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Year : 2020  |  Volume : 15  |  Issue : 2  |  Page : 164-165

Autism spectrum disorder and mammalian target of rapamycin system

1 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
2 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile, Bologna, Italy

Date of Submission21-Dec-2019
Date of Acceptance19-Mar-2020
Date of Web Publication30-Jun-2020

Correspondence Address:
Dr. Annio Posar
IRCCS Istituto delle Scienze Neurologiche di Bologna, via Altura 3, Bologna.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_172_19

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How to cite this article:
Posar A, Visconti P. Autism spectrum disorder and mammalian target of rapamycin system. J Pediatr Neurosci 2020;15:164-5

How to cite this URL:
Posar A, Visconti P. Autism spectrum disorder and mammalian target of rapamycin system. J Pediatr Neurosci [serial online] 2020 [cited 2022 Aug 9];15:164-5. Available from: https://www.pediatricneurosciences.com/text.asp?2020/15/2/164/288310

Dear Editor

Mammalian target of rapamycin (mTOR) is a protein kinase playing a critical regulation role in numerous cellular functions, including cell growth and proliferation, as well as lipid and protein synthesis.[1] The hyperactivation of the mTOR system participates in the pathogenesis of several genetic conditions associated with syndromic autism spectrum disorder (ASD), including tuberous sclerosis, phosphatase and tensin homolog tumor hamartoma syndrome, fragile X syndrome, and neurofibromatosis type 1.[2] This is already interesting from a therapeutic perspective, but today there are even more interesting data: Rosina et al., comparing 33 patients with idiopathic ASD versus 22 typical developed controls, found that an mTOR system dysfunction may be involved also in idiopathic ASD, correlating with autism severity.[3] This is not so surprising given that the mTOR system plays a role also in the regulation of neurogenesis, corticogenesis, synaptogenesis, axonal orientation, and cell migration,[1] which are hypothesized to be altered in ASD. There are, therefore, the conditions for studying the effects of drugs acting on the mTOR system targeting autistic symptoms by themselves, also because rapamycin (acting as a selective mTOR inhibitor) has produced encouraging results on animals regardless of the presence of cortical tubers and epilepsy.[4]

Mizuguchi et al.[5] carried out a randomized, double-blind, placebo-controlled trial, finding a favorable trend in autistic symptoms in a sample of children with tuberous sclerosis treated with everolimus (another selective mTOR inhibitor), but this trend was not supported by a statistical analysis of the data.[5] Overwater et al.[6] carried out another randomized, double-blind, placebo-controlled trial, finding no favorable cognitive or behavioral effects of everolimus in a sample of children with tuberous sclerosis. Note that statistical analysis was carried out in this study, which (also in other respects) appears more solid than the first one.[6] In short, the data from these first trials do not seem encouraging.

But at this point, let us not forget about the time variable. Individuals involved in these two studies were relatively aged,[5],[6] when probably the damage to neuronal development and neural networks was no longer reversible, therefore being too late to obtain significant improvements. Before issuing a final judgment on the efficacy of these innovative pharmacological approaches on autistic symptoms, we should test them on a younger population. This highlights once again the importance of an early clinical diagnosis aimed at a timely intervention. In this regard, Moavero et al.[7] found that already at about 1 year of life it can be predicted with high accuracy whether an individual with tuberous sclerosis will develop ASD or not. Therefore, the real effects of drugs acting on the mTOR system should be tested both in syndromic and in idiopathic ASD cases at the earliest age possible.


The authors would like to thank Cecilia Baroncini for help in editing the text.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Ganesan H, Balasubramanian V, Iyer M, Venugopal A, Subramaniam MD, Cho SG, et al. mTOR signalling pathway - A root cause for idiopathic autism? BMB Rep 2019;52:424-33.  Back to cited text no. 1
Sato A. mTOR, a potential target to treat autism spectrum disorder. CNS Neurol Disord Drug Targets 2016;15:533-43.  Back to cited text no. 2
Rosina E, Battan B, Siracusano M, Di Criscio L, Hollis F, Pacini L, et al. Disruption of mTOR and MAPK pathways correlates with severity in idiopathic autism. Transl Psychiatry 2019;9:50.  Back to cited text no. 3
Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, et al. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 2012;3:1292.  Back to cited text no. 4
Mizuguchi M, Ikeda H, Kagitani-Shimono K, Yoshinaga H, Suzuki Y, Aoki M, et al. Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan. Brain Dev 2019;41:1-10.  Back to cited text no. 5
Overwater IE, Rietman AB, Mous SE, Bindels-de Heus K, Rizopoulos D, Ten Hoopen LW, et al; ENCORE Expertise Centre for Neurodevelopmental Disorders. A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology 2019;93:e200-9.  Back to cited text no. 6
Moavero R, Benvenuto A, Emberti Gialloreti L, Siracusano M, Kotulska K, Weschke B, et al. Early clinical predictors of autism spectrum disorder in infants with tuberous sclerosis complex: results from the EPISTOP study. J Clin Med 2019;8:E788.  Back to cited text no. 7

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