Case series; NUS1 deletions cause a progressive myoclonic epilepsy with ataxia

Mutations in NUS1 cause a neurological congenital glycosylation disorder which encompasses a spectrum from developmental encephalopathy to musculoskeletal, hearing, and visual abnormalities. Pathogenic variants include both point mutations and genomic deletions. We report an adult phenotype of progressive myoclonus epilepsy (PME) and a review of cases with a complete or partial deletion of NUS1.

Our patient, currently age 30, presented with an intellectual disability and developed progressive ataxia with myoclonic tremor, alongside generalised absence and tonic-clonic seizures. At age 28 he was diagnosed with a heterozygous 5.0 Mb deletion of 6q22.1q22.31 involving the NUS1 gene. We are unable to state whether this is a de novo mutation; his mother tested negative for the gene, but his father passed away before any genetic analysis could be performed. Along with the 22 patients reported in published literature, we identified 21 other genetically similar NUS1 deletion variants with sufficient clinical data through ClinVar.

The identification of NUS1 gene deletion disorder does not lead to a change in treatment but predicts a progressive clinical trajectory. Recognition of this helps differentiate neurological progression from the impact of anti-seizure medicine.

Copy number variants are an often-overlooked cause of PME. We also describe features of psychosis and spasticity and suggest that these may also be due to the NUS1 deletion, expanding the literature that exists on the phenotype of this very rare genetic disorder.