Scientists are making significant strides toward understanding the science and genetics of TSC. Researchers identified the TSC1 and TSC2 genes in the 1990s. Technological advances and research since that time have also made it possible to better understand what is happening in the body at a cellular level. This understanding of the genetics of TSC goes hand-in-hand with clinical research and the development of treatments for the disorder.
Identifying TSC Mutations
Using current genetic testing methods, doctors are able to identify a mutation in either the TSC1 or TSC2 gene in about 85 percent of individuals who have been diagnosed with the disorder. In about 15 percent of people who have been diagnosed with TSC, however, doctors are unable to identify a mutation. This may be because there is a third or fourth gene that causes TSC that has not yet been identified. It is also possible that current genetic testing techniques are not yet sensitive enough to pick up all the mutations associated with the disorder.
The Variability of TSC
TSC mutations have highly variable manifestations. Some people are so mildly affected that they show few signs of the disorder. Others show clear signs of the disorder, but suffer few debilitating effects. Still others are dramatically affected by TSC, suffering from seizures, multisystem tumor growth, and serious cognitive dysfunction. Although much more research is necessary to determine what exactly causes the variability and spectrum of the disorder, researchers think that genes may point the way.
While either mutation can be expressed in symptoms both mild and severe, there is some evidence to suggest that a mutation in the TSC2 gene can produce more symptoms with greater severity than can a mutation in the TSC1 gene. This may be explained by the fact that the TSC2 gene is much larger than the TSC1 gene and that, as a result, TSC2 mutations are about six times more prevalent than TSC1 mutations.
Researchers may also find answers by looking to the nucleotides that make up the genes. The TSC1 and TSC2 genes together contain about 90,000 nucleotides. The majority of people diagnosed with TSC have the disorder as a result of a mutation in a single nucleotide pair, and that mutation can happen throughout either gene. In fact, scientists are still finding mutations via genetic testing that they have not seen in other families before. Research in this area may ultimately help scientists understand more about the relationship between the type of mutation and the manifestations of TSC.
Controlling Cell Growth
To understand how a mutation in one of the TSC genes allows tumors to grow, it is necessary to look inside the cell at a process called signal transduction. Signal transduction is the method by which the cell sends and receives signals that start, stop, or regulate activities such as cell division and programmed cell death. The body sends those signals through the proteins in the cell.
There are many protein pathways within the cell. The function of the TSC1 and TSC2 proteins, hamartin and tuberin, is to help regulate cell growth by acting as a brake in the protein signaling pathway.
Normally, the body sends a signal for growth by sending a growth factor, a naturally occurring protein that stimulates a cell to grow and divide. The growth factor triggers the activation of a series of proteins within the cell and, ultimately, the activation of a protein called AKT. AKT then signals the hamartin/tuberin unit and deactivates it. With the brake temporarily turned off, the signal for growth can continue, and cell growth and division can occur.
Most individuals have two functional copies of each of the TSC genes, so that if a sporadic defect occurs in one copy in a cell in some organ of the body, there is a back-up to insure that the brake still works in that cell. It is rare (but not impossible) that both copies would sporadically become defective in a given cell.
However, TSC patients have only one functional copy of one of the TSC genes, and sporadic loss of the remaining functional copy results in a cell—and ultimately a group of cells—without a breaking system. Uncontrolled cell growth eventually leads to the multiorgan tumors associated with TSC. This so-called "second hit" theory, also called loss of heterozygosity, may explain the variability among people with TSC. According to this theory, a "second hit" from a sporadic mutation of the only functional copy of the TSC gene in someone with TSC is required to begin the uncontrolled cell growth that leads to tumor formation. Thus, fewer sporadic mutations would lead to fewer tumors, and more sporadic mutations would lead to more tumors and a more severe case of TSC.
The understanding of the TSC protein signaling pathway is a recent and very promising development. Until now, doctors have only been able to treat the symptoms of TSC. Now there is hope that they will one day be able to control the development of the disorder itself.
Rapamycin is currently in clinical trial for kidney involvement, but it is unlikely that Rapamycin or similar drugs are going to completely solve the problems associated with TSC. This area of research is advancing rapidly, however. The more scientists understand about this pathway, the more likely they are to identify new targets where doctors may intervene with drugs in addition to, or instead of, Rapamycin. Some researchers think that combined therapies will provide the maximum benefit with minimum side effects to people living with TSC. (For more information, see Research.)
It is important to remember:
- TSC is a genetic disorder caused by a permanent change, or mutation, in one of two genes: TSC1 or TSC2.
- Following diagnosis, it is important to determine if the TSC mutation has been passed down through the family or if it is the result of a spontaneous, or new, mutation.
- A mutation to either the TSC1 or TSC2 gene can cause a wide and varied spectrum of symptoms.
- A genetic counselor or geneticist can provide information, support, and help with making various medical and reproductive decisions.
- Doctors recommend that immediate family members (parents and siblings) of those diagnosed with TSC be clinically evaluated for diagnostic signs of the disorder.
- If the TSC mutation has been identified in an affected individual, doctors recommend that his or her immediate family members (parents and siblings) undergo genetic testing for the disorder.
- Research has led to clinical trials involving the drug Rapamyicn, Other drug targets may be identified in the future.