Genetic and Early-Life Vulnerability in Functional Neurological Disorder: A Large-Scale Retrospective Cohort Study - European Medical Journal

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Genetic and Early-Life Vulnerability in Functional Neurological Disorder: A Large-Scale Retrospective Cohort Study

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Neurology
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Authors:
* Ester Ipavic , 1,2 Thomas A. Pollak , 3,4 Timothy R. Nicholson , 3,4 Mark J. Edwards , 3,4 Rok Berlot 1,2
  • 1. Faculty of Medicine, University of Ljubljana, Slovenia
  • 2. Department of Neurology, University Medical Centre Ljubljana, Slovenia
  • 3. Neuropsychiatry Research & Education Group, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
  • 4. South London and Maudsley NHS Foundation Trust, UK
*Correspondence to [email protected]
Disclosure:

Edwards has received grant funding from National Institute for Health and Care Research (NIHR); royalties from Oxford University Press for The Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders; honoraria for medical advice and educational events from Teva Pharmaceuticals; financial support for lectures from the International Parkinson and Movement Disorder Society and the FND Society (FNDS); payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting); is a deputy editor of the European Journal of Neurology; a Medical Advisory Board member of FND Hope and the British Association of Performing Arts Medicine; and holds shares in Brain & Mind (Brain & Mind provides neuropsychiatric and neurological rehabilitation in the independent medical sector). Berlot has received grants from the Slovenian Research and Innovation Agency, supported as a member of the research programme Medical Physics (P1-0389). Nicholson has received grants from the UK National Institute for Health and Care Research (NIHR) and Medical Research Council (MRC), including for studies related to FND; royalties from CRC Press for The Pocket Prescriber textbook series; financial support for lectures from the FND Society (FNDS); payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting, including in cases of FND); is co-chair of the patient liaison committee for FNDS; a Medical Advisory Board member of FND Hope UK; and a Medical Advisory Board member and trustee of FND Action. Pollak is a co-recipient of a grant from OpenAI; has received consultancy fees from Arialys Therapeutics; and payment for expert testimony for personal injury and clinical negligence cases (medical expert reporting, including in casesof FND). Ipavic has declared no conflicts of interest.

Keywords:
Biological vulnerability, early-life vulnerability, functional motor disorder, functional neurological disorder (FND), functional seizures, TriNetX™ (TriNetX, LLC, Cambridge, Massachusetts, USA).
Citation:

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

SUMMARY OF KEY FINDINGS

Background

Functional neurological disorder (FND) is a common and disabling condition with diverse presentations, such as motor (weakness, tremor, dystonia, gait), sensory, cognitive, and seizure-like symptoms, often in combination.1 It is understood as a disorder of brain network dysfunction, in which the brain generates overly strong predictions about body states that override incoming sensory and motor signals, and symptoms arise from this mismatch.2 Historically, FND has been conceptualised in terms of psychological stress or traumatic experiences, often arising in childhood.3 However, contemporary models situate it within a broader biopsychosocial framework, in which early-life biological influences are poorly characterised compared to psychosocial factors. Previously reported inherited and neurodevelopmental associations with FND include Ehlers–Danlos syndrome and hypermobility spectrum disorders,4 autism spectrum disorder,5 and ADHD.6 FND may be more likely to emerge in individuals with less reliable bodily signalling and regulatory systems, which may become apparent in the context of co-existing disease (e.g., FND emerging in Parkinson’s disease).7 Similarly, disturbances of motor, sensory, or integrative processing earlier in life could predispose to FND. The authors compared the prevalence of early-life biological vulnerability factors in FND against comparator cohorts, and examined whether distinct vulnerability profiles are associated with specific FND phenotypes.

