Tuberous Sclerosis (Tuberous sclerosis complex) - Genes TSC1 and TSC2.

Tuberous sclerosis is a multisitémico Neurocutaneous syndrome characterized by a highly variable phenotype and the development of multiple hamartoma distributed throughout the body, particularly in brain, skin, retina, kidney, heart and lung. The classic triad of seizures, mental retardation and angiofibroma (sebaceous adenomas) is present in only 29% of affected individuals, indicating the heterogeneity of the syndrome and therefore difficulty in phenotypic diagnosis. Recent advances in genetics and molecular biology and generalization of diagnostic methods, such as sequencing, have facilitated the understanding of the nature and diagnosis of this complex disease. They also allow early recognition of tuberous sclerosis is essential, since rapid implementation of the diagnostic evaluation can prevent serious clinical manifestations. In most cases, this is not possible through a common diagnosis given the lack of pathognomonic signs until late childhood or even into adulthood.

The clinical features of tuberous sclerosis can be categorized as major and minor. The major features are a high degree of specificity, while the smaller are less specific or less are verified. In any case, it does not present a unique feature in all patients, although hypomelanotic macules are present in 97%, and none is specific complex of tuberous sclerosis. Besides hypomelanotic macules, among the largest features are facial angiofibromas (75-83%), ungual fibromas or Koenen tumors (88%), skin plaques (50%), retinal hamartomas nodular cortical tuber, subependymal nodule , giant cell astrocytoma subepindimario, rhabdomyosarcoma single or multiple heart, and kidney lymphangiomyomatosis angiomyolipoma. Among the minor features, can be found hamartomatous rectal polyps, multiple renal cysts, non - renal hamartomas, bone cysts, gingival fibromas and like skin lesions "confetti".

Tuberous sclerosis is due to mutations in the TSC1 gene, located on the long arm of chromosome 9 (9q34) and TSC2 gene, located on the short arm of chromosome 16 (16p13.3). Protein encoding genes TSC1 and TSC2, and tiberina hamartin respectively involved in controlling the proliferation and cell cycle by the existence of a close interaction between the two proteins, which form a heterodimer suppressor tumors. This complex inhibits mTOR (mammalian target of rapamycin), which is a key regulator of signaling controlling cell proliferation and organ size, phosphorylating two target proteins S6K1 and 4E-BP1 (4E-Binding Protein-1). S6K1 is a kinase that activates S6 ribosomal protein, which causes the ribosome recruitment and protein translation. 4E-BP1 protein represses factor action eukaryotic translation initiation (elF4E), but when it is phosphorylated by mTOR, eIF4E is released from its control.

There are more than 400 mutations in the TSC1 gene and more than 1,100 mutations in the TSC2 gene in individuals with tuberous sclerosis. Most of these mutations involve small deletions or insertions of DNA in the TSC1 gene, and insert or delete base pairs in TSC2. Some mutations create a premature stop signal to encode instructions hamartin or tuberin. People with tuberous sclerosis related TSC1 and TSC2 genes are born with a mutated copy of the gene in every cell. This mutation prevents the cell encodes functional protein from that gene copy. However, it is usually encoded and tuberin hamartin sufficiently from the other normal copy of the gene to regulate cell growth effectively. For some types of tumors to develop, there must be a second mutation affecting the other copy of the gene in certain cells during the life of a person. When both copies of the TSC1 or TSC2 gene are mutated in a particular cell, the cell can not encode functional protein. Loss of these proteins allows the cell to grow and divide uncontrollably to form a tumor. Hamartin deficiency or tuberin also interferes with normal development of certain cells. In individuals with tuberous sclerosis TSC1 and TSC2 related to a second gene mutation in multiple cells generally it occurs during the life of an affected individual. Hamartin loss and tuberin in different types of cells disrupts normal development and leads to the growth of tumors in many different organs and tissues.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to increase the risk of developing tumors and other problems with development. In about a third of cases, an affected person inherits an altered copy TSC1 or TSC2 gene from an affected parent. The remaining two thirds of people are born with new mutations in TSC1 or TSC2 the gene. These cases, described as sporadic, and occur in people with no history of disease in your family. The TSC1 mutations seem to be more common in familial cases of tuberous sclerosis, whereas mutations in the TSC2 gene are more common in sporadic cases.

Tests in IVAMI: in IVAMI perform detection of mutations associated with tuberous sclerosis by complete PCR amplification of the exons of the TSC1 and TSC2, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes. In case of prenatal diagnosis, amniotic fluid or chorionic villi.