Objective: To explore the phenotype of NUS1-related disorders and determine the spectrum of movement disorders in patients with NUS1 pathogenic variants.

Background: A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders (1). De novo loss-of-function variants in NUS1, encoding a transmembrane protein essential for dolichol biosynthesis and protein N-glycosylation, have been identified in cases with DEEs (2). Herein, we report a cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated movement disorders.

Method: Individuals with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform (3). Clinical data were acquired through retrospective case-note review.

Results: We report 15 subjects with pathogenic heterozygous NUS1 variants (9 truncating, 2 missense, 3 whole gene deletions and 1 duplication). Age at last assessment ranged from 4 to 55 years (average 21.6 years ±16.6). All cases presented with motor and language delay and a variable degree of intellectual disability. Generalized epilepsy with onset in early childhood, manifesting with different combinations of seizures (tonic-clonic, myoclonic, tonic, atonic, and absence), was present in 10 cases. Strikingly, 9 cases presented with a progressive movement disorder as the most prominent clinical feature, with onset in the first decade for 8 of these cases and not accompanied by epilepsy in 4. Phenomenology of the observed movement disorders was combined in all 9 cases and specific diagnoses were myoclonus-dystonia (x4), myoclonus-ataxia (x3) with additional late-onset levodopa-responsive parkinsonism in 1 of these cases, and generalized dystonia-parkinsonism (x2). Five cases without a frank movement disorder had mild limb and gait incoordination and intentional tremor, suggesting mild cerebellar dysfunction.

Conclusion: NUS1 pathogenic variants cause a complex neurological disorder, variably featuring DEE and a broad spectrum of movement disorders, which represent the major source of neurological disability in a significant proportion of patients. We did not observe any genotype-phenotype correlation, suggesting that other mechanisms are responsible for this striking phenotypic heterogeneity.

References: 1. Papandreou A, Danti FR, Spaull R, Leuzzi V, McTague A, Kurian MA. The expanding spectrum of movement disorders in genetic epilepsies. Dev Med Child Neurol. 2020;62(2):178-91.
2. Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, et al. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. American journal of human genetics. 2017;101(5):664-85.
3. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928-30.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-spectrum-of-movement-disorders-associated-with-nus1-pathogenic-variants/