Tuberous sclerosis - Research Paper Example

Tuberous sclerosis I. Introduction Tuberous sclerosis is an autosomal dominant genetic disease. It affects different vital organs of the human body. Most commonly tuberous sclerosis provokes formation of tumors in brain, kidney, skin, heart and lungs. These tumors are not cancerous and usually do not cause any serious problems with health. The lesions are caused by mutation in tumor suppressor genes. Without timely diagnose, tumors can cause different symptoms such as epilepsy, disorder of brain functioning, learning and behavior disability in children, defects in the heart and lungs. There is no simple universal treatment for tuberous sclerosis, because of its phenotype variation. The most common drugs to control brain and kidney tumors are mTOR inhibitors such as sirolimus and everolimus. Screening tests such as magnetic resonance imaging (MRI), an ultrasound scan, spirometry, echocardiogram and blood tests can help to identify tumors connected with tuberous sclerosis. Appropriate diagnostic and treatment plans are quite necessary for successful health care and support of patients with tuberous sclerosis. II. Diagnostic criteria, signs,symptoms Tuberous sclerosis the other name tuberous sclerosis complex(TSC) is a genetic disease. It is characterized by the formation of benign, noncancerous tumors in the different organs of human body such as kidney, lungs, brain, heart, eyes and skin. Benign tumors formed in the human body when function of cell growth is damaged. Abnormal quantity of cells formed an extra mass surrounded by outer layer and cause different negative health defects. The statistics show that the most common benign tumors caused by tuberous sclerosis occur in the brain and in skin in 9 causes between 10; kidney and eyes 8 cases between 10; in kidney 8 cases out of 10 and more rarely in the lungs 4 cases between10 especially in women. Tumors in the brain can cause different neurological defects and abnormal brain function. The most common disorder of the nervous system during tuberous sclerosis is epilepsy. It is a long-term neurological defect that characterized by repeated spasms, convulsions and loss of consciousness .This state appeared in the 9 cases out of 10 in people affected with tuberous sclerosis. The other form of epilepsy that usually appeared in infants called infantile spasms. It diagnosed in 7 children between 10 and it leads to brain defects. Infantile spasms occur during first three months of child life. Children have short time numerous convulsions that usually disappeared within few seconds. The other neurological condition is learning disabilities. Mostly half of the children that have tuberous sclerosis will have learning disabilities. It is characterized by bad memory, distraction, difficulties in concentration and organization activities. Behavior and developmental defects are the other one, quite common neurological condition that affects half of all children with tuberous sclerosis. Among them are: autistic spectrum disorders that lead to problems with language, behavior and social interaction; hyperactivity - mental disorder in children characterized by problems with attention and concentration; aggression; anxiety; depression; schizophrenia- neurological state that causes delusions and hallucinations; sleep disorders. In some cases huge benign tumors can be formed and they called subependymal giant cell astrocytomas. They usually occur in adults and can cause serious problems with brain and spine. People with such benign tumors have a high risk of cerebrospinal fluid obstruction that lead to the high pressure in the brain and called hydrocephalus. It is connected with such symptoms as headache, disorientation, nausea, bed appetite and visual problems. Hydrocephalus required medical surgery to remove excess fluid from the brain. People with tuberous sclerosis can have skin tumors formed during childhood. Skin lesions can appear as light patches, thick surface of the skin, red spots and blemishes on the face and skin growing around the nail. The most common skin defects are: angiofibromas- small red papules on the surface of the nose and cheeks; periungual fibromas – small tumors occur in the fingernails and toenails, they can cause bleeding and have to be removed; hypomelanic macules characterized by white patches on the skin that formed as a result of melanin deficiency; shagreen patch – thick area of the skin occurred in the neck. Tumors inside the kidney formed of blood vessels, fat and muscles called angiomyolipomas. Such tumors can grow and have big size and lead to the internal bleeding and pain. Large angiomyolipomas can damage kidney function and eating process and cause different symptoms such as tiredness, blood and protein in the urine, itchy skin. In some cases, people with tuberous sclerosis can have polycystic kidneys that can provoke kidney disease and high blood pressure. It is characterized by the formation of numerous cysts inside the kidneys. A polycystic kidney is the most common reason of kidney failure, in people with tuberous sclerosis. Observed, that approximately 3 people out of 100 with tuberous sclerosis can have type of kidney cancer called renal cell carcinoma. (Hope Northrup, 2011) Heart tumors during tuberous sclerosis is quite small tumors, called cardiac rhabdomyoma and do not provoke any symptoms. They formed in the childhood and it is difficult to diagnose them in adolescences. Sometime heart