Establishing a natural history of X-linked dystonia parkinsonism

Acuña, Patrick; Supnet-Wells, Melanie Leigh; Spencer, Neil A; Guzman, Jan Kristoper de; Russo, Massimiliano; Hunt, Amelia R.; Stephen, Christopher D.; Go, Criscely L.; Carr, Samuel; Ganza, Niecy Grace; Lagarde, J. Benedict B.; Begalan, Shin; Multhaupt‐Buell, Trisha; Aldykiewicz, Gabrielle; Paul, Lisa; Ozelius, Laurie J.; Bragg, D. Cristopher; Perry, Bridget J.; Green, Jordan R.; Miller, Jeffrey W.; Sharma, Nutan

doi:10.1093/braincomms/fcad106

Cited by 13 publications

(4 citation statements)

References 44 publications

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“…This can be rectified by a larger sample size. In addition, although the small sample size invariably does not capture the full range of parkinsonism or dystonia manifestations of XDP, this does cover the most common XDP phenotypes seen 4 , 39 , in addition to pure parkinsonism, which may be more benign 4 , 6 , 39 . The goal of this study was for proof of concept, in that novel preliminary digital identification of overlapping dystonic and parkinsonian motor features was performed, which has not been previously studied.…”

Section: Discussionmentioning

confidence: 99%

“…However, the high prevalence of cognitive deficits in XDP is noted 40 . Formal cognitive testing was not performed at the time that the study data was collected but is included in an ongoing natural history study 39 . The potential role of any cognitive deficits on specific motor task performance was outside the scope of the current paper but could be assessed in larger studies focusing on the interaction between cognition and motor task performance.…”

Section: Discussionmentioning

confidence: 99%

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Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

Parisi,

Corniani,

Bonato

et al. 2024

Sci Rep

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X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

Parisi,

Corniani,

Bonato

et al. 2024

Sci Rep

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“…Diseases with significant changes throughout life may also be more amenable to DBS, as an adjustable therapy. X-link dystonia-parkinsonism, for instance, is characterized by predominance of dystonia during the first years, and then as neurodegeneration progresses, parkinsonism becomes more evident than dystonia [55]. In these types of conditions, where symptomatology evolves with time, the adjustability of DBS may be superior to FUS.…”

Section: Patient-specific Considerationsmentioning

confidence: 99%

Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications

Cummins,

Bernabei,

Wang

2024

Stereotact Funct Neurosurg

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Introduction: MRI-guided focused ultrasound (FUS) is an incisionless thermo-ablative procedure that may be used to treat medication-refractory movement disorders, with a growing number of potential anatomic targets and clinical applications. As of this article’s publication, the only US Food and Drug Administration (FDA)-approved uses of FUS for movement disorders are thalamotomy for essential tremor (ET) and tremor-dominant Parkinson’s Disease (PD), and pallidotomy for other cardinal symptoms of PD. We present a state-of-the-art review on all non-FDA approved indications of FUS for movement disorders, beyond the most well-described indications of ET and PD. Our objective was to summarize the safety and efficacy of FUS in this setting and provide a roadmap for future directions of FUS for movement disorders. Methods: A state-of-the-art review was conducted on use of FUS for non-FDA approved movement disorders. All movement disorders excluding FDA-approved uses for ET and PD were included. Results: A total of 25 studies on 172 patients were included. In patients with tremor plus dystonia syndromes (n = 6), ventralis intermediate nucleus of the thalamus (VIM)-FUS gave >50% tremor reduction, with no improvement in dystonia and worsened dystonia in 2/6 patients. Ventral-oralis complex (VO)-FUS gave >50% improvement for focal hand dystonia (n = 6) and 100% return to musical performance in musician’s dystonia (n = 6). In patients with multiple sclerosis (MS) and tremor (n = 3), improvement in tremor was seen in 2 patients with a favorable skull density ratio; no MS disease change was noted after VIM-FUS. In patients with tremor and comorbid ataxia syndromes (n = 3), none were found to have worsened ataxia after VIM-FUS; all had clinically significant tremor improvement. Subthalamic nucleus (STN)-FUS for PD (n = 49) gave approximately 50% improvement in PD motor symptoms, with dystonia and mild dyskinesias as possible adverse effects. Cerebellothalamic tract (CTT-FUS) for ET (n = 42) gave 55–90% tremor improvement, with gait dysfunction as a rare persistent adverse effect. Pallidothalamic tract (PTT-FUS) for PD (n = 50) gave approximately 50% improvement in motor symptoms, with mild speech dysfunction as a possible adverse effect. Conclusion: VIM-FUS appeared safe and effective for heterogenous tremor etiologies, and VO-FUS appeared most effective for isolated segmental dystonia. STN-FUS was effective for PD symptom reduction; postoperative dystonia and mild on-medication dyskinesias required medical management. Tractography-based targeting with CTT-FUS for ET and PTT-FUS for PD demonstrated promising early results. Larger prospective trials with long-term follow-up are needed to the evaluate the safety and efficacy non-FDA approved indications for FUS.

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“…Despite the presence of the causative XDP-SVA mutation in all cells from birth, the onset of the XDP disease occurs later in life and specifically impacts certain regions of the brain [45][46][47]. The factors initiating the late onset and the brain-specific manifestations remain elusive.…”

Section: Znf91 Expression Decreases With Agementioning

confidence: 99%

ZNF91 is an endogenous repressor of the molecular phenotype associated with X-linked dystonia-parkinsonism (XDP)

Rosenkrantz,

Raghib,

Brandorff

et al. 2023

Preprint

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Background: X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder resulting from the insertion of an intronic SINE-Alu-VNTR (SVA) retrotransposon in the TAF1 gene. Recent research has revealed that the pathogenic XDP-SVA insertion leads to dysregulation of TAF1 transcription, including increased intron retention and decreased expression of exons surrounding the insertion. The Kruppel-associated box (KRAB) zinc finger protein, ZNF91, is a critical repressor of SVA retrotransposons. However, it remains unclear whether ZNF91 is able to repress the XDP-SVA insertion and how this influences the XDP-associated molecular phenotype. In this study, we investigate the role of ZNF91 in repressing the XDP-SVA insertion and its impact on the molecular phenotype associated with XDP. Methods: Here, we used CRISPR/Cas9 to genetically delete ZNF91 in induced pluripotent stem cell (iPSC) lines derived from XDP patients, as well as isogenic control iPSC lines that lack the XDP-SVA insertion. Total RNA sequencing and capture RNA-sequencing were used to confirm ZNF91 deletion and to assess TAF1 transcriptional changes between conditions. Furthermore, publicly available transcriptomic data from whole blood and different brain regions were used to assess ZNF91 expression levels across ages. Results: We found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a potential role of ZNF91 in the age-dependent onset of XDP. Conclusions: These findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 is a critical epigenetic repressor of SVAs, this suggests that epigenetic silencing of the XDP-SVA minimizes the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that modulating ZNF91 levels or targeted repression of the XDP-SVA could be novel therapeutic strategies worth exploring.

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Establishing a natural history of X-linked dystonia parkinsonism

Cited by 13 publications

References 44 publications

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

Focused Ultrasound for Treatment of Movement Disorders: A Review of Non-Food and Drug Administration Approved Indications

ZNF91 is an endogenous repressor of the molecular phenotype associated with X-linked dystonia-parkinsonism (XDP)

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