Draft:Tuberous sclerosis complex 1 and 2

Tuberous sclerosis complex 1 and 2 (TSC 1/2) are tumour suppressor genes, encoding hamartin and tuberin, respectively. Hamartin (TSC 1) is expressed on chromosome 9, and tuberin (TSC 2) - on chromosome 16.

TSC 1/2 localise in the cytoplasm and are active during the resting phase of the cell cycle. In G0, hamartin and tuberin form a heterodimer and, in association with TBC1D7 form a complex functioning as GTPase activating protein (GAP) for the small GTPase Rheb. Rheb is RAS superfamily member highly expressed in the human brain. Of note, rather than activating, TSC 1/2 complex inhibits Rheb by hydrolysing its bound GTP to GDP. GTP hydrolysis inactivates Rheb and inhibits the downstream signaling through the mammalian target of rapamycin complex 1 (mTORC1) – one of two mTOR kinase complexes. mTOR complexes integrate the metabolic and mitogenic cues into cellular proliferation. Two main downstream targets of mTORC1 pathway contributing to cell proliferation are ribosomal subunit S6 kinases and eukaryotic translation initiation factor 4E-binding proteins.

Mutations in TSC 1 and/or 2 lead to mTORC1 signal amplification and the progression through the cell cycle, producing distinct phenotypic presentations that form the basis of tuberous sclerosis complex-associated disorders.

The incidence of TSC disorders is estimated between 1:6000 to 1:10000. The two main clinical presentations of TSC 1/2 related disorders are neurological disorders, such as seizures, attention deficit hyperactivity disorder (ADHD), behavioural disorders and the occurrence of benign tumours, characterised by focal distributions predominantly affecting skin, kidneys, heart, brain and lungs (National Institute of Neurological Disorders and Stroke, 2023). Cortical tubers in the brain are found in over 80% of the patients and are described as cystic or calcified cortical dysplasia. Approximately 90 % of patients suffer from neural disorders presenting through epilepsy, developmental delay and other cognitive disorders. In familial cases, the patients are diagnosed in early childhood by the presence of infantile spasms. It appears that neurological manifestations are mediated through neuroinflammation, aberrations in ion and neurotransmitter transport, abnormal gene expression, dysplastic differentiation of glia, and hypomyelination and dysmyelination of neurons.

Inheritance patterns manifest as an autosomal dominant trait. De novo germline and somatic mutations, as well as mosaicisms, constitute two-thirds of cases. Generally, the mutations in TSC 2 produce more severe phenotypes attributed to TSC 2 catalytic function. Apart from a large number of copy number variations and point mutations in TSC 1 or TSC 2, aberrations in alternative splicing and whole segments of chromosome loss have also been reported.

The current treatments are symptomatic. There is currently no cure for TSC 1/2 disorders. Anticonvulsants such as vigabatrin (GABA transaminase – inhibitor) provide high-efficacy long-term treatment for TSC epilepsy and infantile spasms. Behavioural therapy can also be applied. mTOR inhibitors are popular and are used in neurological as well as tumour symptom alleviation. Tumour management includes surgical resection, chemotherapy and radiotherapy. Most clinical trials focus on either biomarkers, behavioural therapies or known mTOR inhibitors, such as everolimus, to study the drug effects under different circumstances (clinicaltrials.gov, 2023).