Genetics of tuberous sclerosis complex: an update
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ANNUAL ISSUE PAPER
Genetics of tuberous sclerosis complex: an update Daphna Marom 1,2 Received: 21 May 2020 / Accepted: 3 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose To review the current genetic aspects of tuberous sclerosis complex. Methods Review of the literature. Results Tuberous sclerosis complex (TSC), a long known childhood-onset monogenic disorder, characterized by hamartoma formation affecting mainly the brain, heart, kidney, lung, and skin, is associated with a high morbidity burden and risk of a reduced life span. The identification of TSC1 and TSC2, as tumor suppressor genes causative of the disorder, led to the elucidation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and its pivotal role in the pathogenesis of hamartoma formation. This knowledge was translated into standard clinical practice with the discovery of rapamycin, and additional analogues, as inhibitors of mTORC1. Conclusion Next-generation sequencing was proven to be fundamental to drive research of tumorigenesis in TSC, hopefully leading to new therapeutic options in the future. Keywords TSC1 . TSC2 . mTOR pathway . Hamartoma
Tuberous sclerosis complex (TSC) is a well-characterized genetically inherited systemic disorder, with an estimated incidence of 1:6,000–10,000 live births and a population prevalence of 1:20,000, with no known ethnic predilection [1]. This review summarizes the genetic aspects of the disorder, its contribution to the understanding of disease pathogenesis, and the development of precision medicine. The term tuberous sclerosis was first coined by the French neuroscientist Désiré-Magloire Bourneville in 1880. He described autopsy findings of L. Marie, an intellectually disabled 15-year-old girl who suffered uncontrolled epilepsy including focal seizures and episodes of status epilepticus starting at the age of 2 years. The post-mortem examination revealed several sclerotic areas involving cerebral convolutions, termed by Bourneville as tuberous sclerosis of the cerebral convolutions [2]. Others provided descriptions of the typical skin, cardiac, and renal lesions as part of what would later be recognized as a
* Daphna Marom [email protected] 1
Human Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
2
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
multisystem disorder that may affect any human organ. To name a few, Friedrich Daniel von Recklinghausen described cardiac rhabdomyomas and brain scleroses in a deceased newborn in 1862, Félix Balzer; Pierre-Eugène Ménétrier and John James Pringle separately described “adenoma sebaceum” (later understood to be facial angiofibromas) in the late nineteenth century, and Heinrich Vogt related renal nodules (later understood to be angiomyolipomas) as part of TSC in 1908. For many years, the triad described by Vogt, namely seizures, mental handicap, and adenoma sebaceum, was used to clinically diagnose TSC [2]. The pathologic lesion and main morbidity of TSC lie
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