Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.

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.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism.

BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. OBJECTIVE: This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. METHODS: Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). RESULTS: When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (ß = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). CONCLUSIONS: Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset.

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5'-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5'-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = -3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = -41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = -161.09, P = 3.44 × 10-5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = -92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.

Cerebrospinal fluid and blood serum biomarkers in neurodegenerative proteinopathies: A prospective, open, cross-correlation study.

Neurodegenerative diseases are a broad heterogeneous group affecting the nervous system. They are characterized, from a pathophysiological perspective, by the selective involvement of a subpopulation of nerve cells with a consequent clinical picture of a disease. Clinical diagnoses of neurodegenerative diseases are quite challenging and often not completely accurate because of their marked heterogeneity and frequently overlapping clinical pictures. Efforts are being made to define sufficiently specific and sensitive markers for individual neurodegenerative diseases or groups of diseases in order to increase the accuracy and speed of clinical diagnosis. Thus said, this present research aimed to identify biomarkers in the cerebrospinal fluid (CSF) and serum (α-synuclein [α-syn], tau protein [t-tau], phosphorylated tau protein [p-tau], ß-amyloid [Aß], clusterin, chromogranin A [chromogrA], cystatin C [cyst C], neurofilament heavy chains [NFH], phosphorylated form of neurofilament heavy chains [pNF-H], and ratio of tau protein/amyloid beta [Ind tau/Aß]) that could help in the differential diagnosis and differentiation of the defined groups of α-synucleinopathies and four-repeat (4R-) tauopathies characterized by tau protein isoforms with four microtubule-binding domains. In this study, we analyzed a cohort of 229 patients divided into four groups: (1) Parkinson's disease (PD) + dementia with Lewy bodies (DLB) (n = 82), (2) multiple system atrophy (MSA) (n = 25), (3) progressive supranuclear palsy (PSP) + corticobasal syndrome (CBS) (n = 30), and (4) healthy controls (HC) (n = 92). We also focused on analyzing the biomarkers in relation to each other with the intention of determining whether they are useful in distinguishing among individual proteinopathies. Our results indicate that the proposed set of biomarkers, when evaluated in CSF, is likely to be useful for the differential diagnosis of MSA versus 4RT. However, these biomarkers do not seem to provide any useful diagnostic information when assessed in blood serum.

Movement disorders in Indochina: Resource challenges and future solutions.

Movement disorders are a major cause of disability worldwide and their increasing prevalence predicts a substantial future burden of care. Impactful patient care requires availability of, and accessibility to, effective medications, knowledge, and disease awareness among both medical professionals and patients, driven by skilled personnel to harness and manage resources. The highest burden of movement disorders is in low-to-middle income countries where resources are often limited and infrastructure is insufficient to meet growing demands. This article focuses on the specific challenges faced in the management and delivery of care for movement disorders in Indochina, the mainland region of Southeast Asia comprising the neighboring countries of Cambodia, Laos, Malaysia, Myanmar, Thailand, and Vietnam. The first Indochina Movement Disorders Conference was held in August 2022 in Ho Chi Minh City, Vietnam, to provide a platform to better understand the situation in the region. Future management of movement disorders in Indochina will require progressive adaptation of existing practices to reflect modern approaches to care delivery. Digital technologies offer an opportunity to strengthen these processes and address the challenges identified in the region. Ultimately, a long-term collaborative approach by regional healthcare providers is key.

Temperature sensation in Parkinson's disease measured by quantitative sensory testing: a single-center, case-control study.

BACKGROUND: The pathophysiology of abnormal temperature sensation in Parkinson's disease (PD) remains unclear. Abnormal thermal detection does not seem to depend on the dopaminergic deficit, suggesting that other systems play a role in these changes, probably both central and peripheral. METHODS: We measured thermal detection thresholds (TDT) using quantitative sensory testing (QST) in 28 patients with PD and compared them with 15 healthy controls. RESULTS: Of 28 patients, 21% had increased TDT according to the normative data. TDT were higher on the dominant side. No correlation between TDT and disease duration, severity of motor impairment, and dopaminergic therapy was observed. 50% of the patients had difficulty differentiating between warm and cold stimuli, as TDT were within the normal range in most of these patients. CONCLUSIONS: Twenty-one percent of the patients in our study had increased TDT according to the normative data. Abnormal thermal detection was more pronounced on the dominant side. Abnormal differentiation between the thermal stimuli suggest impaired central processing of thermal information.

