INTRODUCTION

Dystonia due to TOR1A gene abnormality (DYT-TOR1A or DYT1) is the most common and well-characterized form of genetically mediated isolated generalized dystonia worldwide. The genetic basis is a GAG trinucleotide deletion in the TOR1A gene (c.907_909delGAG; p.Glu303del) on chromosome 9q32–q34, which encodes TorsinA, a member of the adenosine triphosphatase family (ATPases) [1]. DYT-TOR1A shows autosomal dominant inheritance with incomplete penetrance. Its incidence is approximately 1–2 per 100,000, which is historically higher in Ashkenazi Jews [2]. The prevalence rate of primary dystonia in India is 49.06 per 100,000 population, with a higher occurrence of late-onset primary dystonia [3]. However, reports of DYT-TOR1A from India and, to some extent, from Asia are very limited.

The clinical features and severity of DYT-TOR1A vary widely, with childhood-onset limb dystonia that often spreads and may progress to severe generalized disability. Globus pallidus internus (GPi)-targeted deep brain stimulation (DBS) offers substantial benefit, with up to 70% improvement in medically refractory patients. The present study aimed to characterize the clinical, radiological, therapeutic profile, and DBS outcomes of patients with DYT-TOR1A. We reviewed the Movement Disorder Society Genetic Mutation (MDSGene) database Asian cohort reported to date and compared it with the current cohort.

MATERIALS & METHODS

This is a retrospective chart review of patients with genetically confirmed DYT-TOR1A (heterozygous pathogenic c.907_909delGAG; p.Glu303del variant) evaluated and managed at a tertiary care center in India from 2019–2024. The available demographic, clinical, and investigation data, including imaging and genetic data, and treatment details were collected from the hospital database, and video recordings of the patients were reviewed. When available, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement scores (BFMDRS-M) and disability score (BFMDRS-D) were also recorded. Data are expressed as descriptive statistics either as medians and ranges for continuous variables or as frequencies and percentages for categorical variables. SPSS version 28.0 (IBM Corp.) was used for all statistical computations. The study was conducted with the approval of the National Institute of Mental Health and Neurosciences (NIMHANS) Ethics Committee (No. NIMHANS/13/53rd IEC [BS & NS DIV.]/2025), and patient videos were recorded after written informed consent was obtained. Four of the patients were previously reported [4-6].

RESULTS

Clinical profile

The demographic, clinical, investigative, medical management, and post-DBS details of DYT-TOR1A patients in our cohort are summarized in Table 1 and Figure 1 (representative clinical vignettes are given in Supplementary Material 1 and Supplementary Videos 1-4).

We included 12 patients (11 males, 91.7%) whose median age at disease onset was 10.5 years (range, 8–17 years) and whose median duration of illness was 5 years (range, 2 months–31 years). All patients had an isolated and progressive dystonia phenotype. Ten patients had limb involvement at onset (hand involvement in 6 patients [50%] and leg involvement in 4 patients [33.3%]). The median time to generalization was 2.5 years (range, 2 months–11 years), and the time to generalization was early in patients with lower limb onset dystonia (median duration of 1.5 years) compared with patients with upper limb and cervical onset (median, 4 years for both). None of the patients had cognitive impairment, behavioral symptoms, or dysmorphic features.

Brain magnetic resonance imaging (MRI) was normal in 75% of patients; 25% showed nonspecific findings, such as GPi mineralization or calcification. Exome sequencing was performed in 11 patients, and Sanger sequencing was performed in one patient. All patients contained the pathogenic heterozygous 3-base pair deletion variant (c.907_909delGAG; p.Glu303del) in exon 5 of the TOR1A gene.

Medical management

All patients were on antidystonic medications, most frequently trihexyphenidyl (n=11), with a median dosage of 6 mg per day (range, 3–12 mg), followed by levodopa-carbidopa (n=8), with a median dosage of 300 mg of levodopa (range, 150–400 mg). Subjective mild to moderate clinical improvement was noted in eight patients. Notably, one patient significantly improved after treatment with haloperidol [5]. There were no significant adverse effects except for mild parkinsonism in the patient who was treated with haloperidol at the 3-month followup. Two patients with multifocal dystonia showed significant improvement at follow-up, whereas patients with generalized dystonia reported suboptimal improvement. One patient is currently undergoing a presurgical workup.

