Pediatric delirium in autism spectrum disorders. Clinical and genetic polymorphism, connection with ontogenetic epileptic encephalopathies, schizophrenia, bipolar disorder


  • I.A. Martsenkovsky SI “Research Institute for Psychiatry of the Ministry of Health of Ukraine”, Kyiv, Ukraine, Ukraine
  • I.I. Martsenkovska SI “Research Institute for Psychiatry of the Ministry of Health of Ukraine”, Kyiv, Ukraine, Ukraine
  • H.V. Makarenko SI “Research Institute for Psychiatry of the Ministry of Health of Ukraine”, Kyiv, Ukraine, Ukraine
  • T.O. Skrypnyk SI “Research Institute for Psychiatry of the Ministry of Health of Ukraine”, Kyiv, Ukraine, Ukraine
  • I.F. Zdoryk SI “Research Institute for Psychiatry of the Ministry of Health of Ukraine”, Kyiv, Ukraine, Ukraine



autism spectrum disorders, delirium, catatonic symptoms, epileptic encephalopathy


Psychotic symptoms are diagnosed in 3–16 % of adolescents and young adults with autism spectrum disorder (ASD) and arouse the discussion about their etiopathogenetic conceptualization. Within the 7th Framework Program: PsychGene “Copy Number Variation and Endophenotypes in Psychiatric Disorders, 2009–2012”, after GWAS by the deCODE Genetics’ laboratory (Iceland), more than 40,000 rare mutations were identified that are associated with an increased risk of manifestation of mental disorders in childhood. During 2009–2012, 25 children of preschool and primary school age (mean age 78.0 ± 36.3 months) with ASD with 1q21.1, 15q13.3, 15q24, 2q24.3, 2p16.3, 16p11.2, 7q31.32, 22q13.3, 17p13, 4q35 syndromes and NEXMIF mutations on the X chromosome and 38 children (mean age 48.0 ± 21.8 months) with variants of serotonin 2A receptor gene loci polymorphism (5HTR2A) and dopamine (DRD2) were selected for prospective research in the State Institution “Research Institute for Psychiatry of the Ministry of Health of Ukraine”. By March 2021 (mean duration of longitudinal observations 127.2 ± 12.8 months), 12 clinical cases of psychotic disorders/delirium in patients with ASD and epileptic seizures and 8 cases of ASD with individual psychotic symptoms without impaired consciousness and epileptic seizures were described and studied. The clinical phenotypes of SHANK3, NRXNT, NEXMIF encephalopathies, other complex variants of pervasive developmental disorders with psychotic symptoms, their causal relationships with epileptic encephalopathies, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder have been investigated and described. From a prospective study, therapeutic strategies are discussed. Patients with epileptic encephalopathies do not tolerate therapy with phenytoin, phenobarbital, carbamazepine, and atypical antipsycho-tics. New evidence has been obtained of the possible effectiveness of therapy with lamotrigine, low doses of valproic acid salts, polytherapy with valproate with lamotrigine and lacosamide in such patients. In ASD with epileptic seizures resistant to antiepileptic drugs, delirium with catatonic symptoms, the use of benzodia-zepines (clonazepam) is recommended. When prescribing atypical antipsychotics, quetiapine and aripiprazole are recommended. These drugs are effective in children and young adults with ASD with psychotic symptoms without impairment of consciousness or catatonic symptoms.


Damiani S., Leali P., Nosari G. et al. Association of Autism Onset, Epilepsy, and Behavior in a Community of Adults with Autism and Severe Intellectual Disability. Brain Sciences. 2020. Vol. 10. № 8. P. 486.

Salpekar J.A., Mula M. Common psychiatric comorbidities in epilepsy: how big of a problem is it? Epilepsy & Behavior. 2019. Vol. 98. P. 293-297.

Pacheva I., Ivanov I., Yordanova R. et al. Epilepsy in children with autistic spectrum disorder. Children. 2019. Vol. 6. № 2. P. 15.

Tye C., Runicles A.K., Whitehouse A. J., Alvares G.A. Cha-racterizing the interplay between autism spectrum disorder and comorbid medical conditions: an integrative review. Frontiers in psychiatry. 2019. Vol. 9. Р. 751.

