Objective: To describe the response of dystonia to deep brain stimulation (DBS) of the globus pallidus interna (GPi) in a patient with generalized dystonia due to a VPS16 mutation (DYT30).

Background: VPS16 mutations have been associated with early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement [1]. A limited number of reports have indicated some individuals with DYT30 may benefit from pallidal stimulation, although a case series suggested those with an earlier age of symptom onset (3-10 years) may be less likely to benefit than those with a later onset (11-33 years) [2-3].

Method: We describe a DYT30 patient with early symptom onset who experienced benefit from bilateral pallidal DBS implantation.

Results: A 10-year-old girl with a history of DYT 30 due to heterozygous VPS16 mutation on chromosome 20 (c.1611+1G>A) was referred to our clinic for management of generalized dystonia. Symptom onset was at age 5 with right then left toe flexion, foot inversion, and progressive gait impairment, resulting in wheelchair dependence by age 9. She had trials of carbidopa-levodopa, trihexyphenidyl, clonazepam, gabapentin, dantrolene, and botulinum toxin injections, all either without benefit or with resultant side effects.

At her initial visit, she was noted to have dynamic dystonic posturing of the left arm, bilateral knee flexion with ambulation, and truncal flexion. Burke-Fahn Marsden Dystonia Rating Scale (BFMDRS) total was 50 with a disability scale total of 11.

She subsequently underwent bilateral pallidal DBS implantation. Initial DBS parameters were pulse width of 60 and frequency of 130 with stimulation at second most dorsal contact slowly increased to 3.8 mA bilaterally.  Dystonia was not further improved with trials of higher stimulation at this contact.

At approximately 14 months post-DBS implantation, the patient presented on initial DBS settings as above. Right hemibody and truncal dystonia were resolved. There was residual left hemibody dystonia, characterized by left finger flexion and left ankle inversion. She was able to ambulate independent of assistive aids. BFMDRS total improved to 12 with a disability scale total of 0.

Conclusion: Bilateral pallidal DBS may significantly improve generalized dystonia due to VPS16 mutations, including in individuals with a younger age of symptom onset.

References: 1. Steel D, Zech M, Zhao C, Barwick KES, Burke D, Demailly D, Kumar KR, Zorzi G, Nardocci N, Kaiyrzhanov R, Wagner M, Iuso A, Berutti R, Škorvánek M, Necpál J, Davis R, Wiethoff S, Mankad K, Sudhakar S, Ferrini A, Sharma S, Kamsteeg EJ, Tijssen MA, Verschuuren C, van Egmond ME, Flowers JM, McEntagart M, Tucci A, Coubes P, Bustos BI, Gonzalez-Latapi P, Tisch S, Darveniza P, Gorman KM, Peall KJ, Bötzel K, Koch JC, Kmieć T, Plecko B, Boesch S, Haslinger B, Jech R, Garavaglia B, Wood N, Houlden H, Gissen P, Lubbe SJ, Sue CM, Cif L, Mencacci NE, Anderson G, Kurian MA, Winkelmann J; Genomics England Research Consortium. Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities. Ann Neurol. 2020 Nov;88(5):867-877. doi: 10.1002/ana.25879. Epub 2020 Sep 21. PMID: 32808683.
2. Monfrini E, Avanzino L, Palermo G, Bonato G, Brescia G, Ceravolo R, Cantarella G, Mandich P, Prokisch H, Storm Van’s Gravesande K, Straccia G, Elia A, Reale C, Panteghini C, Zorzi G, Eleopra R, Erro R, Carecchio M, Garavaglia B, Zech M, Romito L, Di Fonzo A. Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia. Mov Disord Clin Pract. 2024 Jan;11(1):87-93. doi: 10.1002/mdc3.13927. Epub 2023 Dec 12. PMID: 38291845; PMCID: PMC10828607.
3. Petry-Schmelzer JN, Park J, Haack TB, Visser-Vandewalle V, Barbe MT, Wunderlich G. Long-term benefit of pallidal deep brain stimulation in a patient with VPS16-associated dystonia. Neurol Res Pract. 2022 May 30;4(1):21. doi: 10.1186/s42466-022-00185-w. PMID: 35644611; PMCID: PMC9150300.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/response-to-bilateral-gpi-dbs-in-a-patient-with-dyt30/