OBJECTIVE: The objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16-related dystonia. METHODS: This observational study collected preoperative and postoperative demographic, clinical, stimulation, genetic, neuroimaging, and neurophysiological data of medically refractory DYT-VPS16 patients with implanted DBS in 10 international centers. Motor symptoms and disability outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale Motor (BFMDRS-M) and Disability (BFMDRS-D) scales. A cut-off threshold for considering response to DBS was set at 25% of BFMDRS-M improvement at the last follow-up (FU) compared to baseline. RESULTS: The cohort consisted of 26 participants (17 men, 65.4%). Age at dystonia onset and surgery was 17.8 ± 10.9 and 35.3 ± 14.8 years, respectively. At the last FU, 102.5 ± 57.3 months (range, 2-216), the mean BFMDRS-M improvement was 41.6 ± 37.3% (26/26 patients) and 34.8 ± 42.6% for the BFMDRS-D (23/26 patients). Most patients (19/26, 73%) were considered responders. Higher motor improvement was associated with stimulation of the ventroposterior portion of the internal globus pallidus. A significant inverse relationship was observed between improvement in BFMDRS-M at last FU, and the presence of spasticity (p = 0.027) and fixed skeletal deformities (p = 0.001) before surgery. Non-responders had a younger age at disease onset and at implantation, shorter disease duration at DBS surgery, and higher baseline BFMDRS scores. INTERPRETATION: DBS was an effective treatment for three-quarters of patients with pathogenic VPS16 variants in our cohort. Mean motor improvement was most pronounced at the 1-year FU, but persisted at the last FU despite disease progression. ANN NEUROL 2025;98:711-725.

Center for Interdisciplinary Biosciences Technology and Innovation Park P J Safarik University Kosice Slovak Republic

Department of Child Neurology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology University College London London UK

Department of Health Psychology and Research Methodology Faculty of Medicine P J Safarik University Kosice Slovak Republic

Department of Neurology Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Praha Prague Czech Republic

Department of Neurology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Neurology Great Ormond Street Hospital for Children London UK

Department of Neurology IRCCS Fondazione Mondino Pavia Italy

Department of Neurology P J Safarik University Kosice Slovak Republic

Department of Neurology Universitätsklinikum Schleswig Holstein Kiel Germany

Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Department of Neurology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Neurology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Neurology University of Würzburg Würzburg Germany

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology University College London London UK

Department of Neurosurgery Gui de Chauliac Hospital University Hospital Montpellier Montpellier France

Department of Neurosurgery P J Safarik University Kosice Slovak Republic

Department of Neurosurgery University Hospital of L Pasteur Kosice Slovak Republic

Department of Neurosurgery University Medical Center Hamburg Eppendorf Hamburg Germany

Developmental Neurosciences Zayed Centre for Research into Rare Disease in Children UCL Great Ormond Institute of Child Health London UK

Division of Neurology CHU of Grenoble Grenoble France

Expertise Center Movement Disorders Groningen University Medical Center Groningen University of Groningen Groningen the Netherlands

Grenoble Alpes University Division of Neurology CHU of Grenoble Grenoble Institute of Neurosciences Grenoble France

Institute for Advanced Study Technical University of Munich Garching Germany

Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany

Institute of Neurogenetics University of Luebeck Luebeck Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Laboratory of Clinical Neurosciences University Science Park MEDIPARK P J Safarik University Kosice Slovak Republic

Movement Disorders Hospital Beelitz Heilstätten Germany

Munich Cluster for Systems Neurology SyNergy Munich Germany

Neurosurgery Department Functional Neurosurgery Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Parkinson and Movement Disorders Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Service of Neurology Department of Clinical Neurosciences Lausanne University Hospital Lausanne Switzerland

The BioRobotics Institute Scuola Superiore Sant' Anna Pisa Italy

Unit of Functional Neurosurgery Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London UK

Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Zobrazit více v PubMed

Steel D, Zech M, Zhao C, et al. Loss‐of‐function variants in HOPS complex genes VPS16 and VPS41 cause early onset dystonia associated with lysosomal abnormalities. Ann Neurol 2020;88:867–877. 10.1002/ana.25879. PubMed DOI

Li X, Wang L, Guo Y, et al. Mutations in the VPS16 gene in 56 early‐onset dystonia patients. Mov Disord 2021;36:780–781. 10.1002/mds.28540. PubMed DOI

Cai X, Chen X, Wu S, et al. Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent‐onset primary dystonia. Sci Rep 2016;6:25834. Published 2016 May 12. 10.1038/srep25834. PubMed DOI PMC

Li LX, Jiang LT, Liu Y, et al. Mutation screening of VPS16 gene in patients with isolated dystonia. Parkinsonism Relat Disord 2021;83:63–65. 10.1016/j.parkreldis.2020.12. PubMed DOI

