Inherited and early-life vulnerability in functional neurological disorder and functional somatic symptoms: A retrospective cohort and case–control study from a large electronic health record database
Ester Ipavic, Thomas A. Pollak, Timothy R. Nicholson, Lily Smythe, Francesca Happé, Mark J. Edwards, Rok BerlotAbstract
Background
Biological factors affecting motor, sensory, and integrative processing may predispose to functional neurological disorder (FND) and functional somatic symptoms. While early-life influences have traditionally been conceptualized within psychological frameworks, the contribution of early-life biological vulnerabilities to symptom expression remains unclear.
Methods
Using TriNetX, a large electronic health records database, we assessed proportions of inherited, congenital, perinatal, and neurodevelopmental diagnoses, capturing a range of early-life conditions. We compared 188,868 individuals with FND and 406,202 with functional somatic symptoms to demographically matched migraine and depression cohorts. Subgroup analyses contrasted motor FND with functional seizures and system-predominant functional somatic symptom clusters (e.g. bowel and bladder) with the general cluster.
Results
Compared with migraine and depression, individuals with FND and functional somatic symptoms showed higher proportions of multiple inherited and early-life vulnerability factors. Congenital and inherited conditions, including Ehlers – Danlos syndrome (OR = 2.1 – 3.6 across comparisons), congenital musculoskeletal malformations (1.7 – 2.0), and chromosomal abnormalities (2.5 – 3.2), were more prevalent. Perinatal factors such as low birth weight (1.8 – 2.4) were enriched, alongside neurodevelopmental disorders, including intellectual disability (1.9 – 5.4) and autism spectrum disorder (1.2 – 3.5). Subgroup analyses revealed phenotype-specific patterns: joint hypermobility and musculoskeletal malformations were more common in functional motor disorder and musculoskeletal functional somatic symptoms, whereas neurodevelopmental disorders were enriched in functional seizures and the general functional somatic symptom cluster.
Conclusions
Inherited and early-life biological vulnerabilities were more common in FND and functional somatic symptom cohorts. Their prevalence differed among phenotypes. Our findings suggest that developmental variation in brain–body systems may influence the risk and clinical expression of functional symptoms.