Findings

Using TriNetX™ (TriNetX, LLC, Cambridge, Massachusetts, USA), a large electronic health records database, the authors assessed rates of genetic, congenital, perinatal, and neurodevelopmental diagnoses, selected to capture a range of early-life conditions, including those that may affect the integrity of the sensory and motor systems. Comparisons were performed between 188,868 individuals with FND and sociodemographically matched migraine and depression cohorts. The prevalence of these factors was also compared between matched cohorts of 42,015 individuals with motor FND and functional seizures. Compared with migraine and depression, FND was associated with increased odds of heritable connective tissue disorders, heritable neuromuscular disorders, and congenital malformations, including those of the musculoskeletal system and sensory organs (odds ratio [OR]: 1.7–3.0). Apart from ADHD, which was more prevalent in the depression cohort, neurodevelopmental disorders were consistently more prevalent in FND (OR: 1.9–5.4), alongside increased rates of perinatal adversity related to short gestation, low birth weight, and newborn respiratory distress (OR: 1.8–2.6; Figure 1A). In the comparison of different clinical phenotypes, motor FND showed stronger associations with connective tissue, neuromuscular, and musculoskeletal conditions, whereas functional seizures were more strongly associated with chromosomal abnormalities and neurodevelopmental disorders (Figure 1B).

Figure 1: Early life biological vulnerability factors in FND versus migraine and depression (A) and early life biological vulnerability factors in functional motor disorder versus functional seizures (B).
ORs (95% CI) are shown on a logarithmic scale. Filled dots indicate significance after Bonferroni correction (p<0.0025).
FND: functional neurological disorder; OR: odds ratio.

Conclusion

FND showed higher rates of early-life biological vulnerability factors than control cohorts with migraine and depression. These factors spanned several domains, indexing a broad early-life and developmental susceptibility. Distinct associations were observed for functional motor and seizure presentations. The authors’ findings support the current move from dichotomous ‘psychogenic–organic’ to more nuanced and biologically informed vulnerability–resilience models of FND accounting for the full range and varying combinations of potential biopsychosocial aetiologies.

WHAT CHALLENGE DOES THIS ADDRESS?

FND research has traditionally focused on psychological stress and trauma as key predisposing factors. While these remain important, this framing may inadvertently reinforce stigma and the outdated psychogenic–organic dichotomy. To move towards a genuinely biopsychosocial model, a better understanding of the biological underpinnings is needed. The authors’ findings represent a step in that direction, suggesting that early-life biological vulnerability factors are more prevalent in FND than in matched control conditions.

RELEVANCE TO EUROPEAN PRACTICE

FND remains under-recognised and under-resourced, with stigma a persistent barrier to care. Evidence of early-life biological vulnerability may support a more comprehensive assessment and strengthen the case for appropriately resourced, multidisciplinary care.

WHAT ARE THE NEXT STEPS FOR THE RESEARCH?

Replication in prospectively recruited FND cohorts is needed, given the limitations of electronic health records. Future studies could assess whether early-life biological vulnerability factors act synergistically, how these profiles influence symptom trajectories and outcomes, and why similar vulnerabilities lead to different clinical presentations.

References
Ipavic E et al. Genetic and early-life vulnerability in functional neurological disorder: a large-scale retrospective cohort study. Eur J Neurol. 2026;33(1):15-16. Hallett M et al. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 2022;21(6):537-50. Yong K et al.; Edinburgh Paediatric FND Study Group. Functional neurological disorder in children and young people: incidence, clinical features, and prognosis. Dev Med Child Neurol. 2023;65(9):1238-46. Fernandez A et al. Functional neurological signs in hypermobile Ehlers–Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain. Brain Behav. 2024;14(2):e3441. Smythe L et al. Co-occurring functional neurological disorder and autism: an exploratory study of comorbidities in a retrospective cohort study using TriNetX. J Neurol. 2025;272(10):653. Tamilson B et al. Perinatal, neurodevelopmental and childhood health factors in patients with functional neurological disorder: a retrospective case-record study in a tertiary neuropsychiatry cohort. BMJ Neurol Open. 2026;8(1):e001515. Pareés I et al. Functional (psychogenic) symptoms in Parkinson’s disease. Mov Disord. 2013;28(12):1622-7.

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