Summary: Researchers have identified a clear relationship between brain overgrowth and the severity of social and communication symptoms in children with autism spectrum disorder (ASD).
A combined analysis of magnetic resonance imaging (MRI) data and laboratory experiments using brain organoids—three-dimensional “mini-brains” grown from induced pluripotent stem cells (iPSCs)—shows that children with the most severe ASD symptoms tend to have significantly larger brains. The enlargement correlates with altered activity of the enzyme Ndel1, a regulator of neuron development, proliferation and migration.
These findings shed light on biological mechanisms that may underlie differences in ASD severity and point toward potential blood-based biomarkers for predicting symptom intensity.
Key Facts:
- Brain overgrowth in children with severe ASD symptoms measured in organoids reached up to 41% larger than controls.
- The enzyme Ndel1, important for embryonic neuron differentiation and cell-cycle regulation, is linked to this enlargement.
- Researchers report increased numbers of mononuclear cells in peripheral blood that correlate with ASD social and communication severity, suggesting promise for blood biomarkers.
Source: FAPESP
Overview of the Study
An international team of researchers from Brazil and the United States published results in the journal Molecular Autism, combining MRI analyses of over 900 children with ASD and laboratory experiments using brain cortical organoids derived from blood samples of participating children. The organoids reproduce key aspects of early brain structure and development, making them a useful model for studying embryonic neurodevelopmental processes linked to ASD.
Across both MRI and organoid datasets, brain enlargement correlated with the severity of social and communication deficits. Organoids grown from children with the most severe social symptoms were substantially larger—up to 41% larger—than those from control participants.
Mirian Hayashi, a senior author and professor in the Department of Pharmacology at the Federal University of São Paulo (EPM-UNIFESP), cautioned that not every child with severe ASD symptoms has brain enlargement, but when enlargement is present, social and communication symptoms tend to be worse.
The pattern of enlargement appears associated with dysregulation of Ndel1 activity. Ndel1 participates in neuron proliferation, differentiation and migration during embryogenesis and has been linked previously to several neurodevelopmental and psychiatric disorders.
The same research group had earlier observed related phenomena in cases of congenital microcephaly caused by Zika virus infection, emphasizing that both extremes of brain size—overgrowth and reduction—can disrupt neural circuit formation and impair function.
Methodology
The study was conducted in two main stages. First, the team analyzed MRI scans and diagnostic assessments from a cohort of more than 900 children with ASD collected in a prior project led by Eric Courchesne at the University of California San Diego (UCSD). This large neuroimaging dataset provided population-level evidence of brain size differences associated with symptom severity.
In the second stage, researchers in Alysson Muotri’s laboratory at UCSD grew brain cortical organoids from iPSCs reprogrammed from blood samples donated by children in the earlier cohort. They generated and measured nearly 5,000 embryonic-stage organoids across several experimental batches to quantify size, growth rates and cellular behavior during early development.
Cellular analyses focused on neural progenitor populations and neurogenesis, while molecular assays measured Ndel1 expression and activity. The team also examined peripheral blood cell profiles to explore clinically accessible biomarkers that might reflect brain developmental processes.
Key Findings
Organoid results showed significantly enlarged size in ASD-derived brain cortical organoids (BCOs), with average increases of roughly 39–41% in two independent experimental batches. Larger embryonic organoid size correlated strongly with more severe social symptoms (correlation coefficients r = 0.719 and r = 0.873 in the two batches). ASD organoids also displayed accelerated growth—nearly three times the growth rate seen in controls.
At the cellular level, enlarged organoids contained increased numbers of neural progenitors and showed altered neurogenesis: many progenitor cells failed to differentiate properly, and neuronal connectivity (synapse formation) was disrupted. The researchers emphasize that healthy brain function depends on balanced neurogenesis and connectivity—both excessive and insufficient neuron production can be harmful.
At the molecular level, Ndel1 activity was closely associated with organoid growth rates and size. The team observed an imbalance in Ndel1 expression and activity in organoids showing overgrowth, suggesting Ndel1-related pathways are involved in dysregulated cell proliferation and neurogenesis in these ASD cases.
Clinically, two embryonic ASD subtypes emerged from the data: one marked by pronounced organoid enlargement, accelerated neurogenesis and a “profound autism” phenotype with severe social deficits, low language ability and reduced cognitive scores; and another subtype with milder organoid enlargement and correspondingly milder symptoms and cognitive differences.
Implications and Future Directions
These findings indicate that biological differences present during embryogenesis can shape divergent ASD developmental trajectories—ranging from mild to profound social and communication impairment. Dysregulated cell proliferation and accelerated neurogenesis appear central to the subtype characterized by brain overgrowth.
The association between blood cell profiles and ASD symptom severity raises the possibility of developing minimally invasive biomarkers to predict or stratify ASD severity. The researchers plan further studies to validate blood-based markers and expand sample sizes to determine whether additional embryonic ASD subtypes exist.
About this autism research news
Author: Heloisa Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Image: The image is credited to Neuroscience News
Original Research: Open access. “Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms” by Mirian Hayashi. Molecular Autism
Abstract
Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms
Background
Social affective and communication difficulties define autism spectrum disorder, but severity varies widely. Some toddlers improve over time and attain functional social and language skills, while others have profound, persistent impairments that require lifelong support. The embryonic biological mechanisms that drive these divergent trajectories were previously unclear.
Methods
The study measured size and early growth in 4,910 embryonic-stage brain cortical organoids generated from 10 toddlers with ASD and 6 controls, averaging about 196 organoids per subject across experimental batches. BCO sizes and growth rates were analyzed alongside extensive behavioral and neurodevelopmental datasets. Cellular markers of neurogenesis and molecular assays—particularly of Ndel1 activity and expression—were used to probe mechanisms tied to proliferation and growth.
Results
BCO size was enlarged by approximately 39–41% in ASD samples across independent batches. Larger organoid size strongly predicted more severe social symptoms and reduced social attention, language ability and cognitive scores. ASD organoids exhibited accelerated growth and neurogenesis, and Ndel1 activity correlated with these growth dynamics. Two ASD embryonic subtypes emerged: one characterized by marked overgrowth and severe clinical phenotype, and another with milder enlargement and milder symptoms.
Limitations
Larger and more diverse samples of ASD-derived organoids and clinical phenotypes are needed to determine whether additional embryonic subtypes exist and to validate candidate biomarkers.
Conclusions
Differences in cell proliferation and neurogenesis during embryogenesis are linked to two distinct ASD subtypes of social severity. The larger the embryonic brain cortical organoid size, the more severe the toddler’s social symptoms, and the greater the associated reductions in social attention, language ability and IQ, along with atypical growth patterns in brain regions tied to social and language function.