Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ).

BACKGROUND: Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are often present but underidentified and undertreated in individuals with tuberous sclerosis complex (TSC). The clinician-completed TAND-Lifetime Checklist (TAND-L) was developed to address this identification and treatment gap. Stakeholder engagement identified the need for a TAND Checklist that can (1) be completed by caregivers or individuals with TSC and (2) quantify TAND difficulties. The aim of this study was to develop a self-report quantified TAND Checklist (TAND-SQ) and conduct feasibility and acceptability testing. METHODS: This aim was addressed in three phases: (1) development of the TAND-SQ Checklist, (2) feasibility and acceptability testing of the "near-final" TAND-SQ Checklist, and (3) preparation of the final TAND-SQ Checklist. Participants included 23 technical experts from the TAND consortium in all phases and 58 lived experts (caregivers and individuals with TSC) in phase 2. All participants completed a TAND-SQ Checklist and a checklist feedback form. RESULTS: Phase 1 additions to the TAND-SQ, when compared with the TAND-L, included four new items and a quantification rating. Phase 2 showed high ratings for the "near-final" TAND-SQ Checklist on comprehensiveness, clarity, ease of use, and overall acceptability. In phase 3, questions on strengths, strategies, and a TAND Cluster Profile were added. CONCLUSION: The TAND-SQ Checklist is presented here for use by individuals with TSC and their caregivers. The next steps as part of the TANDem project include internal and external validation of the checklist and linking of TAND Cluster Profiles generated from the checklist to evidence-informed consensus recommendations within a smartphone application.

Empowering Families Through Technology: A Mobile-Health Project to Reduce the TAND Identification and Treatment Gap (TANDem).

Introduction: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder with various TSC-Associated Neuropsychiatric Disorders (TAND) that significantly impact the mental health and wellbeing of individuals with TSC and their caregivers. TAND represents the number one concern to families worldwide, yet is highly under-identified and under-treated. The clinician-administered TAND-Checklist (Lifetime version, TAND-L) has improved identification of TAND in clinical settings. However, many individuals with TSC and their caregivers still have difficulty accessing suitable support for diagnosis and evidence-informed interventions. The TANDem study is a community-based participatory research project with a broad range of TSC stakeholders aimed at reducing the TAND identification and treatment gap. Objectives: Participatory research identified three priority next steps: 1) development and validation of a self-report, quantified version of the TAND Checklist (TAND-SQ) and building the TAND-SQ into a smartphone application, 2) generation of consensus clinical recommendations for the identification and treatment of TAND, to be incorporated as a TAND toolkit on the app, and 3) establishment of a global TAND consortium through networking, capacity-building and public engagement activities. Methods: TANDem is a four-year project, and includes 24 consortium members from 10 countries representing all World Health Organization regions. Collaborators represent five stakeholder groups (family representatives, technology experts, clinical experts, non-profit organisations and researchers). Here we outline the project study protocol in detail, describing the scientific rationale, the project aims and objectives, the methods involved in participant recruitment, multi-site and multi-phase data collection, data analysis, ethical considerations including informed consent, data protection, privacy and confidentiality considerations related to the European Union General Data Protection Regulation and the USA Health Insurance Portability and Accountability Act. The expected outcomes and potential impact on the TSC community, implementation and dissemination of results, as well as future scale-up and scale-out plans are also discussed. Conclusions: The TANDem project has the potential to transform the global TSC community by empowering families living with TSC through an easily accessible digital solution to allow them to document their own TAND needs linked to an evidence-informed toolkit to enhance personalised healthcare, and by providing healthcare professionals with consensus clinical recommendations to prevent, identify and manage TAND manifestations.

The research landscape of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)-a comprehensive scoping review.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. METHODS: The study was conducted in accordance with stages outlined within the Arksey and O'Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. RESULTS: Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low-middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder-like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). CONCLUSIONS: Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.

Progress in Tuberous Sclerosis Complex Renal Disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects both fetal development and postnatal tissue growth, resulting in altered brain structures and a tumor predisposition syndrome. Although every organ system is affected by the disease, kidney involvement is a leading cause of death in adults with TSC. Over the past decade, significant progress has been made in understanding the renal disease. This review focuses on the cystic and solid renal lesions in TSC, including their pathobiology and treatment.

A step-wise approach for establishing a multidisciplinary team for the management of tuberous sclerosis complex: a Delphi consensus report.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. METHODS: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. RESULTS: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual's needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients' overall care. CONCLUSIONS: The results of our consensus provide guidance to support the initiation of an MDT in TSC.

The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. METHODS: This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m2/day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged <18 years with ≥1 target angiomyolipoma lesion at baseline. Response was defined as the proportion of patients with a ≥50% reduction in the sum volume of target renal angiomyolipomata from baseline, in the absence of new target angiomyolipomata, a >20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed. RESULTS: Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity. CONCLUSIONS: Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex.

OBJECTIVES: To determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients. DESIGN: A pooled analysis from 3 prospective studies consisting of a core phase (≥6 months) and a long-term follow-up open-label extension. SETTING: One phase 2 single-center and two phase 3 multicenter studies. PARTICIPANTS: Data were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus. MAIN OUTCOME MEASURES: Incidence of fertility events. RESULTS: A total of 43/112 patients (38.4%) experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years). A total of 19/92 patients (20.7%) who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%), and follicle-stimulating hormone levels were within normal limits for these patients. CONCLUSIONS: No new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex-associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus. TRIAL REGISTRATION: ClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400.

Tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems and is caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. The disorder can affect both adults and children. First described in depth by Bourneville in 1880, it is now estimated that nearly 2 million people are affected by the disease worldwide. The clinical features of TSC are distinctive and can vary widely between individuals, even within one family. Major features of the disease include tumours of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. TSC1 (also known as hamartin) and TSC2 (also known as tuberin) form the TSC protein complex that acts as an inhibitor of the mechanistic target of rapamycin (mTOR) signalling pathway, which in turn plays a pivotal part in regulating cell growth, proliferation, autophagy and protein and lipid synthesis. Remarkable progress in basic and translational research, in addition to several randomized controlled trials worldwide, has led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas and pulmonary lymphangioleiomyomatosis, but further research is needed to establish full indications of therapeutic treatment. In this Primer, we review the state-of-the-art knowledge in the TSC field, including the molecular and cellular basis of the disease, medical management, major knowledge gaps and ongoing research towards a cure.

The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions.

Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC.

Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata. METHODS: In this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400. RESULTS: 118 patients (median age 31·0 years; IQR 18·0­61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31­53%]) for everolimus and 0% (0 of 39 [0­9%]) for placebo (response rate difference 42% [24­58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]). INTERPRETATION: Everolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis. FUNDING: Novartis Pharmaceuticals.