Genetics and prognosis

Tubersous Sclerosis is an « autosomal dominant » disease. What does it mean? What are the transmission modes?

A genetic disease is said  » autosomal  » when the altered gene is not situated on a sexual chromosome (in this particular case, chromosome 9 or 16 for TSC1 or TSC2). The disease thus affects as much the boys as the girls.

We all have pairs of chromosomes in our cells, and consequently, two allels (or two versions of the same gene). When only one allel has to be affected so that the disease occurs, the allel is then « dominant »; this is the case for Tuberous Sclerosis which is thus called an  » autosomal dominant  » disease.

The Tuberous Sclerosis can be:

- of familial origin (30 % of the cases approximately) if one of the parents is affected

- the result of a neo-mutation (70 % of the cases approximately) when none of the parents is affected by the disease.

1-Family Transmission

When one of the two parents is a carrier of the disease, as the disease is  » autosomal dominant « , there is a 50/50 chance that the child be affected by Tuberous Sclerosis.

Family autosomal dominant transmission:

2-De-novo Transmission or neo-mutation

2a-The parents do not have the disease. A spontaneous mutation arises, randomly and for unknown reasons, in the egg or the sperm cell which will constitute the embryo. It is then a  » de-novo  » mutation, strictly speaking.

2b-In less frequent and particular cases, there is however a situation which is called « germline mosaicism « . The parents do not present the disease but one of the two is carrying a genetic abnormality in some of his reproductive cells (sperm cells or eggs). These disorders are not detectable. Testicles or ovaries present then a double population of cells, certain cells being carriers of the genetic disorder while others are no ; it is what is called  » germline  mosaicism « .

When a child is affected by the disease, and the parents are not, it is recommended to have a genetic advice for the rest of the family. When none of the parents are affected, the probability to have a second child affected by the disease is low, but is not zero. The probability is estimated by the scientific literature at 2 %.

Genetic diagnosis of Tuberous Sclerosis

Intracellular pathways – mTor 1 and 2 – in Tuberous Sclerosis 

Today, diagnosis is mainly based on the association of at least two symptoms  (cardiac, cutaneous, renal, intellectual, etc.).

It is also recommended to have a genetic diagnosis. This genetic diagnosis will  specify witch metabolic pathway is predominently affected.

Genetic studies in Tuberous Sclerosis highlight two genes at the origin of the disease, which are tumor suppressor genes: TSC1 (chromosome 9) and TSC2 (chromosome 16) coding respectively for hamartine and tuberine with consequences on mTORC1 and mTORC2 cell pathways.

What Prognosis for a child with TSC ­?

It is difficult to establish a reliable prognosis and anticipate the psychomotor and social development of a child with Tuberous Sclerosis. The prognosis  depends on the severity of symptoms, which go from slight abnormalities of the skin to diverse degrees of disorders (learning disabilities, epilepsy or  renal insufficiency). Besides, within the same family, each individual can be differently affected by the disease.

The people having mild symptoms will have a normal or quasi-normal life, whereas the individuals with more severe symptoms can have heavy handicaps. However, with appropriate medical care, most of the people with TSC have normal life expectancy.

A clinical trial concerning 30 patients STB asserted that  » the earlier the beginning of the epileptic seizures, the more mental retardations are likely to be important « .

The identification of mutation of TSC 1 (gene on the chromosome 9) is significantly more frequent in family cases than in sporadic cases. TSC 1 mutation is identified in only 20 % to 30 % of the patients.

The frequency of TSC 2 mutation (gene on the chromosome 16) is higher than that of TSC

1. TSC 2 is also associated with a more severe disorders than TSC 1.

TSC 2 may also cause larger genomic deletions. So, the patients affected by TSC 2 are susceptible to have more severe symptoms (largest number of cortical tubers, more severe epilepsy, autism, angiomyolipomas).

It is very likely that the patients with TSC 2 have more important renal impairment given the location of the defective gene close to that of the renal polykystosis.

Can I have children if I am affected by Tuberous Sclerosis ?

It is obviously possible to have children when you are affected by Tuberous Sclerosis. However, it is necessary to know, that according to genetics, there exists a 50/50 chance that your child be also affected, if your spouse is not.

For women affected by STB, it is always desirable that the pregnancy be anticipated and prepared at best to avoid some complications.