Introduction Malnutrition is a leading cause of death for persons living with X-linked dystonia-parkinsonism (XDP), a degenerative disease endemic to the Philippines. Difficulty swallowing has been linked to malnutrition in other populations; however, knowledge of this relationship is limited in XDP. As such, the purpose of this study was to determine the association between dysphagia and malnutrition in this population. Method(s) 21 individuals with XDP, 26 controls, and 18 genetic carriers were included in the final data analysis. Spearman’s rank order correlation coefficient was used to determine an association between baseline EAT-10 total scores and 12-month malnutrition status, and multiple linear regression to evaluate the predictive ability of the EAT-10. A baseline EAT-10 score cut-off point predicting 12-month malnutrition status was estimated. Results For the XDP group, the baseline EAT-10 total scores had a significant negative correlation (r = -0.68, p < 0.001) with and was a significant predictor (p = 0.001) of 12-month BMI. A baseline EAT-10 total score of ≥ 4 predicted malnutrition twelve months after administration (sensitivity = 0.93; specificity = 1; AUC = 0.95). Discussion Dysphagia, as measured using the EAT-10, was associated with BMI in the XDP population. Additionally, an EAT-10 total score ≥ 4 could predict malnutrition in twelve months after test administration. With these findings, healthcare providers could identify patients with XDP at high risk for malnutrition earlier and provide intervention sooner.

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.

Introduction: X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder that may result in severe speech impairment. The literature suggests that there are differences in the speech of individuals with XDP and healthy controls. This study aims to examine the motor speech characteristics of the mixed dystoniaparkinsonism phase of XDP. Method: We extracted acoustic features representing coordination, consistency, speed, precision, and rate from 26 individuals with XDP and 26 controls using Praat, MATLAB, and R software. Group demographics were compared using descriptive statistics. A one-way analysis of variance (ANOVA) with Tukey's post hoc test was used to test for acoustic differences between the two groups. Results: The XDP group had significantly lower consistency, speed, precision, and rate than controls (p < 0.05). For coordination, the XDP group had a smaller ratio of pause duration during transitions when compared to controls. Discussion: To our knowledge, this study is the first to describe the motor speech characteristics of the mixed dystonia-parkinsonism phase of XDP. The motor speech of mixed dystonia-parkinsonism XDP is similar to prior characterizations of mixed hyperkinetic-hypokinetic dysarthria with noted differences in articulatory coordination, consistency, speed, precision, and rate from healthy controls. Identifying the motor speech components of all three phenotypes of XDP (i.e., dystonia-dominant phase, parkinsonism-dominant phase, and mixed dystoniaparkinsonism phase) is needed to establish markers of speech impairment to track disease progression.

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20–40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington’s disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

Objective: To perform quantitative motor analysis in X-linked dystonia parkinsonism (XDP) as a potential clinical trial endpoint. Background: XDP is a neurogenetic mixed movement disorder involving both parkinsonism and dystonia. For clinical trial readiness, rater-independent, quantitative assessments of motor function are urgently needed. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. Design/Methods: 10 symptomatic XDP patients and 4 healthy controls underwent motion sensor analysis with a standardized examination. Disease severity was assessed with the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Burke-Fahn-Marsden scale (BFM). We assessed specific MDS-UPDRS and BFM elements using clinical scores as the dependent variable, segmented the sensor data and derived a set of data features chosen based on prior work. Data feature selection and projection algorithms were used to inspect the data feature space and assess the suitability of the derived data features to build machine learning-based models to estimate clinical scores from sensor data. Results: XDP patients were of varying stages of disease (disease duration 3–28 years) and varied phenotype: parkinsonism-predominant (n=5), dystonia-predominant (n=2) and dystonia parkinsonism (n=3), with BFM scores 0–43.5 and MDS-UPDRS 13–48. Projections showed distinct clusters of data points corresponding to different MDS-UPDRS scores for different tasks (hand pronation/supination, leg agility, foot tapping, finger-to-nose), suggesting that data features derived from the sensor data are suitable to derive reliable estimates of clinical scores. We assessed upper/lower limb and cervical dystonia at rest, during motor tasks and provocative maneuvers, compared to the BFM severity score. Projections of a dystonia-specific features set showed clear cluster separation between controls, XDP with and without dystonia. Conclusions: The analyses of these datasets suggest the feasibility of deriving reliable clinical score estimates from wearable sensor data in detecting both parkinsonian and dystonic features in a complex, mixed movement disorder and suggest the utility of motion sensors in quantifying clinical examination. Disclosure: Federico Parisi has nothing to disclose. Paolo Bonato has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SwanBio Therapeutics. The institution of Paolo Bonato has received research support from National Institutes of Health. The institution of Paolo Bonato has received research support from National Science Foundation. The institution of Paolo Bonato has received research support from Michael J Fox Foundation. The institution of Paolo Bonato has received research support from Mitsui Chemicals. The institution of Paolo Bonato has received research support from Peabody Foundation. The institution of Paolo Bonato has received research support from Department of Defense. The institution of Paolo Bonato has received research support from BIRD Foundation. Mr. Acuna has nothing to disclose. Dr. Go has nothing to disclose. Dr. Sharma has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. Dr. Sharma has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley. Dr. Sharma has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Cambridge Expert Witness. The institution of Dr. Sharma has received research support from NIH. Dr. Stephen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SwanBio Therapeutics. Dr. Stephen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Xenon Pharmaceuticals. The institution of Dr. Stephen has received research support from Sanofi.