Prodromal X-Linked Dystonia-Parkinsonism is Characterized by a Subclinical Motor Phenotype.

BACKGROUND: Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease-modifying therapies at a time point where progressive neurodegeneration can still be modified. OBJECTIVES: The objective of this study was to determine whether motor or non-motor signs of the disease occur as indicators of a prodromal phase of X-linked dystonia-parkinsonism (XDP), a highly-penetrant monogenic movement disorder with striking basal ganglia pathology. METHODS: In addition to a comprehensive clinical assessment, sensor-based balance and gait analyses were performed in non-manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient-boosted trees (GBT) methodology was utilized to classify groups of interest. RESULTS: There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best-performing GBT-based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group. CONCLUSIONS: Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A mixed-ethnicity myoclonus-dystonia patient with a novel SGCE nonsense mutation: a case report.

BACKGROUND: Myoclonus-dystonia is a rare movement disorder with an autosomal dominant inheritance pattern characterized by a combination of myoclonic jerks and dystonia that may have psychiatric manifestations. Our aim is to present neurologic and psychiatric phenotypic characteristics in the first Filipino bi-ethnic myoclonus-dystonia patient and her father. CASE PRESENTATION: We investigated a Filipino myoclonus-dystonia patient with a positive family history. This 21-year-old woman of mixed Filipino-Greek ethnicity presented with involuntary jerking movements of her upper extremities, head, and trunk. Her symptoms affected her activities of daily living which led her to develop moderate depression, mild to moderate anxiety, and mild obsessive-compulsive disorder (OCD). Her 49-year-old Greek father suffered from adolescence-onset myoclonus-dystonia. CONCLUSION: Genetic testing revealed a novel epsilon-sarcoglycan (SGCE) gene nonsense mutation c.821C > A; p.Ser274* that confirmed our clinical diagnosis. For co-morbid anxiety, depression, and OCD, this patient was given duloxetine, in addition to clonazepam for the myoclonus and dystonia.

Efficacy and safety of apomorphine pump infusion in Filipino patients insufficiently controlled on oral anti-Parkinson medications: an open-label, pilot study.

BACKGROUND: Apomorphine hydrochloride is used in the management of advanced Parkinson disease (PD), either as a rescue medication for off periods during levodopa therapy or as a maintenance pump medication. This is the first study to describe the effects of apomorphine in Filipino patients with PD. OBJECTIVE: To evaluate the safety and efficacy of apomorphine ampules (APO-go®) pump infusion in the treatment of motor fluctuations in patients inadequately controlled on oral anti-Parkinson medications. METHODS: Patients diagnosed with PD who developed motor fluctuations with levodopa were evaluated at baseline and at the end of the study using the Modified Hoehn and Yahr (H&Y) Scale, the Unified Parkinson's Disease Rating Scale (UPDRS) and the Abnormal Involuntary Movement Scale (AIMS). After initial assessment, patients were administered 20 ampules of apomorphine hydrochloride 10 mg/mL by infusion pump over 20 days. Intention-to-treat (ITT) analysis included all patients who completed at least one posttreatment assessment. Motor disability based on modified H&Y scores, motor function and complications of therapy pre- and posttreatment were compared using Wilcoxon Signed Rank test. Chi-squared test was used to compare outcomes by age and sex. Frequencies of adverse reactions were recorded to evaluate the tolerability of the medication. RESULTS: Ten patients (mean age 63 ± 9.7 years), 3 male and 7 female, were enrolled in the study. Patients were given apomorphine for at most 16 days. The doses used were 2.5 mg/0.50 mL (n = 2), 3 mg/0.60 mL (n = 6), 4 mg/0.80 mL (n = 1) and 7 mg/1.40 mL (n = 1). After obtaining the threshold dose, two patients discontinued treatment. Eight of nine patients showed significant improvement in H&Y scores after treatment (p < 0.017). There was marked improvement after 10 days of treatment in at least five of 10 patients in terms of motor function using UPDRS, which included tremor (p < 0.034), rigidity (p < 0.002), facial expression (p < 0.014), finger taps (p < 0.008), foot taps (p < 0.014) and gait (p < 0.006). Significant changes from pre- to posttreatment scores in the frequency of dyskinesias (p < 0.010) and dystonia (p < 0.025) were observed. Nine focus areas of AIMS showed significant improvements in the muscles of facial expression (p < 0.020), upper (p < 0.016) and lower extremities (p < 0.010), incapacitation by abnormal movement (p < 0.010) and patients' awareness of abnormal movements (p < 0.039). Six patients experienced adverse events, none of which were related to the study drug. CONCLUSION: Apomorphine hydrochloride pump infusion therapy is potentially effective and safe in the treatment of motor fluctuations in Filipino patients with PD. This pilot study springboards safe engagements of Filipino PD patients in multicenter, large-scale trials.