De Crescenzo F., Postorino V., Siracusano M. et al. Autistic symptoms in schizophrenia spectrum disorders: a systematic review and meta-analysis. Frontiers in psychiatry. 2019. Vol. 10. Р. 78.

De Giorgi R., De Crescenzo F., D’Alò G.L. et al. Prevalence of non-affective psychoses in individuals with autism spectrum disorders: a systematic review. Journal of clinical medicine. 2019. Vol. 8. № 9. Р. 1304.

Chandrasekhar T., Copeland J. N., Spanos M., & Sikich L. Autism, Psychosis, or Both? Unraveling Complex Patient Presentations. Child and Adolescent Psychiatric Clinics. 2020. Vol. 29. № 1. P. 103-113.

Chisholm K., Lin A., Armando M. Schizophrenia spectrum disorders and autism spectrum disorder. Psychiatric symptoms and comorbidities in autism spectrum disorder. Springer, Cham, 2016. P. 51-66.

Mazzone L., Postorino V., Valeri G., Vicari S. Catatonia in patients with autism: prevalence and management. CNS drugs. 2014. Vol. 28. № 3. P. 205-215.

Aziz S., Hendren R.L. Сatatonia in autism spectrum disorder in youth systematic review. International Journal of Autism & Related Disabilities. 2020. 34.

Schieveld J.N.M. Case reports with a child psychiatric exploration of catatonia, autism, and delirium. International review of neurobiology. 2006. Vol. 72. P. 195-206.

Serret S., Thümmler S., Dor E. et al. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder. BMC psychiatry. 2015. Vol. 15. № 1. P. 1-6.

Juarez-Jaramillo A., Ramirez-Bermudez J., Gomez H. et al. Delirium With Catatonic Signs: A Neuropsychiatric Phenotype Associated With Autoimmune Encephalitis? 2020. 2243.

Xiong J., Chen S., Pang N. et al. Neurological diseases with autism spectrum disorder: role of ASD risk genes. Frontiers in Neuroscience. 2019. Vol. 13. P. 349.

Ishii A., Hirose S. New genes for epilepsy-autism comorbidity. Journal of Pediatric Neurology. 2017. Vol. 15. № 3. P. 105-114.

Steinman G., Mankuta D. Gene polymorphism in the genesis of autism. BAOJ Neurol. 2018. Vol. 4. № 2. P. 58-110.

Soler J., Fañanás L., Parellada M. et al. Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review. Journal of psychiatry & neuroscience: JPN. 2018. Vol. 43. № 4. P. 223.

Stefansson H., Ophoff R.A., Steinberg S. et al. Genetic Risk and Outcome in Psychosis (GROUP). Common variants conferring risk of schizophrenia. Nature. 2009. Vol. 460. № 7256. P. 744-747, doi: 10.1038/nature07229.

Steinberg S., de Jong S. et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Human molecular genetics. 2011. Vol. 20. № 20. P. 4076-4081.

Steinberg S., de Jong S., Mattheisen M. et al. Common variant at 16p11. 2 conferring risk of psychosis. Molecular psychiatry. 2014. Vol. 19. № 1. P. 108-114.

Degenhardt F. Copy number variants in psychiatric disorders. Personalized Psychiatry. Academic Press, 2020. P. 357-362.

Niarchou M., Chawner S.J., Doherty J.L. et al. Psychiatric disorders in children with 16p11. 2 deletion and duplication. Translational psychiatry. 2019. Vol. 9. № 1. P. 1-8.

Horev G. et al. Dosage-dependent phenotypes in models of 16p11. 2 lesions found in autism. Proceedings of the National Academy of Sciences. 2011. Vol. 108. № 41. P. 17076-17081.

da Silva Montenegro E.M., Costa C.S., Campos G. et al. Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort. Autism Research. 2020. Vol. 13. № 2. Р. 199-206.

Зенков Л.Р. и др. Бессудорожные эпилептические энцефалопатии, аутизм и другие расстройства психического развития. Аутизм: наука и практика. По страницам журнала «Аутизм и нарушения развития» (2003–2014). 2014. С. 6-21.

Кирилова Л.Г., Мірошников О.О., Юзва О.О. Розлади аутистичного спектра в дітей раннього віку: еволюція поглядів та можливості діагностики (частина 1). Мінародний ендокринологічний журнал. 2020. Т. 16. № 4. С. 37-42.

