What is tuberous sclerosis (Tuberous Sclerosis Complex, TSC)?

From the Guidelines

Tuberous sclerosis complex (TSC) requires a multidisciplinary approach to management, with a focus on regular monitoring of kidney function and imaging to preserve kidney function and prevent complications, as recommended by the most recent consensus statement 1.

Key Considerations

• TSC is a rare genetic disorder characterized by the growth of benign tumors in multiple organs, including the brain, skin, kidneys, heart, lungs, and eyes.
• The condition typically presents in childhood with seizures, developmental delays, and distinctive skin abnormalities.
• Management focuses on symptom control and monitoring for complications, with regular screening essential for early detection and intervention.

Recommendations

• Kidney imaging should be performed at the time of TSC diagnosis, and regularly thereafter, to monitor for kidney involvement and prevent complications 1.
• Patients with TSC should be offered structured, multidisciplinary follow-up visits, ideally on the same day where possible, to ensure comprehensive care 1.
• Clinical assessment, including the collection of complete relevant history, kidney or abdominal imaging, assessment of kidney function proteinuria, and blood pressure, should be conducted at the diagnosis of children and adults with TSC 1.

Treatment and Management

• Seizures are treated with anticonvulsant medications like vigabatrin (particularly for infantile spasms) at doses of 50-150 mg/kg/day, or other anticonvulsants depending on seizure type.
• mTOR inhibitors such as everolimus (starting at 4.5 mg/m² daily) or sirolimus may be prescribed to shrink tumors.
• Regular screening is essential, including brain MRIs every 1-3 years, kidney imaging every 1-3 years, lung function tests, cardiac evaluations, and ophthalmologic exams.

Multidisciplinary Care

• The condition is lifelong and requires multidisciplinary care from neurologists, dermatologists, nephrologists, pulmonologists, cardiologists, and geneticists.
• Genetic counseling is recommended for family planning as tuberous sclerosis follows an autosomal dominant inheritance pattern, meaning affected individuals have a 50% chance of passing the condition to their children.

From the Research

Definition and Prevalence of Tuberous Sclerosis

• Tuberous sclerosis complex (TSC) is a genetic disorder that can affect multiple organ systems, including the brain, heart, skin, kidney, and lung, by formation of benign hamartomas 2.
• The incidence of TSC is approximately 1 in 6,000 live births, but it may be underdiagnosed 2.
• Mutations to either the TSC1 (coding for hamartin) or TSC2 (coding for tuberin) genes are present in 85% of patients with TSC 2.

Clinical Manifestations and Treatment

• TSC can be associated with autism, epilepsy, and other neurocognitive and behavioral disabilities 2, 3.
• The manifestations of TSC usually require management over the entire life of the patient 2.
• Increased understanding of the genetic cause of the disease and the underlying dysregulation of the mTOR pathway has led to clinical trials of mTOR inhibitors including sirolimus and everolimus 2.
• Everolimus was approved as adjunctive therapy for TSC-associated partial-onset seizures 3.
• Everolimus addresses the underlying pathophysiology of TSC and has been shown to improve other TSC manifestations such as subependymal giant cell astrocytomas and renal angiomyolipomas 3.

Epilepsy and Seizure Management

• Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC) 4.
• TSC-associated epilepsy treatment comprises a wide variety of antiseizure drugs (ASDs) 4.
• The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children 4.
• Active screening and early management of epilepsy is recommended in individuals with TSC to limit its consequences and its impact on quality of life, cognitive outcome and the economic burden of the disease 5.

TSC-Associated Neuropsychiatric Disorders (TAND)

• TSC is associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease 6.
• The TANDem project generated consensus recommendations for the identification and treatment of TAND, including ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature 6.
• The overarching recommendation is to "screen" for TAND at least annually, to "act" using appropriate next steps for evaluation and treatment, and to "repeat" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families 6.