is now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.
In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene. The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems. Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy. In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.
Possible Complications
Heart attack (myocardial infarction)
Stroke
How we can help children with Progeria?
Care, Coping and support
Helping the child to cope
Conclusion and General Discussion
Progeria, or Hutchinson-Gilford progeria syndrome, 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; prominent eyes 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. According to reports in the medical literature, individuals with Hutchinson-Gilford progeria syndrome 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 13 years, with a range of about eight to 21 years.
Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception.
REFERENCES
Support Groups
Progeria Research Foundation, Inc. – www.progeriaresearch.org