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Progeria

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Description: Progeria is a rare genetic disorder characterized by accelerated aging in children, leading to symptoms such as growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, and cardiovascular problems.
Type: Progeria is a rare genetic disorder, specifically classified as a segmental progeroid syndrome. Its type of genetic transmission is autosomal dominant. Most cases are caused by a de novo mutation in the LMNA gene, meaning the mutation occurs spontaneously and is not typically inherited from the parents.
Signs And Symptoms: Most children with progeria appear normal at birth and during early infancy. Children with progeria usually develop the first symptoms during their first few months of life. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As a child ages past infancy, additional conditions become apparent, usually around 18–24 months. Limited growth, full-body alopecia (hair loss), and a distinctive appearance (a small face with a shallow, recessed jaw and a pinched nose) are all characteristics of progeria. Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, the condition causes wrinkled skin, kidney failure, loss of eyesight, and atherosclerosis and other 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 older adults. The head is usually large relative to the body, with a narrow, wrinkled face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), 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 typical mental and motor function.
Prognosis: As there is no known cure, few people with progeria exceed 16 years of age. At least 90 percent of patients die from complications of atherosclerosis, such as heart attack or stroke.Mental development is not adversely affected; in fact, intelligence tends to be average to 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 those that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop conditions that are commonly associated with accumulation of damage, such as cataracts (caused by UV exposure) and osteoarthritis.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. People with progeria have normal reproductive development, and there are known cases of women with progeria who delivered healthy offspring.
Onset: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), typically has an onset in early childhood. Signs usually appear within the first two years of life. Children with progeria may initially show symptoms like growth delays and characteristic facial features before developing more specific symptoms related to premature aging.
Prevalence: Progeria, specifically Hutchinson-Gilford Progeria Syndrome (HGPS), is an extremely rare genetic disorder. Its prevalence is estimated to be about 1 in 20 million people worldwide.
Epidemiology: A study from the Netherlands has shown an incidence of 1 in 20 million births. According to the Progeria Research Foundation, as of September 2020, there are 179 known cases in the world, in 53 countries; 18 of the cases were identified in the United States. Hundreds of cases have been reported in medical history since 1886. However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed cases worldwide.There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria. One family from India had four of six children with progeria.
Intractability: Progeria, specifically Hutchinson-Gilford Progeria Syndrome (HGPS), is currently considered intractable. There is no cure for the disease, and treatment focuses on managing symptoms and complications to improve quality of life. Research is ongoing, and some experimental treatments show promise, but as of now, progeria remains a severe and life-limiting condition.
Disease Severity: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare and severe genetic disorder characterized by rapid aging in children. It significantly affects life expectancy, with most patients living into their mid-teens to early twenties. The disease severity is high, leading to numerous health issues such as cardiovascular problems, growth delays, and joint stiffness.
Healthcare Professionals: Disease Ontology ID - DOID:3911
Pathophysiology: Hutchinson-Gilford progeroid syndrome (HGPS) is an extremely rare autosomal dominant genetic disorder in which symptoms resembling aspects of aging are manifested at an early age. Its occurrence is usually the result of a sporadic germline mutation; although HGPS is genetically dominant, people rarely live long enough to have children, preventing them from passing the disorder on in a hereditary manner.
HPGS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The histone mark H4K20me3 is involved and caused by de novo mutations that occur in a gene that encodes lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. Patients also do not have appropriate DNA repair, and they also have increased genomic instability.In normal conditions, the LMNA gene codes for a structural protein called prelamin A, which undergoes a series of processing steps before attaining its final form, called lamin A. Prelamin A contains a "CAAX" where C is a cysteine, A an aliphatic amino acid, and X any amino acid. This motif at the carboxyl-termini of proteins triggers three sequential enzymatic modifications. First, protein farnesyltransferase catalyzes the addition of a farnesyl moiety to the cysteine. Second, an endoprotease that recognizes the farnesylated protein catalyzes the peptide bond's cleavage between the cysteine and -aaX. In the third step, isoprenylcysteine carboxyl methyltransferase catalyzes methylation of the carboxyl-terminal farnesyl cysteine. The farnesylated and methylated protein is transported through a nuclear pore to the interior of the nucleus. Once in the nucleus, the protein is cleaved by a protease called zinc metallopeptidase STE24 (ZMPSTE24), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2, and lamin C, makes up the nuclear lamina, which provides shape and stability to the inner nuclear envelope.
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 mutation in position 1824 of the LMNA gene, which replaces a cytosine with thymine. This mutation creates a 5' cryptic splice site within exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is translated into protein, it produces an abnormal variant of the prelamin A protein, referred to as progerin. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the nuclear envelope with enough structural support, causing it to take on an abnormal shape. Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide. However, defective cell division is unlikely to be the main defect leading to progeria, particularly because children develop normally without any signs of disease until about one year of age. Farnesylated prelamin A variants also lead to defective DNA repair, which may play a role in the development of progeria. Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging.To date over 1,400 SNPs in the LMNA gene are known. They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys, Arg482Gln, Arg527Leu, Arg527Cys, Ala529Val).
Progerin may also play a role in normal human aging, since its production is activated in typical senescent cells.Unlike other "accelerated aging diseases" (such as Werner syndrome, Cockayne syndrome or xeroderma pigmentosum), progeria may not be directly caused by defective DNA repair. These diseases each cause changes in a few specific aspects of aging, but never in every aspect at once, so they are often called "segmental progerias".A 2003 report in Nature said that progeria may be a de novo dominant trait. It develops during cell division in a newly conceived zygote or in the gametes of one of the parents. It is caused by mutations in the LMNA (lamin A protein) gene on chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.

