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Tuberous Sclerosis

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Description: Tuberous sclerosis is a rare genetic disorder characterized by the growth of benign tumors in various organs, including the brain, skin, kidneys, heart, and lungs.
Type: Tuberous sclerosis is a genetic disorder. It is typically transmitted in an autosomal dominant manner.
Signs And Symptoms: The physical manifestations of TSC are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules), and very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizures, intellectual disability, developmental delay, and behavioral problems.
Prognosis: The prognosis for individuals with TSC depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe intellectual disability, uncontrollable seizures, and kidney failure. Those individuals with mild symptoms generally do well and live long, productive lives, while individuals with the more severe form may have serious disabilities. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.A study of 30 TSC patients in Egypt found, "...earlier age of seizures commencement (<6 months) is associated with poor seizure outcome and poor intellectual capabilities. Infantile spasms and severely epileptogenic EEG patterns are related to the poor seizure outcome, poor intellectual capabilities and autistic behavior. Higher tubers numbers is associated with poor seizure outcome and autistic behavior. Left-sided tuber burden is associated with poor intellect, while frontal location is more encountered in ASD [autism spectrum disorders]. So, close follow up for the mental development and early control of seizures are recommended in a trial to reduce the risk factors of poor outcome. Also early diagnosis of autism will allow for earlier treatment and the potential for better outcome for children with TSC."Leading causes of death include renal disease, brain tumour, lymphangioleiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe intellectual disability. Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate but is rarely a problem subsequently. Kidney complications such as angiomyolipoma and cysts are common and more frequent in females than males and in TSC2 than TSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis is only a risk for females with angiomyolipomas. In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas. These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.Detection of the disease should be followed by genetic counselling. It is also important to realize that though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of TSC is important.
Onset: Tuberous sclerosis complex (TSC) can have a highly variable onset, with symptoms potentially appearing at any age. However, most individuals present signs during infancy or early childhood. The nonspecific nature of initial symptoms may delay diagnosis.
Prevalence: Tuberous sclerosis complex (TSC) has a prevalence estimated to be about 1 in 6,000 to 1 in 10,000 live births.
Epidemiology: TSC occurs in all races and ethnic groups, and in both sexes. The live-birth prevalence is estimated to be between 10 and 16 cases per 100,000. A 1998 study estimated total population prevalence between about 7 and 12 cases per 100,000, with more than half of these cases undetected. Prior to the invention of CT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower, and the disease associated with those people diagnosed clinically with learning disability, seizures and facial angiofibroma. Whilst still regarded as a rare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals affected worldwide.
Intractability: Tuberous sclerosis is a complex genetic disorder characterized by the growth of benign tumors in multiple organs, including the brain, skin, kidneys, heart, and lungs. It is not intractable in the sense that the symptoms and complications can often be managed with appropriate treatment. Although there is no cure for tuberous sclerosis, advancements in medical therapies and interventions can help control the condition and improve the quality of life for those affected. Management typically involves a multidisciplinary approach tailored to the specific needs of the patient.
Disease Severity: Tuberous Sclerosis Complex (TSC) exhibits variable disease severity. Some individuals may experience mild symptoms, such as benign skin lesions or asymptomatic findings, while others may suffer from severe complications like epilepsy, intellectual disability, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis. The severity and spectrum of manifestations can differ significantly even among affected family members. Nanotechnology approaches are currently in the research phase and may potentially offer novel ways for early detection or treatment in the future, but they are not yet a clinical standard.
Healthcare Professionals: Disease Ontology ID - DOID:13515
Pathophysiology: Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact with RHEB GTPase, thus sequestering it from activating mTOR signalling, part of the growth factor (insulin) signalling pathway. Thus, mutations at the TSC1 and TSC2 loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors. TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including angiofibroma, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro.Molecular genetic studies have defined at least two loci for TSC. In TSC1, the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear. No missense mutations occur in TSC1. In TSC2, the gene abnormalities are on chromosome 16p13. This gene encodes tuberin, a guanosine triphosphatase–activating protein. The specific function of this protein is unknown. In TSC2, all types of mutations have been reported; new mutations occur frequently. Few differences have yet been observed in the clinical phenotypes of patients with mutation of one gene or the other.Cells from individuals with pathogenic mutations in the TSC2 gene display abnormal accumulation of glycogen that is associated with depletion of lysosomes and autophagic impairment. The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of mTORC1 and is restored, in cultured cells, by the combined use of PKB/Akt and mTORC1 pharmacological inhibitors.
Carrier Status: Tuberous sclerosis is an autosomal dominant genetic disorder. Carrier status is typically not applicable in the traditional sense because only one copy of the altered gene is sufficient to cause the condition. Individuals with tuberous sclerosis may have de novo mutations (new mutations not inherited from either parent), or they may inherit the mutated gene from an affected parent. The nan reference in your query is unclear. If you need further information, please clarify.
Mechanism: Tuberous sclerosis (TSC) is a genetic disorder characterized by the growth of benign tumors in multiple organs. The molecular mechanisms underlying TSC involve mutations in either of two tumor suppressor genes: TSC1 or TSC2. The proteins encoded by these genes, hamartin (TSC1) and tuberin (TSC2), form a complex that plays a crucial role in regulating cell growth and proliferation.

