Individuals & Families

TSC Research Article Summaries: Genetics

Tuberous Sclerosis Complex

Author(s): Elizabeth P. Henske, Sergiusz Jóźwiak, J. Christopher Kingswood, Julian R. Sampson and Elizabeth A. Thiele
Nature Reviews: Disease Primers; Published online 26 May 2016

This article is an overview of tuberous sclerosis complex (TSC) scientific knowledge to date. Much of the information on diagnosis and management of TSC are summarized from publications on the 2012 Consensus Conference, which can be accessed here and here.

Tuberous sclerosis complex (TSC) is a genetic disorder that occurs when either the TSC1 or TSC2 gene is mutated. In around 10% of people with TSC, genetic testing cannot find their mutation. Previously it was suspected that there might be another TSC gene, however a recent study demonstrated that most of these people either have a TSC1 or TSC2 mutation in only some of their cells (mosaicism) or they have mutations in parts of the chromosome near TSC1 or TSC2. Therefore, it is considered unlikely that another TSC gene exists.

Some damage from TSC mutations is thought to occur during brain development of a fetus, perhaps leading to the high tendency toward epilepsy and autism. Other problems such as tumors (like angiomyolipomas, angiofibromas, SEGA) could possibly result from additional damage to the DNA later in life. A study has shown an association between UV skin damage and angiofibromas.

The TSC genes produce proteins (hamartin and tuberin) that together regulate cell growth via the mTOR pathway. When they are damaged, there is too much mTOR and the cell grows out of control. Drugs called mTOR inhibitors seem to do the job of the missing proteins and return the cell to normal behavior, stopping and even reversing tumor growth. Examples of these drugs include rapamycin, sirolimus, everolimus, RAD001, and Afinitor.

In this article the authors review the current therapies and recommendations for each body system affected by TSC, oddly omitting the cardiac (heart). In most cases they recommend earlier and more aggressive treatment of the various manifestations, and advocate for more research regarding preventative use of mTOR inhibitors. For example, patients might begin taking the drugs after diagnosis with TSC but before symptoms like infantile spasms or LAM appear.

While there are not a lot of data about long term use of mTOR inhibitors in TSC, these medications have been used in transplant patients since 1999 and those data have been studied. Concerning side effects include mouth sores, wound-healing, diabetes, high cholesterol, delayed sexual maturity and possible infertility, blood abnormalities, and chronic immune suppression. The authors note that most people suffer mild to moderate adverse effects with these drugs, and many reverse when the treatment is stopped. Some animal studies have shown improved health and lifespan with mTOR inhibitors, so more research could reveal long-term benefits in addition to treating TSC symptoms.

Currently, those who begin treatment with mTOR inhibitors need to stay on them indefinitely or the tumors will likely regrow. Research has shown that it is possible mTOR inhibitors may actually prolong the life of the cell even as it suppresses its tumor growth, so a key area of future research is to find a way to kill the TSC tumor cell. In the meantime, many scientists and clinicians focus on the best way to use the existing treatments such as mTOR inhibitors. An initiative called TSCure has been formed toward this end. This group “aims to tackle issues that are necessary to plan clinical trials of very early treatments to either cure TSC or prevent manifestations of TSC from occurring rather than treating them when they appear.”

This summary was written by Cristy Wade, MS, parent of child with TSC, clinical research coordinator, and peer reviewer for the Tuberous Sclerosis Complex Research Program (September 2016).

Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing

Author(s): Magdalena E. Tyburczy, Kira A. Dies, Jennifer Glass, Susana Camposano, Yvonne Chekaluk, Aaron R. Thorner, Ling Lin, Darcy Krueger, David N. Franz, Elizabeth A. Thiele, Mustafa Sahin, David J. Kwiatkowski
PLOS Genetics  This is an open access article published November 5, 2015.
DOI: 10.1371

What is the topic?

This article focuses on understanding the cause of tuberous sclerosis complex (TSC) in patients whose genetic mutation was not identified by standard genetic testing. About 10-15% of the TSC population is NMI (no mutation identified). Since they have been diagnosed with TSC based on their clinical features and symptoms, researchers expect that there are TSC mutations yet to be discovered.

What did the researchers hope to learn?

They hoped to find the genetic mutation which caused TSC in each NMI patient in the study. The genetic tests currently available can identify mutations on two genes linked to TSC, called TSC1 and TSC2.The researchers had several ideas why no genetic mutation was found some people with TSC: 1] flawed testing; 2] mosaicism (some body cells have the mutation, but some do not); 3] mutations in areas not typically examined in genetic testing; 4] existence of a third TSC gene.

Who was studied?

This study examined 53 NMI children and adults who had a clinical diagnosis of TSC. Samples were taken from some family members of the TSC patients as well.

How was the study conducted?

Researchers took samples from the patients and their parents/relatives including blood, saliva, normal skin, skin tumors (fibromas), and other tissues. They performed more thorough testing of the genetic material than is typical in standard genetic testing; they compared results from blood samples to other tissue samples in the same person; and they compared samples between family members.

What did the researchers find?

Most NMI patients in this study (85%) were found to have mutations in the TSC1 or TSC2 genes. This left only 15% of the subjects whose genetic basis for TSC could still not be identified. The researchers examined several additional genes, however concluded that it is not likely that a TSC3 gene exists.

Of the patients whose mutation was located, most (58%) were found to have mosaicism, where the TSC1 or TSC2 mutation was only found in some of their body cells. The mutation might be found in less than 1% of the blood cells, or only in skin tumor biopsies, making it hard to detect.

Results also showed that 40% of the patients had mutations on the TSC1 or TSC2 genes, but in regions not normally searched with current genetic testing. These include areas called introns that in the past were thought to be “junk DNA.” Some patients fell into both categories, having an intron mutation AND mosaicism.

A few of the patients (11%) had known TSC1 or TSC2 mutations that were just missed by conventional genetic testing the first time (flawed testing).

What were the limitations of the study?

There were still some patients whose mutation could not be identified. About 10-15% of people with TSC are NMI. In this study, 15% of them remained NMI after extensive testing. This represents about 2% of the TSC population whose genetic cause of TSC remains a mystery. Hopefully further studies will be able to examine more patients and use new technologies to locate these mutations.

What do the results mean for you?

These results demonstrate that mosaicism is more common than previously thought. Understanding the frequency of mosaicism could help explain why some cases of TSC are more severe than others, including family members who share the same mutation.

This study also shows the need for more thorough genetic tests of the TSC1 and TSC2 genes, including introns that are not currently examined. Furthermore, the mutation for some people may be hard to detect in blood but testing of other tissues could help locate it.

The methods of deep testing used in this study are not widely available, so patients may not see immediate changes to the current testing. Since finding a patient’s TSC mutation is not currently significant in treating their disease, this type of research is mostly important for genetic counseling and family planning purposes. In the future, understanding the genetic basis for TSC could lead to new treatments or a cure.

This summary was written by Cristy Wade, MS, parent of child with TSC, and consumer reviewer for the Tuberous Sclerosis Complex Research Program (December 2015).