Surgical management

DBS surgery was performed in five patients (41.7%) with severe, disabling generalized dystonia on the basis of higher BFMDRS motor and disability scores, with symptoms mainly affecting walking, dressing, and personal hygiene, reflecting significant impairment in daily activities. All patients underwent simultaneous bilateral posteroventral GPi electrode placement and implantable pulse generator implantation under general anesthesia. There were no significant intraoperative, immediate, or delayed postoperative complications. Initial programming (in monopolar mode) was performed 1 week after the operation. The initial stimulation parameters were a frequency of 130 to 150 Hz, a pulse width of 60 to 120 μs, and an amplitude of 1.0 to 1.5 V/mA. Ventral-most or ventral contacts were stimulated in the initial programming session. Detailed programming was performed 6–8 weeks after the surgery. The parameters were gradually adjusted according to the clinical response at the follow-up visits (The clinical profiles of the 5 patients who underwent DBS are summarized in Supplementary Table 1). The median age of patients who underwent DBS was 12 years (range, 9–17 years). DBS was performed within a median duration of 4 years (range, 2.5–6.5 years) from the onset of symptoms. Patients who underwent DBS at a median duration of 10 months (range, 6–51 months) experienced significant clinical improvement.

DISCUSSION

This study presents the largest reported Indian cohort of 12 patients diagnosed with DYT-TOR1A dystonia (c.907_909delGAG variant), highlighting key clinical, radiological, and therapeutic features. Approximately 30%–40% of patients reported a family history of dystonia, reflecting an autosomal dominant inheritance pattern with reduced penetrance (approximately 30%) [7,8]. A family history of dystonia was identified in 25% of our patients.

The median age of onset was 10.5 years, which aligns with global trends, where childhood onset is predominant [8]. However, a key difference was observed in the duration of illness; compared with the MDSGene Asian cohort (9 years), our patients had a shorter disease duration (5 years) (Supplementary Tables 2 and 3 and Supplementary Material 2). Despite this, the disease progression patterns were similar in some respects, highlighting the variability in disease trajectory. Our patient cohort demonstrated a marked male preponderance, with 91.7% of patients being male, which is notably higher than that reported in most other studies, including the MDSGene Asian cohort (64.5%) [9-13]. This could reflect either sampling bias or potential genetic/environmental influences on disease expression.

Symptoms of DYT-TOR1A typically start in the lower limbs and usually present as foot inversion or abnormal posturing during walking or running [14]. All patients had isolated, progressive dystonia, mostly with upper-limb onset, which is consistent with the findings in other Asian cohorts, whereas non-Jewish Western cohorts predominantly had lower-limb onset [15]. The universal progression to upper limb involvement in our cohort is a striking finding compared with 69.4% in the Asian cohort. This could imply a more aggressive or rapidly generalizing phenotype in our population, despite shorter disease duration.

In many cases, dystonia generalizes within 5 years, especially in those whose symptoms start before age 10, when it progresses from the legs to the trunk and upper limbs while it usually spares the cranial and laryngeal muscles [16]. Generalization of dystonia occurred in 10 out of 12 patients, within a median of 2.5 years from onset. Notably, early generalization (2.5 years) was more frequently seen in patients with initial lower limb involvement.v

DBS was performed in five patients within 4 years of symptom onset, all of whom demonstrated a significant clinical response, whereas the patients on medical management had suboptimal responses to combination antidystonia medications. Compared with those in the Asian cohort, the stimulation parameters at the last visit were lower in amplitude and greater in pulse width. Notably, no complications were reported among the surgically treated patients. These findings underscore the viability and safety of DBS as a treatment option for DYT-TOR1A, particularly in patients with medically refractory symptoms. DBS is most effective when performed early in the disease course, before fixed skeletal deformities develop, as younger patients with shorter disease durations demonstrate better functional outcomes because of greater neural plasticity, which aligns with recommendations for early intervention [17,18].

Recent and past studies (both candidate gene and exomebased) have indicated that DYT-TOR1A is relatively rare in the Indian population, with a significantly lower frequency than in other ethnic groups [19,20]. This suggests possible genetic heterogeneity in dystonia within the Indian population and raises important questions about population-specific genetic risk factors, founder mutations, or underrecognition due to limited access to genetic testing. Further comprehensive, multicenter studies incorporating diverse regional cohorts and employing next-generation sequencing methods are warranted to elucidate the genetic landscape of dystonia in India and to inform personalized diagnostic and therapeutic strategies.