The TSC1-TSC2 complex inhibits the mammalian target of rapamycin complex 1 (mTORC1) pathway by acting on the small GTPase Rheb, keeping it in an inactive GDP-bound state. When either TSC1 or TSC2 is mutated, the TSC1-TSC2 complex is disrupted or dysfunctional, leading to the unchecked activity of mTORC1. Overactive mTORC1 signaling promotes cell growth, proliferation, and protein synthesis, resulting in the formation of the characteristic tumors in TSC.

In summary, the key molecular mechanism in tuberous sclerosis involves loss-of-function mutations in TSC1 or TSC2 genes which leads to hyperactivation of the mTORC1 pathway.
Treatment: Tuberous sclerosis complex (TSC) is typically treated with a combination of medical, surgical, and supportive therapies aimed at managing symptoms and improving quality of life. Treatments may include:

1. **Medications**: mTOR inhibitors like everolimus or sirolimus to shrink tumors and control seizures; antiepileptic drugs to manage seizures; other medications to control behavior problems and other symptoms.
2. **Surgery**: To remove problematic tumors or control seizures when medication is ineffective.
3. **Supportive Therapy**: Behavioral therapy, occupational therapy, educational support, and other interventions to address developmental delays, learning disabilities, and social challenges.
4. **Regular Monitoring**: Regular imaging and other assessments to monitor the growth of tumors and overall health status.

Nanotechnology-based approaches are still under investigation and not yet established as standard treatment for TSC.
Compassionate Use Treatment: Tuberous sclerosis complex (TSC) is a genetic disorder that causes non-cancerous tumors to grow in many parts of the body. For patients with TSC, compassionate use treatments and off-label or experimental treatments often involve medications and interventions aimed at controlling symptoms and improving quality of life.

1. **Compassionate Use Treatment**:
- **Everolimus**: This mTOR inhibitor, approved for certain manifestations of TSC (like SEGA and renal angiomyolipomas), might be considered under compassionate use for other severe, life-threatening complications of TSC that lack alternative therapies.

2. **Off-Label Treatments**:
- **Sirolimus**: Similar to everolimus, sirolimus may be used off-label for its mTOR-inhibiting properties to manage TSC-related symptoms such as skin lesions (like facial angiofibromas) and renal angiomyolipomas.
- **Vigabatrin**: Primarily approved for infantile spasms, it might be used for seizure control in TSC patients.

3. **Experimental Treatments**:
- **Gene Therapy**: Emerging therapies targeting the genetic causes of TSC are in early experimental stages and could offer future treatment possibilities.
- **Checkpoint Inhibitors**: Investigated in clinical trials for their potential to reduce tumor burden by modulating immune responses.

