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Introduction: X-linked dystonia-parkinsonism (XDP) is a progressive neurodegenerative disorder that has been studied well in recent years., Objectives: This scoping review aimed to describe the current state of knowledge about the diagnosis and treatment of XDP, to provide clinicians with a concise and up-to-date overview., Methods: We conducted a scoping review of pertinent literature on the diagnosis and treatment of XDP using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines., Results: There were 24 articles on diagnostic methods and 20 articles on therapeutic interventions for XDP, with 7 review articles describing both. The detection of the SVA retrotransposon insertion within the TAF1 gene is confirmatory for XDP. Oral medications are marginally effective. Chemodenervation with botulinum toxin is an effective treatment. Pallidal deep brain stimulation (DBS) has been shown to provide significant improvement in the dystonia and quality of life of patients with XDP for a longer time. A less invasive surgical option is the transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS), which has shown promising effects with the limited number of case reports available., Conclusion: XDP is a geneti disorder characterized by striatal symptoms and pathology on neuroimaging. No effective oral medications are available for the management of XDP. The use of botulinum toxin is limited by its cost and duration of effects. As of now, pallidal DBS is deemed to be the best option. Another promising option is the tcMRgFUS but still has limited studies on its safety and efficacy in XDP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP)., Methods: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.5 years) and 30 XDP-causing mutation negative healthy men from the same population (age = 37.4 ± 10.5 years) underwent [ 18 F]-fluorodeoxyglucose positron emission tomography. Scans were analyzed using spatial covariance mapping to identify a significant XDP-related metabolic pattern (XDPRP). Patients were rated clinically at the time of imaging according to the XDP-Movement Disorder Society of the Philippines (MDSP) scale., Results: We identified a significant XDPRP topography from 15 randomly selected subjects with XDP and 15 control subjects. This pattern was characterized by bilateral metabolic reductions in caudate/putamen, frontal operculum, and cingulate cortex, with relative increases in the bilateral somatosensory cortex and cerebellar vermis. Age-corrected expression of XDPRP was significantly elevated (p < 0.0001) in XDP compared to controls in the derivation set and in the remaining 15 patients (testing set). We validated the XDPRP topography by identifying a similar pattern in the original testing set (r = 0.90, p < 0.0001; voxel-wise correlation between both patterns). Significant correlations between XDPRP expression and clinical ratings for parkinsonism-but not dystonia-were observed in both XDP groups. Further network analysis revealed abnormalities of information transfer through the XDPRP space, with loss of normal connectivity and gain of abnormal functional connections linking network nodes with outside brain regions., Interpretation: XDP is associated with a characteristic metabolic network associated with abnormal functional connectivity among the basal ganglia, thalamus, motor regions, and cerebellum. Clinical signs may relate to faulty information transfer through the network to outside brain regions. ANN NEUROL 2023;94:684-695., (© 2023 American Neurological Association.)

X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.

Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic ( CCCTCT ) n domain that acts as a genetic modifier of disease onset and expressivity., Methods: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation. We used blood-derived DNA from 96 XDP patients for amplicon-based deep Nanopore sequencing and validated it with fragment analysis which was performed using fluorescence-based PCR. To detect methylation from blood- and brain-derived DNA, we used a Cas9-targeted approach., Results: High concordance was observed for hexanucleotide repeat numbers detected with Nanopore sequencing and fragment analysis. Within the SVA locus, there was no difference in genetic variability other than variations of the repeat motif between patients. We detected high CpG methylation frequency (MF) of the SVA and flanking regions (mean MF = 0.94, SD = ±0.12). Our preliminary results suggest only subtle differences between the XDP patient and the control in predicted enhancer sites directly flanking the SVA locus., Conclusions: Nanopore sequencing can reliably detect SVA hexanucleotide repeat numbers, methylation and, lastly, variation in the repeat motif.

Objective: Presently, there are no epidemiologic data on the prevalence of movement disorders in the Philippines. We aim to describe the most common phenomenologies and movement disorders in two specialty centers in Metro Manila dedicated to movement disorders., Methods: We investigated the clinical spectrum and etiologies of movement disorders referred to our centers from January 2007-December 2019 using a standardized collection form., Results: A total of 1438 patients presenting with complaints relating to movement disorders were evaluated between 2007 to 2019. There were 770 (53.5%) men. The mean age was 57.1 ± 17.9 years. The most common movement disorders were parkinsonism (n=677, 47.1%), myoclonus (n=212, 14.7%) and tremor (n=208, 14.5%). The least common was restless legs syndrome (n=4, 0.3%). There were 78 (37.7% of total dystonia cases) X-linked dystonia-parkinsonism patients referred to our clinic. Majority of the botulinum toxin injections were for hemifacial spasms (n=206). A small number of patients (n=41) were also seen at the center for deep brain stimulation programming., Conclusion: The most common movement disorders managed were parkinsonism, myoclonus and tremor. The most common diagnoses were Parkinson's disease, hemifacial spasm and essential tremor. This study highlights the spectrum of movement disorders encountered in two specialty clinics in two Philippine tertiary hospitals. Given these varied cases, there is also a need for more movement specialists and centers dedicated to movement disorders to manage these cases.

