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Tuberous sclerosis

Types

There is one type, but there are 2 different genes that can cause it.

Clinical signs

The disease involves a large number of body systems. It manifests as a wide variety of lesions, most of which are cutaneous (skin) with a risk of tumors, which are usually benign.

Prominent signs are ash leaf-shaped bright, unpigmented spots. There may be benign tumors in the brain - these can cause severe convulsions (epilepsy) during childhood. It is important to diagnose these early in order to allow effective intervention and prevention of brain damage, which can occur in cases not treated early. Mental retardation can occur in approximately 50% of cases - as noted, mainly in patients with convulsions who are not treated early.

In childhood and adolescence onwards, benign skin tumors, known as adenoma sebaceum, may appear, particularly on the face and around and on the nose - they constitute mainly a cosmetic problem. In addition there may be benign tumors under the nails.

Imaging


In about half of the cases an X-ray of the skull or CT scan of the brain will show characteristic calcifications of the brain - however, these calcifications are not associated with mental retardation, as opposed to the colloquial term -calcified brain-.

There may be characteristic cysts or benign tumors in the kidneys - these are known as angiomyolipomas.

They originate from muscle, fat and blood vessels and can be demonstrated by ultrasound examination.

Complications

There is a slightly increased risk of developing benign tumors in internal organs, around the kidneys, in the meninges, the optic nerves, etc. These tumors can cause local pressure or hemorrhaging and resultant local damage. There may infrequently be other complications as well such as malignant tumors in the brain tissue (astrocytomas) and in other tissues.

In the fetus

There may be tumors in the heart muscle - these are situated in the heart chambers in which the blood flows and can be large. However, in the months after birth, these tumors resolve without treatment.

Inheritance pattern

The disease is transmitted by autosomal dominant inheritance. This is supported by the presence of additional cases of tuberous sclerosis in one of the parents or other family members. However, approximately 85% of cases are born to healthy parents, and in these cases there is a new mutation in that specific fetus.

Penetrance

Usually full - i.e. carriers of the abnormal gene exhibit the characteristic signs of the disease. This means that those family members who do not have the characteristic signs most probably (97% probability) do not carry the abnormal gene. In order to establish that family members do not have signs of the disease, the skin must be examined carefully for unpigmented spots, skin tumors around the nose or masses under the nails, etc. and they should be referred for ultrasound examination of the kidneys and CT scan of the brain,

Sometimes it only becomes apparent that an individual is affected after he or she has undergone a thorough examination in order to look for the signs of the disease. Without asking questions and making an in-depth investigation of the family, it is not always possible to know this, as some cases are expressed very mildly.

If the same condition is found in other family members, including in one of the parents, it can be assumed that this is the familial/hereditary type. This is important for the genetic and molecular investigation of the family.

Associated features demonstrated by imaging tests in pregnancy

Ultrasound scanning can be used during pregnancy to attempt to identify tumors in the fetal heart. Fetal echocardiography can also be performed.

Associated features demonstrated in tests performed during pregnancy

Genetic counseling before pregnancy is important. In these cases, preliminary tests must be carried out on family members and the risk of recurrence ascertained based on the number of patients and their relationship to the patient.

Family preparation for pregnancy: if molecular testing of the couple is required, it must be taken into account that this is a relatively long process that must be started before pregnancy. Only after completing the molecular analysis before pregnancy can prenatal diagnoses be undertaken in subsequent pregnancies.

During the pregnancy, all the data must be assessed, including the results of additional tests performed during the pregnancy such as alpha-fetoprotein, nuchal translucency, echocardiography, molecular tests, etc.

What is the risk of recurrence in a subsequent pregnancy?

A. In cases where the patient is the only one in the family

If this is the first case in the family, there is a high probability that the disease in the child is a result of a new mutation in the gene for tuberous sclerosis - i.e. the hereditary transmission starts with the child, and there is a 50% chance in every pregnancy that he or she will transmit the abnormal gene to his or her offspring. On the other hand, in these cases, the parents and other family members who are not offspring of the patient apparently have only a small risk for having another affected child (approximately 2%).

B. In cases where there are many affected individuals in the family

The situation is different if there are already other cases in the family, because here one of the parents of each affected individual also carries the abnormal gene for tuberous sclerosis, and the risk of transmitting this to the offspring is 50% in every pregnancy, although it may not always be expressed. Because the gene for this disease is not always expressed, one of the parents may carry it without having the disease him- or herself. In such situations, of course, there is a 50% risk of recurrence in every subsequent pregnancy, and the same risk of recurrence also applies to more distant relatives who carry this abnormal gene. The risk of transmitting the condition is less than 2% - 3% if the parents have undergone testing as above and have been found not to carry the abnormal gene, and if there are no other cases of affected family members in previous generations in either of the patient-s parents - i.e. the disease in the child has been caused by a new mutation.

For more distant relatives, the risk is established based on the pedigree, the results of tests such as chromosome analysis, etc.

Molecular genetic information

The gene for the disease

There are at least 2 genes that cause tuberous sclerosis. One is called TS2, which is responsible for 50% of the cases, and the other, TS1, is responsible for the rest. The clinical manifestation cannot be used to determine which of the two genes is responsible for the disease in any specific family. Before any diagnostic testing can be carried out, the gene responsible for the disease in the family in question must be determined.

Location

TS2 is situated on chromosome 16p, and TS1 on chromosome 9q.

Genetic testing

Diagnostic testing

The direct test for identifying the mutation is relatively complex. There are a number of major problems:

There are two genes. In each family, the gene is different. The genes are large and determining the sequence of the bases comprising them in order to identify the mutation is a difficult, time-consuming, expensive and currently impractical process, although it may well become simpler in the future. See information sheet: Finding the defect (mutation) by establishing the gene sequence - autosomal dominant diseases. In special cases such a test may be performed on patients, although it is impractical during pregnancy, in a research setting through genetic institutes.

In the familial cases it is possible to perform indirect testing - such testing is relatively simple, available, and can be completed within a short space of time (about a month). This test is called linkage analysis. Genetic markers that are situated on the chromosome near to the gene for tuberous sclerosis are used - these markers define a unique pattern for each gene without examining whether there is a mutation in the gene. Using these markers, the transmission of the genes in the family is followed - the genetic pattern common to the affected individuals is probably the one containing a mutation. Every individual who in family or fetal tests has been found to have this same pattern will have received the abnormal gene.

Because the test is indirect, and because there are two different genes that can cause the disease, the test is more reliable the more family members that are tested. The more subjects there are in the family, the greater the confidence with which the relationship between a specific pattern and the disease can be established, and the greater the confidence for absolute certainty for which gene (TS1 or TS2) is causing the disease in that specific family. Of course, an error in defining the gene responsible for the disease in the family being investigated will lead to a mistaken conclusion as to the determinant gene in that family.

The test is usually deemed reliable only if at least 5 known affected individuals in the family are tested. When there is no choice, it is possible to manage with fewer patients, but this is undesirable because the reliability of the test is greatly reduced to the point where it is non-contributory. See information sheet: Indirect testing for genetic markers in a family that has a number of patients - when there are a number of genes that can each cause the disease - all genes having been located / identified / mapped - autosomal dominant diseases.

Carrier testing

The test for detecting a carrier of an abnormal gene in an autosomal dominant disease where the condition is not clinically expressed is in fact the same as the diagnostic test.

Fetal testing

This is an indirect test as specified above. See information sheet: Indirect testing for genetic markers in a family that has a number of patients - when there are a number of genes that can each cause the disease - all genes having been located / identified / mapped - autosomal dominant diseases.

 
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