TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study

De Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P, Dahlin M, D'Amato L, D'Augeres GB, Ferreira JC, Feucht M, Fladrowski C, Hertzberg C, Jozwiak S, Kingswood JC, Lawson JA, Macaya A, Marques R, Nabbout R, O'Callaghan F, Qin J, Sander V, Sauter M, Shah S, Takahashi Y, Touraine R, Youroukos S, Zonnenberg B, Jansen AC (2018)

Publication Type: Journal article

Publication year: 2018


Book Volume: 13

Journal Issue: 1

DOI: 10.1186/s13023-018-0901-8


BACKGROUND: Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations. RESULTS: The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance <5th percentile) in 55.7%. Significantly higher rates of overactivity and impulsivity were observed in children and higher rates of anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations were observed in adults. Genotype-TAND correlations showed a higher frequency of self-injury, ASD, academic difficulties and neuropsychological deficits in TSC2. Those with no mutations identified (NMI) showed a mixed pattern of TAND manifestations. Children and those with TSC2 had significantly higher rates of intellectual disability, suggesting that age and genotype comparisons should be interpreted with caution. CONCLUSIONS: These results emphasize the magnitude of TAND in TSC and the importance of evaluating for neuropsychiatric comorbidity in all children and adults with TSC, across TSC1 and TSC2 genotypes, as well as in those with no mutations identified. However, the high rates of unreported or missing TAND data in this study underline the fact that, even in expert centres, TAND remains underdiagnosed and potentially undertreated.

Additional Organisation(s)

Involved external institutions

University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) University of Cape Town (UCT) ZA South Africa (ZA) Shizuoka Institute of Epilepsy and Neurological Disorders JP Japan (JP) "Aghia Sofia" General Children's Hospital GR Greece (GR) Tallinn Children’s Hospital EE Estonia (EE) Universitätsklinikum Ulm DE Germany (DE) Klinikverbund Kempten-Oberallgäu DE Germany (DE) Medizinische Universität Wien AT Austria (AT) Novartis Farma S.p.A IT Italy (IT) Policlinico Tor Vergata IT Italy (IT) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu PL Poland (PL) Sydney Children’s Hospitals Network AU Australia (AU) Centre Hospitalier Universitaire de Saint-Étienne (CHU) FR France (FR) Royal Sussex County Hospital GB United Kingdom (GB) Vivantes - Netzwerk für Gesundheit GmbH DE Germany (DE) Université Claude Bernard Lyon 1 (UCB) FR France (FR) Vrije Universiteit Brussel (VUB) BE Belgium (BE) University College London (UCL) GB United Kingdom (GB) Tuberous Sclerosis Association (TSA) GB United Kingdom (GB) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron ES Spain (ES) Novartis AG CH Switzerland (CH) Karolinska University Hospital / Karolinska Universitetssjukhuset SE Sweden (SE) Peking University (PKU) / 北京大学 CN China (CN) Ljubljana University Medical Centre (Ljubljana UMC) / Univerzitetni klinični center Ljubljana SI Slovenia (SI) Tuberous Sclerosis Association - APS (AST) IT Italy (IT) Pirogov Russian National Research Medical University (RSMU / RNRMU) RU Russian Federation (RU) Association Sclérose Tubéreuse de Bourneville (ASTB) FR France (FR) Centro Hospitalar de Lisboa Ocidental E.P.E. (CHLO) PT Portugal (PT)

How to cite


De Vries, P.J., Belousova, E., Benedik, M.P., Carter, T., Cottin, V., Curatolo, P.,... Jansen, A.C. (2018). TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet Journal of Rare Diseases, 13(1). https://dx.doi.org/10.1186/s13023-018-0901-8


De Vries, Petrus J., et al. "TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study." Orphanet Journal of Rare Diseases 13.1 (2018).

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