In conclusion, this large series of patients from India displays classical features of DYT-TOR1A, including childhood onset, limb-onset pattern, and progressive generalization. However, it is distinguished by a notably greater male predominance and more consistent early involvement of the upper limbs than that reported in regional or global cohorts. Despite a shorter duration of illness, the clinical severity appears comparable or even greater, highlighting the need for early recognition and potential surgical intervention. Significant improvement in both dystonia severity and disability was noted after bilateral GPi-DBS without significant complications. These findings underscore the shared core phenotype of DYT1 dystonia worldwide while also emphasizing the influence of regional and genetic factors on its clinical expression and progression.

Supplementary Materials

Video 1.

Video of Patient 5 with childhood-onset generalized dystonia. Segment 1 demonstrates generalized dystonia with elevation of the right shoulder, lateral trunk bending to the left, with left more than right side finger and toe dystonia. On outstretched hands, there is intermittent dystonic spasms of the left upper limb with flexion at the elbow and wrist, with shoulder elevation. Segment 2 shows inability to hold a pen and write even with the support of the left hand. Segment 3 shows stance with elevation of the right shoulder, lateral trunk bending to the left, and right more than left lower limb dystonia and high-stepping gait. Segment 4 shows significant improvement in the dystonia at 12 months post-bilateral GPi-DBS.

Video 2.

Video of Patient 7 with childhood-onset generalized dystonia. Segment 1 shows scoliosis with convexity to the right side associated with cervical dystonia, head tilted to the left side. Segment 2 shows difficulty in holding the pen. Segment 3 shows stance with opisthotonos, truncal tilt to left side and intermittent spasms. Dystonia of the left leg with abduction, hyperextension and eversion of the foot. Dystonia become more prominent while walking. Segment 4 shows significant improvement in the dystonia at 6 months post bilateral GPi-DBS.

Video 3.

Video of Patient 9 with adolescent-onset multifocal dystonia. Segment 1 shows right upper limb dystonia at rest with flexion at the metacarpophalangeal joint, adduction of the thumb and fingers with wrist extension. Intermittent dystonic spasms are present. Segment 2 shows dystonia with undue flexion of the fingers and difficulty holding the pen properly. Segment 3 shows normal stance with subtle dystonic posturing of the toes.

Video 4.

Video of Patient 10 (father of Patient 9) with adolescent-onset multifocal dystonia. Segment 1 shows subtle dystonic posturing of the fingers with abduction and extension of the thumb bilaterally. Segment 2 shows dystonic tremors while writing. Segment 3 shows normal gait.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was partially funded by Indian Council of Medical Research grant (No. 54/3/2020-HUM/BMS).

Acknowledgments

None

Author Contributions

Conceptualization: Madathum Kuzhiyil Farsana, Vikram V. Holla, Pramod Kumar Pal. Data curation: Madathum Kuzhiyil Farsana, Vikram V. Holla, Debjyoti Dhar, Nishanth Gowda, Hansashree Padmanabha. Formal analysis: Madathum Kuzhiyil Farsana, Vikram V. Holla. Funding acquisition: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Investigation: Madathum Kuzhiyil Farsana, Vikram V. Holla, Debjyoti Dhar, Nishanth Gowda, Babylakshmi Mutuhusamy. Methodology: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Project administration: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal. Resources: Vikram V. Holla, Hansashree Padmanabha, Babylakshmi Muthusamy, Nitish Kamble, Dwarakanath Srinivas, Ravi Yadav, Pramod Kumar Pal. Supervision: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Validation: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Visualization: Vikram V. Holla, Babylakshmi Muthusamy, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Writing—original draft: Madathum Kuzhiyil Farsana. Writing—review & editing: all authors.

Figure 1.

Overview of clinical findings and disease progression in the DYT-TOR1A cohort. A and B: Pie chart depicting distribution based on age at onset (A) and type of dystonia (B). C: Pictorial representation of the body distribution (body parts affected at onset and later involvement). D: Bar diagram depicting the presence of other findings.

