A mutation in the TSC2 gene causes Tuberous Sclerosis Complex (TSC). This disorder is characterized by the growth of non-cancerous tumors, called hamartomas, in various organs, including the brain, skin, kidneys, and heart. TSC2 mutations account for the majority of TSC cases and often result in a more severe disease presentation compared to mutations in the related TSC1 gene.
The Normal Function of the TSC2 Gene
The TSC2 gene instructs cells to manufacture the large protein tuberin. Tuberin partners with the hamartin protein, the product of the TSC1 gene, to form a complex. This complex is important for regulating cell size, growth, and division.
The complex acts as a tumor suppressor, controlling cellular proliferation. It integrates environmental cues, such as nutrient availability, to determine if a cell should grow or remain quiescent. Hamartin stabilizes tuberin and prevents its degradation within the cell.
Tuberin contains a specialized region that functions as a GTPase Activating Protein (GAP). This GAP domain regulates the small protein Rheb, which acts as a switch for cell growth. By converting the active form of Rheb (Rheb-GTP) into the inactive form (Rheb-GDP), the tuberin-hamartin complex keeps cell growth in check.
Molecular Mechanism: Disruption of the mTOR Pathway
A mutation in the TSC2 gene results in tuberin protein that is absent, truncated, or non-functional. Since hamartin is unstable without tuberin, the entire tumor-suppressor complex is compromised. The loss of functional tuberin releases the control on cell growth.
This failure leads to the hyperactivation of the Mechanistic Target of Rapamycin (mTOR) pathway, a master regulator of cell metabolism and growth. The mTOR pathway normally drives protein synthesis and cell growth, but it is tightly controlled by the tuberin-hamartin complex. When faulty tuberin cannot inactivate Rheb, the Rheb switch remains perpetually “on,” causing uncontrolled activation of mTOR.
Overactive mTOR signaling causes cells to grow too large and divide too frequently, which is the underlying mechanism for hamartoma formation. Cells in various organs lose the ability to regulate their size and proliferation, leading to these non-cancerous growths. Tuberous Sclerosis Complex is now classified as an “mTORopathy” due to the central role of this pathway’s dysregulation.
Clinical Manifestations of Tuberous Sclerosis Complex
The effects of the TSC2 mutation and mTOR hyperactivation are multisystemic, resulting in diverse symptoms that vary significantly among individuals. Since the TSC2 mutation generally causes a more complete loss of function, it is often associated with a more severe disease presentation than TSC1 mutations. Symptoms primarily arise from the growth of hamartomas in different organs.
Brain and Neurological System
Neurological involvement is the most common and often the most debilitating aspect of TSC, affecting up to 90% of patients. Epilepsy is highly prevalent, occurring in over 80% of individuals, with seizures often starting early and frequently becoming resistant to standard medications. Brain tumors associated with TSC include cortical tubers, which are malformations in the brain’s outer layer, and subependymal nodules (SENs).
A more concerning growth is the Subependymal Giant Cell Astrocytoma (SEGA). Although benign, SEGAs can grow large enough to block the flow of cerebrospinal fluid, potentially causing hydrocephalus. The mutation also leads to neurodevelopmental and behavioral issues, collectively called TSC-Associated Neuropsychiatric Disorders (TAND). TAND includes intellectual disability, autism spectrum disorder, anxiety, hyperactivity, and aggression.
Skin and Dermatological System
Nearly all individuals with TSC develop dermatological manifestations. One of the earliest signs is the presence of hypomelanotic macules, often called ash-leaf spots, which are patches of skin lacking typical pigmentation. These spots can be numerous and are often best visualized under a Wood’s lamp.
Other common skin findings appear later in childhood:
- Facial angiofibromas, which present as small, reddish bumps, usually across the cheeks and nose.
- Shagreen patches, which are areas of thickened, rough, and elevated skin.
- Ungual fibromas, which are growths found around or under the fingernails and toenails.
Kidneys, Heart, and Lungs
The kidneys are commonly affected by renal angiomyolipomas (AMLs), which are benign tumors made of blood vessels, muscle, and fat. AMLs occur in about 75% of patients by age ten, and the risk for spontaneous bleeding increases significantly as they grow larger. Kidney disease is a leading cause of mortality in individuals with TSC.
The heart often develops cardiac rhabdomyomas, which are benign muscle tumors sometimes detected before birth. While they can cause arrhythmias or heart failure in infancy, these tumors frequently regress or shrink as the child gets older. Lymphangioleiomyomatosis (LAM) is a lung condition that primarily affects women with TSC. LAM involves the abnormal growth of smooth muscle-like cells, which can lead to cysts, shortness of breath, and lung collapse.
Diagnosis and Management Strategies
Diagnosis of Tuberous Sclerosis Complex is based on specific clinical features identified through physical examination and imaging techniques. Updated international diagnostic criteria require identifying a certain number of major and minor clinical features to confirm the condition. Genetic testing is also used to confirm the molecular diagnosis by identifying a pathogenic variant in the TSC1 or TSC2 gene.
Management is a multidisciplinary process focused on controlling symptoms and reducing hamartoma size. A major advancement involves targeted therapy using mTOR inhibitors, such as everolimus or sirolimus. These medications directly block the overactive mTOR pathway, which is the root cause of cellular overgrowth.
mTOR inhibitors are effective in reducing the size of specific tumors, including SEGAs and renal AMLs, and help manage refractory epilepsy. Supportive treatments are also employed, such as anti-seizure medications and neurosurgical intervention for SEGAs causing acute symptoms. Regular surveillance using imaging of the brain, kidneys, and lungs is recommended to monitor for tumor growth and manage complications proactively.