Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6-24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development-BSID, and Autism Diagnostic Observation Schedule-ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy-Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6-12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies.

Amsterdam UMC University of Amsterdam Department of Pathology Amsterdam Neuroscience Meibergdreef 9 1105 AZ Amsterdam The Netherlands

Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Via Montpellier 1 00133 Rome Italy

Child Neurology Unit Neuroscience and Neurorehabilitation Department Bambino Gesù Children's Hospital IRCCS P zza S Onofrio 4 00165 Rome Italy

Department of Biomedicine and Prevention Tor Vergata University of Rome Via Montpellier 1 00133 Rome Italy

Department of Biotechnological and Applied Clinical Sciences University of L'Aquila 67100 L'Aquila Italy

Department of Child Neurology Brain Center University Medical Center Utrecht 3584 Utrecht The Netherlands

Department of Child Neurology Charité University Medicine Berlin Augustenburger Platz 1 13353 Berlin Germany

Department of Child Neurology Medical University of Warsaw Warsaw Poland Zwirki i Wigury 63A 02 091 Warsaw Poland

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven 3000 Leuven Belgium

Department of Neurology and Epileptology The Children's Memorial Health Institute Al Dzieci Polskich 20 04 730 Warsaw Poland

Department of Pediatric Neurology Reference Centre for Rare Epilepsies Necker Enfants Malades Hospital University Paris Descartes Imagine Institute 75015 Paris France

Department of Pediatrics University Hospital Vienna 1090 Vienna Austria

Diagnose und Behandlungszentrum für Kinder und Jugendliche Vivantes Klinikum Neuköln 12351 Berlin Germany

Motol University Hospital Charles University 150 06 Prague Czech Republic

Neuroscience Unit Queensland Children's Hospital 501 Stanley Street South Brisbane QLD 4101 Australia

Pediatric Neurology Unit UZ Brussel 1050 Brussels Belgium

School of Clinical Medicine University of Queensland St Lucia QLD 4072 Australia

Stichting Epilepsie Instellingen Nederland The Netherlands

Transition Technologies ul Pawia 5 01 030 Warsaw Poland

Warsaw University of Technology Institute of Heat Engineering 00 661 Warsaw Poland

Zobrazit více v PubMed

Curatolo P., Bombardieri R., Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657–668. doi: 10.1016/S0140-6736(08)61279-9. PubMed DOI

O’Callaghan F.J., Shiell A.W., Osborne J.P., Martyn C.N. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet. 1998;351:1490. doi: 10.1016/S0140-6736(05)78872-3. PubMed DOI

Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315. doi: 10.1016/0092-8674(93)90618-Z. PubMed DOI

van Slegtenhorst M., de Hoogt R., Hermans C., Nellist M., Janssen B., Verhoef S., Lindhout D., van den Ouweland A., Halley D., Young J., et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808. doi: 10.1126/science.277.5327.805. PubMed DOI

Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr. Neurol. 2015;52:281–289. doi: 10.1016/j.pediatrneurol.2014.10.028. PubMed DOI

Chu-Shore C.J., Major P., Camposano S., Muzykewicz D., Thiele E.A. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010;57:1236–1241. doi: 10.1111/j.1528-1167.2009.02474.x. PubMed DOI PMC

Moavero R., Napolitano A., Cusmai R., Vigevano F., Figa-Talamanca L., Calbi G., Curatolo P., Bernardi B. White matter disruption is associated with persistent seizures in tuberous sclerosis complex. Epilepsy Behav. 2016;60:63–67. doi: 10.1016/j.yebeh.2016.04.026. PubMed DOI

Kaczorowska M., Jurkiewicz E., Domanska-Pakiela D., Syczewska M., Lojszczyk B., Chmielewski D., Kotulska K., Kuczynski D., Kmiec T., Dunin-Wasowicz D., et al. Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex. Epilepsia. 2011;52:22–27. doi: 10.1111/j.1528-1167.2010.02892.x. PubMed DOI

Capal J.K., Bernardino-Cuesta B., Horn P.S., Murray D., Byars A.W., Bing N.M., Kent B., Pearson D.A., Sahin M., Krueger D.A., et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 2017;70:245–252. doi: 10.1016/j.yebeh.2017.02.007. PubMed DOI PMC

Curatolo P., Aronica E., Jansen A., Jansen F., Kotulska K., Lagae L., Moavero R., Jozwiak S. Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC. Eur. J. Paediatr. Neurol. 2016;20:203–211. doi: 10.1016/j.ejpn.2015.12.005. PubMed DOI

American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorder. 5th ed. CBS Publisher & Distribution; Washington, DC, USA: 2013.