Кирилова Л.Г., Мірошников О.О., Юзва О.О. Розлади аутистичного спектра в дітей раннього віку: еволюція поглядів та можливості діагностики (частина 2). Мінародний ендокринологічний журнал. 2020. Т. 16. № 5. С. 48-53.

Final Report Summary — PSYCHCNVS (Copy number variations conferring risk of psychiatric disorders in children.

Голимбет В.Е., Корень Е.В Вариации числа копий в геноме — новая страница в в генетических исследованиях в области психиатрии: международный проект PsychCNVs. Журнал неврологии и психиатрии им. С.С. Корсакова. 2010. Т. 110. № 1. С. 107-109.

Zhou W.Z., Zhang J., Li Z. et al. Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype – phenotype correlations. Human mutation. 2019. Vol. 40. № 6. Р. 801-815.

Blazejewski S.M., Bennison S.A., Smith T.H. et al. Neurodevelopmental genetic diseases associated with microdeletions and microduplications of chromosome 17p13.3. Frontiers in genetics. 2018. Vol. 9. Р. 80.

Huynh M.T., Lambert A.S., Tosca L. et al. 15q24. 1 BP4-BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24. 2q24. 3 duplication in a patient with epilepsy, psychomotor delay, overweight, ventricular arrhythmia. European journal of medical genetics. 2018. Vol. 61. № 8. Р. 459-464.

Grabowski P.A.P., Bello A.F., Rodrigues D.L. et al. Deletion involving the 7q31-32 band at the CADPS2 gene locus in a patient with autism spectrum disorder and recurrent psychotic syndrome triggered by stress. Case reports in psychiatry. 2017. Vol. 2017.

Bernier R., Steinman K.J., Reilly B. et al. Clinical phenotype of the recurrent 1q21. 1 copy-number variant. Genetics in Medicine. 2016. Vol. 18. № 4. Р. 341-349.

Lowther C., Costain G., Stavropoulos D.J. et al. Delineating the 15q13. 3 microdeletion phenotype: a case series and comprehensive review of the literature. Genetics in Medicine. 2015. Vol. 17. № 2. Р. 149-157.

Basel-Vanagaite L., Goldberg-Stern H., Mimouni-Bloch A. et al. An emerging 1q21.1 deletion-associated neurodevelopmental phenotype. Journal of child neurology. 2011. Vol. 26. № 1. Р. 113-116.

Dibbens L.M., Mullen S., Helbig I. et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: pre-cedent for disorders with complex inheritance. Human molecular genetics. 2009. Vol. 18. № 19. С. 3626-3631.

Stamberger H., Hammer T.B., Gardella E. et al. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genetics in Medicine. 2021. 23(2). 363-373.

Голимбет В.Е. Молекулярно-генетический полиморфизм и клиническая гетерогенность эндогенных психозов: Автореф. дис... д-ра биол. наук. М, 2003. 225 c.

Egger J.I.M., Verhoeven W.M., Groenendijk-Reijenga R. et al. Phelan-McDermid syndrome due to SHANK3 mutation in an intellectually disabled adult male: successful treatment with lithium. Case Reports. 2017. Vol. 2017. bcr-2017-220778.

Verhoeven W.M.A., Egger J.I.M., de Leeuw N. A longitudinal perspective on the pharmacotherapy of 24 adult patients with Phelan McDermid syndrome. European journal of medical genetics. 2020. Vol. 63. № 3. С. 103751.

Denayer A., Van Esch H., De Ravel Т. et al. Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Molecular syndromology. 2012. Vol. 3. № 1. Р. 14-20.

Alsubaie L., Aloraini T., Amoudi M. et al. Genomic testing and counseling: The contribution of next generation sequencing to epilepsy genetics. Annals of Human Genetics. 2020. Vol. 84. № 6. Р. 431-436.

Angione K., Eschbach K., Smith G. et al. Genetic testing in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy research. 2019. Vol. 150. Р. 70-77.

Keller R., Basta R., Salerno L. et al. Autism, epilepsy, and synaptopathies: a not rare association. Neurological Sciences. 2017. Vol. 38. № 8. Р. 1353-1361.

Ogasawara M., Nakagawa E., Takeshita E. et al. Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with ­NEXMIF Mutation: Case Report. Molecular Syndromology. 2020. Vol. 11. № 4. Р. 232-238.





Original Researches