Participation in clinical trials is often necessary to access these off-label and experimental treatments, and careful consideration of potential risks and benefits should be made in consultation with healthcare providers.
Lifestyle Recommendations: Individuals with tuberous sclerosis should focus on the following lifestyle recommendations:

1. **Regular Medical Follow-ups:** Consistent monitoring with healthcare professionals, including the management of seizures, kidney health, and other associated complications.
2. **Medication Adherence:** Strict adherence to prescribed medications to manage symptoms and prevent complications.
3. **Balanced Diet:** A nutritious diet to support overall health, maintaining a healthy weight and managing any specific complications like kidney issues.
4. **Physical Activity:** Regular physical activity tailored to individual capability, which may help improve strength, coordination, and overall well-being.
5. **Avoidance of Stress:** Stress management techniques such as relaxation exercises, mindfulness, and adequate rest, as stress can exacerbate symptoms like seizures.
6. **Routine Screenings:** Regular screenings for potential complications like renal issues, lung problems, and neurological assessments.
7. **Educational Support:** For children with tuberous sclerosis, individualized educational plans to support cognitive development and learning challenges.
8. **Social Support:** Engagement with support groups and networks to share experiences and strategies for coping with the disease.

It's essential to consult with healthcare providers to customize these recommendations according to individual needs and medical advice.
Medication: The management of tuberous sclerosis complex (TSC) often includes medications to address various symptoms and manifestations of the disease. Specific options include:

1. **Antiepileptic Drugs (AEDs)**: Used to control seizures, which are common in TSC.
2. **mTOR Inhibitors**: Such as everolimus or sirolimus, used to shrink renal angiomyolipomas, subependymal giant cell astrocytomas (SEGAs), and other tumors.
3. **Behavioral and Psychiatric Medications**: Prescribed to manage related behavioral issues, autism, and psychiatric disorders.

These medications are part of a comprehensive treatment plan that may also include other therapeutic approaches. Always consult a healthcare provider for diagnosis and treatment plans.
Repurposable Drugs: For tuberous sclerosis, some repurposable drugs include:

1. **Everolimus (Afinitor)**: Originally used for certain cancers, it is now repurposed to treat tumors associated with tuberous sclerosis by inhibiting the mTOR pathway.
2. **Sirolimus (Rapamune)**: Similar to Everolimus, it is used for organ transplant rejection but shows efficacy in treating tumors in tuberous sclerosis.

These drugs help manage the growth of non-cancerous tumors and other symptoms related to tuberous sclerosis.
Metabolites: Tuberous sclerosis is a genetic disorder that can lead to the development of benign tumors in multiple organs. In terms of metabolites, alterations may occur due to the involvement of pathways like the mTOR (mechanistic target of rapamycin) pathway, which is regulated by the TSC1 and TSC2 genes. Key metabolites that can be impacted include:

1. **Amino acids** - Changes in levels of certain amino acids may be observed, reflecting altered protein synthesis and mTOR pathway activity.
2. **Lipids** - Disruptions in lipid metabolism may occur due to effects on cellular growth and proliferation.
3. **Nucleotides** - Variations in the metabolism of nucleotides could result from increased cell turnover and tumor growth.
4. **Lactate and pyruvate** - Altered glycolysis and energy metabolism may be reflected in changes in lactate and pyruvate levels.

Normalization or changes in these metabolites could potentially be indicators of disease presence or progression, although specific diagnostic use would require clinical correlation and further investigation.
Nutraceuticals: Tuberous sclerosis is a genetic disorder characterized by the growth of noncancerous tumors in various parts of the body. There is limited evidence supporting the use of nutraceuticals specifically for the treatment of tuberous sclerosis. Nutraceuticals are products derived from food sources that offer additional health benefits beyond basic nutritional value. Typical management of tuberous sclerosis involves medical therapies like mTOR (mammalian target of rapamycin) inhibitors, surgical interventions if necessary, and supportive care for symptoms.

However, it's essential to consult a healthcare provider before considering any nutraceuticals or alternative treatments. They can offer guidance tailored to the specific needs and conditions of the individual with tuberous sclerosis.
Peptides: Tuberous sclerosis is a genetic disorder characterized by the growth of benign tumors in various organs. While peptides are not the primary focus of traditional treatments for this condition, research into peptide-based therapies may be ongoing. "Nan" remains unclear in this context; could you please provide more details or clarify?