Mariel Pullman1, Deborah Raymond1, Walter Molofsky1, Naomi Lubarr1, Katherine Leaver1, Roberto Ortega1, Maya Rawal1, Steffany Bennett2, Evan Bushnik2, Azita Khorsandi3, Fedor Panov4, Jean Paul Vonsattel5, Laurie Ozelius6, Rachel Saunders-Pullman1, Susan Bressman1
1Neurology, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, 2Biochemistry, Microbiology and Immunology, and Chemistry, Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, University of Ottawa, 3Radiology, 4Neurosurgery, Icahn School of Medicine at Mount Sinai, 5Neuropathology, Columbia University Medical Center, 6Neurology, Massachusetts General Hospital and Harvard Medical School
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.