• Tuberous sclerosis complex (TSC) is a rare genetic disorder that causes benign tumors and lesions to develop in multiple organ systems.
• TSC is the leading genetic cause of both epilepsy and autism spectrum disorder.
• There’s no cure for TSC, but advances in treatment give people living with the condition more options for greater epilepsy control.

Tuberous sclerosis complex is a rare genetic disorder. It’s a type of neurocutaneous syndrome, which are disorders that cause tumors (or lesions), seizures, brain development problems, and intellectual disabilities. The tumors — also known as hamartomatous lesions and tubers — are benign (noncancerous) and can form in the skin, bones, brain, and other organs.

TSC’s effects on different parts of the body vary greatly from person to person, in both severity and symptoms. TSC typically presents in early infancy. Seizures known as infantile spasms usually start during the first year. A person with TSC can develop other types of seizures over time.

TSC is a lifelong, chronic (ongoing) condition that currently has no cure. However, TSC is manageable. With early diagnosis and intervention, specialized health care, and frequent monitoring, people with TSC often live high-quality, productive lives and have a normal life expectancy.

According to the TSC Alliance, an estimated 1 million people are thought to have TSC worldwide, about 50,000 of whom live in the United States. Individuals with TSC often go undiagnosed until they’re adults.

What Causes Tuberous Sclerosis Complex?

In most cases, TSC is caused by a gene mutation that occurs on the TSC1 or TSC2 gene. The TSC1 gene is thought to control a protein called hamartin that suppresses tumor growth. The TSC2 gene controls a protein called tuberin that moderates cell growth. Scientists believe the TSC genes control the growth and size of cells and tumors. The TSC gene mutation prevents the proteins from functioning properly, which leads to rapid growth of the tubers and lesions. Although benign, they’re still potentially dangerous.

For about two-thirds of people with TSC, neither of their parents has TSC or the TSC gene mutations. This is called spontaneous or sporadic mutation. In approximately 33 percent of cases, the TSC mutation is inherited from a parent. TSC is an autosomal dominant disease, meaning just one parent needs to carry the gene mutation or have TSC to pass it on. Each child of someone with TSC (or one of the gene mutations) has a 50 percent chance of being born with TSC.

In very rare cases, although neither parent has tuberous sclerosis, the TSC mutation can be passed on to a child through a process known as germline or gonadal mosaicism. When neither parent has TSC but one child does, any of their siblings have a 1 percent to 2 percent chance of having TSC as well.

How Is Tuberous Sclerosis Complex Diagnosed?

Diagnosing tuberous sclerosis entails a thorough medical exam. The doctor will take a detailed medical history, conduct a TSC diagnostic assessment, and examine the skin — sometimes with a special ultraviolet light called a Wood’s lamp to help spot skin anomalies.

Diagnostic Criteria

To diagnose tuberous sclerosis, doctors will look for 18 symptoms, divided into 11 major features and seven minor features.

A definite diagnosis of TSC must have two or more major features, or one major feature and two or more minor features of the disorder. A possible TSC diagnosis has either just one major feature or two or more minor features. In most cases, health care providers with experience diagnosing TSC are able to confirm a TSC diagnosis with the criteria alone.

Laboratory Tests

Genetic tests can identify a TSC1 or TSC2 mutation. The presence of a gene mutation confirms a TSC diagnosis. The absence of a TSC mutation, however, does not rule out tuberous sclerosis. Approximately 15 percent of people diagnosed with TSC show no TSC1 or TSC2 mutations.

Imaging

Once a doctor makes a definite TSC diagnosis, they may order some of the following tests. The tests described below are necessary to set baseline measurements and assess organ function and health:

• CT scans use rotating X-rays to detect the presence of tumors in the brain, lungs, and kidneys.
• MRI uses strong magnetic fields to detect tubers on the brain’s surface and identify subependymal giant cell astrocytomas (SEGAs) before the tumors obstruct normal functioning.
• An electroencephalogram (EEG) monitors brain waves for irregular activity through electrodes affixed to the scalp. This can help diagnose seizures.
• Echocardiography uses sound waves to study the heart’s functionality and movement. It can be used to evaluate the heart for the presence of benign tumors known as rhabdomyomas.
• Electrocardiograms monitor and record the heart’s electrical impulses and may reveal abnormal electrical patterns.
• Renal ultrasonography uses sound waves and radio waves to take pictures of internal organs to identify and measure renal cysts (round, fluid-filled pouches that form on or in the kidneys).