X-linked dystonia-parkinsonism (XDP) is a debilitating movement disorder endemic to the Panay Island, Philippines. Most studies focus on motor symptoms, hence we reviewed the neurocognitive profile of XDP patients. Neurocognitive testing of XDP patients focused on five domains: general intellectual functioning, episodic memory, language, attention and executive function, and affect. Twenty-nine genetically confirmed patients were included. Twenty-six (89.6%) had impairments in one or more domains, while only three had no impairment in any domain. Attention and executive function was the most commonly affected domain (n = 23, 79.3%). Deficits in general intellect, episodic memory, attention and executive function and affect were seen in our subset of XDP patients. The striatal pathology affecting the frontostriatal circuitry mandating these cognitive processes is mainly implicated in these impairments. The results of our study provided further evidence on the extent of cognitive impairment in XDP using a select battery of neurocognitive tests.

X-linked dystonia parkinsonism (XDP) is a neurodegenerative disorder that has received significant interest on several fronts. Although much still remains to be elucidated regarding the disease cause, a robust amount of data has been produced in recent years compared to when it was first described in 1976. The debilitating nature of the overlapping dystonia and parkinsonism that characterizes this disorder has fueled much of the interest in unraveling its cause, clinical presentation, symptom progression, treatment and impact on the afflicted patients as well as their caregivers. Having made several significant advances in genetic studies, neuropathology, neurophysiology and clinical characterization, we are entering a new threshold in the study of this disorder, hopefully bringing us closer to potential treatments and possible cures. This review will focus on new information gathered regarding the motor and non-motor features of XDP, deep brain stimulation (DBS) as a potential treatment for XDP and the utility of the recently validated XDP-Movement Disorder Society of the Philippines (MDSP)-rating scale.

X-Linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease affecting individuals with ancestry to the island of Panay in the Philippines. In recent years there has been considerable progress at elucidating the genetic basis of XDP and candidate disease mechanisms in patient-derived cellular models, but the neural substrates that give rise to XDP in vivo are still poorly understood. Previous studies of limited XDP postmortem brain samples have reported a selective dropout of medium spiny neurons within the striatum, although neuroimaging of XDP patients has detected additional abnormalities in multiple brain regions beyond the basal ganglia. Given the need to fully define the CNS structures that are affected in this disease, we created a brain bank in Panay to serve as a tissue resource for detailed studies of XDP-related neuropathology. Here we describe this platform, from donor recruitment and consent to tissue collection, processing, and storage, that was assembled within a predominantly rural region of the Philippines with limited access to medical and laboratory facilities. Thirty-six brains from XDP individuals have been collected over an initial 4 years period. Tissue quality was assessed based on histologic staining of cortex, RNA integrity scores, detection of neuronal transcripts in situ by fluorescent hybridization chain reaction, and western blotting of neuronal and glial proteins. The results indicate that this pipeline preserves tissue integrity to an extent compatible with a range of morphologic, molecular, and biochemical analyses. Thus the algorithms that we developed for working in rural communities may serve as a guide for establishing similar brain banks for other rare diseases in indigenous populations.

