VPS16 ‐Related Dystonia: Expanding the Clinical Spectrum and Therapeutic Insights

Abstract

Background

DYT‐VPS16 is a rare monogenic form of dystonia caused by pathogenic variants in the vacuolar protein sorting 16 homolog (VPS16) gene. Although increasingly recognized, the clinical spectrum and therapeutic responsiveness, particularly to deep brain stimulation (DBS), remain incompletely defined.

Cases

We report six affected individuals (5 males, 1 female) from five unrelated Indian families harboring VPS16 variants. The median age at onset was 16.5 years (range, 8–18 years). Dystonia began in the cervical (n = 2), upper limb (n = 2), or laryngeal (n= 2) regions. Additional features included tremor (n = 2) and sleep disturbances (n = 1).

Literature Review

A structured literature review identified 34 previously reported DYT‐VPS16 cases treated with DBS. Pooled analysis revealed a responder rate (defined as ≥30% improvement in BFMDRS‐M) of 0.57 (95% CI: 0.31–0.81; I² = 22.9%) suggesting a favorable therapeutic response in this subgroup.

Conclusion

Our findings broaden the genotypic and phenotypic landscape of DYT‐VPS16, suggesting a more motor‐predominant and potentially milder expression in South Asian patients. DBS appears to confer meaningful clinical benefit in selected cases, highlighting the importance of early genetic diagnosis in guiding treatment.

VPS16‐related dystonia (DYT‐VPS16) is a genetic disorder caused by monoallelic variants in the vacuolar protein sorting 16 homolog (VPS16) gene. ¹ It accounts for an estimated 0.9% to 4% of genetically confirmed dystonias. ² The disease typically presents in childhood or early adulthood (mean age ~14 years; range 3–50 years) with focal onset, most frequently involving the limbs (54%), followed by axial (36%) and cranial/bulbar (20%) regions. ¹ , ³ While most patients exhibit isolated dystonia, a subset present with myoclonic features or a more complex neurological phenotype, including intellectual disability, peripheral neuropathy, and neuropsychiatric manifestations such as impulsivity and mood disturbances. ⁴ Biallelic variants reported are typically associated with more severe clinical presentations. ⁵

Given the heterogeneous phenotype and frequent refractoriness to medical therapy, Deep Brain Stimulation (DBS) targeting the globus pallidus interna (GPi) has emerged as a viable therapeutic option for severe VPS16‐related dystonia. In other monogenic dystonias, such as DYT‐TOR1A, GPi‐DBS yields good outcomes, with 60–90% improvement in motor symptoms. ⁶ Conversely, dystonias like DYT‐THAP1 and DYT‐SGCE show variable responses, and others, such as DYT‐ATP1A3, are typically unresponsive. DYT‐KMT2B, another early‐onset genetic dystonia characterized by generalized dystonia with intellectual and craniofacial features, has recently shown promise with DBS. ⁷ The therapeutic response in VPS16‐dystonia remains incompletely characterized, with only sporadic cases of DBS‐treated individuals reported to date. As genetic testing becomes increasingly integrated into dystonia management, it is imperative to define which genetic subtypes benefit most from DBS. Our study presents a series of DYT‐VPS16 patients from India and a review of the published literature. Our objectives were to broaden the phenotypic spectrum and evaluate clinical outcomes following DBS in patients with DYT‐VPS16 variants.

Case Series

Case 1

A 43‐year‐old man presented with a 35‐year history of progressive abnormal posturing and involuntary movements (Video 1). His symptoms began insidiously at age 8 with right arm involvement, followed by voice changes at age 10, left arm posturing by age 15, and jerky head and neck movements by age 19. Over time, he also developed dystonic posturing of the trunk while walking. He denied slowness of movement, gait instability, cognitive or behavioral disturbances, and seizures. Symptoms remained stable throughout the day, with no response to levodopa. A family history revealed task‐specific focal hand dystonia in his sister (genetic testing data not available). On examination, he exhibited a generalized dystonia phenotype with prominent craniofacial, oromandibular, laryngeal, cervical, upper limb, and truncal involvement, along with mild dystonia in the right lower limb. There were no features of parkinsonism, cerebellar ataxia, or pyramidal tract signs, and his cognitive functions were intact. MRI of the brain was normal. Whole‐exome sequencing (WES) identified a novel pathogenic heterozygous frameshift variant in the VPS16 gene (c.2066del in Exon 21), leading to a premature truncation of the protein (p.Gly689fs*4). The patient underwent bilateral GPi DBS using directional leads, resulting in a notable clinical response. His BFMDRS‐Motor (BFMDRS‐M) score improved from 32.5 preoperatively to 24.5 postoperatively, and further to 24 at 10 months. Correspondingly, his BFMDRS‐Disability (BFMDRS‐D) score dropped from 8 to 1 immediately after surgery and remained at 3 during the 10‐month follow‐up. (Video 2 and Table S1 and S2).