Tuberous Sclerosis Complex and Epilepsy

Epilepsy is the most common neurological symptom of TSC. Around 80 percent of people living with TSC also have epilepsy. People with TSC can experience many types of seizures, including:

• Absence seizures
• Atonic seizures
• Focal seizures
• Infantile spasms
• Myoclonic seizures
• Tonic-clonic seizures

Antiepileptic drugs (AEDs) can help control seizures. Some people have what’s called refractory — or drug-resistant — epilepsy. Refractory seizures don’t respond to medication. Uncontrolled seizures can lead to status epilepticus, a life-threatening condition.

Although epilepsy is usually one of the first signs of TSC, a person with the condition can develop seizures at any age, and seizures often change as a person grows older. Infantile spasms, also known as West syndrome, usually show up in the first year of life and affect nearly 35 percent of babies born with TSC. West syndrome often leads to pediatric epilepsies, such as Lennox-Gastaut syndrome (LGS) and other drug-resistant types of epilepsy. West syndrome and LGS can cause major cognitive and developmental delays, as well as intellectual deficits. They can also stall or regress (move backward) a baby’s developmental progress.

Tuberous Sclerosis Complex and the Brain

TSC causes different types of brain abnormalities, the impact and severity of which vary depending on their location, size, and growth rate. These brain abnormalities include:

• Cortical tubers — These lesions develop and harden over time, usually on the brain’s surface.
• Subependymal nodules — These collections of cells are situated on the cerebral ventricle walls (areas of the brain that contain cerebrospinal fluid). Often, they harden by accumulating calcium.
• SEGAs — These benign tumors can become large enough to restrict the flow of cerebrospinal fluid in the brain and spine. As SEGAs grow, they can cause headaches and blurred vision, leading to fluid buildup around the brain.

TSC-associated neuropsychiatric disorders are the cognitive, developmental, behavioral, intellectual, and psychosocial complications often associated with tuberous sclerosis. Between 25 percent and 50 percent of people living with TSC may develop autism spectrum disorder. Learning disabilities affect at least 50 percent of people with TSC, and 30 percent have severe IQ impairments.

Children with TSC may be more likely to have emotional regulation or behavioral problems, which can make managing the condition even more challenging.

Tuberous Sclerosis Complex and the Skin

Among the major features are the following four skin symptoms:

• Angiofibromas — A type of facial rash often characterized by small pink, red, reddish-brown, or dark brown spots that spread across the cheeks and nose in a butterflylike pattern; can also appear around the scalp, forehead, and nails

• Hypomelanotic macules — Light patches shaped like leaves of an ash tree (and sometimes referred to as ash-leaf spots); one of the first skin symptoms to appear in people with TSC

• Shagreen patches — Skin-colored lesions of irregular shape and thickness that usually form on the lower back but also can develop on the buttocks or upper thighs

• Ungual fibromas — Smooth, hard lumps that develop around and under fingernails and toenails, generally the same color as a person’s skin; can also cause grooves and red or white streaks in nails

Tuberous Sclerosis Complex and Major Organs

Almost half of all people with TSC experience a form of renal (kidney) disease at some point in their life. Three common types of renal disorders associated with TSC are:

• Renal angiomyolipomata (or angiomyolipomas) — These benign tumors in the kidney don’t cause symptoms but can grow or hemorrhage (bleed), which can be dangerous. Around 80 percent of people with TSC develop renal angiomyolipomata, and 20 percent of the time, it can be life-threatening. These tumors usually present in late childhood or adolescence.
• Renal cysts — About 50 percent of people with TSC will develop these “holes” in the kidney, which are often small and filled with benign fluid. The cysts can cause increased blood pressure and, if too many form, lead to kidney impairment or failure.
• Renal cell carcinoma — Although very rare, this type of cancerous growth is also associated with TSC.

Approximately 50 percent of people with TSC have cardiac tumors called rhabdomyomas. Rhabdomyomas can grow smaller over time but occasionally lead to problems like cardiac arrhythmias and congestive heart failure.

