In June of this year, the TS Alliance held its biennial international research conference in Washington, D.C. The conference was held over four days, bringing together scientists, clinicians and families to “examine the state of current knowledge, identify gaps, and discuss ideas for the next steps in basic, translational and clinical research.”
Tuberous Sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 genes and is characterised by the growth of benign tumors in the brain, eyes, heart, kidney, skin and lungs. Symptoms generally develop in early childhood, and can sometimes be detected in utero during routine ultrasound screening if cardiac rhabdomyoma is present. Children can also develop cognitive delay and impairment, autism and intractable epilepsy. Pulmonary LAM, a cystic lung disease, is also a symptom of TSC, with women more likely to be affected. TSC is a rare disease, with an estimated 1 million patients worldwide. Last year, the TS Alliance hosted a Clinical Consensus Conference, and the recommendations from this meeting have been submitted for publication.
As shown on our signalling diagram, the causative genes of TSC, TSC1 and TSC2, form a heterodimer which inhibits Rheb, and consequently mTOR signalling, via TSC2’s GAP domain. Professor Brendan Manning presented data on TBC1D7, which has been reported to form part of the TSC1-TSC2 complex and is required for Rheb inactivation (Dibble et al., 2012). Given the overlapping symptoms between TSC and BHD, and that the proteins seem to act within similar pathways, new proteins implicated in TSC are of interest to BHD researchers. Indeed, TBC1D7 has been reported to be required for primary cilium formation (Yoshimura et al., 2007). This is particularly interesting in the light of the recent report that FLCN is involved in the initiation of ciliation and that BHD might be a ciliopathy, suggesting that aberrant ciliary development may also be an underlying factor in the pathogenesis of some or all of the symptoms of TSC.
A prominent theme of the conference was the use of mTOR inhibitors as a potential therapy for a whole range of TSC symptoms including kidney angiomyolipoma, LAM, brain tumours, epilepsy and autism. Early data suggest that while mTOR inhibitors halt the progression of disease, they do not reverse damage, meaning that symptoms resume progression upon treatment cessation (McCormack et al., 2011). However, a number of studies were presented showing that mTOR inhibitor therapy in combination with other drugs may be able to reverse disease progression. Of note, Professor Frank McCormack spoke about the challenges in implementing the MILES trial (McCormack et al., 2011); Professor Lisa Henske presented data that has formed the basis of the SAIL trial, which is currently enrolling and will test combined Rapamycin and Chloroquine therapy for the treatment of LAM; and Professor Vera Krymskaya presented data showing that Rapamycin combined with Simvastatin treatment partially reversed the lung damage seen in a mouse model of LAM (Goncharova et al., 2012).
As previously mentioned, children with TSC sometimes develop a range of cognitive, neurological and psychiatric disorders, including developmental delay, intellectual impairment, intractable epilepsy and autism. Due to the difficulty in diagnosing some of these conditions, and as symptoms can change over time, few TSC patients receive appropriate clinical assessment and treatment for these manifestations. Loren Leclezio, of the University of Cape Town, spoke about the work of the 2012 Neuropsychiatry Consensus Panel, who met at the 2012 International TSC Consensus Conference. An important outcome of this meeting was the development of the TSC-Associated Neuropsychiatric Disorders (TAND) checklist tool, which serves as an aide-memoire to allow systematic evaluation of neuropsychiatric TSC manifestations and will be freely available.
Since the TS Alliance was founded in 1974 by four mothers of children with TSC, the organisation has funded $16.5 million of research, helped set up five specialist TSC Clinics in the US, funded two clinical trials which have led to FDA approval of Everolimus for the treatment of brain tumours and renal angiomyolipoma; and has founded a TSC Natural History Database. Additionally, the TS Alliance runs a number of patient support, awareness, fundraising and advocacy programmes, comprising online resources and local, national and international meetings for patients and their families. The next World TSC Conference will be held in Washington D.C. on 3-6 July, 2014 and will include the Third Annual Step Forward to Cure TSC National Walk on the Mall.
- Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, & Manning BD (2012). TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Molecular cell, 47 (4), 535-46 PMID: 22795129
- Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, & Krymskaya VP (2012). Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4 (154) PMID: 23035046
- McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC, National Institutes of Health Rare Lung Diseases Consortium, & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-606 PMID: 21410393
- Yoshimura S, Egerer J, Fuchs E, Haas AK, & Barr FA (2007). Functional dissection of Rab GTPases involved in primary cilium formation. The Journal of cell biology, 178 (3), 363-9 PMID: 17646400
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.