VPS16-Associated Dystonia: A Cohort-Based Clinical, Imaging and Genetic Profile.

Background: Monoallelic variants in VPS16 are associated with early-onset dystonia (VPS16-associated dystonia) with a frequency of less than 4%.

Objective: Description of the clinical, imaging, and genetic profile of VPS16-associated dystonia and comparison of the findings of the Indian cohort with that of the Chinese and European cohorts.

Methods: Report of a single patient with VPS16-associated dystonia and review of reported cases of genetically confirmed DYT-VPS16 since 2016 from Indian, Chinese and European cohorts.

Results: There were a total of 3 cases from India, 10 cases from China, and 34 cases from Europe. The median age at onset was similar in all cohorts. The median duration of disease was 26 years in the European cohort but a shorter duration was noted in the Indian and Chinese cohorts (13-14 years). Dystonia was the common symptom observed in all cohorts with associated myoclonus, intellectual disability, and psychiatric symptoms commonly reported from European cohort. The onset of dystonia was primarily noticed in the limb/cervical region in all cohorts. Partial to good response to globus pallidus interna deep brain stimulation (DBS) was reported from the European cohort. Brain magnetic resonance imaging was usually normal in all the cohorts. Frameshift and stop-gain variants were common in the European and Indian cohorts, whereas missense variants were common in the Chinese group. Segmental dystonia was common in frameshift variants (70%) and generalized dystonia in stop-gain variants.

Conclusion: Our study showed geographically diverse differences in the phenotypic presentation of VPS16-associated dystonia as myoclonus, intellectual disability, and psychiatric symptoms were more common in the European cohort. Segmental dystonia was commonly observed in the frameshift variants and generalized dystonia in stop-gain variants.

Highlights: VPS16-associated dystonia is a new genetically mediated dystonic syndrome. The clinical presentation is heterogeneous in terms of intrafamilial and interfamilial variability of age at onset and severity of dystonia. We aimed to study the ethnic phenotypic and genotypic differences of VPS16-associated dystonia. Our study showed geographically-diverse differences in the phenotypic presentation as myoclonus, intellectual disability, and psychiatric symptoms were more common in the European cohort. Patients with frameshift variants had segmental dystonia, whereas those with stop-gain variants had generalised dystonia.