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

Research output: Contribution to journalArticle


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.


  • TOSCA Consortium and TOSCA Investigators
  • Olof Rask (Contributor)
External organisations
  • University of Cape Town
  • Russian National Research Medical University
  • Hospital Louis Pradel
  • Tor Vergata University Hospital
  • Novartis Farma S.p.A
  • Tuberous Sclerosis Association, France
  • Centro Hospitalar de Lisboa Ocidental (CHLO)
  • Universitatsklinik fur Kinder-und Jugendheilkunde, Vienna
  • European Tuberous Sclerosis Complex Association
  • Vivantes Hospital Neukölln
  • Medical University of Warsaw
  • Royal Sussex County Hospital
  • Sydney Children's Hospital
  • Vall d'Hebron University Hospital
  • University of León
  • Paris Descartes University
  • University College London Hospital
  • Peking University People's Hospital
  • Tallinn Children's Hospital
  • Klinikverbund Kempten-Oberallgäu gGmbH
  • Novartis Healthcare Pvt. Ltd, Hyderabad
  • National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders
  • Hopital Nord CHU de Sainte-Etienne
  • Aghia Sophia Children's Hospital
  • University Medical Center Utrecht
  • Vrije Universiteit Brussel (VUB)
  • University Children's Hospital
  • TSA Tuberous Sclerosis Association, UK
  • Karolinska University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Psychiatry


  • Adolescent, Adult, Anxiety Disorders/genetics, Attention Deficit Disorder with Hyperactivity/genetics, Autism Spectrum Disorder/genetics, Child, Child, Preschool, Depressive Disorder/genetics, Female, Genotype, Humans, Intellectual Disability/genetics, Male, Mutation/genetics, Neuropsychological Tests, Tuberous Sclerosis/genetics, Tuberous Sclerosis Complex 1 Protein/genetics, Tuberous Sclerosis Complex 2 Protein/genetics, Young Adult
Original languageEnglish
Pages (from-to)157
JournalOrphanet Journal of Rare Diseases
Issue number1
Publication statusPublished - 2018 Sep 10
Publication categoryResearch