Epilepsy Phenotypic Spectrum of NUS1-Related Disorder: A Case Series

Epilepsy with myoclonic and atonic seizures (EMAtS), also known as Doose syndrome, accounts for 1%-2% of childhood epilepsies, and various genes have been implicated in causing this epilepsy syndrome. NUS1 encodes for Nogo-B receptor (NgBR), which stabilizes the dehydrodolichyl-diphosphate synthase complex in the endoplasmic reticulum, promoting its enzymatic activity (cis-IPTase) and thereby regulating cholesterol biosynthesis. Pathogenic variants in NUS1 have been associated with movement disorder and epilepsy; however, the spectrum of epilepsy and electroencephalogram (EEG) phenotype has not been well characterized.

We describe a single-center case series of five patients with NUS1-related disorder.

In our cohort, three patients met the diagnostic criteria of EMAtS, and the remainder had a milder form of generalized epilepsy. Four patients had a pathogenic variant in NUS1 on one allele, and one patient had a missense change of unclear significance but fit the phenotype of NUS1-related disorder. All patients bearing the pathogenic variants in NUS1 had normal to mild developmental delay at the onset of epilepsy, with normal brain magnetic resonance imaging. Age of seizure onset in these patients was 1-7 years, and patients responded to levetiracetam and/or valproic acid. The EEG findings for these patients included the presence of spike and slow wave discharges, as well as the presence of generalized, invariant monomorphic theta range activity in the awake state, which was seen in four out of the five patients.

Taken together, NUS1 variants are associated with generalized epilepsy phenotype and an invariant EEG pattern of monomorphic theta activity.