ATP1A3-related disorders are characterized by genetic heterogeneity and phenotypic pleiotropy, posing significant challenges for classification. Although canonical phenotypes have traditionally guided decision-making, increasing evidence highlights their limitations in capturing the clinical complexity. The aims of this study were to characterize movement disorders, paroxysmal features, and genotype-phenotype relationships; to build a curated video archive; and to assess alignment with canonical phenotypes. This is an observational study of 88 individuals with pathogenic or likely pathogenic variants in ATP1A3 who were evaluated in specialized movement disorders programs. Age at last clinical follow-up ranged from 0.1 to 63 years; 80.7% were pediatric patients. Chronic movement disorders were present in 68 of 88 individuals (75%); most had two or more coexisting phenomenologies. Dystonia was most common (47/88, 53%), followed by spasticity (28/88, 32%) and ataxia (28/92, 32%). Paroxysmal events occurred in 78 of 88 (88%) patients, including dystonic spells (45/78, 58%), abnormal eye movements (39/78, 50%), and hemiplegic episodes (37/78, 47%). Common comorbidities included epilepsy (21/88, 24%), cognitive impairment (41/88, 47%), and neuropsychiatric disorders. Only 22 of 88 (25%) fulfilled criteria for a single canonical phenotype; 28 of 88 (32%) met canonical criteria plus additional features, 18 of 88 (20%) satisfied criteria for ≥2 canonical phenotypes, and 20 of 88 (23%) fit no canonical category. We identified 43 distinct ATP1A3 variants; recurrent variants (eg, p.Arg756His, p.Asp801Asn, p.Glu818Lys) showed variable expressivity across categories. The extensive clinical heterogeneity in ATP1A3-related disorders challenges rigid phenotypic classifications. The predominance of patients with overlapping or atypical features supports a shift toward flexible, symptom-based clinical approaches rather than strict reliance on canonical phenotype recognition. © 2026 International Parkinson and Movement Disorder Society.
Transcranial temporal interference stimulation (TIs) targeting the subthalamic nucleus (STN) is a novel noninvasive neuromodulation approach with potential to improve motor symptoms in Parkinson's disease (PD). However, its underlying neuroimaging mechanisms remain unclear. Changes in functional connectivity (FC) of the STN and the cortical-basal ganglia-thalamic-cortical (CBTC) circuit are central to PD pathophysiology. This randomized, double-blind, crossover study aimed to examine the effects of STN-TIs on FCs of the STN and regions in the CBTC circuit in PD. 23 participants with mild-to-moderate PD received a 20-minute session of 130 Hz TIs targeting the STN of the contralateral hemisphere of the patient's severely affected side (or the dominant side in case of bilateral disturbance), and active sham stimulation in randomized order. Resting-state functional magnetic resonance imaging (fMRI) and Part III of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) were completed before and after stimulation. The STN and regions in the CBTC circuit were defined as regions of interest (ROI) for ROI-to-ROI FC analysis. Compared to sham stimulation, 130 Hz STN-TIs induced a connectivity-specific effect, including the decreased FCs between the targeted side of STN and putamen (P = 0.004-0.046) and caudate (P < 0.001), and increased FC between the targeted side of STN and M1 (P = 0.002-0.004). No severe side effects were reported. Our study provides preliminary but novel evidence for the potential modulatory effect of STN-TIs on resting-state neural activities in the motor circuit. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Neurodevelopmental disorders feature various symptoms that frequently include seizures and motor manifestations, but their attribution to disruptions of specific circuits and molecular alterations is notoriously hard to establish, which limits therapeutic interventions. Among these, is the GNAO1 disorder a severe pediatric encephalopathy associated with mutations in a gene encoding G protein subunit Gαo, a key transducer of neuromodulatory responses mediated by a vast number of G protein-coupled receptors. In this study, we introduce a unique approach to modeling GNAO1 disorder, and neurodevelopmental disorders in general, by creating a conditional knock-in mouse model of a severe dominant negative GNAO1 variant G203R that allows circuit-specific induction of the mutation. A comprehensive battery