REFERENCES

• 1. Ozelius L, Kramer PL, Moskowitz CB, Kwiatkowski DJ, Brin MF, Bressman SB, et al. Human gene for torsion dystonia located on chromosome 9q32-q34. Neuron 1989;2:1427–1434.ArticlePubMed
• 2. Zilber N, Korczyn AD, Kahana E, Fried K, Alter M. Inheritance of idiopathic torsion dystonia among Jews. J Med Genet 1984;21:13–20.ArticlePubMedPMC
• 3. Das SK, Banerjee TK, Biswas A, Roy T, Raut DK, Chaudhuri A, Hazra A. Community survey of primary dystonia in the city of Kolkata, India. Mov Disord 2007;22:2031–2036.ArticlePubMedPDF
• 4. Dhar D, Holla VV, Kamble N, Yadav R, Srinivas D, Pal PK. Surgical outcomes in rare movement disorders: a report of seventeen patients from India and review of literature. Tremor Other Hyperkinet Mov (N Y) 2022;12:22.ArticlePubMedPMC
• 5. Katragadda P, Holla VV, Kamble N, Yadav R, Pal PK. Haloperidol in managing DYT-TOR1A dystonia: unveiling a dramatic therapeutic response. J Mov Disord 2024;17:342–344.ArticlePubMedPMCPDF
• 6. Dhar D, Holla VV, Kumari R, Yadav R, Kamble N, Muthusamy B, et al. Clinical and genetic profile of patients with dystonia: an experience from a tertiary neurology center from India. Parkinsonism Relat Disord 2024;120:105986.ArticlePubMedPMC
• 7. Grundmann K, Laubis-Herrmann U, Bauer I, Dressler D, Vollmer-Haase J, Bauer P, et al. Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. Arch Neurol 2003;60:1266–1270.ArticlePubMed
• 8. Ozelius LJ, Bressman SB. Genetic and clinical features of primary torsion dystonia. Neurobiol Dis 2011;42:127–135.ArticlePubMedPMC
• 9. Im JH, Ahn TB, Kim KB, Ko SB, Jeon BS. DYT1 mutation in Korean primary dystonia patients. Parkinsonism Relat Disord 2004;10:421–423.ArticlePubMed
• 10. Kim MJ, Jeon SR, Yoo HW, Kim GH, Lee MC, Chung SJ. Effect of thalamotomy on focal hand dystonia in a family with DYT1 mutation. Mov Disord 2008;23:2251–2255.ArticlePubMed
• 11. Ma J, Wang L, Yang YM, Wan XH. Targeted gene capture sequencing in diagnosis of dystonia patients. J Neurol Sci 2018;390:36–41.ArticlePubMed
• 12. Goto S, Yamada K, Shimazu H, Murase N, Matsuzaki K, Tamura T, et al. Impact of bilateral pallidal stimulation on DYT1-generalized dystonia in Japanese patients. Mov Disord 2006;21:1785–1787.ArticlePubMed
• 13. Lin YW, Chang HC, Chou YH, Chen RS, Hsu WC, Wu WS, et al. DYT1 mutation in a cohort of Taiwanese primary dystonias. Parkinsonism Relat Disord 2006;12:15–19.ArticlePubMed
• 14. Ozelius L, Lubarr N. DYT1 early-onset isolated dystonia. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993 [accessed on 2025 May 25]. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1492/.
• 15. Lee WW, Ahn TB, Chung SJ, Jeon BS. Phenotypic differences in Dyt1 between ethnic groups. Curr Neurol Neurosci Rep 2012;12:341–347.ArticlePubMedPDF
• 16. Petrucci S, Valente EM. Genetic issues in the diagnosis of dystonias. Front Neurol 2013;4:34.ArticlePubMedPMC
• 17. Bronte-Stewart H, Taira T, Valldeoriola F, Merello M, Marks WJ Jr, Albanese A, et al. Inclusion and exclusion criteria for DBS in dystonia. Mov Disord 2011;26(Suppl 1):S5–S16.PubMedPMC
• 18. Sarva H, Rodriguez-Porcel F, Rivera F, Gonzalez CD, Barkan S, Tripathi S, et al. The role of genetics in the treatment of dystonia with deep brain stimulation: systematic review and meta-analysis. J Neurol Sci 2024;459:122970.ArticlePubMed
• 19. Saini A, Singh I, Kumar M, Radhakrishnan DM, Agarwal A, Garg D, et al. Genetic landscape of dystonia in Asian Indians. Mov Disord Clin Pract 2025;12:594–601.ArticlePubMedPMC
• 20. Naiya T, Biswas A, Neogi R, Datta S, Misra AK, Das SK, et al. Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta Neurol Scand 2006;114:210–215.ArticlePubMed

Figure & Data

References

Citations

Citations to this article as recorded by  

Comments on this article