Rogers S.J., Vismara L., Wagner A.L., McCormick C., Young G., Ozonoff S. Autism treatment in the first year of life: A pilot study of infant start, a parent-implemented intervention for symptomatic infants. J. Autism Dev. Disord. 2014;44:2981–2995. doi: 10.1007/s10803-014-2202-y. PubMed DOI PMC

Jones E.J., Venema K., Earl R., Lowy R., Barnes K., Estes A., Dawson G., Webb S.J. Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: A longitudinal prospective study of infants at high familial risk. J. Neurodev. Disord. 2016;8:7. doi: 10.1186/s11689-016-9139-8. PubMed DOI PMC

Jeste S.S., Wu J.Y., Senturk D., Varcin K., Ko J., McCarthy B., Shimizu C., Dies K., Vogel-Farley V., Sahin M., et al. Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex. Neurology. 2014;83:160–168. doi: 10.1212/WNL.0000000000000568. PubMed DOI PMC

Rague L., Caravella K., Tonnsen B., Klusek J., Roberts J. Early gesture use in fragile X syndrome. J. Intellect. Disabil. Res. 2018;62:625–636. doi: 10.1111/jir.12498. PubMed DOI PMC

Jeste S.S., Sahin M., Bolton P., Ploubidis G.B., Humphrey A. Characterization of autism in young children with tuberous sclerosis complex. J. Child Neurol. 2008;23:520–525. doi: 10.1177/0883073807309788. PubMed DOI

Leclezio L., de Vries P.J. Advances in the treatment of tuberous sclerosis complex. Curr. Opin. Psychiatry. 2015;28:113–120. doi: 10.1097/YCO.0000000000000136. PubMed DOI

Curatolo P., Moavero R., de Vries P.J. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14:733–745. doi: 10.1016/S1474-4422(15)00069-1. PubMed DOI

De Vries P.J., Wilde L., de Vries M.C., Moavero R., Pearson D.A., Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) Am. J. Med. Genet. C Semin. Med. Genet. 2018;178:309–320. doi: 10.1002/ajmg.c.31637. PubMed DOI PMC

Numis A.L., Major P., Montenegro M.A., Muzykewicz D.A., Pulsifer M.B., Thiele E.A. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology. 2011;76:981–987. doi: 10.1212/WNL.0b013e3182104347. PubMed DOI PMC

Bombardieri R., Pinci M., Moavero R., Cerminara C., Curatolo P. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 2010;14:146–149. doi: 10.1016/j.ejpn.2009.03.003. PubMed DOI

Cusmai R., Moavero R., Bombardieri R., Vigevano F., Curatolo P. Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav. 2011;22:735–739. doi: 10.1016/j.yebeh.2011.08.037. PubMed DOI

Jozwiak S., Kotulska K., Domanska-Pakiela D., Lojszczyk B., Syczewska M., Chmielewski D., Dunin-Wasowicz D., Kmiec T., Szymkiewicz-Dangel J., Kornacka M., et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur. J. Paediatr. Neurol. 2011;15:424–432. doi: 10.1016/j.ejpn.2011.03.010. PubMed DOI

Dragoumi P., O’Callaghan F., Zafeiriou D.I. Diagnosis of tuberous sclerosis complex in the fetus. Eur. J. Paediatr. Neurol. 2018;22:1027–1034. doi: 10.1016/j.ejpn.2018.08.005. PubMed DOI

Wortmann S.B., Reimer A., Creemers J.W., Mullaart R.A. Prenatal diagnosis of cerebral lesions in Tuberous sclerosis complex (TSC). Case report and review of the literature. Eur. J. Paediatr. Neurol. 2008;12:123–126. doi: 10.1016/j.ejpn.2007.06.006. PubMed DOI

Northrup H., Krueger D.A., International Tuberous Sclerosis Complex Consensus Group Tuberous sclerosis complex diagnostic criteria update: Recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 2013;49:243–254. doi: 10.1016/j.pediatrneurol.2013.08.001. PubMed DOI PMC

Capal J.K., Horn P.S., Murray D.S., Byars A.W., Bing N.M., Kent B., Bucher L.A., Williams M.E., O’Kelley S., Pearson D.A., et al. Utility of the Autism Observation Scale for Infants in Early Identification of Autism in Tuberous Sclerosis Complex. Pediatr. Neurol. 2017;75:80–86. doi: 10.1016/j.pediatrneurol.2017.06.010. PubMed DOI PMC

McDonald N.M., Varcin K.J., Bhatt R., Wu J.Y., Sahin M., Nelson C.A., Jeste S.S. Early autism symptoms in infants with tuberous sclerosis complex. Autism Res. 2017;10:1981–1990. doi: 10.1002/aur.1846. PubMed DOI PMC

Libertus K., Sheperd K.A., Ross S.W., Landa R.J. Limited fine motor and grasping skills in 6-month-old infants at high risk for autism. Child Dev. 2014;85:2218–2231. doi: 10.1111/cdev.12262. PubMed DOI PMC