Video 1.

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Video of Case 1 (Pre‐DBS) showing generalized dystonia, including craniofacial, orofacial, oromandibular, laryngeal, and cervical dystonia with head and neck jerks, as well as upper limb and trunk dystonia, along with mild dystonia in the right lower limb.

Video 2.

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Post‐DBS video shows improvement in the dystonia. BFMDRS‐M reduced from 32.5 to 24.5 immediately post‐op, and the Dystonia Disability score decreased from 8 to 1, with benefits sustained at 6 months.

Case 2

A 20‐year‐old male presented with generalized, isolated dystonia. Onset was at age 18 with cervical involvement, which rapidly progressed to affect cranial, upper limb, lower limb, cervical, and trunk regions (Video 3). There was no associated tremor, parkinsonism, ataxia, chorea, myoclonus, spasticity, or autonomic dysfunction, though the patient reported sleep disturbances. Family history was negative. Genetic testing (WES) identified a heterozygous VPS16 nonsense variant (c.1813C>T; p.Arg605Ter) in exon 18, classified as pathogenic based on its predicted loss‐of‐function effect. His BFMDRS‐M and BFMDRS‐D scores were 48 and 7, respectively.

Video 3.

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The video of Case 2 shows upper and lower craniofacial dystonia, with marked jaw‐opening dystonia and lingual dystonia, contributing to impaired speech and oral motor control. Adductor dysphonia is noted, characterized by strained and effortful voice quality. There is a combination of rotacollis to the left and retrocaput. Dystonic movements are also seen in both upper and lower limbs, along with axial dystonia manifesting as trunk lateroflexion.

Case 3

A 45‐year‐old man with a negative family history presented with focal, isolated dystonia. Symptoms began at age 15 with dystonic posturing of the right upper limb along with tremor, but no parkinsonism, ataxia, chorea, myoclonus, spasticity, or other neurological signs. Family history was negative for dystonia or other movement disorders. Genetic testing (WES) revealed a heterozygous VPS16 variant (c.156C>A; p.Asn52Lys), a missense substitution in exon 3, classified as Variant of Uncertain Significance (VUS). His BFMDRS‐M and BFMDRS‐D scores were 12 and 6, respectively.

Cases 4–5

A 25‐year‐old woman (Case 4) and her 20‐year‐old brother (Case 5) from Family 4 presented with adolescent‐onset dystonia beginning at age 18. The sister initially developed retrocollis, with progression to upper limb and laryngeal involvement, while the brother presented with isolated laryngeal dystonia that later spread to the upper limbs. Both had multifocal dystonia, remained ambulant, and lacked additional neurological features such as seizures or myoclonus. Neuroimaging was unremarkable in both, and genetic testing (WES) revealed a heterozygous pathogenic VPS16 variant (c.1174C>T; p.Glu392*) in Case 4, which was also present in Case 5 as confirmed on Sanger Sequencing. Botulinum toxin injections provided moderate relief, particularly for laryngeal dystonia, alongside oral baclofen and benzodiazepines.

Case 6

In Family 5, a 13‐year‐old boy developed dystonia at age 10, beginning with laryngeal involvement and later affecting the neck, limbs, and trunk (Video 4). He had no associated cognitive, parkinsonian, or myoclonic features. The birth and developmental history were unremarkable; the brain MRI appeared normal, and he did not respond to levodopa. Genetic analysis (WES) identified a Variant of Uncertain Significance (VUS) VPS16 variant (c.2084C>T; p.Ser695Phe), with moderate symptomatic benefit from oral medications. The details of each of these cases are summarized in Table 1 and S3.