Transcriptional Alterations in X-Linked Dystonia-Parkinsonism Caused by the SVA Retrotransposon.

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.

Botulinum toxin therapy of dystonia.

Botulinum toxin (BT) is used to treat a large number of muscle hyperactivity syndromes. Its use in dystonia, however, is still one of the most important indications for BT therapy. When BT is injected into dystonic muscles, it produces a peripheral paresis which is localised, well controllable and follows a distinct and predictable time course of around 3 months. Adverse effects are always transient and usually mild, long-term application is safe. With this profile BT can be used to treat cranial dystonia, cervical dystonia and limb dystonia including writer's and musician's cramps. The recent introduction of BT high dose therapy also allows to treat more wide-spread dystonia including segmental and generalised dystonia. BT can easily be combined with other anti-dystonic treatments such as deep brain stimulation and intrathecal baclofen application. Best treatment results are obtained when BT therapy is integrated in the multimodal and long-term 'multilayer concept of treatment of dystonia'. The biggest challenge for the future will be to deliver state of the art BT therapy to all dystonia patients in need, regardless of whether they live in developed countries or beyond.

X-linked dystonia Parkinsonism: crossing a new threshold.

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.

Contemporary clinical neurophysiology applications in dystonia.

The complex phenomenological understanding of dystonia has transcended from the clinics to genetics, imaging and neurophysiology. One way in which electrophysiology will impact into the clinics are cases wherein a dystonic clinical presentation may not be typical or a "forme fruste" of the disorder. Indeed, the physiological imprints of dystonia are present regardless of its clinical manifestation. Underpinnings in the understanding of dystonia span from the peripheral, segmental and suprasegmental levels to the cortex, and various electrophysiological tests have been applied in the course of time to elucidate the origin of dystonia pathophysiology. While loss of inhibition remains to be the key finding in this regard, intricacies and variabilities exist, thus leading to a notion that perhaps dystonia should best be gleaned as network disorder. Interestingly, the complex process has now spanned towards the understanding in terms of networks related to the cerebellar circuitry and the neuroplasticity. What is evolving towards a better and cohesive view will be neurophysiology attributes combined with structural dynamic imaging. Such a sound approach will significantly lead to better therapeutic modalities in the future.

Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Imaging gradual neurodegeneration in a basal ganglia model disease.

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.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.

DNA Methylation as a Potential Molecular Mechanism in X-linked Dystonia-Parkinsonism.

BACKGROUND: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X-linked dystonia-parkinsonism, 3 disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X-linked dystonia-parkinsonism. METHODS: DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell-derived cortical neurons and brain tissue from X-linked dystonia-parkinsonism patients and age- and sex-matched healthy Filipino controls in a prospective study. RESULTS: Compared with controls, X-linked dystonia-parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation-sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA-protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. CONCLUSIONS: We identified altered DNA methylation in X-linked dystonia-parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation-modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Expanding Data Collection for the MDSGene Database: X-linked Dystonia-Parkinsonism as Use Case Example.

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.

Botulinum neurotoxin injections for muscle-based (dystonia and spasticity) and non-muscle-based (neuropathic pain) pain disorders: a meta-analytic study.

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.