BCL11B-related dystonia is an emerging monogenic cause of early-onset generalized dystonia, for which therapeutic data remain limited and reported outcomes of deep brain stimulation (DBS) are variable. A recent report by Garone et al1 in Movement Disorders Clinical Practice, described limited and unsustained benefit from bilateral globus pallidus internus deep brain stimulation (GPi-DBS) in a patient with BCL11B-related dystonia, raising concerns regarding the therapeutic potential of DBS in this condition. Given the growing recognition of BCL11B-associated movement disorders, additional clinical data are needed. Here, we report two siblings with genetically confirmed BCL11B-related dystonia, 2 who experienced striking and durable benefit from GPi-DBS. BCL11B encodes a transcription factor essential for striatal development, medium spiny neuron survival, and immune system maturation. 3 Pathogenic variants have been associated with neurodevelopmental syndrome including intellectual disability, dysmorphic features, and combined immunodeficiency. 4 Movement disorders, particularly generalized dystonia, have increasingly been reported as part of the phenotype. 5 However, information on DBS outcomes remains scarce, with prior reports ranging from modest to disappointing benefit. 1, 6, 7 Nevertheless, at the mechanistic level, BCL11B deficiency disrupts cyclic adenosine monophosphate (cAMP) –protein kinase A (PKA) signaling in medium spiny neurons, pathways known to underlie other hyperkinetic disorders responsive to deep brain stimulation (DBS). 8 Patient 1, a 28-year-old woman, experienced onset of truncal dystonia at age 13 years, with subsequent cervical, cranial and upper limb involvement. At the time of DBS implantation at age 23 years, she presented with severe generalized dystonia (Burke-Fahn-Marsden Dystonia Rating Scale motor subscore BFMDRS-M: 57), with significant impairment in daily activities. Twelve months after surgery, her BFMDRS-M improved to 32. 5 points (43% reduction), with clinically meaningful improvements in gait, posture, and upper limb function. At her most recent follow-up, 60 months post-DBS, her BFMDRS-M score was 26 (54% improvement). While her dystonia improved significantly, the patient developed new non-motor symptoms over the follow-up period, including fear of walking and agoraphobia which limited her ability to walk independently and required minimal help as shown in Suppl. Video S1. Patient 2, her 27-year-old sister, presented with dystonia starting in the legs at age 5, which later spread to arms, trunk, neck, and head. At DBS implantation (age 23), she was wheelchair-bound, anarthric, and severely disabled (BFMDRS-M: 90). Within 1 month of stimulation she regained independent ambulation (BFMDRS-M: 64; 29% reduction). At 48 months follow-up, she was able to walk unaided, communicate with largely intelligible speech, and had achieved a 60% reduction in BFMDRS-M (score 36pts) (see Video S2). Neither sibling experienced serious adverse events or stimulation-related complications throughout follow-up. In both cases pharmacotherapy as well as botulinum toxin therapy were ineffective or limited by side effects. DBS was not considered earlier as both patients were followed in non-specialized neurological care. Both patients had mild anxiety prior to surgery. Genetic diagnosis was established using whole-genome sequencing, which identified a shared heterozygous frameshift variant in BCL11B (c. 753₉70del, p. Ser256Profs188). 2 Similar clinical manifestations were also reported in the deceased mother of the siblings; however, genetic testing could not be performed. Our findings provide a contrast to the low DBS response described by Garone et al. 1 Several factors may explain this discrepancy. First, mutation type appears relevant: their patient carried a missense change (c. 2507G>A, p. Ser836Asn), while our siblings harbored a frameshift deletion (c. 753₉70del, p. Ser256Profs*188). Differences in protein disruption may translate into distinct phenotypic trajectories and therapeutic responsiveness. Second, the clinical phenotype varied: Garone's patient exhibited prominent bulbar involvement with early loss of ambulation, whereas our patients had more predominant cervical, truncal and limb dystonia. Third the timing of intervention might also have played a role—although both our patients had longstanding disease, DBS was performed before the development of fixed skeletal deformities, which might have contributed to a more favorable outcome. Martindale et al7 recently reported a family with BCL11B-related dystonia who showed early clinical improvement 2 months after GPi-DBS. Our findings are consistent with these