Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

BACKGROUND: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD). OBJECTIVES: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes. METHODS: We screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature. RESULTS: We identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic. CONCLUSION: This study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Association between early lactate-related variables and 6-month neurological outcome in out-of-hospital cardiac arrest patients.

INTRODUCTION: The role of lactate measurement in out-of-hospital cardiac arrest (OHCA) survivors remains controversial. We assessed the association between early lactate-related variables, OHCA characteristics, and long-term neurological outcome. METHODS: In OHCA patients who received targeted temperature management, lactate levels were measured at 0, 12, and 24 h after the return of spontaneous circulation. We calculated lactate clearance and time-weighted cumulative lactate (TWCL), which represent the area under the time-lactate curve. The area under the receiver operating characteristic curve (AUC) and the adjusted odds ratios (AORs) of lactate-related variables for predicting 6-month poor outcome (Cerebral Performance Category 3-5) were evaluated. Interactions between lactate variables and characteristics of OHCA were evaluated by a multivariable logistic model with interaction terms and subgroup analysis. RESULTS: A total of 347 OHCA patients were included. After adjustment, higher lactate levels at the three time points were associated with a poor outcome (AOR 1.10 [95% CI, 1.03-1.18], AOR 1.15 [95% CI, 1.02-1.29], and AOR 1.36 [95% CI, 1.15-1.60], respectively), while TWCL was the only lactate kinetics variable associated with a poor outcome (AOR 1.29 [95% CI, 1.12-1.49]). We identified several interactions between lactate-related variables and OHCA characteristics. In particular, the AUC of TWCL was excellent in cases of noncardiac etiology (AUC 0.92 [95% CI, 0.86-0.96] but only moderate in cardiac etiology (AUC 0.69 [95% CI, 0.62-0.75]). CONCLUSIONS: Early lactate levels, especially at 24 h, and TWCL were independent predictors of neurologic outcome in these patients, whereas lactate clearance was not. The prognostic ability of lactate-related variables varied depending on the OHCA characteristics.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

Interrater reliability of motor severity scales for hemifacial spasm.

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants' motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee's scale), clinical grading of spasm intensity (Chen's scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc's scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from "poor" to "moderate"; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee's, Chen's, and Tunc's scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc's scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc's scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training.

The effect of continuous positive airway pressure (CPAP) on the quality of life in patients with multiple system atrophy.

PURPOSE: To evaluate the effect of continuous positive airway pressure (CPAP) on the quality of life (QoL) in patients with multiple system atrophy (MSA) and their caregivers. METHODS: We reviewed the electronic medical records of patients with MSA treated with CPAP (n = 15). After CPAP treatment, we checked the patient global impression of change (PGI-C) scale for sleep complaints and QoL for six patients who continued to use CPAP. QoL was also assessed for five caregivers of these patients. RESULTS: A total of 15 patients (6 women) were included. The mean age was 63.6 ± 8.1 years old and the mean disease duration was 4.9 years. The mean duration of CPAP treatment was 22.1 ± 10.6 months and the average compliance was 90%. Three patients died during CPAP treatment, and two patients discontinued CPAP after tracheostomy. For six patients who continued to use CPAP, sleep complaints minimally improved. Five patients reported an improved QoL, and all five caregivers reported improved caregivers' QoL. CONCLUSION: This study showed that the use of CPAP has a beneficial effect on sleep complaints and QoL of patients with MSA and their caregivers.

