Tuberous Sclerosis Complex (TSC)

1. Genetics

• Inheritance: Autosomal Dominant with high penetrance but variable expressivity.
• Sporadic vs. Familial:
  • ~2/3 cases are sporadic (de novo mutations).
  • ~1/3 cases are familial.
• Causative Genes:
  • TSC1 Gene: Located on Chromosome 9q34. Codes for Hamartin.
  • TSC2 Gene: Located on Chromosome 16p13. Codes for Tuberin.
• Genotype-Phenotype Correlation:
  • TSC2 mutations are more common and generally associated with a more severe phenotype (higher burden of tubers, earlier seizures, more intellectual disability) than TSC1.
  • Contiguous Gene Syndrome: TSC2 lies adjacent to PKD1; large deletions can cause severe early-onset Polycystic Kidney Disease.

2. Cellular Defect and Pathogenesis

• Normal Physiology: Hamartin (TSC1) and Tuberin (TSC2) form a heterodimer complex. This complex acts as a GTPase-Activating Protein (GAP) for the small G-protein Rheb. Its function is to inhibit the mTOR (Mechanistic Target of Rapamycin) pathway.
• The Defect: Loss-of-function mutation in TSC1 or TSC2 leads to failure of the complex to inhibit Rheb.
• Consequence: Constitutional hyperactivation of the mTORC1 pathway.
  • This leads to uncontrolled protein synthesis, cell growth, and proliferation.
  • Result: Formation of Hamartomas (benign tumors with disorganized tissue) in multiple organ systems.

3. Clinical Manifestations

TSC is a multi-system disorder. Key manifestations include:

4. Diagnosis (2021 International Consensus Criteria)

The identification of a pathogenic variant in either the TSC1 or TSC2 gene is sufficient to make a diagnosis of Definite TSC, regardless of the clinical findings. This allows for diagnosis in individuals who may not yet meet the clinical criteria.

Based on the clinical features listed below, the certainty of the diagnosis is classified as follows:

• Definite TSC:
  • Presence of 2 Major features OR
  • Presence of 1 Major feature PLUS $\ge$ 2 Minor features.
• Possible TSC:
  • Presence of 1 Major feature OR
  • Presence of $\ge$ 2 Minor features.

*(Note: LAM and AML together count as only one Major feature if no other features exist).

Management of Tuberous Sclerosis Complex (TSC)

1. General Principles

• Multidisciplinary Approach: Requires coordination between neurology, nephrology, cardiology, dermatology, and genetics.
• Goal: Symptomatic management of epilepsy, surveillance for tumors (SEGA, AML), and addressing neuropsychiatric comorbidities (TAND).

2. Surveillance (Monitoring)

Life-long surveillance is critical to detect complications early.

• Brain: MRI Brain every 1–3 years (until age 25) to monitor for Subependymal Giant Cell Astrocytoma (SEGA).
• Kidney: MRI Abdomen every 1–3 years to monitor Angiomyolipoma (AML) size and renal cysts.
• Heart: Echocardiography every 1–3 years in asymptomatic patients (more frequent if rhabdomyomas are symptomatic).
• Lung: High-resolution CT chest (females >18 years) to screen for Lymphangioleiomyomatosis (LAM).
• Neuropsychiatric: Annual screening for TAND (TSC-Associated Neuropsychiatric Disorders).

3. Management of Specific Manifestations

A. Epilepsy (Neurologic)

• Infantile Spasms (West Syndrome):
  • Drug of Choice: Vigabatrin (First-line for TSC-associated spasms).
  • Alternative: ACTH or Oral Prednisolone.
• Focal Seizures:
  • First-line: Levetiracetam, Oxcarbazepine, Carbamazepine.
  • Adjunctive: Everolimus (mTOR inhibitor) is FDA-approved for refractory seizures in TSC.
• Refractory Epilepsy: Ketogenic Diet, Vagus Nerve Stimulation (VNS), or Epilepsy Surgery (tuberectomy) if a dominant epileptogenic tuber is identified.

B. Subependymal Giant Cell Astrocytoma (SEGA)

• Medical: mTOR Inhibitors (Everolimus/Sirolimus) are first-line for growing, asymptomatic SEGAs. They cause tumor regression.
• Surgical: Resection indicated if there is acute hydrocephalus or if the tumor does not respond to medical therapy.

C. Renal Angiomyolipoma (AML)

• Asymptomatic (<3 cm): Observation.
• Large (>3 cm) or Growing:
  • First-line: mTOR Inhibitors (Everolimus) to shrink the tumor and prevent bleeding.
  • Embolization/Nephron-sparing Surgery: If acute hemorrhage occurs or medical therapy fails.

D. Dermatologic

• Facial Angiofibromas:
  • Topical Sirolimus (Rapamycin) ointment: Highly effective and safe.
  • Laser Therapy: Pulsed dye laser for larger/vascular lesions.

E. Neuropsychiatric (TAND)

• Management of Autism Spectrum Disorder (ASD), ADHD, anxiety, and intellectual disability via behavioral therapy and pharmacotherapy.