Objective: Describe a rare cause of progressive myoclonus, ataxia, developmental delay

Background: 37-year-old man with normal birth but delays in developmental milestones presented for evaluation of movement disorder. He had epilepsy starting age 2 with good motor control until his mid-20s, at which time he developed diffuse jerky movements, worsening cognitive skills, and impaired balance, which have slowly worsened. Father had tremor and died in 30s with unclear diagnosis. He also has urinary urgency, poor sleep, weight gain fatigue, and hearing loss. Primidone, carbamazepine, clonazepam, topiramate, propranolol, amantadine, and levitiracitam were only marginally helpful and titration limited by fatigue.

Method: Case report and literature review

Results: Examination showed overweight patient with blunted affect, episode of incontinence, moderate dysarthria, reduced fund of knowledge and cognitive impairment. He had facial myoclonus, tremulous tongue, hypomimia, diffuse psychomotor slowing, bilateral kinetic and intention tremor worse on left, 2-4 Hz, with superimposed myoclonic jerks without reflex stimulus. Reduced vibration distal legs, dysmetric with finger-to-nose, and broad-based gait with titubation of trunk, difficulty coordinating gait with walker.

Repeated EEG monitoring did not show evidence of current seizures. Multiple brain MRI scans showed only mild calcifications in left dentate nucleus. Extensive metabolic and immune testing was negative. Whole exome sequencing revealed a likely pathogenic variant in the NUS1 gene, which is associated with autosomal dominant mental retardation type 55 with seizures (MRD55). The gene encodes a membrane protein (dehydrodolichyl diphosphate synthase subunit), leading to a congenital disorder of glycosylation. The variant is predicted to disrupt this highly conserved acceptor splice site. No relevant mitochondrial variants were noted.

Conclusion: Genes that unify ataxia, epilepsy, myoclonus are rare and difficult to identify without broad genetic analysis. NUS1 gene mutations manifest in a wide array of different neurologic symptoms which are seen in this patient: developmental delay, moderate to severe intellectual disability, dysarthria, ataxic gait, clumsiness, poor fine motor skills, tremor, myoclonic seizures, early seizures of multiple types, and autism spectrum disorder. NUS1 mutations should be considered in the differential of progressive myoclonic encephalopathy syndromes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nus1-mutation-causing-ataxia-myoclonus-and-progressive-encephalopathy/