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset ( p < 5 × 10 −8 ). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2 , the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.

Background: Cervical dystonia (CD) is a rare disorder, and health care providers might be unfamiliar with its presentation, thus leading to delay in the initial diagnosis. The lack of awareness displays the need to highlight the clinical features and treatment in cervical dystonia. In our cohort, we have identified an earlier age of onset in men, despite an overall preponderance of affected women. Objective: We aim to identify the prevalence, age of onset, spread, and treatment modalities of CD in the population. We also highlight the barriers which patients encounter related to diagnosis, follow-up, and treatment. Methods: We reviewed 149 CD patients who attended specialized Dystonia Clinics over a 14-year period. Dystonia severity was rated using the Burke-Fahn-Marsden (BFM), Tsui, and Toronto Western Spasmodic Torticollis Rating Scales (TWSTRS). Mood and quality of life were assessed using Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and 36-Item Short Form Health Survey (SF-36). Results: CD patients were majority White (91.3%) and more commonly female (75.8%). Men had an earlier median age of onset, 40.5 years ( p = 0.044). BAI revealed a mean score of 7.2 (±6.4, n = 50) indicating minimal anxiety while BDI revealed a mean score of 7.30 (±7.6, n = 50) indicating minimal depression. The only SF-36 subscales associated with CD severity were physical functioning ( p = 0.040) pain ( p = 0.008) and general health ( p = 0.014). Conclusion: There appear to be gender differences in both the prevalence and age of onset of the disease. There was a 3-fold higher incidence in women than in men. CD patients of both sexes experience barriers to care, which can be reflected in their quality of life and time-to-diagnosis. In addition, males were less likely to experience an objective benefit with botulinum toxin treatment and more likely to discontinue care. Greater awareness of CD by health care providers is important to reduce the time-to-diagnosis.

Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP prefrontal cortex (PFC) compared to control. Furthermore, there is a significant increase in histone H3 citrullination (H3R2R8R17cit3) with a concomitant increase in peptidylarginine deaminase 2 (PAD2) and 4 (PAD4), the enzymes catalyzing citrullination, in XDP post-mortem PFC. While there is a significant increase in myeloperoxidase (MPO) levels in XDP PFC, neutrophil elastase (NE) levels are not altered, suggesting that MPO may be released by activated microglia or reactive astrocytes in the brain. Similarly, there was an increase in H3R2R8R17cit3, PAD2 and PAD4 levels in XDP-derived fibroblasts. Importantly, treatment of fibroblasts with Cl-amidine, a pan inhibitor of PAD enzymes, reduced histone H3 citrullination and pro-inflammatory chemokine expression, without affecting cell survival. Taken together, our results demonstrate that inflammation is increased in XDP post-mortem brain and fibroblasts and unveil a new epigenetic potential therapeutic target.

Background X-linked dystonia parkinsonism (XDP) is a rare disorder characterized by adult-onset, progressive dystonia that, over time, is combined with or replaced by features of parkinsonism. Gait impairment is common. Methods Case series of 4 XDP patients with a unique gait disorder. Results The patients displayed a characteristic gait disorder with combined dystonic and parkinsonian gait features, with phasic knee bending. Of these patients, all had parkinsonism and three-quarters had prominent dystonic features, but 1 had predominant parkinsonism and subtle dystonic features. Conclusion Although XDP is a classic form of dystonia parkinsonism, some cases can mimic idiopathic Parkinson's disease. We describe a gait disorder which appears unique to XDP, involving phasic dystonic knee bending superimposed on parkinsonian shuffling, and may help clinically differentiate one of our parkinsonian-predominant patients from more-common forms of parkinsonism. The gait is distinct from other complex dystonic disorders with gait involvement.