Video 4.

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The video of Case 6 showing generalized dystonia with laryngeal, neck, limbs and trunk involvement.

TABLE 1.

Clinical and Genetic Characteristics of our cohort of cases of VPS16‐associated dystonia

Family No.	Case.No	c.Variant	p.Number	P/LP/VUS	Age at assessment (yr)	Age of onset (yr)	Sex	Initial presentation	Current sites involved	Additional phenotypic features	MRI
Family‐1	Case‐1	c.2066del (Exon 21)	p.Gly689fs*4	P	43	8	M	Upper Limb dystonia	Cranial, Cervical, Laryngeal, Upper Limb, Trunk, Limb	Tremor	N/A
Family‐2	Case‐2	c.1813C>T (Exon 18)	p.Arg605*	P	20	18	M	Cervical dystonia	Cranial, Cervical, Upper limb, Lower limb, Trunk	Sleep disturbances	Normal
Family‐3	Case‐3	c.156C>A (Exon 3)	p.Asn52Lys	VUS	45	15	M	Upper Limb dystonia	Upper Limbs only	Tremor	Normal
Family‐4	Case‐4	c.1174C>T (Exon 12)	p.Glu392*	P	25	18	F	Cervical dystonia (retrocollis)	Cervical, Upper limb, Laryngeal	None	Not done; CT normal
	Case‐5	c.1174C>T (Exon 12)	p.Glu392*	P	20	18	M	Laryngeal dystonia	Laryngeal, Upper Limb	None	Normal
Family‐5	Case‐6	c.2084C>T (Exon 21)	p.Ser695Phe	VUS	13	10	M	Laryngeal dystonia	Laryngeal, Cranial, Cervical, Upper Limb, Trunk, Lower Limb	None	Normal

Abbreviations: P‐Pathogenic, LP‐Likely pathogenic, VUS‐Variant of Uncertain Significance, VPS16‐vacuolar protein sorting 16 homolog.

Literature Review

A comprehensive systematic review of the literature was conducted on April 5, 2025, and further updated on June 23, 2025, using three electronic databases—MEDLINE, Scopus, and EMBASE—to identify studies reporting genetically confirmed VPS16 variants in individuals with dystonia. The following Boolean search terms were applied: (“VPS16” OR “Vacuolar Protein Sorting 16”) AND (“dystonia” OR “movement disorder” OR “extrapyramidal” OR “mutation” OR “variant”). Filters were applied to include only human studies, publications in English, and studies providing clinical and/or genetic data relevant to VPS16. All references were imported into a reference management software (Rayyan), and duplicates were removed. Two independent reviewers (B.P. and D.M.R.) screened the titles and abstracts for relevance, followed by a full‐text review based on predefined eligibility criteria. Discrepancies were resolved through discussion, with input from a third reviewer (R.R.) when required. Inclusion criteria were: (1) studies reporting individuals with genetically confirmed pathogenic or likely pathogenic VPS16 variants associated with dystonia; (2) English‐language publications regardless of study design, including case reports, case series, cohort studies, and conference abstracts. Studies that did not involve human subjects or lacked individual‐level data were excluded. For the meta‐analysis, the primary outcome was the proportion of responders, defined as individuals demonstrating ≥30% improvement in the BFMDRS‐M score (Burke–Fahn–Marsden Dystonia Rating Scale–Movement score) from baseline following DBS. Meta‐analyses were performed using the “meta” and “metafor” packages, with random‐effects models applied to account for between‐study heterogeneity. Statistical heterogeneity was assessed using the I² statistic.