tumors can block blood flow inside the heart and cause arrhythmia. Eye tumors are also not dangerous. They formed on the outer layer of the retina and do not grow as large to affect a human vision. Lung tumors appeared mostly in 40-60% of women and called lymphangioleiomyomatosis. It can develop at the age of 20-40 years and rarely provokes asthma like symptoms. It is quite difficult to diagnose the tuberous sclerosis because of its numerous phenotype variations. Recent investigations showed diagnostic criteria for tuberous sclerosis, which are: facial angiofibromas, ungual fibroma, hypomelanotic macules, shagreen patch, retinal nodular hamartomas, cortical tuber, subependymal nodule, subependymal giant cell astrocytomas, cardiac rhabdomyoma, lymphangioleiomyomatosis and renal angiomyolopomas. Revised criteria showed that appeared lesions of two or more organs or dissimilar lesions of one organ have to be diagnosed to confirm the tuberous sclerosis.( Roach ES, 2004.) III. Etiology of diagnosis Tuberous sclerosis is a hard detected disease, because it has a lot of features, signs and symptoms. But a careful clinical examination can identify this disorder. There are several ways to diagnose this genetic disease, based upon clinical criteria described above. The easiest signs to recognize this disease are delay in development, seizures, and white skin patches. To detect all defects caused by tuberous sclerosis different medical tests may be used. Computed tomography or magnetic resonance imaging of the brain can help to detect such signs as brain tubers. Abdominal ultrasound can help to examine the kidney and availability of tumors inside the kidney. Ultraviolet light examination of the skin is the way to detect any signs of skin tumors that are usually hard to see. The other way to examine tuberous sclerosis is DNA testing of two genes, TSC1 and TSC2 associated with this disease. TSC1 and TSC2 genes control production of such proteins as hamartin and tuberin. Their main function inside the cells is to regulate cell size and growth. Therefore these genes functioned as tumor suppressors. People with tuberous sclerosis usually have one mutated copy of these two genes in each cell. For development of some tumors two mutated copies of these genes required. In this case TSC1 and TSC2 genes do not produce proteins and cell growth in uncontrolled way and tumors form in the different organs. (Roach ES, 2004.) IV. Progress of diagnosis The diagnosis of tuberous sclerosis is usually can be made when physicians detect any two main features of this disease. The most common feature is cardiacrhabdomyoma, untypical growth in the heart muscle that can be detected in young children or during pregnancy after ultrasound examination. The other easy detected feature is abnormal skin lesions or pigmentation. Nowadays National Institutes of Health (NIH) conduct a lot of scientific research on tuberous sclerosis. They are working on TSC1 and TSC2 genes that cause disorders. Scientist studies protein complex of tuberin and hamartin produced by these genes. Further investigations will help to improve genetic testing for tuberous sclerosis and help to find new methods of diagnosis and treatment for tuberous sclerosis. Nowadays there is no genetic test that can easily detect tuberous sclerosis, because of numerous mutations of genes. After clinical diagnostics mutation can be found. Such genetic testing as preimplantation diagnosis is available since 2006. It can help to diagnose any genetic diseases in embryos. Clinical trials of tuberous sclerosis are looking for a drug rapamycin that may reduce growth of hamartomas and help to control cell growth that is done by TSC1 and TSC2 genes in healthy cells. Also prenatal testing can become available. (Gipson TT,2014) V. Prevalence Tuberous sclerosis is a rare disease. That’s proved by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). Tuberous sclerosis affects 50.000 people in the United States population by 2012. 1 million of tuberous sclerosis cases were fixed all over the world. That’s approximately 1 case per 10,000 people. The live birth prevalence is from 10 to 16 cases per100, 000. But the quantity of people affected with tuberous sclerosis increased with time. In 1956 was fixed 1 case per 150.000, in 1968 1 case per 100.000, in 1971 1: 70.000, in 1984 1 case per 34.000 and in 1998 1 case per 12.500. Therefore we can see that prevalence of tuberous sclerosis keep growing with time, despite that this disease has status as a rare. It is a quite common genetic disease compared to others. The Tuberous Sclerosis Alliance reported that approximately 1/3 of all cases are inherited and 2/3 of all cases are spontaneous mutation. Children have 50% of chance to inherit tuberous sclerosis if one parent has this genetic disease. (Hope Northrup, 2011.) VI. Treatment modalities including psychopharmacology and effectiveness Tuberous sclerosis is not a curable disease. But there are several treatments for tuberous sclerosis symptoms. Epilepsy can be controlled using antiepileptic drugs such as vigabatrin. This drug was approved in the United States by Food and Drug Administration (FDA) to treat seizures especially infantile spasms. Observed that vigabartin controls infantile spasms in 73% of children with tuberous sclerosis in the United States. But vigabatrin has some adverse effects. Mutation in the TSC1 and TSC2 genes provoke hyperactivation of the mammalian target of rapamycin (mTOR) that controls cell