OBJECTIVE:To characterize the evolution of swallowing and voice in patients with X-linked dystonia parkinsonism (XDP). STUDY DESIGN:Retrospective case series. METHODS:Retrospective review of 59 patients with XDP from January 2016 to January 2018. All patients underwent complete examinations and quality of life (QOL) surveys (Swallowing Quality of Life questionnaire [SWAL-QOL], Voice-Related Quality of Life [V-RQOL], and Voice Handicap Index [VHI]), and functional endoscopic examination of swallowing. We excluded patients with incomplete records or patients lost to follow-up. Univariate analysis was used to compare 2016 to 2018 Penetration-Aspiration Scale (PAS), SWAL-QOL, V-RQOL, and VHI scores. RESULTS:Ten patients met the inclusion criteria. Nine patients had oromandibular dystonia. Voice-related measures significantly worsened with an increase in mean VHI from 81 to 109.9 (P = 0.026) and decrease in mean V-RQOL from 58 to 28 (P = 0.013). Vocal strain also significantly worsened 0.4 to 1.4 (P = 0.001). Mean PAS scores increased from 4.2 to 5.1 (P = 0.068) and mean SWAL-QOL decreased from 50.4 to 43.5 (P = 0.157). In the SWAL-QOL, the mean Eating Duration score worsened from 0.9 to 0.4 (P = 0.052) and Mental Health score declined from 10.1 to 6.1 (P = 0.077). CONCLUSIONS:Both vocal strain and voice-related QOL measures considerably worsened over the 2-year interval in our limited group of XDP patients with no significant change in PAS scores or swallowing QOL. The findings demonstrated that the pace of disease affecting voice symptoms was different from swallowing symptoms in our study group and that changes in communication ability may be a more sensitive marker for disease progression than swallowing dysfunction.

ABSTRACTBackgroundX‐linked dystonia‐parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full‐length mRNA transcript.ObjectivesThe objective of this study was to discover cell‐based and biofluid‐based biomarkers for X‐linked dystonia‐parkinsonism.MethodsRNA from patient‐derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet‐digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5′ and 3′ to the retrotransposon insertion and the disease‐specific splice variant TAF1‐32i in whole‐blood RNA. Plasma levels of neurofilament light chain were measured using single‐molecule array.ResultsIn neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1‐3′/5′ ratio was lower in patient samples, whereas TAF1‐32i expression is higher relative to controls. In whole‐blood RNA, both TAF1‐3′/5′ ratio and TAF1‐32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79.ConclusionsTAF1 dysregulation in blood serves as a disease‐specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Wednesday, April 29April 14, 2020Free AccessQuantitative oculomotor assessment in X-linked dystonia parkinsonism: a potential motor biomarker (1996)Christopher Stephen, David Balkwill, Patrick Acuna, Susan King, Richard Lewis, and Nutan SharmaAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1996 Letters to the Editor

X-linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease linked to an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This SVA insertion induces aberrant TAF1 splicing and partial intron retention, thereby decreasing levels of the full-length transcript. Here we sought to determine if these altered transcriptional dynamics caused by the SVA are also accompanied by local changes in histone acetylation, given that these modifications influence gene expression. Because TAF1 protein may itself exhibit histone acetyltransferase activity, we also examined whether decreased TAF1 expression in XDP cell lines and post-mortem brain affects global levels of acetylated histone H3 (AcH3). The results demonstrate that total AcH3 are not altered in XDP post-mortem prefrontal cortex or cell lines. We also did not detect local differences in AcH3 associated with TAF1 exons or intronic sites flanking the SVA insertion. There was, however, a decrease in AcH3 association with the exon immediately proximal to the intronic SVA, and this decrease was normalized by CRISPR/Cas-excision of the SVA. Collectively, these data suggest that the SVA insertion alters histone status in this region, which may contribute to the dysregulation of TAF1 expression.

Tuesday, April 28April 14, 2020Free AccessProspective Characterization of Genetically Confirmed X-linked Dystonia Parkinsonism patients and their families: A 1 year longitudinal feasibility study (2854)Patrick Acuna, Jan Kristoper De Guzman, Niecy Ganza-Bautista, John Benedict Lagarde, Criscely L. Go, and Nutan SharmaAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.2854 Letters to the Editor

To systematically characterize and describe voice and swallowing manifestations in patients with X‐linked dystonia parkinsonism (XDP) and correlate with quality‐of‐life (QOL) measures.