Tuberous Sclerosis Complex

What Causes Tuberous Sclerosis Complex?

TSC is caused by abnormal changes (called a mutation) in one of two different genes. The TSC1 gene is responsible for producing the protein: hamartin; the TSC2 gene is responsible for another protein: tuberin. Together, these proteins regulate cell growth, preventing cells from growing too big or reproducing too rapidly. If the proteins aren’t present, cells can grow out of control and develop into tumors.

People with TSC have at least one of the disorder-causing mutations in the TSC1 or TSC2 gene in each of their cells. However, each cell has two copies of each gene, and the unmutated copy of the gene usually produces enough protein to limit tumor growth. Scientists believe the TSC tumor growth may occur when another spontaneous mutation affects the second gene in specific cells, leading to a deficit of the tumor-suppressing proteins.

Is Tuberous Sclerosis Complex Hereditary?

In about two-thirds of all cases of TSC, the gene mutation happens spontaneously as a fetus develops. The mutation is not passed to the child from either parent, and there is no family history of the disorder.

In the remaining one-third of cases, a TSC1 or TSC2 gene mutation is passed directly from a parent to the child. In these cases, the disorder is inherited in an autosomal dominant pattern. The child only has to inherit one copy of the mutation from one of their parents to develop the condition. A parent with TSC has a 50 percent chance of passing the disorder to each of their children.

How Is Tuberous Sclerosis Complex Detected?

One of the most common early signs of TSC is the onset of seizures in infancy, often between four and six months. Seizures are the most significant factor in developing intellectual and cognitive impairment, making early seizure-controlling intervention crucial.

Most cases of TSC are detected in the first few months after birth because tumors are already present. Research has suggested that early diagnosis and preventive treatment for seizures may prevent or lessen future neurodevelopmental complications.

How Is Tuberous Sclerosis Complex Diagnosed?

A doctor may suspect TSC when a child presents one or more of the disorder’s characteristic symptoms. Common early symptoms include:

• Seizures
• Developmental delays
• Light patches on the skin
• Heart tumors

Further exams can detect tumors in other parts of the body and help confirm a diagnosis of TSC. Commonly used exams include:

• Brain imaging scans (magnetic resonance imaging (MRI) or computerized tomography (CT) scans)
• Ultrasound scans of the heart, liver, or kidneys
• Exams of teeth, gums, and eyes
• Examination of the skin using ultraviolet light to detect abnormalities

Genetic testing may also be used to detect TSC1 or TSC2 mutations.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Tuberous Sclerosis Complex Treated?

TSC has no cure. Treatment of the disorders focuses on alleviating symptoms and preventing complications. Common treatments include:

• Anti-seizure medications
• Medications to treat specific tumors
• Medications to treat mental health or behavioral issues
• Surgery for specific tumors or complications arising from them
• Physical therapy
• Occupational therapy
• Speech therapy
• Psychotherapy
• Special education programs
• Ongoing monitoring of symptoms and progression of the disorder

How Does Tuberous Sclerosis Complex Progress?

TSC varies in severity, and people with mild symptoms may have a normal life expectancy with no life-threatening complications. However, tumor growth in vital organs and systems is possible in anyone with the disorder. Some complications can be fatal, and careful monitoring of the disorder’s progression is essential.

Severe and potentially life-threatening complications of TSC can include:

• Heart problems, including irregular heartbeat or blood-flow restrictions
• Accumulation of fluid in the brain
• Kidney failure
• Accumulation of fluid in the lungs or lung collapse
• Vision impairment

How Is Tuberous Sclerosis Complex Prevented?

There is no known way to prevent TSC when the disease-causing gene mutations are present. People who have TSC or have a family history of the disorder may want to consult a genetic counselor to assess their risk before having children.

Tuberous Sclerosis Complex Caregiver Tips

TSC is a life-long disorder, and people with the condition must learn how to live with it. For parents of children with TSC, the challenge of living with the disorder starts early. If your child has TSC, keep these basic guidelines in mind.

