What I know best: Tuberous Sclerosis Complex Prof Petrus de Vries Sue Struengmann Professor of Child & Adolescent Psychiatry University of Cape Town South Africa
Red Cross War Memorial Children s Hospital, Cape Town
Conflicts of interest Study Steering Group for EXIST-1, EXIST-2 and EXIST-3 trials funded by Novartis Co-PI on 2 phase II studies part-funded by Novartis Advisory Board Member/Working Committee of TOSCA Registry, funded by Novatis All honoraria received donated to SSBP, BDT or Universities of Cambridge/Cape Town
Outline Update on TSC Current status of clinical trials of mtor inhibitors Revised Diagnostic Criteria Revised Surveillance and monitoring guidelines TSC-Associated Neuropsychiatric Disorders (TAND)
Tuberous Sclerosis Complex (TSC)
Tuberous Sclerosis Complex (TSC) Bourneville, 1880 & 1881 Archives of Neurology Paris Encephalite ou sclerose tubereuse des circonvolutions cerebrales
Rayer s Atlas. 1835
Tuberous Sclerosis Complex (TSC) Incidence 1:6,000 1-2 million people worldwide 70% sporadic cases 30% familial (autosomal dominant) M=F Multi-system genetic disorder
TSC: a multi-system genetic disorder - skin Facial angiofibroma Shagreen patch White patches Ungual fibromas
2+ 3+
TSC: a multi-system genetic disorder other organ systems Eye lesions Eye mulberry lesions, achromic patches, other Heart cardiac rhabdomyomas; Wolff Parkinson White Renal angiomyolipomas(aml), cysts, polycystic kidneys Lung lymphangioleiomyomatosis(lam)
Krueger et al 2013
TSC: a multi-system genetic disorder brain Cortical tubers (CT) Subependymal nodules (SEN) Subependymal giant cell astrocytoma (SEGA)
Krueger et al 2013
GROUP T UBER DENSI T Y low high high low TSC: a multi-system genetic disorder - brain Widespread white and grey matter deficits over and above CT, SEN, SEGA Ridler et al, 2001, 2004, 2007
Age-related expression of manifestations in Tuberous Sclerosis Complex Curatolo et al., Lancet, 2008
The genetics of TSC TSC is caused by mutations in one of two genes -TSC1(9q34) or TSC2 (16p13.3) Multiple mutation types and locations have been identified Northrup et al, JCN, 2004 Curatolo et al 2008
The TSC1 and TSC2 proteins are multicomponent proteins Serfontein et al., Beh Genet, 2011
TSC1 (hamartin) and TSC2 (tuberin) act as an intracellular complex
TSC1 and TSC2 act as a molecular switchboard mutations lead to mtor overactivation
Knowledge of the molecular mechanisms has helped to understand the physical features of TSC Crino et al, NEJM, 2006 and has led to clinical trials of molecularly targeted treatments
Rapamycinis an mtor inhibitor
Rapamycinreduces size of AMLs in kidney In animal modelsof TSC In humanswith TSC AML and LAM (Phase II) USA -Bissler et al., NEJM, 2008 UK -Davies et al., NEJM, 2008 UK Davies et al., CCR, 2011
Bissleret al., Lancet, 2013
Rapamycinreduces the size of SEGA in the brain Franz et al., 2006, Krueger et al., 2010
Franz, et al., Lancet, 2013
Rapamycinalso reduces facial angiofibromas Hofbauer et al, 2008
The Neuropsychiatry of TSC I: Behavioural level II: Psychiatric level III: Global Intellectual Abilities IV: Academic/Scholastic Skills V: Neuropsychological level VI: Psycho-social VII: Biological
Behavioural and Psychiatric Behavioural level: Very high rates of a range of behavioural abnormalities Psychiatric level: Very high rates of ADHD (>50%) Very high rates of depressive and anxiety disorders in adults Very high rates of Autism spectrum disorders (25% autism + 25% ASD) 1-4% of autism is attributable to TSC TSC is therefore one of the medical conditions MOST HIGHLY associated with autism Bolton et al, 2002; Prather & de Vries, 2004; de Vries et al, 2005; de Vries et al, 2007
Intellectual Ability Normal distribution in the general population 20 70 100 de Vries & Prather, 2007
Intellectual Ability Normal Distribution (ND) TSC phenotype 70% Normal distribution in the general population 20 70 100 de Vries & Prather, 2007
Intellectual Ability Profound (P) TSC phenotype Normal Distribution (ND) TSC phenotype 30% 70% Normal distribution in the general population 20 70 100 de Vries & Prather, 2007
Academic or scholastic skills Reading, writing, spelling, mathematics Very limited direct data in TSC Rating scale measures by parents suggest 36% of school-aged children with normal IQ are at high risk of significant scholastic difficulties
