Dystonia with myoclonus and vertical supranuclear gaze palsy associated with a rare GNB1 variant (P11-11.008)

Abstract

<h3>Objective:</h3> We report a case of <i>GNB1</i> encephalopathy arising from a <i>de novo</i> mutation in an uncommon locus presenting with a unique phenotype consisting of dystonia with myoclonus and vertical supranuclear gaze palsy (VSGP). <h3>Background:</h3> <i>GNB1</i> encephalopathy (OMIM: 616973), caused by pathogenic variants in the <i>GNB1</i> gene, is a rare neurodevelopmental syndrome variably co-occurring with movement disorders, with dystonia being the most frequently reported. Myoclonus occurring alongside dystonia and VGSP are uncommon findings. Most pathogenic variants occur in exons 6 and 7, which are considered to be mutational hotspots. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> This 27-year-old female presented with hypotonia and global developmental delay, intellectual disability, short stature, low body weight, dysarthria, a wide-based gait, and dystonia. She only had partial improvement with a trial of amantadine, and did not respond to dopaminergic therapy. In the ensuing years, she developed myoclonus, which persisted despite a gradual tapering off of amantadine. At 12 years of age, further examination disclosed a VSGP. Her axial dystonia, posture, and gait significantly improved with botulinum toxin (BoNTA) injections to the paraspinal muscles beginning at 18 years of age. Investigations including blood work, CSF neurotransmitters, imaging, and metabolic parameters were unrevealing. Electrophysiologic testing were consistent for both myoclonus superimposed on dystonia. Initial genetic investigations, which also included a proband whole exome sequencing (WES) were nondiagnostic. Updated trio WES six years after identified a <i>de novo</i>, heterozygous missense, likely pathogenic variant in the <i>GNB1</i> gene (c.1009A&gt;C (p.Lys337Gln); exon 11). <h3>Conclusions:</h3> Our case illustrates the evolving clinical phenotypes of <i>GNB1</i> encephalopathy and highlights its importance as a diagnostic consideration for neurodevelopmental syndromes presenting with movement disorders and gaze abnormalities. In cases where the constellation of clinical findings suggests a genetic syndrome yet ascertainment of diagnosis is challenging, our experience highlights the value of repeating next-generation sequencing tests. <b>Disclosure:</b> Dr. Reyes has nothing to disclose. Dr. Garbin Di Luca has nothing to disclose. Dr. McNiven has nothing to disclose. Dr. Lang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions, Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion. The institution of Dr. Lang has received research support from AbbVie. Dr. Lang has received publishing royalties from a publication relating to health care.