As many as 50 percent of people with TSC also have eye involvement. It is important to routinely check the eyes and identify any lesions in the retina.

How Are Seizures in Tuberous Sclerosis Complex Treated?

TSC is a lifelong condition that requires specialized care from pediatricians, neurologists, dermatologists, and cardiologists with TSC expertise. Tuberous sclerosis symptoms differ from person to person. Individual TSC treatment plans need to aggressively and promptly meet an individual’s unique, often-changing needs.

Antiepileptic Drugs

AEDs — also called antiseizure medications — are the primary treatment for recurrent seizures, and they successfully control epilepsy in about 70 percent of people who take them. TSC-related epilepsies are challenging to treat and even harder to treat long term. About half of TSC-related epilepsy cases are or become intractable (resistant to medication).

Two medications are approved by the U.S. Food and Drug Administration (FDA) to treat infantile spasms: Sabil (a formulation of vigabatrin) and H.P. Acthar Gel (a repository corticotropin). Both medications can have serious side effects.

Several efforts focus on repurposing already-approved drugs to treat TSC. Afinitor, a formulation of everolimus, is FDA-approved to treat SEGAs and advanced renal cell carcinoma. Everolimus also shows off-label promise as an antiepileptic drug. While not yet FDA-approved, rapamycin treatment has shown efficacy (works as expected) in shrinking SEGAs. Further studies exploring rapamycin’s effectiveness on other TSC-associated tumors are underway.

In 2020, the FDA approved Epidiolex (a formulation of cannabidiol, or CBD) for treating seizures associated with TSC in people ages 1 and older.

Devices and Surgery

Depending on the type and region of a person’s seizure activity, epilepsy surgery may bring seizures under control. If the seizure focus can be targeted through precise brain imaging and an EEG, and if it’s in a part of the brain that won’t affect critical function or quality of life, surgery could reduce or eliminate epilepsy.

Vagus nerve stimulation (VNS) is a type of neuromodulation therapy approved by the FDA as an add-on treatment for refractory epilepsy in children 4 years old and up. VNS involves a small device, similar to a pacemaker, implanted in the chest. A person can also use a handheld magnet to deliver extra stimulus between the device’s regularly programmed pulses.

In small studies among people living with TSC, VNS was shown to be effective in decreasing seizure frequency in some individuals. Responsive neurostimulation is a similar type of neuromodulation therapy also used to treat epilepsy. This closed-loop brain stimulation system detects electrical activity in the brain and provides electrical stimulation to lessen seizure frequency. The FDA approved the Neuropace RNS System in 2013 for treating focal or partial seizures in adults 18 and up.

Dietary Therapy

Dietary therapy can be used with AEDs to help control seizures. A ketogenic diet is a strict regimen of high-fat and low-carbohydrate foods. It has proved effective in helping control some epilepsy conditions — including TSC — in some individuals. The modified Atkins diet is similar to the ketogenic diet but includes more carbohydrates and greater flexibility.

What Is the Prognosis for Someone Living With Tuberous Sclerosis Complex?

The prognosis (outlook) for people living with TSC varies, as it depends on which organs are affected and the severity of symptoms. Symptoms may change, and new symptoms can arise over time.

A small-scale 2019 study noted a higher mortality rate among people with late-onset TSC, possibly due to kidney disease and illness related to dementia. Similarly, a small 2016 study of people with TSC found that kidney disease was a prominent cause of death and that people with learning disabilities may be at a higher risk of dying at an earlier age from complications of TSC.

With early diagnosis, lifelong monitoring of TSC symptoms, and a close partnership with a skilled treatment team, most people living with the condition have a normal life expectancy. Some children diagnosed with TSC may require lifelong care, and parents must learn to advocate for their changing health needs. Ongoing scientific research offers new discoveries and treatment possibilities, as well as hope for a cure.

Meet Your Team

MyEpilepsyTeam is an online community where more than 112,000 people with epilepsy and their loved ones share their experiences and advice. Several members of MyEpilepsyTeam or their children have been diagnosed with tuberous sclerosis complex.

Have you or a loved one been diagnosed with TSC? Do you have questions about symptoms or treatments? Comment below or post on your Activities page.