Genetics
TSC is a genetic disorder with an autosomal dominant pattern of inheritance, variable expressivity, and incomplete penetrance. Two-thirds of TSC cases result from sporadic genetic mutations, not inheritance, but their offspring may inherit it from them. Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease. So far, it has been mapped to two genetic loci, TSC1 and TSC2.TSC1 encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. TSC2 encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. TSC2 is contiguous with PKD1, the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop polycystic kidney disease in childhood. TSC2 has been associated with a more severe form of TSC. However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by TSC2 range from 55% to 90%.TSC1 and TSC2 are both tumor suppressor genes that function according to Knudsons "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its high penetrance, TSC has wide expressivity. Pathophysiology
Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division.
Cardiac allograft vasculopathy (CAV) is a progressive type of coronary artery disease in people who have had a heart transplant. As the donor heart has lost its nerve supply there is typically no chest pain, and CAV is usually detected on routine testing. It may present with symptoms such as tiredness and breathlessness.It arises when the blood vessels supplying the transplanted heart change in structure. They gradually narrow and restrict its blood flow, subsequently leading to impairment of the heart muscle or sudden death. In addition to the same risk factors for coronary artery disease due to the build up of plaque, CAV is more likely to occur if the donor was older or died from explosive brain death, and if there is cytomegalovirus infection. Its mechanism involves immunological (innate and adaptive) and nonimmunological factors, with distinct features on histological samples of coronary arteries. Other major causes of death following heart transplantation include graft failure, organ rejection and infection.Diagnosis is by regular follow-up and monitoring of the transplanted heart for early signs of disease. Tests include coronary angiography, intravascular ultrasound, dobutamine stress echocardiography, positron emission tomography, computed tomographic angiography (CT angiography) and several biomarkers.Statins and aspirin are commenced early after transplantation and on detection of CAV. Medications including sirolimus and everolimus can slow disease progression. A repeat heart transplantation may be required.CAV affects around half of heart transplant recipients within 10 years. It contributes to the death of 11-13% one year from heart transplantation.