Gu X, Lin J, Hou Y, et al. De novo missense mutation of PubMed DOI PMC

Ostrozovicova M, Jech R, Steel D, et al. A recurrent VPS16 p.Arg187* nonsense variant in early‐onset generalized dystonia. Mov Disord 2021;36:1984–1985. 10.1002/mds.28647. PubMed DOI

Pott H, Brüggemann N, Reese R, et al. Truncating VPS16 mutations are rare in early onset dystonia. Ann Neurol 2021;89:625–626. 10.1002/ana.25990. PubMed DOI

Pullman M, Raymond D, Molofsky W, et al. Clinical and pathological characterization of VPS16 dystonia. Neurology 2023;17:2737. 10.1212/WNL.0000000000202761. DOI

Park J, Reilaender A, Petry‐Schmelzer JN, et al. Transcript‐specific loss‐of‐function variants in PubMed DOI PMC

Shashi S, Nashi S, Arunachal G, et al. DYT30 due to VPS16 mutation: an etiology of childhood‐onset generalized dystonia. Ann Indian Acad Neurol 2023;26:286–288. 10.4103/aian.aian5923. PubMed DOI PMC

Santos M, Massano J, Lopes AM, et al. Aberrant splicing caused by a novel VPS16 variant linked to dystonia type 30. Neurogenetics 2023;24:215–218. 10.1007/s10048-023-00720-0. PubMed DOI

Vimercati A, Tannorella P, Orlandini E, et al. Case report: atypical Silver‐Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum [published correction appears in PubMed DOI PMC

Monfrini E, Avanzino L, Palermo G, et al. Dominant VPS16 pathogenic variants: not only isolated dystonia. Mov Disord Clin Pract 2024;11:87–93. 10.1002/mdc3.13927. PubMed DOI PMC

Artusi CA, Dwivedi A, Romagnolo A, et al. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta‐analysis. J Neurol Neurosurg Psychiatry 2020;91:426–433. 10.1136/jnnp-2019-322169. PubMed DOI

Jinnah HA, Alterman R, Klein C, et al. Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing. J Neural Transm (Vienna) 2017;124:417–430. 10.1007/s00702-016-1656-9. PubMed DOI PMC

Coubes P, Roubertie A, Vayssiere N, et al. Treatment of DYT1‐generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000;355:2220–2221. 10.1016/S0140-6736(00)02410-7. PubMed DOI

Brüggemann N, Kühn A, Schneider SA, et al. Short‐ and long‐term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia. Neurology 2015;84:895–903. 10.1212/WNL.0000000000001312. PubMed DOI PMC

Rocha H, Linhares P, Chamadoira C, et al. Early deep brain stimulation in patients with myoclonus‐dystonia syndrome. J Clin Neurosci 2016;27:17–21. 10.1016/j.jocn.2015.08.034. PubMed DOI

Abejero JEE, Jamora RDG, Vesagas TS, et al. Long‐term outcomes of pallidal deep brain stimulation in X‐linked dystonia parkinsonism (XDP): up to 84 months follow‐up and review of literature. Parkinsonism Relat Disord 2019;60:81–86. 10.1016/j.parkreldis.2018.09.022. PubMed DOI

Rajan R, Garg K, Saini A, et al. GPi‐DBS for PubMed DOI PMC

Ahn JH, Kim AR, Kim NKD, et al. The effect of Globus pallidus Interna deep brain stimulation on a dystonia patient with the GNAL mutation compared to patients with DYT1 and DYT6. J Mov Disord 2019;12:120–124. 10.14802/jmd.19006. PubMed DOI PMC

Decraene B, Smeets S, Remans D, et al. Deep brain stimulation for GNAO1‐associated dystonia: a systematic review and meta‐analysis. Neuromodulation 2024;27:440–446. 10.1016/j.neurom.2023.10.187. PubMed DOI

Tisch S, Kumar KR. Pallidal deep brain stimulation for monogenic dystonia: the effect of gene on outcome. Front Neurol 2021;11:630391. Published 2021 Jan 8. 10.3389/fneur.2020.630391. PubMed DOI PMC

Brücke C, Horn A, Huppke P, et al. Failure of pallidal deep brain stimulation in a case of rapid‐onset dystonia parkinsonism (DYT12). Mov Disord Clin Pract 2014;2:76–78 2014 Dec 30. 10.1002/mdc3.12124. PubMed DOI PMC

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424. 10.1038/gim.2015.30. PubMed DOI PMC

Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021;596:583–589. 10.1038/s41586-021-03819-2. PubMed DOI PMC

Varadi M, Bertoni D, Magana P, et al. AlphaFold protein structure database in 2024: providing structure coverage for over 214 million protein sequences. Nucl Acids Res 2024;52:D368–D375. 10.1093/nar/gkad1011. PubMed DOI PMC

