AUTHOR=de Vries Petrus J. , Belousova Elena , Benedik Mirjana P. , Carter Tom , Cottin Vincent , Curatolo Paolo , Dahlin Maria , D'Amato Lisa , Beaure d'Augères Guillaume , Ferreira José C. , Feucht Martha , Fladrowski Carla , Hertzberg Christoph , Jozwiak Sergiusz , Lawson John A. , Macaya Alfons , Marques Ruben , Nabbout Rima , O'Callaghan Finbar , Qin Jiong , Sander Valentin , Sauter Matthias , Shah Seema , Takahashi Yukitoshi , Touraine Renaud , Youroukos Sotiris , Zonnenberg Bernard , Kingswood John C. , Jansen Anna C. , TOSCA Investigators , Shinohara Nobuo , Horie Shigeo , Kubota Masaya , Tohyama Jun , Imai Katsumi , Kaneda Mari , Kaneko Hideo , Uchida Yasushi , Kirino Tomoko , Endo Shoichi , Inoue Yoshikazu , Uruno Katsuhisa , Serdaroglu Ayse , Yapici Zuhal , Anlar Banu , Altunbasak Sakir , Lvova Olga , Belyaev Oleg Valeryevich , Agranovich Oleg , Levitina Elena Vladislavovna , Maksimova Yulia Vladimirovna , Karas Antonina , Jiang Yuwu , Zou Liping , Xu Kaifeng , Zhang Yushi , Luan Guoming , Zhang Yuqin , Wang Yi , Jin Meiling , Ye Dingwei , Liao Weiping , Zhou Liemin , Liu Jie , Liao Jianxiang , Yan Bo , Deng Yanchun , Jiang Li , Liu Zhisheng , Huang Shaoping , Li Hua , Kim Kijoong , Chen Pei-Lung , Lee Hsiu-Fen , Tsai Jeng-Dau , Chi Ching-Shiang , Huang Chao-Ching , Riney Kate , Yates Deborah , Kwan Patrick , Likasitwattanakul Surachai , Nabangchang Charcrin , Chomtho Lunliya Thampratankul Krisnachai , Katanyuwong Kamornwan , Sriudomkajorn Somjit , Wilmshurst Jo , Segel Reeval , Gilboa Tal , Tzadok Michal , Fattal-Valevski Aviva , Papathanasopoulos Panagiotis , Papavasiliou Antigone Syrigou , Giannakodimos Stylianos , Gatzonis Stylianos , Pavlou Evangelos , Tzoufi Meropi , Vergeer A. M. H. , Dhooghe Marc , Verhelst Hélène , Roelens Filip , Nassogne Marie Cecile , Defresne Pierre , Waele Liesbeth De , Leroy Patricia , Demonceau Nathalie , Legros Benjamin , Bogaert Patrick Van , Ceulemans Berten , Dom Lina , Castelnau Pierre , Martin Anne De Saint , Riquet Audrey , Milh Mathieu , Cances Claude , Pedespan Jean-Michel , Ville Dorothee , Roubertie Agathe , Auvin Stéphane , Berquin Patrick , Richelme Christian , Allaire Catherine , Gueden Sophie , Tich Sylvie Nguyen The , Godet Bertrand , Rojas Maria Luz Ruiz Falco , Planas Jaume Campistol , Bermejo Antonio Martinez , Dura Patricia Smeyers , Aparicio Susana Roldan , Gonzalez Maria Jesus Martinez , Pison Javier Lopez , Barca Manuel Oscar Blanco , Laso Eduardo Lopez , Luengo Olga Alonso , Rodriguez Francisco Javier Aguirre , Dieguez Ignacio Malaga , Salas Ana Camacho , Carrera Itxaso Marti , Salcedo Eduardo Martinez , Petri Maria Eugenia Yoldi , Candela Ramon Cancho , Carrilho Ines da Conceicao , Vieira Jose Pedro , Monteiro José Paulo da Silva Oliveira , Leao Miguel Jorge Santos de Oliveira Ferreira , Luis Catarina Sofia Marceano Ribeiro , Mendonca Carla Pires , Endziniene Milda , Strautmanis Jurgis , Talvik Inga , Canevini Maria Paola , Gambardella Antonio , Pruna Dario , Buono Salvatore , Fontana Elena , Bernardina Bernardo Dalla , Burloiu Carmen , Cosma Iuliu Stefan Bacos , Vintan Mihaela Adela , Popescu Laura , Zitterbart Karel , Payerova Jaroslava , Bratsky Ladislav , Zilinska Zuzana , Gruber-Sedlmayr Ursula , Baumann Matthias , Haberlandt Edda , Rostasy Kevin , Pataraia Ekaterina , Elmslie Frances , Johnston Clare Ann , Crawford Pamela , Uldall Peter , Uvebrant Paul , Rask Olof , Bjoernvold Marit , Brodtkorb Eylert , Sloerdahl Andreas , Solhoff Ragnar , Jaatun Martine Sofie Gilje , Mandera Marek , Radzikowska Elzbieta Janina , Wysocki Mariusz , Fischereder Michael , Kurlemann Gerhard , Wilken Bernd , Wiemer-Kruel Adelheid , Budde Klemens , Marquard Klaus , Knuf Markus , Hahn Andreas , Hartmann Hans , Merkenschlager Andreas , Trollmann Regina
TITLE=Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND): New Findings on Age, Sex, and Genotype in Relation to Intellectual Phenotype
JOURNAL=Frontiers in Neurology
VOLUME=11
YEAR=2020
URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.00603
DOI=10.3389/fneur.2020.00603
ISSN=1664-2295
ABSTRACT=Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort.
Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype (TSC1 vs. TSC2) stratified by IA levels were examined using the Cochran–Mantel–Haenszel tests.
Results: Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association (P < 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity (P = 0.12), overactivity (P = 0.26), mood swings (P = 0.08), hallucinations (P = 0.20), psychosis (P = 0.06), depressive disorder (P = 0.23), and anxiety disorder (P = 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals with TSC2 mutations.
Conclusions: Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association between TSC2 and IA but, once controlling for IA, disproves the previously reported TSC2 association with ASD and with most other TAND manifestations.