Initial searches yielded 99 results from MEDLINE, 108 from Scopus and 134 from EMBASE (Fig. S1). 14 manuscripts met the eligibility criteria and were included in the qualitative synthesis, revealing an additional 75 cases of VPS16‐related dystonia reported as of June 23, 2025 (Table S4). ¹ , ² , ⁴ , ⁵ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ Most cases were of European ancestry (82.7%) with 13.3% of Asian descent. The country‐wise distribution of variant count, along with the most common variant identified in each country is presented in Figure 1. The mean (SD) age at onset was 16.6 (11.1) years, ranging from 3 to 52 years, and generalized dystonia was the predominant clinical phenotype, observed in 77% of cases. Segmental (14.9%), multifocal (6.8%), and focal (1.4%) dystonia were less common). Cervical was the most frequently affected region (29.3%), presenting in isolation or in combination with speech (5.3%), limb (1.3%), or facial involvement (1.3%). Neuropsychiatric symptoms were reported in 37.3% of cases, followed by myoclonus in 13.3%, intellectual disability in 12.3%, and tremor in 9.3%. MRI findings were normal in 65.7% of patients with available imaging data. The rest demonstrated structural abnormalities, including mineral deposition in the globus pallidus (11.4%), diffuse or focal cerebral atrophy (11.4% and 8.6%, respectively), and other anomalies such as gray matter heterotopia, cerebellar cysts, multiple sclerosis‐like lesions, and hypothalamic hamartoma. The most frequently reported variant was c.1903C>T (p.Arg635*), particularly in patients with European ancestry (Table 2). Pharmacological therapies yielded inconsistent and generally mild benefits. Levodopa showed improvement in 16.0% of cases, trihexyphenidyl in 27.8%, and tetrabenazine was beneficial in selected individuals. Botulinum toxin demonstrated a good response in 42.4% of cases, particularly in those with focal dystonia (Table S4).

Figure 1.

Country‐wise distribution of variant count and the most common variant identified in each country contributing at least five variants. Lower left portion of the figure provides information on the zygosity.

TABLE 2.

Common Genetic Variants reported to be associated with VPS16 dystonia in the literature

VPS16 c.Variant	p. Number	Number of reported cases	Ethnicity
c.1903C>T	p.Arg635*	13	European
c.1939C>T	p.Arg647*	7	European
c.559C>T	p.Arg187*	6	European
c.156C>A	p.Asn52Lys	5	Chinese
c.1389C>G	p.Tyr463*	4	European

A total of 34 patients across four published studies were evaluated for outcomes following DBS in VPS16‐associated dystonia (Fig. 2). Steele et al reported five cases: two showed no significant improvement, one exhibited partial improvement, and two demonstrated marked clinical benefit. ⁴ However, the study did not clearly define the criteria for “significant improvement.” For one patient (7C), quantitative outcomes were available, with the BFMDRS‐M and D scores decreasing from 39.5 and 6 to 9 and 2, respectively, at 3.5 years postoperatively. Pott et al reported one patient with a favorable clinical response, although no numerical scores were provided. ² Park et al described a patient with a significant reduction in dystonic symptoms, with the BFMDRS score decreasing from 10 to 1.5 and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score from 16 to 7 at 12 months post‐DBS. ¹⁰ Ostrozovicova et al documented two cases with notable improvement, but without quantitative metrics. ¹¹ Schmelzer et al reported a sustained response over three years, with BFMDRS‐M improving from 16 to 1, TWSTRS‐I from 16 to 0, TWSTRS‐II from 13 to 1, and TWSTRS‐III from 5 to 4—all without the need for adjunctive pharmacotherapy. ¹² Monfrini et al reported three cases with significant benefit from bilateral GPi‐DBS, although improvements in non‐dystonic hyperkinetic movements were limited. ¹⁴ In a multicenter cohort of 26 patients with DYT‐VPS16 undergoing DBS, 19 (73%) met the study response criterion, defined as ≥30% improvement in BFMDRS‐M at last follow‐up, of whom 13 achieved a ≥50% improvement. ¹⁷

Figure 2.

BFMDRS‐M reduction before and after DBS.

In the pooled analysis, including our single patient, the proportion of responders was 0.57 (95% CI: 0.31–0.81) under the random‐effects model (Fig. 3), with heterogeneity (I² = 22.9%).

Figure 3.

Forest plot showing pooled proportion of responders defined as ≥30% improvement in the BFMDRS‐M scores following DBS in patients with DYT‐VPS16.

