Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference

Abstract

On March 10–12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. This review summarizes outcomes from the extensive pre-meeting deliberations and final workshop recommendations, and includes: 1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex; 2) the key gaps, needs and challenges that hinder progress in tuberous sclerosis complex research; and 3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five- to ten-year timeframe.

Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

“…Cortical tubers, a form of focal cortical dysplasia, are thought to be major contributors to these disabling neurological manifestations in TSC and are targeted for surgical resection in TSC patients with pharmacologically intractable epilepsy 6 – 8 . Although the current surgical and pharmacological management of seizures in TSC often provide significant benefits 5 , 7 , 9 , 10 , there is further need for a better understanding of the molecular and physiological basis of the neurological manifestations seen in TSC 11 .…”

Neurobiological bases of autism–epilepsy comorbidity: a focus on excitation/inhibition imbalance

“…123 I‐iomazenil SPECT and 1 H‐MRS revealed a significant decrease in GABA A receptor binding and increased GABA levels in cortical tubers from tuberous sclerosis complex (TSC) patients (Mori et al ., ). TSC presents a high degree of ASD–epilepsy comorbidity (Sahin & Sur, ; Buckley & Holmes, ; Sahin et al ., ). The authors hypothesized that seizures in TSC might be caused by decreased inhibition that was secondary to the reduced levels of GABA receptors in the cortical tubers, increased GABA levels being a compensatory mechanism for reduced inhibition (Mori et al ., ).…”

Applying the Lessons of Tuberous Sclerosis: The 2015 Hower Award Lecture

“…72,76 Impaired local protein synthesis in axonal growth cones and synapses could represent a unifying mechanism for these seemingly different processes. 77 There are now several animal models of TSC, 78 but mice with prenatal loss of neuronal TSC1 by Meikle et al 79 was a notable early contribution because the animals replicated several of the clinical and neuropathological features of TSC in humans. These mice failed to thrive and experienced sometimes fatal seizures, typically dying between three weeks and two months of age.…”