Objective: To describe two cases of myoclonic ataxia due to two novel NUS1 pathogenic variants

Background: The genetic bases of myoclonus is not well defined. Myoclonus is often associated with epileptic encephalopathy or cerebellar symptoms. The identification of gene variants in undiagnosed cases will help defining the genetic architectures of this disorder.

Method: Patients were evaluated by movement disorders specialists, underwent EEG, brain MRI, and video-recording. Targeted gene sequencing and whole-exome sequencing were performed on genomic DNA.

Results: Case 1 was a 14-year-old boy with infantile onset of motor clumsiness, upper limbs myoclonus since the age of 11, and mild intellectual disability. At the age of 14 he presented multifocal myoclonus in his face, tongue, and upper limbs, and mild dysdiadochokinesis. EEG was unrevealing. Brain MRI showed mild atrophy of the rostral part of the cerebellar vermis. WES variant prioritization revealed a frameshift insertion in exon 4 of NUS1, causing a premature stop codon (NM_138459.5: c.754_755insGTTTTCTTCCCTGGCACATCAG, p.Thr261Serfs*9), confirmed at Sanger sequencing. This variant was not present in his mother. The father was not available for testing but was reportedly healthy, thus the variant was supposed to be de novo.
Case 2 was a 28 year old woman with onset of myoclonus at the age of 3 years, generalized seizures since the age of 13 years, and mild intellectual disability. Previous genetic test, including 21 genes of progressive myoclonic epilepsy and DRPLA, were negative. Targeted gene testing of NUS1 revealed a novel point mutation in the NUS1 gene, c.868C>T (p.R290C). The mutation was not present in her parents and thus was re-classified as likely pathogenic.

Conclusion: NUS1 gene encodes a transmembrane receptor for the neural and cardiovascular regulator Nogo-B (NUS1 or NgBR) and is essential for dolichol synthesis and protein glycosylation in the endoplasmic reticulum (ER). To date, 25 disease-causing mutations of NUS1 have been reported, which are responsible for various phenotypes, including epileptic encephalopathies, ataxia, myoclonus-epilepsy syndromes, dystonia, developmental delay, psychosis, as well as congenital disorder of glycosylation. Here we described two new variants of NUS1, one associated with myoclonus-epilepsy, and the other to myoclonus and cerebellar features without seizures. NUS1 should be included in all panels of genetic myoclonus.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/two-cases-of-myoclonic-ataxia-with-and-without-epilepsy-associated-with-nus1/