Dr. Elizabeth Thiele
The Carol and James Herscot Center for Tuberous Sclerosis Complex (TSC) at Massachusetts General Hospital and MassGeneral Hospital for Children sees over 250 patients per year. A first diagnosis can take place anywhere from five months old (but sometimes even before birth) to over seventy years of age – quite a broad spectrum, which provides some insight as to how complicated and variable this disease can be.
TSC is a genetic disorder that causes benign tumors to grow throughout the body. Even though these tumors are rarely malignant or cancerous, they affect various organs and organ systems, which can pose a variety of serious health problems throughout an individual’s life. The most common symptom of TSC is epilepsy, and at least 85 percent of people with the condition experience seizures.
The disorder is caused by a mutation in one of two genes, TSC1 or TSC2. A mutation in either of these genes interferes with the body's ability to control cell growth and division. The disorder can occur sporadically as the result of a spontaneous mutation, or it can be genetically inherited.
Scientists have found that the TSC1 and TSC2 proteins are key components of the mTOR pathway – a heavily-trafficked area within cells as a main throughway for metabolic processes. A recent NIH conference demonstrated how prominently these genes factor in cancer, cognition and memory ability, and growth and nutrition. As these genes prove a vital part of metabolic processes, and show up in many diseases and disorders, Tuberous Sclerosis Complex can be used as a model to show which molecules introduced into the system (such a new drugs) can help reduce or eliminate the abnormal functioning that causes problems within the pathways – be it tumor growth or obesity.
Though tumors in TSC patients are generally benign, scientists are beginning to see them as a means to help them better understand the biological components of cancerous ones. They may hold clues to understanding tumor biology and pathways. Although there are drugs that are created to treat cancerous tumors, their trials often take a long time to produce results, mainly because patients are often followed for the rest of their lives before any conclusions are made. Recently, some of these drugs have been found to shrink tumors in TSC patients.
“In a patient with TSC, we can see if a tumor has shrunk within a few months,” says Elizabeth Thiele, MD, PhD, director of the Herscot Center. “If the drug is making tumors shrink in multiple patients, I know it’s something that I should have available to prescribe to the appropriate patients.”
Thiele says the results gleaned from TSC patient studies may be applicable to cancer patients. New options may be made available in a more timely and less costly fashion because researchers are only testing for tumor size, not improved survival. If the tumor has shrunk throughout the trial, they know they’re onto something. The hope is that the same therapies used to shrink the benign tumors in TSC could be used to shrink and eliminate the cancerous ones.
The neurocognitive team at the Herscot Center has extensive experience with the learning, cognitive, and behavioral aspects of TSC, including autism. Autism occurs in up to 40 percent of people with TSC – a statistic Dr. Thiele finds fascinating.
“As a population, individuals with TSC have one of the highest incidences of autism,” says Thiele. Though this link to autism has been characterized in TSC since the early thirties, the medical community is still searching for the genetic reason why. “If we can gain a better understanding of autism in TSC, it might lead us to a better understanding of autism in the general population.”
Researchers are taking a closer look at TSC patients to try to identify genes specific to autism. They do this by studying TSC patients with autism and comparing them to TSC patients without autism. If they can identify a modifier gene in this group, they can then see if this gene is the same in autistic patients without TSC, which could help the medical community find more targeted therapies for this population.
Obesity is a rapidly growing problem in this country, as well as in many other parts of the world. While it remained an adult issue for some time, we are now seeing an increase in obese children. One out of three children in the United States is considered overweight, and the trend seems to be increasing.
As previously noted, the TSC1 and TSC2 proteins play a major role in the metabolic processes of cells. Researchers wonder whether further study of these proteins could shed some light on the obesity epidemic in the modern world and possibly lead to therapies that would inhibit the body from becoming obese.
“Since it is known that the mTOR pathway is vital in human growth and nutrition, it is feasible that developing a better understanding of how the pathway is deregulated in individuals with TSC may lead to a better of understanding of the mechanisms involved in obesity,” says Thiele.