• Learn all you can about the disorder. TSC is a complex disorder that can impact your and your child’s lives in many different ways. The more you know about the condition, the better able you’ll be to cope and support your child.
• Educate others, and be an advocate for your child. Ensure essential people in your child’s life, including family members and teachers, understand how the disorder affects your child. When it comes to educational resources, know your child’s rights, and be prepared to stand up for them.
• Get support. The TSC Alliance can help put you in touch with local communities that can provide support and education about the disorder.

Many people with TSC also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the conditions commonly associated with TSC:

• People with TSC often have co-morbid anxiety disorders.
• Attention-deficit/hyperactivity disorder (ADHD) and autism are sometimes associated with TSC.
• Obsessive-compulsive disorder (OCD) is also sometimes associated with TSC.

Tuberous Sclerosis Complex Brain Science

Researchers are working to understand better how TSC1 and TSC2 mutations affect cell function. Areas of recent research include:

• Study of the role of hamartin and tuberin, as well as another protein, called mTOR, in the suppression and growth of tumors, especially in the central nervous system
• Study of seizures and epilepsy in people with TSC. The research aims to understand precisely how TSC tumors cause seizures.
• Study of the effectiveness of treatments and therapies, such as the anti-seizure drug vigabatrin and the mTOR inhibitor sirolimus.

Tuberous Sclerosis Complex Research

Title: Studies in Patients With Tuberous Sclerosis Complex

Stage: Recruiting

Principal Investigator: Vinodh Narayanan, MD

Translational Genomics Research Institute

Phoenix, AZ

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurogenetic disorder caused by heterozygous mutations in at least two different genes, TSC1 and TSC2. It is estimated to affect 1 in 6000 and demonstrates both phenotypic and genetic heterogeneity. It is characterized by a variety of symptoms, including skin lesions, renal angiomyolipomas, cardiac rhabdomyomas, seizures, and cognitive delay (mental retardation, autism, and behavior problems). The severity of the disease varies widely among patients with TSC in general, and variability in phenotype is detectable within single families, where all affected individuals have the same TSC1 or TSC2 mutation. Neurocognitive phenotypes in TSC vary from profound mental retardation, intractable epilepsy, and autism, to normal cognition and only a mild behavioral phenotype. However, the basis of this phenotypic variability is not understood. A growing body of literature implicates genetic variation in “modifier genes” as an agent for phenotypic heterogeneity in Mendelian disorders, such as TSC. However, the role of genetic modifiers on disease severity has not yet been studied in familial TSC and sporadic TSC. This study aims to conduct a systematic analysis to examine the effects of genetic variants other than TSC genes on phenotypic variability in familial TSC patients (affected parent, child, and unaffected siblings) and sporadic TSC.

Title: JASPER Early Intervention for Tuberous Sclerosis (JETS)

Stage: Recruiting

Principal Investigator:  Shafali Jeste

University of California, Los Angeles

Los Angeles, CA

The investigators are running an intervention study for young children with Tuberous Sclerosis Complex (TSC). The study will include free play-based behavioral intervention, administered remotely, that may improve social and communication skills in children with TSC. Eligible families will have a child in the age range of 12-36 months with a diagnosis of TSC. Children with TSC below 12 months may be eligible for an early markers study before enrollment in the intervention trial.

The intervention will focus on teaching caregivers skills to improve the social and communication outcomes of their children. The content of the intervention will be individually tailored to the child’s developmental level. The intervention involves (4) on-site assessment visits and (12) weekly intervention sessions, administered in-person and remotely. The intervention focuses on improving social communication and play skills.

Title: Stopping TSC Onset and Progression 2: Epilepsy Prevention in TSC Infants (STOP2)

Stage: Recruiting

Principal Investigator: Darcy Krueger, MD, PhD

Cincinnati Children’s Hospital

Cincinnati, OH

Tuberous Sclerosis Complex (TSC) is caused by genetic mutation in TSC1 or TSC2, resulting in dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway. Age at the time of seizure onset in TSC infants has been linked to long-term neurodevelopmental outcome in this high-risk population. TAVT-18 is a novel formulation of sirolimus, an mTOR inhibitor. This will be the first study to clearly evaluate a targeted, disease-modifying drug therapy for preventing or delaying seizure onset in TSC using a rational, mechanism-based therapeutic approach.