Neuropsychological Deficits in TSC The majority of individuals with TSC have some neuropsychological deficits, including those with Normal Intellectual Ability Verbal and Spatial Memory (Recall, not recognition) Executive skills (planning, set-shifting) Attentional skills (particularly dual-tasking) Visuo-constructional skills
Psycho-social level Self-esteem Psychological impact of the disorder Self-efficacy Family Stressors Resilience Factors
TSC-Associated Neuropsychiatric Disorders (TAND) Together, almost 90% of people with TSC will have some TSC-associated neuropsychiatric disorder Fewer than 20% ever receive appropriate assessment and/or treatment
What are the mechanisms for the neuropsychiatric features in TSC? TSC mutation Cortical Tubers? Neurocognitive deficits Seizures? direct molecular route
CNS energy sensing and regulation & astrocyte morphology LTP and synaptic plasticity ERK1/2 p38mapk PI3K LKB1 AMPK REDD1? MK2 TSC2- TSC1 Akt GSK3β PTEN myelination CDK1 Rheb Rac1 Rho Actin cytoskeleton Forebrain development mtor Rapamycin eif4e 4E-BP1 S6K1 Cell Growth & Proliferation de Vries & Howe, TIMM, 2007
Tsc1 +/- mouse Utrecht No structural brain abnormalities, no seizures Significant spatial learning deficits Significant socialisation deficits Probe day 9 wt Tsc1 +/- Goorden et al, Ann Neurol, 2007
Tsc2 +/- mouse UCLA No seizures No structural lesions in brain Significant spatial learning deficits No socialisation deficits Ehninger et al, NMed, 2008
TSC2 +/- mice Learning Deficits Rapamycin IP for 5 days Learning deficits reversed to be similar to WT mice Ehningeret al, N Med, 2008
Autism-related behavioursreversed by intraperitonealrapamycin Tsai et al, Nature, 2012
RapamycinPhase II trial (TESSTAL -UK) Open label, multi-centre trial Efficacy and safety Rapamycin(Sirolimus) TSC AML + LAM Selected measures of memory Baseline, 4 months, 12 months Measures selected with parallel versions (reduce practice effects) Neuropsychologist blind to patient status and to hypothesis (reduce expectance effects) Control tasks (recognition) Davies, de Vries et al., CCR 2011
Experimental task Control task Improvement in immediate recall memory scores in 7/8 subjects after 12 months on Rapamycin (between 0.5SD and 3SD change) No improvement in recognition memory after 12 months
Experimental task Control task Improvement in immediate recall memory scores in 7/8 subjects after 12 months on Rapamycin (between 0.5SD and 3SD change) No improvement in recognition memory after 12 months 4 improved by >1SD
Current Status SEGA: Phase III trial completed; Everolimuslicencedby FDA and EMA for SEGA not amenable to surgery Angiomyolipoma: Phase III trial completed; FDA and EMA approved for AML>3cm; 2012 International consensus panel recommended mtorinhibitor as 1 st line treatment for AML>3cm Skin: Phase III trial underway for topical preparation Neuropsychiatric: 2 xphase II trials underway Epilepsy: Phase III underway
Diagnostic Criteria (revised from Roach et al 1998) Roach et al 1998 Krueger et al 2013 Definite/Probable/Possible Definite/Possible Genetic test results Quantification (3+FA or fibrous plaque, 3+HM >0.5cm; 2+UF) Terminology Cortical dysplasias(include CT and migration lines) Angiomyolipomas(2+) Minor features (Rationalization; removal of bone cysts)
Baseline evaluations 2013 Krueger et al., Ped Neurol 2013
Ongoing monitoring 2013
Conclusion TSC has great variability of features Age-related expression of physical features and TAND Revised diagnostic criteria Revised monitoring guidelines mtor inhibitors FDA and EMA approved Global efforts to improve knowledge and treatment for those who live with TSC
Europe: Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany,Greece, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom Australasia: Australia Asia: China, Israel, Korea, Taiwan, Thailand, Turkey Eurasia: Russia Africa: South Africa
Unanswered Questions: variability Possible predictors of response variability: Pharmacological: dose, duration, trough levels, compliance Molecular: functional consequences of mutations on mtor activation status
Bissler et al Lancet 2013
Franz et al Lancet2013
Acknowledgements Cambridge: Christopher Howe Jaco Serfontein Kevin Tierney Howard Wong Anna Whiteley Birmingham: Deborah McCartney Cardiff: Julian Sampson TESSTAL and TRON Trial Groups Cape Town: Rehana Effendi Loren Leclezio Heidelberg: Robert Waltereit Bonn: Dan Ehninger UCLA: Alcino Silva Boston: Mustafa Sahin and team Cincinnatti: David Franz Darcy Krueger Anna Byars Funding: TSA, TSAlliance, Autism Speaks, Novartis, UCT, Struengmann Fund