The Spectrum of Neurologic Phenotypes Associated With NUS1 Pathogenic Variants: A Comprehensive Case Series

Abstract

Objective: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders.

Methods: Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review.

Results: We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation.

Interpretation: Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025;98:561-572.

FIGURE 1

NUS1 variant map. (A) Protein map positions of NUS1 pathogenic variants. For each variant, associated clinical phenotypes are represented by color coding to indicate the presence of movement disorders, epilepsy, or both. (B) The proportion of NUS1 cases with both epilepsy and movement disorders (56.1%), movement disorders alone (31.7%), or epilepsy alone (12.2%) is shown.

FIGURE 2

NUS1 and DHDDS protein structure. (A) The crystal structure (PDB: 7PAX) of the complex between NUS1 (green) and DHDDS (magenta). Substrates of the complex are shown in orange, whereas a magnesium cofactor is shown in gray. Residues with missense mutations identified in this study are shown in yellow. Inset: The residue C208 at the interface between NUS1 and DHDDS, with the sulfur atom colored darker. (B) Surface hydrophobicity map at the interface between NUS1 (left) and DHDDS (right) containing residue C208 (yellow).

FIGURE 3

Generalized epileptiform discharges on electroencephalogram. (A, B) Case 2 ambulatory EEG at age 32 years demonstrating interictal 4 to 6 Hz generalized, bifrontally predominant spike–wave activity (A) and increased EMG with and without corresponding spike–wave activity during a period of patient‐reported “Head jerking, eyelid fluttering and shoulder jerking” (B). EEG settings = 10 μV/mm and 10 s/page. (C, D) Case 2 routine EEG at age 38 years demonstrating interictal 4 to 6 Hz generalized bifrontally predominant spike–wave activity during drowsiness (C) and paroxysmal fast and spike‐ wave activity during an axial myoclonic jerk (D). EEG settings = 10 μV/mm and 10 s/page. (E, F) Case 9 EEG at age 9 years demonstrating photoparoxysmal response (E). Photoparoxysmal response was seen for all frequencies 5 to 25 Hz. EEG settings = 10 μV/mm and 20 s/page. EEG at age 12 years demonstrating 4 to 5 Hz, generalized, bifrontally maximal spike–wave activity without clinical correlate (F). EEG settings = 10 μV/mm and 10 s/page. EEG = electroencephalogram; EMG = electromyography; Hz = hertz.