Beyond diagnostic categories: A narrative review of transdiagnostic mechanisms in neurodevelopmental disorders

AI Summary

Shift from categorical diagnoses to a transdiagnostic mechanistic framework integrating shared neural circuit, excitatory-inhibitory, synaptic and immune-metabolic disruptions.
Gene-environment and epigenetic interactions during early development demand biomarker-driven, patient-derived model approaches for earlier diagnosis and personalised interventions.
Time-sensitive, biologically grounded precision strategies including neuromodulation, immune and microbiota therapies, and gene editing promise more effective lifelong care.

TL;DR (AI Generated)

Traditionally classified as discrete clinical entities, NDDs such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID) are now increasingly understood as overlapping, multifactorial conditions shaped by converging genetic, epigenetic, immune, and environmental influences.

This review synthesizes current evidence challenging categorical diagnostic boundaries and instead proposes a transdiagnostic and mechanistic framework that integrates shared disruptions in neural circuits, excitatory/inhibitory balance, synaptic architecture, and immune-metabolic signalling.

We explore how genes and environment interact during early development, how epigenetics influences long-term outcomes, and how these insights are driving a shift toward precision medicine guided by biomarkers and patient-derived models.

Basic summary

Prog Neuropsychopharmacol Biol Psychiatry. 2026 Nov 5:111994. doi: 10.1016/j.pnpbp.2026.111994. Online ahead of print.

ABSTRACT

Neurodevelopmental disorders (NDDs) represent a heterogeneous class of early-onset conditions marked by impairments in cognition, reduced social function, hyperactivity and repetitive-stereotyped behaviour. Traditionally classified as discrete clinical entities, NDDs such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID) are now increasingly understood as overlapping, multifactorial conditions shaped by converging genetic, epigenetic, immune, and environmental influences. This review synthesizes current evidence challenging categorical diagnostic boundaries and instead proposes a transdiagnostic and mechanistic framework that integrates shared disruptions in neural circuits, excitatory/inhibitory balance, synaptic architecture, and immune-metabolic signalling. We explore how genes and environment interact during early development, how epigenetics influences long-term outcomes, and how these insights are driving a shift toward precision medicine guided by biomarkers and patient-derived models. Emerging therapies include neuromodulation, immune and microbiota-based interventions, and gene editing, supported by insights from animal and iPSC models. A time-sensitive and biologically grounded approach is needed, moving beyond symptom-based classifications to allow for earlier diagnosis, personalized treatment, and the development of innovative interventions. This paradigm shift aligns with precision approaches already transforming other biomedical domains and holds the potential to more effectively address the complex and lifelong challenges posed by NDDs.

PMID:42988144 | DOI:10.1016/j.pnpbp.2026.111994

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