Abstract
Understanding rare genetic brain disorders with overlapping neurological and psychiatric phenotypes is of increasing importance given the potential for developing disease models that could help to understand more common, polygenic disorders. However, the traditional clinical boundaries between neurology and psychiatry result in frequent segregation of these disorders into distinct silos, limiting cross-specialty understanding that could facilitate clinical and biological advances. In this Review, we highlight multiple genetic brain disorders in which neurological and psychiatric phenotypes are observed, but for which in-depth, cross-spectrum clinical phenotyping is rarely undertaken. We describe the combined phenotypes observed in association with genetic variants linked to epilepsy, dystonia, autism spectrum disorder and schizophrenia. We also consider common underlying mechanisms that centre on synaptic plasticity, including changes to synaptic and neuronal structure, calcium handling and the balance of excitatory and inhibitory neuronal activity. Further investigation is needed to better define and replicate these phenotypes in larger cohorts, which would help to gain greater understanding of the pathophysiological mechanisms and identify common therapeutic targets.
Key points
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Rare genetic brain disorders frequently involve both neurological and psychiatric phenotypes, but detailed, cross-spectrum clinical phenotyping is rarely undertaken.
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Improved clinical phenotypic understanding of these single gene disorders is important, given the potential for developing genetic model systems to aid understanding of the underlying pathophysiological mechanisms.
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Potential shared pathophysiological mechanisms include disruption to synaptic plasticity, synaptic and neuronal structure, the balance of excitatory and inhibitory neuronal activity and calcium handling.
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Further mechanistic understanding of the overlap between neurological and psychiatric phenotypes will increase opportunities for discovery of novel therapeutic targets in multiple brain disorders.
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Peall, K.J., Owen, M.J. & Hall, J. Rare genetic brain disorders with overlapping neurological and psychiatric phenotypes. Nat Rev Neurol 20, 7–21 (2024). https://doi.org/10.1038/s41582-023-00896-x
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DOI: https://doi.org/10.1038/s41582-023-00896-x
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