growth. To avoid this FDA accepted mTOR inhibitors such as sirolimus and everolimus to treat angiomyolopoma, kidney tumors and subependymal giant cell astrocytomas or brain tumors. Everolimus was a first mTOR inhibitor approved in the United States and Europe to treat subependymal giant cell astrocytomas connected with tuberous sclerosis. The action of mTOR inhibitors is similar. They bind to the intracellular binding protein FK506 that binds to the mTOR. In this way mTOR inhibitors repress signaling of mTOR. Renal angiomyolipomas can cause pain. Persons with angiolypomas greater than 3.5-4cm need renal sparring surgery or renal emobilization. Recent study showed that alternative treatments for renal angiomyolypomas can be pharmacologic therapy with anti-angiogenics and mTOR inhibitors or ablation surgical removal of tumor tissue. Lymphangioleiomyomatosis that affects mostly women can be treated with medroxy-progesterone that reduces estrogen production that causes smooth muscle cell growth in the lungs. But, side effects for this treatment vary from one person to another. Clinical trials showed an efficiency of mTOR inhibitors for tuberous sclerosis therapy, but the FDA did not approved these drugs for lymphangioleiomyomatosis and renal angiomyolipomas treatment. ( Paolo Curatolo,2012) VII. Assessment Researchers observed that tuberous sclerosis is a brain disorder with cognitive and behavioural defects. These difficulties are required intensive support and help. Early detection of neurological disorders is quite important. Children must be checked by assessment tests and healthcare professionals have to offer individual plan for children with tuberous sclerosis. It is not a good practice to put such children without previous assessment into a situation where they will fail and only after this assess them. Early assessment will help to decrease risk of developing complications and avoid the emotional trauma of patients with tuberous sclerosis. Assessment should be done in appropriate age. Pre-school assessments can help to detect behavioural and developmental impairments.( Gipson TT,2014.) VIII. Care Planning including Interventions and Rationales Tuberous sclerosis is a life-long genetic disease that needs appropriate support and care of healthcare professionals. The care planning has to be constructed from a young age to adolescence. Care plan for children may include regular visiting of healthcare professionals. Children with tuberous sclerosis have to be examined by educational physiologist to detect any physiological, emotional and behavioral disorders; neurologist to see any changes in nervous system functioning; cardiologist; ophthalmologist and genetic counselor. It is quite important to maintain regular examination of children by healthcare professionals to detect any disorders connected with tuberous sclerosis and propose treatment to control symptoms. Surveillance screening tests are also quite necessary. These tests can help to monitor the function of the organs most sensitive to the tuberous sclerosis, such as brain, kidneys, and lungs. Screening tests may contain magnetic resonance imaging (MRI), an ultrasound scan, spirometry, echocardiogram and blood tests. Special care plan is needed for children with detected learning and behavioural problems. It may include an appropriate educational plan for children to provide the most effective plan of studying. Also children with tuberous sclerosis can study in special educational centers or attend mainstream schools, but in this case they will need additional support. (Gipson TT,2014) IX. Treatment Plan There is not a universal treatment for tuberous sclerosis, because symptoms are different in individuals. Therefore treatment plan must respond need of each patient’s symptoms. Physicians have to conduct regular control and monitoring of patients with tuberous sclerosis throughout their life. The following monitoring and treatment plan is recommended for patients with tuberous sclerosis: Cranial MRI every 1 to 2 years for asymptomatic patients and every 5 years for asymptomatic. If subependymal giant cell astrocytomas are identified in the brain after a regular screening it is necessary to surgically remove them. Otherwise brain tumors can provoke a build-up of fluid in the brain. Renal imaging. Ultrasonography every 1 to 3 years in patients with no previous detected renal tumors. Half-yearly for individuals with angiomyolipomas smaller than 3.5-4cm in diameter. Everolimus can prevent growing of kidney tumors and bleeding. Also bleeding of kidney tumors can controlled using embolisation, blocking of blood that supply the tumor. Examination of neurocognition and neurodevelopment in response to changes in behavior, learning in children. Skin tumors usually are not dangerous and can be treated with laser therapy (Roach ES, 2004.) X. Appendix/ Bibliography 1. Hope Northrup, 2011. Tuberous sclerosis complex.[Online].Available at: < http://www.ncbi.nlm.nih.gov/books/NBK1220/ >. 2. Roach ES, 2004. Diagnosis of tuberous sclerosis complex.[ Online].Available at: < http://www.ncbi.nlm.nih.gov/pubmed/15563009>. 3. Paolo Curatolo,2012. mTOR inhibitors in tuberous sclerosis complex. [Online].Available at: < http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520048/>. 4. Gipson TT,2014. Early neurodevelopmental screening in tuberous sclerosis complex: a potential window of opportunity. [Online].Available at:< http://www.ncbi.nlm.nih.gov/pubmed/25160545>. Read More