A subset of progeria patients with heterozygous mutations of LMNA have presented an atypical form of the condition, with initial symptoms not developing until late childhood or early adolesence. These patients have had longer lifespans than those with typical-onset progeria. This atypical form is extremely rare, with presentations of the condition varying between patients with even the same mutation. The general phenotype of atypical cases is consistent with typical progeria, but other factors (severity, onset, and lifespan) vary in presentation.
Carrier Status: Progeria, specifically Hutchinson-Gilford Progeria Syndrome (HGPS), is not typically inherited in the traditional sense, making carrier status irrelevant. The condition usually arises from a de novo mutation in the LMNA gene, meaning it occurs sporadically without a previous family history.
Mechanism: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare genetic disorder characterized by rapid aging in children.

**Mechanism:**
The primary cause of HGPS is a mutation in the LMNA gene, which encodes for the lamin A protein. This protein plays a crucial role in maintaining the structure and function of the cell nucleus.

**Molecular Mechanisms:**
The specific mutation often involves a de novo point mutation (C1824T) in the LMNA gene, leading to the creation of an abnormal version of lamin A, known as progerin. Progerin affects the nuclear envelope, causing nuclear instability and cellular damage. This abnormal protein disrupts various cellular functions, including gene expression, DNA repair, and chromatin organization.

The accumulation of progerin in cells leads to progressive cellular damage and contributes to the symptoms of premature aging observed in individuals with progeria. Research in this area continues to explore ways to intervene and potentially correct the aberrant cellular processes caused by progerin.
Treatment: In November 2020, the U.S. Food and Drug Administration approved lonafarnib, which helps prevent buildup of defective progerin and similar proteins. A clinical trial in 2018 points to significantly lower mortality rates – treatment with lonafarnib alone compared with no treatment (3.7% vs. 33.3%) – at a median post-trial follow-up time span of 2.2 years. The drug, given orphan drug status and Pediatric Disease Priority Review Voucher, is taken twice daily in the form of capsules and may cost US$650,000 per year, making it prohibitive for the vast majority of families. It is unclear how it will be covered by health insurance in the United States. Common side effects of the drug include "nausea, vomiting, diarrhea, infections, decreased appetite, and fatigue".Other treatment options have focused on reducing complications (such as cardiovascular disease) with coronary artery bypass surgery and low-dose acetylsalicylic acid.Growth hormone treatment has been attempted. The use of Morpholinos has also been attempted in mice and cell cultures in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used.A type of anticancer drug, the farnesyltransferase inhibitors (FTIs), has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI lonafarnib began in May 2007. In studies on the cells another anti-cancer drug, rapamycin, caused removal of progerin from the nuclear membrane through autophagy. It has been proved that pravastatin and zoledronate are effective drugs when it comes to the blocking of farnesyl group production.Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed 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 occur because that attachment occurs, 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 now has a more normal state.Studies of sirolimus, an mTOR Inhibitor, demonstrate that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are abolishing nuclear blebbing, degradation of progerin in affected cells, and reducing insoluble progerin aggregates formation. These results have been observed only in vitro and are not the results of any clinical trial, although it is believed that the treatment might benefit HGPS patients.Recently, it has been demonstrated that the CRM1 protein (a key component of the nuclear export machinery in mammalian) is upregulated in HGPS cells, which drives to the abnormal localization of NES containing proteins from the nucleus to the cytoplasm. Moreover, the inhibition of CRM1 in HGPS alleviates the associated-senescence phenotype as well as the mitochondrial function (an important determinant in senescence) and lysosome content. These results are under in vivo validation with selinexor (a more suitable CRM1 inhibitor for human use).
Compassionate Use Treatment: Progeria, specifically Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare genetic condition characterized by accelerated aging in children. Current options for management include:

1. **Compassionate Use Treatment:**
- **Lonafarnib:** Originally developed for cancer, this farnesyltransferase inhibitor has been made available on a compassionate use basis and has shown some efficacy in improving cardiovascular and bone health, increasing survival rates.

