Abstract Details

Title Novel Mutation of NUS1 Gene Presenting With Developmental and Epileptic Encephalopathy and Movement Disorders

Topic Movement Disorders

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 10-051

Objective NA

Background NA

Design/Methods A 53-year-old right handed man presented with developmental regression, childhood onset seizures, and abnormal body movements to our neurogenetics clinic. Age of onset for seizures was 3-4 years. Seizure semiology consisted of absence, atonic (At) and generalized tonic clonic (GTC) seizures. Patient remains seizure free on combination of levetiracetam, clonazepam and phenobarbital. Pertinent neurological exam findings included cognitive impairment, dysarthria, impaired saccades, spasticity of legs with grade 4 hyperreflexia, action myoclonus of arms, facial myoclonus and mild appendicular ataxia with intentional tremors. There was no significant past medical or family history. MRI Brain showed mild global parenchymal volume loss. MRI cervical spine showed moderate canal stenosis without cord signal changes. Whole exome sequencing was performed which reported a novel heterozygous pathogenic loss of function mutation c.99dupG(p.Asn34Glufs*100) in exon 1 of the NUS1 gene. This mutation was absent in mother and father’s sample was unavailable.

Results NUS1 encodes a subunit of dehydrodolichyl diphosphate synthase (DHDDS). Along with DHDDS, NUS1 is critical for protein glycosylation and also plays an important role in regulating the nascent lysosomal NPC2 protein. To date, heterozygous NUS1 gene mutations have been described in only 3 cases with developmental and epileptic encephalopathy (DEE). Movement disorders description in previous cases has been limited to either ataxia or tremors. Our patient presents with both ataxia and intentional tremor along with prominent action myoclonus of arms and facial myoclonus, likely due to cortical and cerebellar involvement.

Conclusions Our case confirms NUS1 mutations as a cause of DEE and expands the spectrum of movement disorders associated with this condition. Functional studies are warranted to explore whether NUS1 mutations lead to abnormal glycosylation and maturation of NPC2 protein with lysosomal storage abnormality as underlying pathology.

Authors/Disclosures
Neha Prakash, MD (University of Connecticut Health Center) PRESENTER	The institution of Dr. Prakash has received research support from UCB Biosciences Inc.. The institution of Dr. Prakash has received research support from Parkinson Foundation.
Cindy Zadikoff, MD (AbbVie)	Dr. Zadikoff has received personal compensation for serving as an employee of AbbVie.
	No disclosure on file
	No disclosure on file
Niccolò Mencacci	No disclosure on file
Dimitri Krainc, MD, PhD (Northwestern University)	Dr. Krainc has nothing to disclose.

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