Choi B., Leech K.A., Tager-Flusberg H., Nelson C.A. Development of fine motor skills is associated with expressive language outcomes in infants at high and low risk for autism spectrum disorder. J. Neurodev. Disord. 2018;10:14. doi: 10.1186/s11689-018-9231-3. PubMed DOI PMC

Winarni T.I., Schneider A., Borodyanskara M., Hagerman R.J. Early intervention combined with targeted treatment promotes cognitive and behavioral improvements in young children with fragile x syndrome. Case Rep. Genet. 2012;2012:280813. doi: 10.1155/2012/280813. PubMed DOI PMC

Jones E.J.H., Dawson G., Kelly J., Estes A., Jane Webb S. Parent-delivered early intervention in infants at risk for ASD: Effects on electrophysiological and habituation measures of social attention. Autism Res. 2017;10:961–972. doi: 10.1002/aur.1754. PubMed DOI PMC

Emberti Gialloreti L., Mazzone L., Benvenuto A., Fasano A., Alcon A.G., Kraneveld A., Moavero R., Raz R., Riccio M.P., Siracusano M., et al. Risk and Protective Environmental Factors Associated with Autism Spectrum Disorder: Evidence-Based Principles and Recommendations. J. Clin. Med. 2019;8:217. doi: 10.3390/jcm8020217. PubMed DOI PMC

Curatolo P., Napolioni V., Moavero R. Autism spectrum disorders in tuberous sclerosis: Pathogenetic pathways and implications for treatment. J. Child Neurol. 2010;25:873–880. doi: 10.1177/0883073810361789. PubMed DOI

Nolan S.O., Jefferson T.S., Reynolds C.D., Smith G.D., Holley A.J., Hodges S.L., Lugo J.N. Neuronal deletion of Pten results in cerebellar motor learning dysfunction and alterations in intracellular signaling. CNS Neurol. Disord. Drug Targets. 2019;30 doi: 10.2174/1871527318666190312122753. PubMed DOI PMC

Magdalon J., Sanchez-Sanchez S.M., Griesi-Oliveira K., Sertie A.L. Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder? Int. J. Mol. Sci. 2017;18:659. doi: 10.3390/ijms18030659. PubMed DOI PMC

Rosina E., Battan B., Siracusano M., Di Criscio L., Hollis F., Pacini L., Curatolo P., Bagni C. Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Transl. Psychiatry. 2019;9:50. doi: 10.1038/s41398-018-0335-z. PubMed DOI PMC

Ehninger D., Han S., Shilyansky C., Zhou Y., Li W., Kwiatkowski D.J., Ramesh V., Silva A.J. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 2008;14:843–848. doi: 10.1038/nm1788. PubMed DOI PMC

Sato A., Kasai S., Kobayashi T., Takamatsu Y., Hino O., Ikeda K., Mizuguchi M. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat. Commun. 2012;3:1292. doi: 10.1038/ncomms2295. PubMed DOI PMC

Tsai P.T., Hull C., Chu Y., Greene-Colozzi E., Sadowski A.R., Leech J.M., Steinberg J., Crawley J.N., Regehr W.G., Sahin M. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488:647–651. doi: 10.1038/nature11310. PubMed DOI PMC

Schneider M., de Vries P.J., Schonig K., Rossner V., Waltereit R. mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus. Eur. Arch. Psychiatry Clin. Neurosci. 2017;267:455–463. doi: 10.1007/s00406-016-0703-8. PubMed DOI

Wesseling H., Elgersma Y., Bahn S. A brain proteomic investigation of rapamycin effects in the Tsc1(+/−) mouse model. Mol. Autism. 2017;8:41. doi: 10.1186/s13229-017-0151-y. PubMed DOI PMC

Kilincaslan A., Kok B.E., Tekturk P., Yalcinkaya C., Ozkara C., Yapici Z. Beneficial Effects of Everolimus on Autism and Attention-Deficit/Hyperactivity Disorder Symptoms in a Group of Patients with Tuberous Sclerosis Complex. J. Child Adolesc. Psychopharmacol. 2017;27:383–388. doi: 10.1089/cap.2016.0100. PubMed DOI

Curatolo P., Franz D.N., Lawson J.A., Yapici Z., Ikeda H., Polster T., Nabbout R., de Vries P.J., Dlugos D.J., Fan J., et al. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: Post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc. Health. 2018;2:495–504. doi: 10.1016/S2352-4642(18)30099-3. PubMed DOI

Mizuguchi M., Ikeda H., Kagitani-Shimono K., Yoshinaga H., Suzuki Y., Aoki M., Endo M., Yonemura M., Kubota M. Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan. Brain Dev. 2019;41:1–10. doi: 10.1016/j.braindev.2018.07.003. PubMed DOI

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex

mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?