Discussion

Our study presents a series of six individuals from five unrelated Indian families with DYT‐VPS16, contributing valuable insights into this rare but increasingly recognized form of monogenic dystonia, including one patient (Case 1) who underwent DBS. Our series significantly adds to the existing literature by providing a comprehensive systematic review of all known VPS16 variants, their associated phenotypes to date and response to DBS.

A striking feature of VPS16‐related dystonia is its phenotypic heterogeneity. While generalized dystonia, with a predilection for cranio‐laryngeal involvement seems to be the most frequent presentation, additional complex features were reported in a subset of the published cases. However, despite the relatively early age of onset in our cohort (ranging from 8 to 18 years), neurodevelopmental delay, intellectual disability (reported in 12.3% of global cases), and neuropsychiatric comorbidities (observed in 37.3%) were absent. This suggests a potentially milder or more motor‐predominant phenotype in South Asian populations. Whether this difference arises from genetic background, variant‐specific effects, or underreporting of non‐motor symptoms remains speculative and warrants further investigation.

From a therapeutic perspective, our review highlights the clinical relevance of genetic insights in managing dystonia, particularly in the context of surgical therapy. The pooled analysis reinforces the case for surgical intervention in VPS16‐related dystonia, particularly in patients with significant disability who are refractory to pharmacotherapy.

Our study has several limitations. Notably, most studies included in our review did not use uniform measures to quantify improvements after drug use, and the responses were predominantly subjective, with most cases involving a combination of drugs. Consequently, it was not possible to pinpoint the specific effectiveness of individual treatments. However, being a rare disease with few reports of DBS worldwide, we chose to perform as inclusive a review as possible, documenting individual cases, including those from underrepresented populations. Indeed, one of the key strengths of our study is the integration of original clinical data with a comprehensive review of all reported VPS16 variants and their associated phenotypes. By compiling genotype–phenotype correlations across 81 patients (75 published and six new), we offer an extensive dataset on DYT‐VPS16. Our pooled patient analysis findings are novel and suggest the significant benefit of DBS in this group. Another limitation of our study is the lack of detailed data on neuropsychiatric symptoms, an underexplored yet clinically relevant domain in dystonia. Additionally, other non‐motor features such as sleep, pain, and fatigue were not systematically assessed in our cohort or in many previously published cases. Future studies with comprehensive phenotyping should aim to quantify these non‐motor domains to understand the full spectrum of VPS16‐related dystonia better.

In conclusion, DYT‐VPS16 typically presents as early‐onset dystonia with predominant involvement of the cranio‐cervical, laryngeal, oromandibular, and upper limb regions. It shares overlapping phenotypic features with other monogenic dystonias, including DYT‐KMT2B, DYT‐THAP1, DYT‐TOR1A, DYT‐PRKRA, DYT‐TUBB4A, and DYT‐KMT2B and often progresses to a generalized distribution. Our review highlights that VPS16‐related disorders extend beyond isolated dystonia, encompassing a broader spectrum of neurological and neurodevelopmental manifestations such as neuropsychiatric symptoms, seizures, myoclonus, intellectual disability, and basal ganglia mineralization. In addition, it substantially builds upon the existing MDSGene dataset, capturing newly reported cases, additional variant types, and broader phenotypic presentations, thereby reflecting the current and evolving landscape of VPS16‐related dystonia. Deep brain stimulation yields a favorable response in approximately 57% of reported cases, underscoring its therapeutic relevance in this population.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

B.P.: 1A, 1B, 1C, 2A, 2B, 3A

D.M.R.: 1A, 1B, 1C, 2A, 2B, 3B

A.S.:1A, 1B, 1C, 3B

D.G.:1C, 2C, 3B

C.R.: 1C, 3B

A.A.: 1C, 3B

G.S.: 1C, 3B

A.D.:1C, 3B

E.A.: 1C, 3B

A.A.: 3B

A.G.: 3B

A.K.P.: 3B

V.Y.V.: 3B

M.B.S.: 3B

R.B.: 3B

R.K.:1C.

A.K.S.: 3B

R.R.:1A, 1B, 1C, 2C, 3B

Disclosures

Ethical Compliance Statement: (1) The authors confirm that the approval of an institutional review board was not required for this work. (2) Declaration of patient consent: Detailed written informed consent was obtained from all the six patients reported in the study. (3) We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Data S1.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.