Objective: To report a novel case of NUS1 spectrum with childhood-onset abnormal movements and adult-onset psychiatric manifestations.

Background: The NUS1 gene is associated with developmental and epileptic encephalopathies, cognitive and motor impairment, and adult-onset Parkinson’s disease (1). Neuropsychiatric disorders reported in the literature primarily include anxiety related disorders and autism spectrum disorders, however, hallucinations and delusions are rare manifestations with only one patient reported in literature thus far who developed hallucinations and delusions in early childhood (1, 2).

Method: A case report

Results: We present a 48 year-old right-handed woman with early-onset intellectual disability, childhood epilepsy, and myoclonus, followed by late onset auditory hallucinations and paranoid delusions. Her history was notable for intellectual disability and longstanding complex jerking movements of her entire body, largely affecting the upper extremities and head and face since she was around six years old. At age 13, she developed seizures. In her 40’s, she developed new-onset auditory hallucinations and paranoid delusions. At the time of assessment, her neurologic exam was notable for bilateral symmetric kinetic tremor, multi-focal myoclonus, and ataxia with dysdiadochokinesia on rapid alternating movements and wide-based gait. Diagnostic testing included MRI brain, CSF studies, and autoimmune workup that were all unremarkable. EEGs were notable for right hemispheric slowing and generalized polymorphic spike and wave discharges. Subsequent genetic testing revealed a de novo pathogenic variant, c.302del (p.Met101Argfs*4) of the NUS1 gene.

Conclusion: Pathogenic mutations in NUS1 gene have been associated with multiple childhood-onset and adult-onset cognitive, behavioral, and movement abnormalities. This case is novel in that the motor manifestations began in childhood, while her auditory hallucinations and paranoid delusions emerged only in the fifth decade of life precipitating further workup including genetic testing, aiding in diagnostic clarity.

References: [1] Brooker SM, Novelli M, Coukos R, et al. The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series. Annals of neurology. 2025;98(3):561-572. doi:https://doi.org/10.1002/ana.27272
[2] Sau C, López-Rodríguez S, Falip M, et al. Expanding the spectrum of NUS1-related progressive myoclonic epilepsy: a novel variant and exploratory use of metformin. Frontiers in Genetics. 2025;16. doi:https://doi.org/10.3389/fgene.2025.1665623

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-of-nus1-spectrum-disorder-with-adult-onset-psychosis/