Generality
Progeria is a rare genetic disorder that causes rapid aging.
Unfortunately, there is no cure for progeria and the prognosis is poor. However, therapeutic countermeasures can be put into practice, capable of extending the life of patients by a few years. In the near future, great advances in research are expected, which sees progeria as a model of study to understand human aging.
DNA, RNA and proteins
To understand the causes of progeria, it is appropriate to make a brief review of what DNA, RNA and proteins are and what is meant by gene expression.
- DNA contains genetic information, that is genes
- RNA is the transcription of genetic information into a "simpler" language to be translated into proteins
- Proteins are the "operational" form of DNA genes.
For the gene expression system to work properly, it is necessary that the DNA is not damaged and that the translation into proteins is faithful and error-free.
What is progeria
Progeria (from the Greek, πρό Œ = before, early; and γῆρας = old age) is a genetic disease of childhood, which leads to premature aging . It is also known as Hutchinson-Gilford syndrome .
Children who are affected start to show the first signs already during the first year of life. In a short time, the symptoms gradually become more severe, leading to the death of patients during adolescence. Although rarely, some individuals can even reach 20 years.
Progeria does not alter the mental faculties of young patients, who, from this point of view, are exactly like their peers.
Epidemiology
Progeria is a very rare disease: it affects one child for every 8 million newborns. It appears that the confirmed cases are currently around one hundred. However, it is suspected that there are another 100-150 undiagnosed patients in the world.
Most affected children die around the age of 13 due to cardiovascular problems; cardiovascular disorders, which are, by far, the main causes of death.
WHY STUDY THE PROGERIA?
Progeria, as has been said, has a very low incidence. However, it draws the attention of several researchers, as it could serve as a model of study to understand how normal human aging works. In this regard, common mechanisms and treatments with satisfactory results are being sought.
Causes
Premise: a genetic disease, like progeria, is caused by the mutation of one of the many genes that make up DNA. A gene, when mutated, produces an abnormal protein, instead of the normal healthy one. If the affected protein is vital, the effects of this mutation endanger the life of the organism involved.
The researchers found that the gene responsible for progeria is the so-called LMNA . The LMNA gene is located on chromosome 1 and produces a protein called lamina A.
Figure: comparison between the cellular nuclei of a healthy cell (top) and of a cell without lamina A (bottom). From //it.wikipedia.org/wiki/Progeria
WHAT IS LAMINA A? WHAT FUNCTIONS DOES IT WORK?
Lamin A protein provides fundamental structural support to the cell nucleus. Without it, the nucleus takes on a different, deformed appearance. A deformed nucleus, lacking the support offered by lamina A, compromises many vital cell functions, such as mitosis.
LA LAMINA A and PROGERIA
In progeria patients, lamina A has a small difference compared to lamina A of a healthy person. The difference concerns only one amino acid: this small detail is enough to determine dramatic circumstances.
Below is an in-depth sheet, dedicated to readers who want to know exactly what happens to lamina A.
In-depth card
In progeria, the mutated lamina A presents, with respect to the healthy lamina A, a different amino acid in the position 1824. Instead of a cytosine, there is a thymine. This small difference is sufficient to change the maturation of the protein itself. In fact, the lamina A, before acting on the nucleus, must undergo small structural adjustments, fundamental to make it functional.
One of these adjustments is the union of the protein with a molecule, called farnesil. In the case of healthy lamina A, the bond is temporary and the farnesyl is removed; in the case of lamina A mutated, farnesyl remains bound to the protein.
Lamina A and farnesil, if they remain together, they form an abnormal protein, called progerina precisely, since it determines the progeria.
WHEN DOES MUTATION COME? IS PROGERIA TRANSMITTED BY PARENTS?
Being a genetic disease, it is questionable whether progeria is also a hereditary disease. Well, a 2003 study, published in Nature, showed that progeria arises due to a spontaneous mutation, which affects a gamete (egg or sperm cell), or an embryo in the early stages. Therefore, parents are healthy, not carriers. This event is called de novo mutation in genetics.
On the other hand, it could not be otherwise: most patients die in adolescence, even before they can have children.
Symptoms, signs and complications
To learn more: Symptoms Progeria
The first symptoms of progeria appear just after birth, within the first twelve months of life. They consist of:
- Slow growth
- Scleroderma
In a few years, the symptomatological picture is completed with the appearance of the following pathological manifestations:
- Small and narrow face
- Large head and disproportionate to the face
- Beak nose
- Prominent eyes
- Loss of hair, eyelashes and eyebrows ( total alopecia areata )
- Thin lips
- Small and lowered jaw (micrognathia)
- Obvious veins
- High pitch of the voice
- Abnormal and delayed dentition
- Decreased muscle tone and body fat
- Joint stiffness
- Hip dislocation
- Insulin resistance
- arrhythmias
COMPLICATIONS
Patients with progeria inevitably experience various complications. In fact, cardiovascular problems, atherosclerosis, renal failure, loss of vision and progressive musculoskeletal degeneration arise . Those affected are fragile and unable to perform the same motor activities as their peers.
