Phenotypic Variability in Tuberous Sclerosis Complex (TSC)
Abstract
Tuberous sclerosis complex (TSC) is caused by mutation of one of two genes, TSC1 or TSC2, which results in hyperactivation of the mTOR signaling pathway. Patients with TSC can range from having profound intellectual disability to normal intelligence, from intractable epilepsy to no seizures at all, and from being completely dependent on others for the entirety of their care to being highly skilled professionals in society. However, it is not known what factors account for this variation in disease severity. In fact, one can see dramatic variation in disease severity even within a single family in which all affected individuals have the same gene mutation. This observation suggests that factors other than the primary gene mutation determine disease severity. Our goal is to define these factors. The mTOR pathway is a critical integrator involved in growth regulation of all cells in the body. Research advances in this field have led to the development of mTOR inhibitors as treatments for complications such as SEGAs (subependymal giant cell astrocytoma) and renal AMLs (angiomyolipomas) that are experienced by TSC patients. Current practice consists of using mTOR inhibitors only following progressive enlargement of these types of lesions. Traditionally, treatment for TSC patients has been completely based on symptoms -- anticonvulsants for epilepsy, surgery for acute hydrocephalus or intractable epilepsy, vascular procedures for renal angiomyolipomas, or conventional psychoactive drugs for behavioral problems. Drugs that inhibit mTOR offer the possibility of fundamentally altering the course of disease in patients with TSC. These drugs, however, do have significant potential adverse effects (mucosal ulcers, immunosuppression, non-infectious pneumonitis, hypercholesterolemia, hypertriglyceridemia) and thus should be used only when their long-term benefits outweigh risks of treatment. Currently, patients are being diagnosed with TSC at a very young age, and sometimes prenatally. These young infants are typically asymptomatic and develop more typical features of TSC with age. Unfortunately, genetic testing during infancy is not predictive of which patients will progress to develop severe disease or mild disease. Ideally, one would select patients for treatment with disease modifying drugs such as mTOR inhibitors before they developed serious symptoms. This is not possible now due to the lack of a method for predicting disease severity. In this application, we propose that modifying genetic factors involved in the mTOR pathway contribute to modulation of disease severity. A key innovative aspect of research design is the recruitment of parent-child pairs with TSC, both with the same genetic mutation. We focus on P-C pairs where the parent is mildly affected and the child is severely affected, eliminating patient age as a confounding factor. By applying the latest in next-generation whole exome and RNA sequencing technologies, comparing parent to child in each pair, we expect to identify genetic changes that account for the differences in disease severity between parent and child. We hope to define a blood-based molecular profile or molecular signature that will allow us to predict disease severity in a given patient. The results of this research will be readily applicable to human patients with TSC. We expect that, if our ideas are validated, we will be able to develop a blood test that can be used to select patients for pre-symptomatic treatment with disease modifying drugs such as mTOR inhibitors. An added benefit of this research is to uncover other potential novel therapeutic targets that may modify disease severity.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710151
Entities
People
- Vinodh Narayanan
Organizations
- Translational Genomics Research Institute
- United States Army