Clinical Study Managing tuberous sclerosis in the Asia-Pacific region: Refining practice and the role of targeted therapy John A. Lawson a,⇑ , Chi-Fung Chan b , Ching-Shiang Chi c , Pi-Chuan Fan d , Heung Dong Kim e , Ki Joong Kim f , Surachai Likasitwatanakul g , Marilyn Ortiz h,i , Kate Riney j , Stacey Kiat-Hong Tay k,l , Chee-Kian Tham m a Department of Neurology, Sydney Children’s Hospital and University of NSW, High Street, Randwick, NSW 2031, Australia b Department of Pediatrics & Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong c Pediatric Neurology, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan d Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan e Division of Pediatric Neurology, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, South Korea f Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea g Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand h Child Neuroscience Center, Philippine Children’s Medical Center, Quezon City, Philippines i International Institute for Neurosciences, St. Luke’s Medical Center, Quezon City, Philippines j Neurosciences Unit, Mater Children’s Hospital, Brisbane, QLD, Australia k Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore l Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore m Department of Medical Oncology, National Cancer Centre, Singapore article info Article history: Received 24 December 2012 Accepted 24 June 2013 Available online xxxx Keywords: Asia-Pacific Management mTOR inhibitor TSC Tuberous sclerosis abstract Tuberous sclerosis complex (TSC) is a multisystem genetic disorder, with heterogeneous manifestations that pose major diagnostic and management challenges and incur considerable chronic disease burden on patients, their caregivers and healthcare systems. This survey of clinical practice in the Asia-Pacific region highlights priorities for improving TSC management in the region. The prevalence of TSC in non-Caucasians is uncertain and more data are needed to assess its impact and health-economic burden. There are unmet needs for access to genetic testing and earlier diagnosis and intervention. TSC manage- ment is multidisciplinary and largely based on experience, backed by international guidelines; however, physicians in the Asia-Pacific region feel isolated and lack local or regional guidance and support struc- tures to implement best-practice. Raising awareness of TSC and increasing trans-regional collaboration are particular priorities. Understanding of TSC pathophysiology has enabled the development of targeted therapies. Encouraging data indicate that mammalian target of rapamycin (mTOR) inhibitors can amelio- rate TSC-related lesions and may potentially change the treatment paradigm. Ultimately, improving out- comes for TSC patients in the region requires greater collaboration and a holistic, patient-focused, continuum of care that is maintained through the transition from pediatric to adult care. Ó 2013 Elsevier Ltd. All rights reserved. 1. Context 1.1. Pathophysiology Tuberous sclerosis complex (TSC) is an autosomal dominant ge- netic disorder with heterogeneous manifestations that affect mul- tiple organs and systems. The classic clinical presentation includes epilepsy, skin lesions and intellectual impairment [1]; however, only 29% of TSC patients have all these symptoms and 6% have none of them [2]. TSC results from mutations in TSC1, which encodes hamartin, or TSC2, encoding tuberin [1]. The hamartin-tuberin heterodimer sta- bilizes tuberin, which in turn inactivates the protein Ras homolog enriched in brain (Rheb) that activates the mammalian target of rapamycin (mTOR) (Fig. 1). Consequently, TSC expression down- regulates aberrant and potentially oncogenic and epileptogenic mTOR-driven cell growth, proliferation and protein synthesis [3– 5]. TSC mutations account for approximately 85% of diagnosed TSC patients; two-thirds of which are due to new mutations [1]. TSC mutations exhibit variable expression; some affected patients remain asymptomatic, whereas others have life-threatening com- plications [6,7]. Mutations in TSC2 appear to cause more severe http://dx.doi.org/10.1016/j.jocn.2013.06.029 0967-5868/Ó 2013 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +61 2 9382 1658; fax: +61 2 9382 1580. E-mail address: Lawson@sesiahs.health.nsw.gov.au (J.A. Lawson). Journal of Clinical Neuroscience xxx (2014) xxx–xxx Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn Please cite this article in press as: Lawson JA et al. Managing tuberous sclerosis in the Asia-Pacific region: Refining practice and the role of targeted therapy. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2013.06.029