Varadi M, Anyango S, Deshpande M, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein‐sequence space with high‐accuracy models. Nucleic Acids Res 2022;50:D439–D444. 10.1093/nar/gkab1061. PubMed DOI PMC

Burke RE, Fahn S, Marsden CD, et al. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73–77. 10.1212/wnl.35.1.73. PubMed DOI

Pauls KAM, Krauss JK, Kämpfer CE, et al. Causes of failure of pallidal deep brain stimulation in cases with pre‐operative diagnosis of isolated dystonia. Parkinsonism Relat Disord 2017;43:38–48. 10.1016/j.parkreldis.2017.06.023. PubMed DOI

Duga V, Giossi R, Romito LM, et al. Long‐term Globus pallidus internus deep brain stimulation in pediatric non‐degenerative dystonia: a cohort study and a meta‐analysis. Mov Disord 2024;39:1131–1144. 10.1002/mds.29815. PubMed DOI

Horn A, Li N, Dembek TA, et al. Lead‐DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage 2019;184:293–316. 10.1016/j.neuroimage.2018.08.068. PubMed DOI PMC

Horn A, Reich MM, Ewert S, et al. Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia. Proc Natl Acad Sci U S A 2022;119:e2114985119. 10.1073/pnas.2114985119. PubMed DOI PMC

Reich MM, Horn A, Lange F, et al. Probabilistic mapping of the antidystonic effect of pallidal neurostimulation: a multicentre imaging study. Brain 2019;142:1386–1398. 10.1093/brain/awz046. PubMed DOI

Kaymak A, Colucci F, Ahmadipour M, et al. Spiking patterns in the globus pallidus highlight convergent neural dynamics across diverse genetic dystonia syndromes. Ann Neurol 2025;97:826–844. 10.1002/ana.27185. PubMed DOI PMC

Thomsen M, Lange LM, Klein C, Lohmann K. MDSGene: extending the list of isolated dystonia genes by VPS16, EIF2AK2, and AOPEP. Mov Disord 2023;38:507–508. 10.1002/mds.29327. PubMed DOI

Petry‐Schmelzer JN, Park J, Haack TB, et al. Long‐term benefit of pallidal deep brain stimulation in a patient with VPS16‐associated dystonia. Neurol Res Pract 2022;4:21 10.1186/s42466-022-00185-w. PubMed DOI PMC

Van der Kuy C, Kubben PL, Ackermans L, et al. Deep brain stimulation in a patient with dystonic tremor with a novel familial VPS16 gene mutation. Deep Brain Stimul 2024;6:20–22 2949‐6691;. 10.1016/j.jdbs.2024.10.001. DOI

Krause P, Völzmann S, Ewert S, et al. Correction to: long‐term effects of bilateral pallidal deep brain stimulation in dystonia: a follow‐up between 8 and 16 years. J Neurol 2022;269:540. 10.1007/s00415-021-10863-5. PubMed DOI PMC

Kupsch A, Benecke R, Müller J, et al. Pallidal deep‐brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006;355:1978–1990. 10.1056/NEJMoa063618. PubMed DOI

Yu H, Takahashi K, Bloom L, et al. Effect of deep brain stimulation on swallowing function: a systematic review. Front Neurol 2020;11:547. 10.3389/fneur.2020.00547. PubMed DOI PMC

Cif L, Demailly D, Lin JP, et al. KMT2B‐related disorders: expansion of the phenotypic spectrum and long‐term efficacy of deep brain stimulation. Brain 2020;143:3242–3261. 10.1093/brain/awaa304. PubMed DOI PMC

Honey CR, Krüger MT, Almeida T, et al. Thalamic deep brain stimulation for spasmodic dysphonia: a phase I prospective randomized double‐blind crossover trial. Neurosurgery 2021;89:45–52. 10.1093/neuros/nyab095. PubMed DOI PMC

Hart MG, Polyhronopoulos N, Sandhu MK, et al. Deep brain stimulation improves symptoms of spasmodic dysphonia through targeting of thalamic sensorimotor connectivity. Neurosurgery 2024; 94:1291–1300. 10.1227/neu.0000000000002836. PubMed DOI PMC

Graham SC, Wartosch L, Gray SR, et al. Structural basis of Vps33A recruitment to the human HOPS complex by Vps16. Proc Natl Acad Sci U S A 2013;110:13345–13350. 10.1073/pnas.1307074110. PubMed DOI PMC

Tisch S, Zrinzo L, Limousin P, et al. Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia. J Neurol Neurosurg Psychiatry 2007;78:1314–1319. 10.1136/jnnp.2006.109694. PubMed DOI PMC

Cheung T, Noecker AM, Alterman RL, et al. Defining a therapeutic target for pallidal deep brain stimulation for dystonia. Ann Neurol 2014;76:22–30. 10.1002/ana.24187. PubMed DOI