Early Clinical Predictors of Autism Spectrum Disorder in Infants with Tuberous Sclerosis Complex: Results from the EPISTOP Study

Romina Moavero, Arianna Benvenuto, Leonardo Emberti Gialloreti, Martina Siracusano, Katarzyna Kotulska, Bernhard Weschke, Kate Riney, Floor E Jansen, Martha Feucht, Pavel Krsek, Rima Nabbout, Anna C Jansen, Konrad Wojdan, Julita Borkowska, Krzystof Sadowski, Christoph Hertzberg, Hanna Hulshof, Sharon Samueli, Barbora Benova, Eleonora Aronica, David J Kwiatkowski, Lieven Lagae, Sergiusz Jozwiak, Paolo Curatolo, Romina Moavero, Arianna Benvenuto, Leonardo Emberti Gialloreti, Martina Siracusano, Katarzyna Kotulska, Bernhard Weschke, Kate Riney, Floor E Jansen, Martha Feucht, Pavel Krsek, Rima Nabbout, Anna C Jansen, Konrad Wojdan, Julita Borkowska, Krzystof Sadowski, Christoph Hertzberg, Hanna Hulshof, Sharon Samueli, Barbora Benova, Eleonora Aronica, David J Kwiatkowski, Lieven Lagae, Sergiusz Jozwiak, Paolo Curatolo

Abstract

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.

Keywords: EPISTOP; autism; developmental delay; diagnosis; epilepsy; intellectual disability; markers; risk factors; treatment; tuberous sclerosis complex.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Developmental trajectories of children with (orange line) and without (blue line) ASD in the three areas explored by BSID. Differences are evident already at six months of age both in cognitive and motor areas; thereafter there is a clearer differentiation of neurodevelopmental skill acquisitions. Cog DQ: cognitive developmental quotient; lang DQ: language developmental quotient.
Figure 2
Figure 2
Individual developmental trajectories (every single infant is represented by a different color) in the three areas explored by BSID (cognitive, language, and motor), representing the changes of DQ over time (six to 24 months of age). Left column contains data of children with a diagnosis of autism spectrum disorder (ASD) at 24 months, right column those of children without ASD.
Figure 3
Figure 3
Distribution of ADOS total scores at 12 and 18 months of age in children with (group 1) and without (group 0) a diagnosis of ASD at 24 months. The chart shows a clear differentiation of distribution, already present at 12 months.
Figure 4
Figure 4
Receiver operating characteristic (ROC) curve of ADOS and BSID scores combined at 18 months, measuring their ability of predicting ASD at 24 months. AUC: area under the curve; AUC = 0.944 (95% CI: 0.873–1.000).
Figure 5
Figure 5
Different scores in the various ADOS sub-items in infants receiving a diagnosis of ASD (orange curve) and in those without (blue curve) at 24 months of age. ADOS sub-items: B5: integration of eye contact; B6: shared enjoyment; B7: response to name; B8: ignoring; B9: asking; B12: showing; B13: begin to joint attention; B14: response to joint attention; B15: quality of social engagement; B16b: frequency of social engagement to parents; B18: quality of general interaction; A3: verbalizations’ tone; DI: abnormal sensorial interests; D2: stereotyped movements; D5: stereotyped behaviors.

References

    1. Curatolo P., Bombardieri R., Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657–668. doi: 10.1016/S0140-6736(08)61279-9.
    1. 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.
    1. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315. doi: 10.1016/0092-8674(93)90618-Z.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorder. 5th ed. CBS Publisher & Distribution; Washington, DC, USA: 2013.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.

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