emerging data, illustrating that selected patients with this genetic form of dystonia may experience meaningful and sustained benefit. In our two siblings, DBS led to long-term improvement in motor symptoms and better speech intelligibility, suggesting potential benefits beyond motor control in some cases. Nevertheless, given the limited number of reported patients and variable outcomes, the overall efficacy of DBS in BCL11B-related dystonia remains to be established. Taken together, current evidence indicates that DBS response in this condition is likely heterogeneous and may depend on the underlying mutation, clinical phenotype, and timing of intervention (Table 1). Non-motor symptoms, especially anxiety and specific forms of phobia are relatively common in monogenic forms of dystonia, although often underdiagnosed. 9 In our cohort, anxiety-related symptoms emerged during follow-up in one patient and limited functional independence despite substantial motor improvement after DBS, consistent with recent reports in BCL11B-related dystonia. 7 While non-motor symptoms may influence functional outcomes, they represent only one of several factors contributing to DBS response variability. Other determinants include genetic variant type, clinical phenotype, disease duration, and fixed skeletal deformities. Recognition of this multifactorial framework is essential for appropriate patient selection and realistic outcome expectations. Our findings support accumulating evidence that genetically determined dystonias, including BCL11B-related dystonia, may respond to GPi-DBS. Delayed consideration of DBS in advanced disability may limit recovery, particularly in long-standing disease with secondary complications. Although definitive recommendations on timing cannot be drawn from isolated cases, our observations suggest that earlier evaluation in medically refractory genetic dystonias may enable more meaningful and sustained outcomes. (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. V. M.: 1A, 1B, 1C, 2A, 2B, 3A. T. S.: 1C, 2C, 3B. V. H.: 1C, 2C, 3B. J. B.: 1C, 2C, 3B. V. K.: 1C, 2C, 3B. A. K.: 1C, 2C, 3B. K. K.: 1C, 2C, 3B. M. O.: 1B, 1C, 2B, 3B. M. Z.: 1B, 1C, 2A, 2B, 3B. M. S.: 1A, 1B, 1C, 2A, 2B, 3A. Ethical Compliance Statement: This study was approved by the Institutional Review Board of the University Hospital of L. Pasteur in Košice, Slovakia. Written informed consent for the surgical procedure, data collection, and publication of anonymized clinical information and molecular data was obtained from both patients and their legal guardians. 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: This study was funded by the Slovak Grant and Development Agency under contracts APVV-22-0279 and by the EU Renewal and Resilience Plan “Large projects for excellent researchers” under grant No. 09I03-03-V03-00007. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. MZ received research support from the German Research Foundation (DFG 458949627). MZ acknowledges grant support from the EJP RD (EJP RD Joint Transnational Call 2022) and the German Federal Ministry of Education and Research (BMBF, Bonn, Germany), awarded to the project PreDYT (PREdictive biomarkers in DYsTonia, 01GM2302), and from the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder, as well as by the Technical University of Munich —Institute for Advanced Study. MZ's research is supported by a “Schlüsselprojekt” grant from the Else Kröner-Fresenius-Stiftung (2022EKSE. 185). Author disclosures are available in the Supporting Information. The data that supports the findings of this study are available in the supplementary material of this article. Video S1 First segment of the video shows Patient 1 prior to surgery with prominent upper body and especially cervical dystonia. The second segment of the video shows Patient 1 55 months after surgery with clear improvement of her cervical and limb dystonia, however, with difficulty to walk independently due to fear of falling and agoraphobia, with necessity of minimal support from her spouse. Video S2 Segment 1 of the video shows Patient 2 immediately after surgery but with DBS still switched off. The patient presents with severe generalized dystonia, including prominent bulbar involvement and inability to walk. Segment 2 shows patient 2 1 month after switching DBS therapy ON, there is improvement of dystonia and patient is able to walk independently. Segment 3 shows patient 2 26 months after surgery with improved dystonia and improved functionality of independent walking. Data S1 Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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Magocova et al. (Thu,) studied this question.