2. **Off-label or Experimental Treatments:**
- **Rapamycin (Sirolimus):** This immunosuppressant and anti-cancer drug has shown potential in experimental treatments to reduce cellular defects associated with progeria.
- **Everolimus:** Similar to rapamycin, everolimus is another mTOR inhibitor being explored for its potential benefits in progeria.
- **Gene Therapy:** Researchers are investigating CRISPR and other gene-editing technologies to correct the underlying genetic mutation responsible for progeria.
- **Protein Replacement Therapy:** Targeting dysfunctional proteins in progeria cells to restore normal function is another experimental approach under investigation.
- **Antioxidants and Anti-inflammatory Drugs:** These are also being studied to manage symptoms and improve quality of life.

Patients with progeria should be under the care of a specialized medical team to explore these options and participate in clinical trials when available.
Lifestyle Recommendations: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is an extremely rare genetic disorder characterized by rapid aging in children. Due to the unique challenges associated with progeria, certain lifestyle recommendations can help manage the symptoms and improve the quality of life:

1. **Regular Medical Check-ups**: Frequent consultations with a range of specialists, including cardiologists, dermatologists, and orthopedists.

2. **Balanced Diet**: A nutritious, well-balanced diet to support overall health. Caloric intake might need to be monitored due to limited growth.

3. **Physical Activity**: Moderate, low-impact exercises such as swimming to maintain mobility and cardiovascular health, while avoiding high-impact activities that might stress fragile bones.

4. **Skin Care**: Effective skincare to manage the dryness and fragility typical of the condition, using gentle, moisturizing products.

5. **Dental Care**: Regular dental check-ups and proper oral hygiene because children with progeria often have dental issues.

6. **Emotional and Social Support**: Psychological counseling and support groups to cope with emotional challenges and ensure that the child enjoys social interaction.

Close coordination with healthcare providers is essential in establishing a tailored lifestyle plan that addresses the individual's specific needs.
Medication: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), has no cure, but certain treatments can help manage symptoms and potentially extend lifespan. One of the drugs used is lonafarnib, originally developed for cancer treatment, which has shown some effectiveness in improving various conditions associated with progeria by inhibiting farnesyltransferase. Other supportive treatments may include low-dose aspirin to prevent heart attacks and strokes, growth hormone to help increase height and weight, and other medications to manage specific symptoms like heart disease. Regular medical monitoring is essential to manage complications.
Repurposable Drugs: For progeria, a rare genetic disorder characterized by accelerated aging, some repurposable drugs have shown potential in research settings. One key example is **lonafarnib**, originally developed for treating cancer, which has been repurposed to address the buildup of defective progerin protein in progeria patients. Other drugs being explored include **pravastatin** (a statin) and **zoledronic acid** (a bisphosphonate), both of which are under investigation to reduce progerin toxicity and improve lifespan and health outcomes in affected individuals.
Metabolites: In Hutchinson-Gilford Progeria Syndrome (progeria), studies have indicated metabolic abnormalities that involve altered lipid metabolism, oxidative stress, and dysfunctional protein processing. Some specific metabolites associated with progeria include:

1. **Lamin A Protein Fragments**: Progeria is characterized by the accumulation of a defective, truncated form of the lamin A protein called progerin. This disrupts nuclear architecture and cellular functions.

2. **Oxidative Stress Markers**: Elevated levels of reactive oxygen species (ROS) and oxidative stress markers are observed, indicating increased cellular damage and aging processes.

3. **Fatty Acids and Cholesterol**: Abnormal lipid profiles and cholesterol metabolism have been reported, leading to cardiovascular complications common in progeria patients.

There is currently insufficient data on the specific role of nanoparticles (nan) in the diagnosis or treatment of progeria, though research on nanotechnology may eventually provide innovative therapeutic approaches.
Nutraceuticals: Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare genetic disorder characterized by accelerated aging in children. Nutraceuticals are food-derived products that provide health benefits, and some are being explored for their potential role in managing progeria. For example, antioxidants like resveratrol and substances that can improve cellular health are under investigation, though there is no definitive evidence yet that they significantly alter the disease course.

Regarding nanotechnology, advancements in nanomedicine may offer potential future therapies for progeria. Nanoparticles can be engineered to deliver drugs directly to affected cells, potentially improving efficacy and reducing side effects. Current research is still in preliminary stages, but it holds promise for developing targeted treatments for genetic disorders like progeria.
Peptides: Progeria, also known as Hutchinson-Gilford Progeria Syndrome, is a rare genetic disorder characterized by accelerated aging in children. Research on peptides and nanoparticles (nan) is ongoing, with some studies exploring their potential therapeutic benefits.

1. **Peptides**: Specific peptides are being investigated for their ability to target and potentially modify the abnormal lamin A protein (progerin) that causes progeria. For example, farnesyltransferase inhibitors (FTIs) are a class of drugs that include peptide-like molecules designed to inhibit the farnesylation of progerin, which could help reduce its toxic effects on cells.

2. **Nanoparticles (nan)**: Nanoparticles are being studied as delivery systems to enhance the uptake and effectiveness of therapeutic agents in progeria. They can encapsulate drugs, peptides, or genetic material and deliver them directly to affected cells, potentially improving the precision and efficacy of treatments while minimizing side effects.

While promising, these approaches are still under investigation, and more research is needed to determine their safety and efficacy in treating progeria.