TSC Causes

Tuberous sclerosis complex (TSC) is a genetic disorder that results from a mutation in one of two genes that are present in virtually all the cells of the body at birth. 

It can't be "caught," in the way that an infectious disease can be caught, nor is it a disease like diabetes or cancer, which results from a combination of genetic and environmental factors.

Genetics and TSC

Every one of our cells (except red blood cells) contains a nucleus. Inside the nucleus are 23 pairs of chromosomes: one half of each pair is inherited from our mother, and the other half from our father. Chromosomes are built from two long strands of a molecule called deoxyribonucleic acid (DNA). Our genetic information is coded in these DNA molecules. DNA encodes all the instructions necessary for a living organism to grow.

The twisted-ladder-shaped DNA molecule is made of smaller molecules called nucleotides, or bases, that form pairs. Although there are only four different types of nucleotides in a strand of DNA (usually referred to by the first letter of their chemical name: A, T, C, and G), these molecules are repeated again and again—three billion times in every complete set of chromosomes. Genes are specific sequences of DNA located on chromosomes that provide instructions to make proteins. Each gene has a specific location on a particular chromosome. Humans have approximately 30,000 genes, including TSC1 and TSC2, two genes that code for proteins that help regulate cell growth and division.

A genetic disorder is a medical condition caused by permanent changes, or mutations, in the DNA sequence of a gene or a number of genes that interfere with the normal production of proteins. TSC is caused by a mutation in the DNA of either the TSC1 or TSC2 gene. The TSC1 gene is found on chromosome 9 and codes for the protein called hamartin. The TSC2 gene is found on chromosome 16 and codes for the protein called tuberin.

The reason a mutation in either the TSC1 or TSC2 gene can cause the same disorder is that the gene products, hamartin and tuberin, are analogous to two Lego pieces coming together to form a single unit. The normal function of this unit is to prevent cells from growing and dividing too fast or in an uncontrolled way. Hamartin and tuberin are called tumor suppressors because they work to keep the cells in check. If either part of the unit is missing or dysfunctional, the unit cannot perform its job well or at all. If that happens, cells can grow out of control, leading to the tumors that are characteristic of TSC.

TSC From Birth

Doctors refer to TSC as a congenital disorder, which means that it is present at birth. There are three ways in which a TSC mutation can occur in an individual.

All genes come in pairs. Some genetic conditions are called "dominant" because it takes a mutation in only one copy of the gene to cause the condition, despite the presence of one normal copy of the gene. In other genetic conditions, called "recessive," both copies of the gene must have a mutation to cause symptoms.

In inherited TSC, which accounts for about one-third of all TSC cases, a mutation is passed from a parent who has the disorder to a child. The disorder is passed down by autosomal dominant transmission, which means that only one copy of a gene, inherited from either the mother or the father, needs to have the mutation for the child to have the disorder. If a parent has TSC, with each pregnancy there is a 50 percent chance of passing the copy of the gene with the mutation—and TSC—to the child. If the parent passes on the copy of the gene that doesn't have the mutation, the child will not have TSC. Each person who inherits the TSC mutation will also have a 50 percent chance of passing the mutation on to his or her children.

About two-thirds of the cases of TSC are due to a spontaneous, or new, mutation. In these cases, known as sporadic TSC, neither parent carries the mutation. Instead, the mutation occurs in the affected individual during the earliest stages of development, at or just after fertilization.

Each time a cell divides, it must first replicate its DNA. Each division requires that billions of nucleotides be copied correctly. Inevitably mistakes occur, in which one nucleotide is substituted for another or a small stretch of DNA goes uncopied altogether. All of us have such mistakes, or mutations, in our DNA. Fortunately, most mutations occur in areas of the DNA strand, including portions of genes, that are not responsible for creating proteins. Mutations that do not interfere with protein synthesis and do not cause medical conditions are called benign polymorphisms.

Other mutations occur spontaneously in parts of the gene responsible for protein synthesis, and these are the mutations that cause genetic conditions such as TSC. Mutations that affect the ability of the TSC1 and TSC2 genes to synthesize hamartin and tuberin give rise to the manifestations associated with TSC. Those affected by this type of mutation also have a 50 percent chance with each birth of passing the mutation on to the next generation.

In a relatively rare phenomenon known as germline mosaicism, parents who show no signs of TSC can have multiple children who share a common mutation and have the disorder. In such cases, doctors usually conclude that the mutation arose at the germ line, or gonadal level, meaning that either some of the mother's eggs or some of the father's sperm cells carried the mutation. The other cells in the body do not have the mutation, and the parent doesn't show any symptoms. TSC results when an egg or a sperm cell that carries the mutation is involved in fertilization. The resulting child can then pass the mutation to future generations through autosomal dominance inheritance described above. Because of the occurrence of germline mosaicism the recurrence risk for a couple with a sporadically affected child to have another child with TSC is 1 to 3 percent.

When a person is diagnosed with TSC, it is important to determine if any other family members also have the disorder. Doctors encourage all immediate family members (parents and siblings) to undergo a full clinical evaluation, so that those who have the disorder can receive the monitoring and care they need.

It is important to determine if the mutation was passed down through the family, or if it arose spontaneously. If the mutation has been identified in one family member, doctors recommend that all immediate family members undergo genetic testing to determine if they too have the mutation. A genetic counselor or geneticist can help make those determinations and assist people in making future medical and reproductive decisions. (For more information, see Genetic Counseling.)

Promises of Research

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.

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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 braking 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.

Next Steps

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 Rapamycin, and other drug targets may be identified in the future