Since Thomas Bourgeron (Institut Pasteur) identified a genetic mutation linked to autism some twenty years ago, several hundred mutations have been suggested as contributing to this syndrome. Autism Spectrum Disorder (ASD) has since been classified as a genetically based syndrome, disregarding the major role of the environment. Yet despite repeated promises, and unless I am mistaken, nothing seems to be on the horizon despite an approach that has long been considered a priority and well-supported. This is not surprising for several reasons:
- The identification of genetic mutations is based on techniques that are open to criticism in many respects (twins and GWAS), as my colleague Ertiene Danchin and I explained in an article published in late 2025 and discussed in my blog and in articles by experts in human genetics (see also Génin and Clerget-Darpoux 2015 – Robette, Génin, and Clerget-Darpoux 2022)
- ASDs “originate” in utero, as we demonstrated five years ago. By retrospectively analyzing data collected in maternity wards (over 150 non-genetic parameters) using machine learning, we can identify at birth nearly half of the babies who will be autistic and all those who will not be (Caly et al. 2021). This Pelargos project—currently undergoing validation in 5–6 university hospitals/maternity wards—is a world first and, if validated, will enable the early implementation of behavioral techniques, which are all the more effective when used early. The parameters that allow us to identify babies who will be autistic at birth help us better understand how the syndrome develops.
- Experimental approaches converge to suggest the absence of direct links between a genetic mutation and the syndrome. Indeed, any disruption in maturation results in aberrant neural networks, which are the direct and ultimate cause of the resulting impairments. They are also the logical target for treatments capable of blocking their activity—a form of pharmaceutical surgery.
- Based on this approach, we have been able to develop a treatment that blocks these aberrant activities with considerable success. We began with two Phase 2 trials showing that Bumetanide alleviates ASDs in over a hundred children (Lemonnier et al. 2012)(Lemonnier et al. 2017). These trials were validated in five similar trials conducted in different countries, yielding nearly identical results and involving numerous children on this treatment (Xiao et al. 2024). We were able to conduct a large Phase 3 trial with the company Servier—intended to bring the product to market. Contrary to expectations, this trial (covering the entire pediatric age range from 2 to 18 years) failed (Fuentes et al. 2023). However, given the extreme heterogeneity of ASDs, we reanalyzed all this data (over 420 children recruited in Australia, Brazil, and several European countries) and discovered that, in fact, 30 to 40% of children meeting specific clinical criteria respond to the treatment (Rabiei et al. 2026). In summary, the trial failed due to the treatment, and a trial with inclusion criteria restricted to those we have identified will allow for effective treatment for a significant percentage of them.
In conclusion, it is clear that by ignoring the importance of intrauterine events and relying on a direct link between a genetic mutation and ASDs, the therapeutic promises of genetic interventions for autism are likely to be in vain. In any case, we would be delighted to be proven wrong, as the essential goal is to alleviate the suffering of autistic children. Beyond this conclusion, it is regrettable to note the conceptual weakness of the genetic approach, which ignores brain maturation and, despite these unfulfilled promises, remains the preferred approach of scientific authorities and political bodies. To treat this syndrome like others that originate in utero, we must study developmental biology and determine the changes caused by any pathological event, including a genetic mutation. Innovation always comes from approaches that think outside the box! In my next blog posts, I will present the various environmental factors during pregnancy that are responsible for ASDs.
- SOURCES:
- Caly, Hugues, Hamed Rabiei, Perrine Coste-Mazeau, Sebastien Hantz, Sophie Alain, Jean Luc Eyraud, Thierry Chianea, et al. 2021. “Machine Learning Analysis of Pregnancy Data Enables Early Identification of a Subpopulation of Newborns with ASD.” Scientific Reports 11 (1): 1–14. https://doi.org/10.1038/s41598-021-86320-0.
- Fuentes, Joaquin, Mara Parellada, Christina Georgoula, Guiomar Oliveira, Stéphane Marret, Véronique Crutel, Cristina Albarran, et al. 2023. “Bumetanide Oral Solution for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Results from Two Randomized Phase III Studies.” Autism Research, no. July: 1–14. https://doi.org/10.1002/aur.3005.
- Génin, Emmanuelle, and Françoise Clerget-Darpoux. 2015. “The Missing Heritability Paradigm: A Dramatic Resurgence of the GIGO Syndrome in Genetics.” Human Heredity 79 (1): 1–4. https://doi.org/10.1159/000370327.
- Lemonnier, E., N. Villeneuve, S. Sonie, S. Serret, A. Rosier, M. Roue, P. Brosset, et al. 2017. “Effects of Bumetanide on Neurobehavioral Function in Children and Adolescents with Autism Spectrum Disorders.” Translational Psychiatry 7: 1–9. https://doi.org/10.1038/tp.2017.10.
- Lemonnier, E, Degrez C., Phelep M., Tyzio R., Josse F., Grandgeorge M., Hadjikhani N., and Ben-Ari Y. 2012. “A Randomised Controlled Trial of Bumetanide in the Treatment of Autism in Children.” Translational Psychiatry.
- Rabiei, Hamed, Marilyn Begnis, Eric Lemonnier, and Yehezkel Ben-Ari. 2026. “Treating Autism with Bumetanide: Identification of Responders Using Q-Finder Machine Learning Algorithm.” Translational Psychiatry 16 (1). https://doi.org/10.1038/s41398-026-03848-3.
- Robette, Nicolas, Emmanuelle Génin, and Françoise Clerget-Darpoux. 2022. “Heritability: What’s the Point? What Is It Not for? A Human Genetics Perspective.” Genetica 150 (3–4): 199–208. https://doi.org/10.1007/s10709-022-00149-7.
- Xiao, Hong Li, Han Zhu, Jia Qi Jing, Si Jia Jia, Su Hong Yu, and Chang Jiang Yang. 2024. “Can Bumetanide Be a Miraculous Medicine for Autism Spectrum Disorder: Meta-Analysis Evidence from Randomized Controlled Trials.” Research in Autism Spectrum Disorders 114 (February): 102363. https://doi.org/10.1016/j.rasd.2024.102363.
