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.
Although experts still aren't sure why, the same mutation of a TSC gene can affect different people differently. For example, a mildly affected parent can have severely affected children, despite the fact that they share the same mutation.
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.
Genetic Counseling and Testing
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.)