Clinical and Pathological Characterization of VPS16 Dystonia (P11-11.005)

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Objective: To expand the clinical, radiologic and pathologic understanding of VPS16 related dystonia. Background: Variants in VPS16 have been associated with isolated dystonia in 35 cases from Chinese and European cohorts, including report of brainstem signal change on MRI. Design/Methods: We describe clinical features in 10 additional individuals with isolated dystonia and VPS16 variants, including neuroimaging on a subset and pathology in one, and perform pooled analysis with published cases. Results: 80% were men, mean age onset was 14.1 years (range 5–30), and mean age at exam was 35.89 years (range 11–73). Four began with arm, 3 with leg, and 3 with neck dystonia. Only one remained focal (arm); others became generalized (7), multifocal (1) or segmental (1). Brachial involvement was present in 90%, with 80% crural, 70% cranial/bulbar, and 50% cervical involvement. Two individuals underwent deep brain stimulation and one thalamotomy. Four cases were related, and five others had family history. MRI was available in two cases and demonstrated red nucleus and cerebral peduncle T2 hypointensity. Neuropathologic evaluation in one case (post bilateral GPi DBS) demonstrated asymmetric severe gliosis and marked neuronal loss of the left subthalamic nucleus with optically empty vacuoles and much less right-sided involvement. Pooled analysis with 34 additional published cases showed 62.22% male and average onset of 14.53 years (range 3–50). Onset site was 20.45% cranial/bulbar, 54.55% limb, and 36.36% axial (cervical or trunk); 75% of cases exhibited cranial/bulbar symptoms, 90.9% limb and 81.82% axial involvement. Conclusions: Expansion of known cases of VPS16 dystonia further support that it is a childhood-or adolescent-onset disorder, typically with limb or cervical onset that often spreads to the arm and leg. Additional histopathologic and metabolomic evaluation is underway to better understand the lysosomal and endolysosomal pathophysiology that may contribute to both vacuolization in the subthalamic nucleus as well as T2 brainstem hypointensities. Disclosure: The institution of Dr. Pullman has received research support from Empire Clinical Research Investigator Program. The institution of Ms. Raymond has received research support from NIH. Dr. Molofsky has nothing to disclose. Dr. Lubarr has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for applied therapeutics. Dr. Leaver has nothing to disclose. Roberto Ortega has nothing to disclose. Ms. Rawal has nothing to disclose. The institution of Dr. Bennett has received research support from Prevail. Mr. Bushnik has nothing to disclose. Dr. Khorsandi has nothing to disclose. Fedor Panov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for neuropace. Fedor Panov has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for zimmer biomet. Jean Paul Vonsattel has nothing to disclose. The institution of Dr. Ozelius has received research support from NIH. Dr. Ozelius has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Saunders-Pullman has received research support from NIH, Bigglesworth Family Foundation, Empire Clinical Research Investigatory Program. The institution of Dr. Bressman has received research support from Michael J Fox Foundation . The institution of Dr. Bressman has received research support from NIH .

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