Tuberous sclerosis is a genetic disorder that is caused by a mutation in the TSC1 or TSC2 gene. The gene mutations may occur spontaneously or be inherited from a parent that possesses the defected gene.
This gene mutation causes changes to the function of certain proteins and leads to abnormal cell growth and the appearance of hamartomas in various organs of the body. The size, number and location of these tumors can vary greatly between patients and the factors that affect this are not well known at this point in time.
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TSC1 and TSC2 Gene Defects
TSC1 exists on chromosome 9 and is responsible for the production of hamartin protein, whereas the TSC2 gene is on chromosome 16 and produces tuberin protein.
It is believed that these proteins play a key role as growth suppressors that inhibit the activation of the kinase mTOR. When a gene defect alters the production and function of the hamartin or tuberin proteins, abnormal cell development and differentiation can occur, leading to enlarged cells and lesions in the body.
The exact mechanism of action of hamartin and tuberin is not fully understood and an alternative explanation is seen in Knudon’s 2-hit model of tumor genesis, which involves loss of heterozygosity that is found in many hamartomas around the bodies of people with tuberous sclerosis.
The defected TSC1 and TSC2 gene can be passed on to a child from a parent that carries the gene or can occur spontaneously in an individual with no family history of the condition.
Defected TSC1 and TSC2 genes follow an autosomal dominant pattern of inheritance. This means that both males and females are affected equally as it affects genes of neutral gender and that either parent with the gene may pass it on directly to any offspring.
If one member of a couple possesses the gene, all children have a 50% chance of inheriting the gene and having tuberous sclerosis. The symptoms that affect the child may differ considerably from the parent and may be milder or more severe.
Gonadal mosaicism is a form of inherited tuberous sclerosis that involves the gene defects present in some of the reproductive cells of the parent, even though the parent themselves do not carry the mutated genes. In this case, a blood test to detect gene mutations is futile as the parent is not affected but their reproductive cells affect the child.
The majority of cases of tuberous sclerosis occur as a result of sporadic genetic mutations in children with parents that are not affected by the disease. Rather than inheriting the mutated TSC1 or TSC2 gene, the mutation occurs in the individual and causes the disease to present.
It is worth noting that an individual with tuberous sclerosis that occurred sporadically is capable of passing the gene on to any children. In the same way as someone who inherits the gene, their children have a 50% chance of acquiring the gene and disease.
Genetic tests designed to recognize the presence of tuberous sclerosis can be used to confirm the diagnosis of symptomatic patients, to test family members of those with the disease or to make a prenatal diagnosis.
The genetic tests used in practice today are able to detect a mutation in the TSC1 or TSC2 gene in approximately 80% of those diagnosed with tuberous sclerosis, leaving approximately 1 in 5 symptomatic patients without definite genetic confirmation of the diagnosis.