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. 2022 Feb 13;14(1):13.
doi: 10.1186/s11689-022-09423-3.

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

Stephanie Vanclooster #  1 , Stacey Bissell #  2 , Agnies M van Eeghen  3   4 , Nola Chambers  5 , Liesbeth De Waele  6   7 , Anna W Byars  8 , Jamie K Capal  9 , Sebastián Cukier  10 , Peter Davis  11 , Jennifer Flinn  12 , Sugnet Gardner-Lubbe  13 , Tanjala Gipson  14   15 , Tosca-Marie Heunis  1 , Dena Hook  16 , J Christopher Kingswood  17   18 , Darcy A Krueger  19   20 , Aubrey J Kumm  5 , Mustafa Sahin  21 , Eva Schoeters  22 , Catherine Smith  16 , Shoba Srivastava  5   23 , Megumi Takei  24 , Robert Waltereit  25 , Anna C Jansen  1   26 , Petrus J de Vries  27
Affiliations

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

Stephanie Vanclooster et al. J Neurodev Disord. .

Abstract

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.

Keywords: Autism; Behaviour; Intellectual; Neuropsychological; Psychiatric; Psychosocial; Scholastic; Scoping review; TSC-associated neuropsychiatric disorders; Tuberous sclerosis complex.

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Conflict of interest statement

SB is funded by Cerebra to investigate sleep and behaviour in rare genetic syndromes, including TSC. PD receives partial salary support from the NIH for participation in studies related to TSC, as well as from Aucta Pharmaceuticals for a study of topical sirolimus for facial angiofibromas in TSC and Marinus Pharmaceuticals for a study of ganaxolone for TSC-related epilepsy. DAK reports grants from National Institutes of Health (NINDS) during the conduct of the study as well as the personal fees from Novartis Pharmaceuticals, personal fees from Greenwich Bioscience, grants from Marinus Pharmaceuticals, personal fees from Nobelpharma America, personal fees from REGENXBIO, and grants and non-financial support from TSC Alliance outside the submitted work. CS receives salary support from the TSC Alliance, a non-profit organisation which reports revenue from individual donors and corporations including Greenwich Biosciences, GW Pharma, Mallinckrodt, Nobelpharma, Novartis, Ovid, UCB and Upsher-Smith. PJdV was a study steering committee member of three phase III trials sponsored by Novartis. He and AJ were also on the scientific advisory group of the TOSCA international disease registry sponsored by Novartis. MS reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio and Aucta, and has served on Scientific Advisory Boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram of study selection. Please note that articles are referred to as ‘records’ before full-text screening and as ‘studies’ once included in the review
Fig. 2
Fig. 2
Number of TAND studies across years based on study type. *The search was completed in March 2020. As a result, the column does not represent all TAND studies published in 2020
Fig. 3
Fig. 3
World map depicting the geographical location of the 341 research sites identified across the 230 studies. Darker colours depict a greater number of research sites per country
Fig. 4
Fig. 4
Research of different TAND levels based on study type (animal, case studies, cohort studies). The psychiatric, intellectual, academic and psychosocial levels were not applicable to animal studies and were therefore not shown
Fig. 5
Fig. 5
Research on different TAND clusters based on study type (animal, case studies, cohort studies). The scholastic cluster was not applicable to animal studies and was therefore not shown
See this image and copyright information in PMC

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