Elsevier

Brain and Development

Volume 31, Issue 2, February 2009, Pages 104-113
Brain and Development

Review article
Recent advances in neurobiology of Tuberous Sclerosis Complex

https://doi.org/10.1016/j.braindev.2008.09.013Get rights and content

Abstract

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with variable phenotypic expression, due to a mutation in one of the two genes, TSC1 and TSC2, and a subsequent hyperactivation of the downstream mTOR pathway, resulting in increased cell growth and proliferation. The central nervous system is consistently involved in TSC, with 90% of individuals affected showing structural abnormalities, and almost all having some degree of CNS clinical manifestations, including seizures, cognitive impairment and behavioural problems. TSC is proving to be a particularly informative model for studying contemporary issues in developmental neurosciences. Recent advances in the neurobiology of TSC from molecular biology, molecular genetics, and animal model studies provide a better understanding of the pathogenesis of TSC-related neurological symptoms. Rapamycin normalizes the dysregulated mTOR pathway, and recent clinical trials have demonstrated its efficacy in various TSC manifestations, suggesting the possibility that rapamycin may have benefit in the treatment of TSC brain disease.

Introduction

Tuberous Sclerosis Complex (TSC) is a dominantly inherited disease of high penetrance, pathologically characterized by the presence of tumour-like lesions (hamartomas) in multiple organ systems, caused by mutations in one of the tumour suppressor genes, TSC1 or TSC2 [1]. The most common neurological manifestations of TSC are epilepsy, mental retardation, cognitive impairment, challenging behavioral problems, and autism [2]. Progress in structural and functional imaging has led to further characterization of the brain lesions, including cortical tubers, subependymal nodules (SENs), subependymal giant cells tumors (SGCTs) and white matter abnormalities [3], [4]. The TSC1/TSC2 complex plays an important role during cortical development and growth control. At distinct stages of central nervous system (CNS) development, including morphogenesis, cell adhesion/migration and cell fate determination, a precise interaction of tuberin and hamartin appears critical. Gene mutations in either of the two TSC genes influence neural precursors between weeks 7 and 20 of gestation to result in disrupted cell division, abnormal cell differentiation, dysregulated cell size control and abnormal cellular migration [5].

While the molecular basis of TSC is well established, far less is known about the pathogenetic mechanisms of the neurological manifestations in this disorder. This review highlights the most recent significant advances in the neurobiology of TSC that come from molecular biology, molecular genetics and animal model studies. These advances provide exciting clues to the underlying neurological abnormalities in TSC, and point towards new therapies for this complex and severe disorder.

Section snippets

Genotype/phenotype correlations

TSC is due to inactivating mutations in either of two genes, TSC1 (on chromosome 9q34) encoding hamartin, or TSC2 (on chromosome 16p13.3) encoding tuberin. 393 TSC1 and 1118 TSC2 unique allelic variants have been reported [6], [7], [8], [9], [10] (http://chromium.liacs.nl/lovd/index.php?select_db=TSC1or_db=TSC2). These mutations comprise the usual mix of nonsense, missense, insertion and deletion mutations, involving nearly all of the exons of TSC1 and TSC2.

New mutations have been implicated in

Recent advances in epileptogenesis

In TSC seizures represent the most common symptom, and the most common medical problem [22]. The majority of children with TSC have their seizure onset during the first year of life, and up to one third of them will develop infantile spasms [1]. Presently, the treatment of epilepsy remains a major challenge. Many patients with TSC continue to have intractable seizures, with a poor response to both established and new anticonvulsant medications [23]. Furthermore, in approximately one third of

Recent advances in the pathogenesis of cognitive and behavioural phenotypes

Similarly to the physical manifestations there is a striking variability of neurocognitive manifestations and psychopathologies in TSC [45]. Around 45% of individuals with TSC have some degree of cognitive impairment, ranging from profound disabilities to mild learning problems [46]. Approximately 30% of individuals with TSC are profoundly impaired, and show little or no developmental gain overtime. In the same family some individuals are profoundly impaired and have severe autism and

Recent advances in animal models

Analyses of “historical” animal models used for TSC (TSC1–2+/− mice, and Eker rats) have not greatly advanced our understanding of mechanisms of CNS dysfunction in TSC; however these findings established the absolute requirement of both the TSC1 and TSC2 genes for early rodent development and indicated the need for alternative experimental systems to study CNS function. One such approach used the Cre/LoxP system to conditionally inactivate the TSC1 gene in mice using the human glial fibrillary

New therapeutic approaches

Rapamycin is a potent translational modifier in neurons although its effects on gene transcription and neuronal development are poorly understood. Rapamycin mediates protein synthesis stimulated by brain derived neurotrophic factor and has also been shown to have direct neurophysiological effects [70], [71]. The single channel activity of the Ca2+-dependent K+ channel is modulated by rapamycin through its direct association with the FK506 binding protein-12 (FKBP12) [72]. Rapamycin might also

Future directions

As the functions of the TSC1 and TSC2 gene products are now better defined, a clearer understanding of how these genes regulate normal cortical development will be generated. Several important questions remain that are under intense investigation. Understanding the exact relationship between tuberin and hamartin function and neuroglial proliferation, and the role that TSC mutations may play in aberrant neural migration, will provide critical insights into the pathogenesis of tubers and SGCTs

Acknowledgement

This paper was read at International Symposium Celebrating the 50th Meeting of the JSCN on May 2008, Part I: Recent Advances in Child Neurology.

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