A novel cardiac arrest severity score for the early prediction of hypoxic-ischemic brain injury and in-hospital death.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) outcomes are unsatisfactory despite postcardiac arrest care. Early prediction of prognoses might help stratify patients and provide tailored therapy. In this study, we derived and validated a novel scoring system to predict hypoxic-ischemic brain injury (HIBI) and in-hospital death (IHD). METHODS: We retrospectively analyzed Korean Hypothermia Network prospective registry data collected from in Korea between 2015 and 2018. Patients without neuroprognostication data were excluded, and the remaining patients were randomly divided into derivation and validation cohorts. HIBI was defined when at least one prognostication predicted a poor outcome. IHD meant all deaths regardless of cause. In the derivation cohort, stepwise multivariate logistic regression was conducted for the HIBI and IHD scores, and model performance was assessed. We then classified the patients into four categories and analyzed the associations between the categories and cerebral performance categories (CPCs) at hospital discharge. Finally, we validated our models in an internal validation cohort. RESULTS: Among 1373 patients, 240 were excluded, and 1133 were randomized into the derivation (n = 754) and validation cohorts (n = 379). In the derivation cohort, 7 and 8 predictors were selected for HIBI (0-8) and IHD scores (0-11), respectively, and the area under the curves (AUC) were 0.85 (95% CI 0.82-0.87) and 0.80 (95% CI 0.77-0.82), respectively. Applying optimum cutoff values of ≥6 points for HIBI and ≥7 points for IHD, the patients were classified as follows: HIBI (-)/IHD (-), Category 1 (n = 424); HIBI (-)/IHD (+), Category 2 (n = 100); HIBI (+)/IHD (-), Category 3 (n = 21); and HIBI (+)/IHD (+), Category 4 (n = 209). The CPCs at discharge were significantly different in each category (p < 0.001). In the validation cohort, the model showed moderate discrimination (AUC 0.83, 95% CI 0.79-0.87 for HIBI and AUC 0.77, 95% CI 0.72-0.81 for IHD) with good calibration. Each category of the validation cohort showed a significant difference in discharge outcomes (p < 0.001) and a similar trend to the derivation cohort. CONCLUSIONS: We presented a novel approach for assessing illness severity after OHCA. Although external prospective studies are warranted, risk stratification for HIBI and IHD could help provide OHCA patients with appropriate treatment.

Serum Inflammatory Markers and Progression of Nonmotor Symptoms in Early Parkinson's Disease.

BACKGROUND: The influence of peripheral inflammation on nonmotor symptoms (NMSs) in Parkinson's disease (PD) remains unclear. OBJECTIVE: The aim of this study was to explore whether serum inflammatory marker profiles are associated with the progression of NMSs in early PD. METHODS: We included 45 patients with early PD and 20 healthy control subjects. Six inflammatory markers, including interleukin (IL)-1ß, IL-2, IL-6, IL-10, tumor necrosis factor-α, and high-sensitivity C-reactive protein, were measured. NMSs were assessed using the Non-Motor Symptoms Scale, Montreal Cognitive Assessment, and Composite Autonomic Symptom Score-31 at baseline and after 3 years. RESULTS: Principal component (PC) analysis showed that only PC3 scores, mainly loaded by IL-2 and IL-6, were significantly elevated in the PD group compared with the control group. Higher PC3 scores in the PD group were associated with faster progression of Non-Motor Symptoms Scale total and mood/apathy domain scores. There were no significant associations of PC scores with Montreal Cognitive Assessment and Composite Autonomic Symptom Score-31 score changes. CONCLUSIONS: Peripheral inflammation may be related to the evolution of NMSs, particularly mood symptoms, in the early stages of PD. © 2022 International Parkinson and Movement Disorder Society.

Wireless interfaces for brain neurotechnologies.

Wireless interfaces enable brain-implanted devices to remotely interact with the external world. They are critical components in modern research and clinical neurotechnologies and play a central role in determining their overall size, lifetime and functionality. Wireless interfaces use a wide range of modalities-including radio-frequency fields, acoustic waves and light-to transfer energy and data to and from an implanted device. These forms of energy interact with living tissue through distinct mechanisms and therefore lead to systems with vastly different form factors, operating characteristics, and safety considerations. This paper reviews recent advances in the development of wireless interfaces for brain neurotechnologies. We summarize the requirements that state-of-the-art brain-implanted devices impose on the wireless interface, and discuss the working principles and applications of wireless interfaces based on each modality. We also investigate challenges associated with wireless brain neurotechnologies and discuss emerging solutions permitted by recent developments in electrical engineering and materials science. This article is part of the theme issue 'Advanced neurotechnologies: translating innovation for health and well-being'.

Impact of COVID-19 pandemic on patients with cardio/cerebrovascular disease who visit the emergency department.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic situation is a state that has had a great impact on the medical system and society. To respond to the pandemic situation, various methods, such as a pre-triage system, are being implemented in the emergency medical field. However, there are insufficient studies on the effects of this pandemic situation on patients visiting the emergency department (ED), especially those with cardio/cerebrovascular diseases (CVD)1 classified as time-dependent emergencies. METHODS: We performed a retrospective analysis of a cohort of patients from April 2020 to December 2020 (April 2020 was when the pre-triage system was established) compared to a parallel comparison patient cohort from 2019. The primary outcome was in-hospital mortality. CVD was defined by the patient's final diagnosis. RESULTS: During the same period, the number of patients who had visited the ED after COVID-19 had decreased to 79.1% of the number of patients who had visited the ED before COVID-19. The overall patient mortality and the mortality in the patients cardiovascular disease had both increased, while the mortality from cerebrovascular disease did not increase. Meanwhile, the ED length of stay had increased in all patients but did not increase in the patients with cardiovascular disease. CONCLUSION: As with prior studies conducted in other regions, in our study, the total number of ED visits were decreased compared to before COVID-19. The overall mortality had increased, particularly in the patients with cardiovascular disease.

