TSC and rare neurodevelopmental diseases

• Rare disease

  Condition that affects less than 1/2000 people
• More than 7000 rare diseases exist
• While rare individually, 1/17 people will get a rare disease at some point in their life
• Causes of rare diseases

  • Genetic causes (e.g. TSC)
  • Dysregulation in immune function (e.g. lupus, vitiligo)
  • Allergies (e.g. acuagenic urticaria)
  • Neurodegenerative conditions (e.g. motor neuron disease, frontotemporal dementia)
  • Cancer (e.g. thyroid, penile)
• Many rare diseases are incurable, and many have mental health comorbidities associated with their condition
• Studying rare diseases creates an opportunity to understand mechanisms with broader applications which can contribute to therapeutic targets and technological advances
• Ways to help with rare diseases

  • Faster diagnosis (importance of testing at younger ages and newborn screening)
  • Increasing awareness (GPs are less aware so there needs to be an increase in training to reduce this gap in knowledge)
  • Better coordination of care
  • Improving access (most rare diseases don't have treatment, more funding needed)
• Issues with rare diseases

  • Drug economics (small patient population make it less appealing for pharmaceutical companies to invest into treatments)
  • Orphan drug design (governments design these, benefits pharmaceutical companies encouraging them to invest in the development of treatment for rare diseases)
  • All rare disease research are fighting for the same pot of government funding and charities
• Metabolic epilepsy


  Type of epilepsy linked to metabolic disorders
• Mutations in 600 genes are linked to metabolic epilepsy, representing around 37% of all inherited metabolic disorders
• More than 100 additional genes have been found to cause rare epilepsy forms, at least 700 in total
• Metabolic epilepsy is challenging to treat because they don't respond well to current available medications, making them difficult to manage or control
• Mitochondrial dysfunction

  Common factor among rare diseases, problems in mitochondria producing energy can contribute to various health issues
• Lysosomal dysfunction

  Underlies a lot of rare diseases, lysosomes are responsible for breaking down and recycling substances within cells, lysosomal storage disorders result from inborn errors of metabolism and accumulation of deposits or substrates within cells due to defect in lysosomal function
• Autophagy is the degradation of dysfunctional or unnecessary cellular components and recycling them by lysosomes, when defective it has been found in almost all RDs. Accumulation of damaged proteins and organelles like mitochondria = promote further damage by oxidative stress and apoptosis
• Tuberous sclerosis complex (TSC)

  Multi-systemic genetic disease that affects many organs, caused by a mutation in TSC1 (Hamartin protein) or TSC2 (Tuberin protein)
• 80-90% of people with TSC develop a severe form of epilepsy
• TSC has variable expressivity, not everybody with the genotype will express the phenotype (incomplete penetrance)
• Hamartin and tuberin proteins

  Tumour suppressor proteins that are defective in TSC, leading to the development of tumours
• TSC two-hit hypothesis

  You need the TSC1 or TSC2 mutation, plus a random mutation, to cause the variability in TSC
• Brain manifestations of TSC

  • Formation of hamartia (malformed tissue, e.g. cortical tubers in cerebral cortex)
  • Astrocytoma (brain tumours originating from astrocytes)
  • Subependymal nodules (small growth nodules on the lining of ventricles, can transform into subependymal giant cell astrocytoma)
• Other manifestations of TSC

  • Angiomyolipoma (benign tumours in various organs, commonly in the kidneys)
  • LAM (abnormal proliferation of smooth muscle cells, disease of the lungs)
• mTOR

  Mutations in TSC1 or TSC2 cause an increase in mTORC1 activity, leading to uncontrolled growth due to uncontrolled activation of mTOR
• mTORC1 stimulates the biosynthesis of macromolecules and cell cycle progression, important for generation of new cells
• Rheb

  GTPase that activates mTORC1 when bound to GTP, inhibited by TSC1 and TSC2
• AMPK

  Energy sensing enzyme that monitors the status of cellular energy, activated by LKB1, inhibits the activity of mTORC1
• AKT

  Oncoprotein that inhibits the GTPase activity of TSC1 and TSC2, activating the PI3K-AKT pathway which is the major pathway activated in human cancer
• Phosphorylation of ribosome S6 is an indicator for increased mTOR activity
• mTOR inhibitors

  • Rapamycin (binds to and inhibits mTOR, shown to shrink tumours)
  • Everolimus (applied to cell, after 30 mins we lose phosphorylation of S6 so less mTORC1 activity)
• Other treatments/approaches for epilepsy in TSC

  • Targeting metabolic imbalance to selectively kill TSC and LAM tumour cells
  • Brain surgery for drug resistant epilepsy (removal of tubers, but may experience recurrence of seizures)
  • Vigabatrin (inhibitor of GABA-aminotransferase, alternative antiepileptic drug)
  • Cannabidiol (derived from cannabis, trials shown reduction in seizures by 50%)
• Future treatments for TSC

  • Basimglurant (negative allosteric modulator of mGLuR5 glutamate receptor, corrects seizures and behavioural phenotypes in mice)
  • Metformin (drug repurposing, reduced 43.7% seizure frequency and effectiveness in SEGA but not angiomyolipoma's)
  • Gene therapy using viral vector to deliver condensed form of tuberin gene
  • Gene therapy using antisense oligonucleotide to knock down expression of target gene
• TSC can present with various clinical features such as seizures, intellectual disability, behavioral problems, skin lesions, kidney tumors, lung cysts, cardiac rhabdomyomas, and neurological symptoms including cognitive impairments, motor deficits, and sleep disturbances.
• Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes.
• The diagnosis of TSC involves genetic testing or imaging studies to identify characteristic brain abnormalities called cortical dysplasia or subependymal nodules.
• In addition to pharmacological interventions, other approaches being explored include dietary modifications, physical therapies, and surgical procedures.