The main cause of death, which occurs during adolescence, is linked, above all, to heart and vascular disorders (more than 90% of deaths).
Contrary to what one might think, premature aging does not determine a particular predisposition to tumors or neurodegenerative diseases, typical of old age.
| The most common cardiac and vascular disorders, with a lethal outcome, are: |
| Heart attack Congestive heart failure Stroke Coronary insufficiency |
DEPRESSION
As stated at the beginning, the patient with progeria does not show mental delays: he, from the point of view of brain development, is like his peers. The patient is lucid and, therefore, even more aware of the physical differences between him and boys of the same age. This makes it even more difficult to accept the situation and the inevitable destiny that the affected individual will encounter. From here, depression and a feeling of strong moral discomfort are born.
Diagnosis
The diagnosis of progeria is based on the finding by the doctor of the characteristic signs of the disease. Over all:
- Growth slowed
- Total alopecia areata
- The hardening of the skin at the ends of the body (scleroderma)
For an unequivocal confirmation, the doctor can subject the patient to a genetic test, which assesses the presence or absence of mutations in the LMNA gene.
Therapy
Unfortunately, there is no specific therapy for the treatment of progeria. However, the researchers are doing their utmost to set up a drug, known as the " farnesyltransferase inhibitor " ( FTI ), which appears to be providing appreciable results (see the chapter on research).
Pending further developments, the only therapeutic measures that can be implemented today are:
- Reduce the severity of symptoms and complications
- Prolong patients' lives by a few years
Cardiovascular disorders are deserving the most attention from the attending physician. These should be monitored daily.
Physiotherapy, an accurate diet and the moral support of a psychotherapist are also very important.
TREATMENT OF CARDIOVASCULAR DISORDERS
For some patients, it may be vital to undergo coronoaric bypass surgery and angioplasty . In this way, the circulation of the heart is promoted and the possibility of a myocardial infarction is avoided, albeit temporarily.
We also recommend taking low doses of aspirin, statins and anticoagulants.
| Drugs for cardiovascular disorders | Purpose |
| Aspirin | Prevents heart attacks and strokes |
| Statin | It keeps cholesterol levels low |
| anticoagulants | Avoid blood clots |
PROMOTE GROWTH
To promote the growth of young patients, we sometimes resort to a therapy based on growth hormone . The effects are not always satisfactory.
PHYSIOTHERAPY, ACTIVITY? PHYSICS AND ORTHOPEDIC TRICKS
Physical activity and physiotherapy are essential to cope with progressive joint stiffness and decreased muscle tone, which causes, for example, hip dislocation.
Furthermore, the constant loss of body fat causes a painful sensation in the feet, especially if the patient has walked a long time. In these situations, it is very useful to equip the patient with special shoes, with an internal padding that absorbs impacts with the ground.
DIET
Patients with progeria suffer from scleroderma . Therefore, they benefit from constant hydration. It is recommended to drink frequently, especially during the warmer seasons.
Moreover, it has been observed that the muscular and growth deficits are attenuated with a constant caloric intake and higher than normal. In this regard, patients are advised to divide the three standard daily meals into snacks, so as to avoid a potential fasting situation.
PSYCHOTHERAPY
It is used to treat depression, which often affects the progeria patient.
The psychotherapist also advises the family and the patient to turn to support groups, specifically created to help those who suffer from incurable diseases and their families. In these venues, as far as possible, we try to alleviate the discomfort due to an inevitable destiny, and to teach our closest relatives how to best relate to the suffering individual.
Prognosis
The prognosis of progeria can never be positive, since there is no cure and treatments provide little effect. Some individuals benefit more than others, prolonging their lives by a few years. However, death almost always comes before the age of 20.
Therefore, the affection of family members and a welcoming and informed school environment are of fundamental importance.
Research (February 2014)
The hope of a cure for progeria is an anti-tumor drug, an inhibitor of farnesyltransferase. It is also known as Lonafarnib .
Researchers are doing considerable research on this and it seems that it favors the detachment of the farnesyl group from lamina A (see the in-depth sheet). In animal models, the experiment gave positive results: the separation of the farnesyl group from lamina A occurred and the cell nucleus resumed its normal form; the mice were also better. In May 2007, Phase II of the Lonafarnib human experimentation began and developments are awaited.
Comforting results also come from some studies on two drugs, already on the market for other purposes: Pravastatin and Zoledronate . The first is to lower cholesterol, the second is taken against hypercalcaemia. Administered in association with Lonafarnib, it seems to be able to prevent, more effectively, the bond between the farnesyl group and lamina A. That this may be the solution to progeria?