Arching deep brain stimulation in dystonia types.

Although medical treatment including botulinum toxic injection is the first-line treatment for dystonia, response is insufficient in many patients. In these patients, deep brain stimulation (DBS) can provide significant clinical improvement. Mounting evidence indicates that DBS is an effective and safe treatment for dystonia, especially for idiopathic and inherited isolated generalized/segmental dystonia, including DYT-TOR1A. Other inherited dystonia and acquired dystonia also respond to DBS to varying degrees. For Meige syndrome (craniofacial dystonia), other focal dystonia, and some rare inherited dystonia, further evidences are still needed to evaluate the role of DBS. Because short disease duration at DBS surgery and absence of fixed musculoskeletal deformity are associated with better outcome, DBS should be considered as early as possible when indicated after careful evaluation including genetic work-up. This review will focus on the factors to be considered in DBS for patients with dystonia and the outcome of DBS in the different types of dystonia.

Bilateral subthalamic nucleus deep brain stimulation is an effective treatment for diphasic dyskinesia.

BACKGROUND AND PURPOSE: The purpose was to assess the effect of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on diphasic dyskinesia in patients with Parkinson disease (PD) and to assess the factors associated with the remission of diphasic dyskinesia. METHODS: Medical records for PD patients who underwent bilateral STN DBS at the Movement Disorder Center of Seoul National University Hospital from March 2005 to November 2016 were reviewed. Patients were evaluated preoperatively and at 3, 6 and 12 months after surgery, and annually thereafter. The presence of peak-dose dyskinesia and diphasic dyskinesia is based on the interview and examination of patients at baseline and at each follow-up. RESULTS: Amongst 202 patients who underwent STN DBS, 66 patients who had diphasic dyskinesia preoperatively were included in the analysis. Diphasic dyskinesia disappeared in 49 (74%) after surgery. In 27 (55.1%) patients whose diphasic dyskinesia disappeared after DBS, peak-dose and diphasic dyskinesia disappeared persistently from as early as 3 months postoperatively. Age at onset was younger and disease duration at surgery was longer in patients whose diphasic dyskinesia persisted compared with patients whose diphasic dyskinesia disappeared. Multivariate Cox regression analysis demonstrated that patients with greater postoperative decrease of dopaminergic medications were more likely to have remission of diphasic dyskinesia. CONCLUSION: This study showed that bilateral STN DBS is effective in controlling diphasic dyskinesia and should be considered in PD patients with diphasic dyskinesia.

Reduced oligodendrocyte exosome secretion in multiple system atrophy involves SNARE dysfunction.

Transportation of key proteins via extracellular vesicles has been recently implicated in various neurodegenerative disorders, including Parkinson's disease, as a new mechanism of disease spreading and a new source of biomarkers. Extracellular vesicles likely to be derived from the brain can be isolated from peripheral blood and have been reported to contain higher levels of α-synuclein (α-syn) in Parkinson's disease patients. However, very little is known about extracellular vesicles in multiple system atrophy, a disease that, like Parkinson's disease, involves pathological α-syn aggregation, though the process is centred around oligodendrocytes in multiple system atrophy. In this study, a novel immunocapture technology was developed to isolate blood CNPase-positive, oligodendrocyte-derived enriched microvesicles (OEMVs), followed by fluorescent nanoparticle tracking analysis and assessment of α-syn levels contained within the OEMVs. The results demonstrated that the concentrations of OEMVs were significantly lower in multiple system atrophy patients, compared to Parkinson's disease patients and healthy control subjects. It is also noted that the population of OEMVs involved was mainly in the size range closer to that of exosomes, and that the average α-syn concentrations (per vesicle) contained in these OEMVs were not significantly different among the three groups. The phenomenon of reduced OEMVs was again observed in a transgenic mouse model of multiple system atrophy and in primary oligodendrocyte cultures, and the mechanism involved was likely related, at least in part, to an α-syn-mediated interference in the interaction between syntaxin 4 and VAMP2, leading to the dysfunction of the SNARE complex. These results suggest that reduced OEMVs could be an important mechanism related to pathological α-syn aggregation in oligodendrocytes, and the OEMVs found in peripheral blood could be further explored for their potential as multiple system atrophy biomarkers.

Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement.

PURPOSE: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. METHODS: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. RESULTS: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. CONCLUSIONS: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Unsupervised clustering of dopamine transporter PET imaging discovers heterogeneity of parkinsonism.

Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18 F-fluoropropyl-carbomethoxyiodophenylnortropane (FP-CIT) PET as a data-driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP-CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow-up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP-CIT PET data of a single-center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster "0" and "2." Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP-CIT PET-derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.

Motor complications in Parkinson's disease: 13-year follow-up of the CamPaIGN cohort.

BACKGROUND: Long-term population-representative data on motor fluctuations and levodopa-induced dyskinesias in Parkinson's disease is lacking. METHODS: The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias and risk factors were assessed using Kaplan-Meyer and Cox regression analyses. RESULTS: Cumulative incidence of motor fluctuations and levodopa-induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS-total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini-mental State Examination and GBA mutations predicted levodopa-induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa-induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years). CONCLUSIONS: Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 International Parkinson and Movement Disorder Society.

Replication-Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease.

BACKGROUND: SNCA multiplication is a genomic cause of familial PD, showing dosage-dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. OBJECTIVES: We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole-genome sequencing data to elucidate the mechanism of SNCA duplication. METHODS: Six patient samples with SNCA duplication underwent whole-genome sequencing. The duplicated regions were defined with nucleotide-resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non-B DNA-forming sequences and stem-loop structure predictions was conducted. RESULTS: Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2-4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem-loop structures. CONCLUSION: Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem-loop structures suggest that replication-based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society.

Urinary Symptoms and Urodynamic Findings in Patients with Spinocerebellar Ataxia.

Urinary dysfunctions are not considered symptoms of spinocerebellar ataxias (SCAs). However, given that a patient with SCAs without a family history might be misdiagnosed as MSA-C when having urinary dysfunctions, characterization of urinary dysfunctions in SCAs is needed not only to understand SCAs but also to correctly diagnosis patients with ataxia. We retrospectively reviewed medical records of 143 patients with genetically confirmed SCA1, 2, 3, 6, 7, 17, and DRPLA. Twenty-two patients (men n = 9; age 62.1 ± 10.9; disease duration 8.2 ± 2.9 years) who had lower urinary track symptoms (LUTS) were included in this study. Six patients underwent urodynamic study (UDS), and 2 underwent uroflowmetry. LUTS was present in 1 of 11 patients with SCA1, in 4 of 51 with SCA2, in 2 of 26 with SCA3, in 3 of 20 with SCA6, in 2 of 4 with SCA7, in 8 of 26 with SCA17, and in 2 of 5 with DRPLA. Overall, urinary frequency was the most common symptom (16 patients, 72.7%) followed by voiding difficulty. In three of the 6 patients with UDS, post-micturition residuals were > 100 ml. Detrusor overactivity was noted in three patients. Detrusor areflexia was observed in one. Four patients were diagnosed with a neurogenic bladder, 3 with a storage problem, and 1 with both storage and voiding problems. Fifteen percent of the patients with SCAs had LUTS, and LUTS occurred in various types of SCAs. Our results indicate that SCAs should be considered in patients with progressive cerebellar ataxia and urinary dysfunctions.

Alternating Hemiplegia of Childhood in Korea: a Case Report.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder characterized by recurrent paroxysmal hemiplegic attacks that affect one or the other side of the body. Up to 74% of patients with AHC have a pathologic variant in the ATP1A3 gene. After the introduction of next-generation sequencing, intermediate cases and atypical cases have expanded the clinical spectrum of ATP1A3-related disorders. Herein, we report the first case of AHC in Korea. A 33-year-old man visited our hospital with recurrent hemiplegic and dystonic episode after his first birthday. He was completely normal between episodes and did not have any ataxia, but brain magnetic resonance imaging showed cerebellar atrophy. He also had pes planovalgus deformity. Whole exome sequencing revealed a heterozygous G947R variant in the ATP1A3 gene (c.2839G > C, rs398122887), which is a known pathologic variant. This atypical case of AHC demonstrates the importance of the clinical approach in diagnosing ATP1A3-related disorders.