MDSGene is an online database on movement disorders that collates genetic and clinical knowledge using a standardized published literature abstraction strategy. This review is dedicated to X-linked dystonia-parkinsonism (XDP). We screened 233 citations and curated phenotypic and genotypic data for 414 cases. To reduce data missingness, we (1) contacted authors and engaged the research community to provide additional clinical and genetic information, and (2) revisited previously unpublished data from a cohort of XDP patients seen at our institution. Using these approaches, we expanded the cohort to 577 cases and increased information available for important clinical and genetic features such as age at onset, initial manifestation, predominant motor symptoms, functional impairments, and repeat size information. We established the use of mining unpublished data to expand the MDSGene workflow and present an up-to-date description of the phenomenology of XDP using an extensive collection of previously reported and unreported data. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease with adult onset dystonia and subsequent parkinsonism. Postmortem and imaging studies revealed remarkable striatal pathology, with a predominant involvement of the striosomal compartment in the early phase. Here, we aimed to disentangle sequential neurodegeneration in the striatum of XDP patients, provide evidence for preferential loss of distinct striatal areas in the early phase, and investigate whether iron accumulation is present., Methods: We used multimodal structural magnetic resonance imaging (voxel-based morphometry and relaxometry) in 18 male XDP patients carrying a TAF1 mutation and 19 age-matched male controls., Results: Voxel-based relaxometry and morphometry revealed (1) a cluster in the anteromedial putamen showing high iron content and severe atrophy (-55%) and (2) a cluster with reduced relaxation rates as a marker for increased water levels and a lower degree of atrophy (-20%) in the dorsolateral putamen. Iron deposition correlated with the degree of atrophy (ρ = -0.585, p = 0.011) and disease duration (ρ = 0.632, p = 0.005) in the anteromedial putamen. In the dorsolateral putamen, sensorimotor putamen atrophy correlated with disease severity (ρ = -0.649, p = 0.004)., Interpretation: This multimodal approach identified a patchy pattern of atrophy within the putamen. Atrophy is advanced and associated with iron accumulation in rostral regions of the striatum, whereas neurodegeneration is moderate and still ongoing in dorsolateral areas. Given the short disease duration and predominant dystonic phenotype, these results are well in line with early and preferential degeneration of striosome-rich striatal areas in XDP. ANN NEUROL 2019;86:517-526., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background: X-linked dystonia-parkinsonism (XDP) is characterized by the unique transition of dystonia to parkinsonism and striatal degeneration. Slowing of saccades on clinical examination has been taken as suggestive of a progressive supranuclear palsy (PSP) phenotype., Objectives: To elucidate whether eye movement abnormalities in XDP patients reflect striatonigral impairment or deficits in the brainstem saccade generator as present in PSP., Methods: Eye movements of 18 male XDP patients from the Philippines and 16 ethnically and age-matched, healthy control participants were analyzed and the results related to morphometric frontostriatal changes., Results: There was moderate saccade hypometria in XDP but velocity of visually guided saccades was normal. XDP patients showed an increased antisaccade error rate which correlated with the reduction of (i) the volume of the pallidum and putamen as well as (ii) the volume and cortical thickness in dorsolateral prefrontal cortex. Amplitude of memory-guided saccades was smaller and latency prolonged. Horizontal smooth pursuit eye movements were impaired., Conclusions: Oculomotor abnormalities in XDP resemble those of patients with the Parkinsonian type of multiple system atrophy and - to a lesser degree - Parkinson's disease, but are not compatible with PSP. They indicate striatal impairment and may represent preclinical signs of the parkinsonian stage of XDP. The increasing failure of response inhibition in the antisaccade task with increasing striatal atrophy may indicate an endophenotype for striatal degeneration. Dorsolateral prefrontal degeneration can be inferred from the failure in initiating antisaccades, prolonged latency of memory-guided saccades and the reduction of dorsolateral prefrontal volume and cortical thickness., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: X-linked dystonia-parkinsonism (XDP/DYT3/Lubag) patients had improved dystonia and parkinsonism with bilateral pallidal deep brain stimulation (DBS) in the literature., Method: We reviewed eleven XDP patients who underwent bilateral pallidal DBS from October 2009 to September 2018. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Unified Parkinson's Disease Rating Scale (UPDRS)-III scores were reviewed from baseline up to the longest follow-up together with the demographic and clinical data. The published case reports on DBS in XDP were also reviewed., Results: The mean age was 39 ± 9.2 years with a mean disease duration of 3 years (range 1-9 years). An immediate response for dystonia post-DBS (1 month) was seen in all cases, with a mean BFMDRS score of 23.3 ± 12.12 [from a mean baseline of 36.3 ± 12.1] and a small change in the mean UPDRS-III score of 20 ± 10.39 [from a mean baseline of 24.04 ± 8.74]. At 12 months (n = 10), the mean BFMDRS score was 13.7 ± 10.63 and the mean UPDRS-III score was 19 ± 13.19. There was improvement in the clinical and functional stage of the patients, with majority in Stage 1 (n = 3) and Stage 2 (n = 5) at their last follow-up., Conclusion: Bilateral pallidal DBS should be considered as a treatment option for XDP. It is effective in the first 12 months in controlling dystonia with variable response in controlling parkinsonism. It may be effective in up to 72-84 months, as seen in three patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy., Objective: To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes., Design, Setting, and Participants: This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected., Exposures: All patients underwent bilateral GPi-DBS in Lübeck, Germany., Main Outcomes and Measures: Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes., Results: The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004)., Conclusions and Relevance: Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)