Tuberous sclerosis complex is a constellation of signs and symptoms that constitute the diagnosis. In this update, the authors give a succinct overview of the topic while outlining advances in the treatment of multiple manifestations of the disease. New trials for the management of multiple clinical manifestations using precision medicine with mTOR inhibitors, with specific attention on neurologic issues, are discussed.
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• Tuberous sclerosis is a neurocutaneous disorder with significant neurologic implications, especially with regards to epilepsy and cognition. There have been tremendous gains made in recognizing and managing the protean disease manifestations just in the last decade.
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• Epilepsy is a common manifestation early in life.
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• Autism spectrum disorder are a very frequent manifestation of this disease, affecting about half of all patients.
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• TAND, tuberous sclerosis complex associated neuropsychiatric disorders, are increasingly recognized and include a wide range of disorders such as behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties.
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• Tumors are common and have a significantly improved prognosis with advances in treatment.
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• Significant progress has occurred in the last 15 years in the management of the clinical features of the disease based on advances in understanding of the pathogenesis and pathophysiology, specifically with the use of mTOR inhibitors.
Historical note and terminology
Désiré-Magloire Bourneville reported “tuberous sclerosis of cerebral circumvolutions” with “confluent vesiculopapular eruption on her nose, cheeks and forehead” in the necropsy of a young girl who had recurrent status epilepticus (14). The term “tuberous sclerosis” here refers solely to the discrete pathologic entity in the brain – a distinctive cortical pathology of raised, opaque, and sclerotic cerebral gyri with a potato-like firmness. Interestingly, almost 20 years previously, and perhaps unbeknownst to him, Von Recklinghausen had reported of a newborn infant with several cardiac "myomata" and numerous scleroses in the brain (119). Bourneville also reported periventricular white nodules projecting into the lateral ventricles of the brain, and tumors in the kidneys (14).
Subsequently, dermatologists in France (05) and in England (90) described a facial hamartoma, namely adenoma sebaceum, which was subsequently linked to seizures and mental retardation. Later, many authors reported of the association of “tuberous sclerosis” with dermatologic (85; 87), renal, cardiac, and pulmonary (73) abnormalities. The term “tuberous sclerosis complex,” therefore, best reflects involvement of multiple organ systems with development of distinctive tumors, or hamartomas. These associations in general and the Vogt triad (epiloia, an acronym for epilepsy, low IQ, and "adenoma sebaceum") in particular helped diagnose tuberous sclerosis complex in the living (118).
Recognition of the hereditary nature (07) of tuberous sclerosis, its wide clinical spectrum and evolution of the concept of "phacomatoses" (Greek "phakos" meaning "mother spot") (114) were seminal advances in the history of tuberous sclerosis complex. The radiological identification of intracranial calcification in tuberous sclerosis in 1924 (74) and the publication of a classic paper on this disease (19) were landmarks. Molecular techniques leading to identification of 2 tuberous sclerosis genes, TSC1 in chromosome 9q34.3 (40) and TSC2 in 16p13.3 (53) have been of momentous significance.
In 2006, the first case series reporting success in treating human astrocytomas with tuberous sclerosis complex by targeting mammalian (now mechanistic) target of rapamycin (mTOR) with oral rapamycin was published (38). Subsequently, reports of success of rapamycin (sirolimus) and everolimus in renal angiomyolipoma and lymphangioleiomyomatosis were published (122; 12). Everolimus and sirolimus (rapamycin) are being evaluated for multiple indications in tuberous sclerosis complex including epilepsy, subependymal giant cell astrocytomas, angiolipomas, and other tumors in multiple trials.