Maternal Folate Receptor Alpha Autoantibodies and Increased Fetal Nuchal Translucency as Potential Early Markers of Autism Spectrum Disorder.

Researchers studied pregnant women whose ultrasounds showed thicker neck tissue in their babies (a finding that can sometimes indicate problems). They tested the mothers' blood for specific antibodies and followed the children's development. All four mothers who had these antibodies in their blood had children later diagnosed with autism, while most mothers without the antibodies had typically developing children. This suggests these blood antibodies might help identify autism risk early in pregnancy.

This study investigated whether maternal folate receptor alpha autoantibodies (FRAA) and increased fetal nuchal translucency could serve as early markers for autism spectrum disorder risk. Among 27 fetuses with markedly increased nuchal translucency (≥3.5mm), 11 had negative genetic testing and were followed longitudinally. Four mothers tested positive for FRAA, and all four of their children were subsequently diagnosed with ASD by 36 months using standardized assessments. In contrast, only one of seven FRAA-negative mothers had a child diagnosed with ASD.

The findings suggest an immune-metabolic mechanism may contribute to ASD development, with FRAA potentially serving as an early biomarker for increased ASD risk.

Results suggest potential for prenatal ASD risk assessment through maternal FRAA testing when increased nuchal translucency is detected. Findings support investigating folinic acid supplementation as a potential preventive intervention, though larger studies are needed to validate these preliminary results.

Very small sample size (11 pregnancies followed longitudinally). Single-center study limits generalizability. No information provided on study methodology or control groups. Short follow-up period (36 months) may miss later-emerging developmental concerns.

To investigate the association between increased fetal nuchal translucency (NT) and maternal folate receptor alpha autoantibodies (FRAA) positivity, and to evaluate the subsequent risk of non-syndromic autism spectrum disorder (ASD) in offspring. A total of 3600 first-trimester ultrasounds were screened at a fetal medicine center. Among these, 27 fetuses with markedly increased NT (≥ 3.5 mm) underwent invasive prenatal diagnosis, including karyotyping, CGH array, and postnatally whole-exome sequencing (WES) when standard tests were negative. Maternal serum samples were tested for FRAA using ELISA.

Eleven pregnancies with negative genetic testing were followed longitudinally, and neurodevelopmental outcomes in children were assessed up to 36 months using ADOS-2 and DSM-5 criteria. Among the 11 fetuses with negative genetic outcomes, 4 mothers tested positive for FRAA. All four FRAA-positive offspring were later diagnosed with ASD, while only one of the seven FRAA-negative offspring received an ASD diagnosis. FRAA-positive cases exhibited markedly increased NT (≥ 3.5 mm) but no pathogenic genetic variants, suggesting an immune-mediated etiology.

FRAA levels persisted in maternal and neonatal serum, implying ongoing exposure during gestation. FRAA positivity in pregnancies with isolated markedly increased NT may serve as an early biomarker of increased ASD risk in offspring. These findings support the hypothesis of an immune-metabolic mechanism contributing to ASD and suggest potential preventive interventions such as folinic acid supplementation.