Autosomal dominant loss-of-function NUS1 variants cause a rare spectrum of neurological disorders, including developmental and epileptic encephalopathies and movement disorders, typically presenting in childhood. NUS1 encodes Nogo-B receptor, essential for dolichol biosynthesis. We describe an adult with a novel pathogenic NUS1 start codon variant with progressive cortical myoclonus without clinical seizures, who remained functionally independent into her seventh decade.

A 67-year-old woman with lifelong neurodevelopmental delay was evaluated for strabismus, ataxia, and chronic myoclonic jerks since adolescence. A possible familial history was noted, as her mother and brother had similar symptoms and are now deceased; however, genetic confirmation in relatives was not available. 

Due to early neurodevelopmental delay and abnormal movements, biochemical and genetic testing were pursued. Comprehensive evaluation revealed features consistent with progressive myoclonus syndrome. Brain MRI showed non-specific T2/FLAIR hyperintensities in the centrum semiovale and pons. EEG demonstrated subclinical generalized spike-and-wave discharges indicating interical cortical hyperexcitability. Initial genetic epilepsy panel testing classified the NUS1 start codon variant c.1A>G (p. Met1?) as variant of uncertain significance; subsequent whole exome sequencing reclassified it as pathogenic, consistent with loss-of-function. Brivaracetam reduced myoclonic jerks and falls.

This is the oldest reported patient with a novel start codon variant NUS1-related disorder with Epilepsy-myoclonus-ataxia syndrome without definite cortical myoclonus. She has never had a generalized tonic clonic seizure, but her frequent EEG surface negative myoclonus is responsive to brivaracetam. This patient highlights the phenotypic variability of this disorder. Initial clinical and neuroimaging features raised consideration of a mitochondrial etiology, highlighting the phenotypic overlap with Leigh-like disorders and the importance of comprehensive genetic testing in progressive myoclonus syndromes.