of behavioral tests, together with electrophysiological recordings and proteomic analysis, was used to assess motor performance, seizure susceptibility, as well as molecular and functional alterations associated with the disorder. The model allowed parsing out circuit-specific contributions of Gαo dysfunction to motor and epileptic manifestations across neurons in striatum and forebrain. We further established molecular profiles of the disorder in a region-specific manner and documented the impact on synaptic transmission. This information guided the development of an intervention strategy using caffeine, which effectively rescued motor abnormalities. Our results point to the essential role of Gαo in maintaining neural circuit homeostasis. This advances our understanding of GNAO1 disorder-related disease mechanisms and lays foundation for rational, circuit-based therapeutic strategies. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
SRRM4 is an exclusively neural-expressed splicing-factor gene not yet associated with a monogenic condition. We sought to delineate movement disorders caused by SRRM4 variants. De novo splice-donor-site variants at position +2 of intron 5 of SRRM4 (c.464+2T>C, c.464+2T>A) occurred in three unrelated patients with dystonia and chorea. We present detailed phenotypic information on these individuals and characterize the effect of the splice-site alteration. Exome and genome sequencing were used to identify SRRM4 variants. To assess the consequence of a mutant +2 residue at the affected splice donor of SRRM4, we performed transcriptomic analyses using short-read and long-read RNA-sequencing in patient fibroblasts in which SRRM4 expression was induced by genome editing. Clinical presentations were characterized by infantile combined dystonic and choreatic syndromes or chorea-predominant disease. Studies in SRRM4 expression-activated cells revealed two variant-specific SRRM4-mRNA isoforms including one that was characterized by a 69-nucleotide in-frame insertion without creation of a premature termination codon, suggestive of a mechanism other than loss-of-function. Additionally, we uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts, such as a conserved AP1S2 microexon. AP1S2 is linked to a monogenic syndrome with abnormal movements and missplicing of its microexon is a well-established outcome in neural models of SRRM4 disruption. We conclude that the patients' phenotypes are caused by a previously undiagnosed SRRM4-related disorder, offering a basis for improved understanding of mechanistic convergence in genetic movement disorders and potential therapeutic targeting of the misregulated splicing events. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Hyperkinetic movement disorders arise from dysfunction within cortico-basal ganglia-cerebellar loops. They frequently involve psychiatric and cognitive symptoms, reflecting impairment of both motor and non-motor domains within these loops. ADCY5 (MxMD-ADCY5) and SGCE (MYC/DYT-SGCE) related movement disorders are childhood-onset monogenic hyperkinetic conditions, both characterized by myoclonus, dystonia, and frequent psychiatric manifestations. Previous evidence suggests predominant basal ganglia involvement in MxMD-ADCY5 and cerebellar involvement in MYC/DYT-SGCE. The aim was to determine how basal ganglia and cerebellar dysfunction drives cortical dysregulation in hyperkinetic movement disorders. Resting-state functional magnetic resonance imaging (fMRI) was used to examine effective connectivity in motor and non-motor cortico-basal ganglia-cerebellar loops. Findings were validated using leave-one-out cross-validation. Microstructural properties of regions within these loops were assessed with diffusion-weighted imaging, using neurite orientation dispersion and density measures. We enrolled 21 patients with MxMD-ADCY5, 24 with MYC/DYT-SGCE, and matched healthy controls. Both patient groups exhibited elevated rates of psychiatric comorbidities. In MxMD-ADCY5, abnormal basal ganglia connectivity influenced the cerebellum, which in turn modulated cortical activity across motor and non-motor loops. Reduced neurite density was observed in the subthalamic nucleus, a relay between basal ganglia and cerebellum. In MYC/DYT-SGCE, the cerebellum showed predominant influence on cortical activity, with downstream modulation of basal ganglia activity, but no microstructural alterations were detected. Cross-validation largely confirmed the connectivity patterns' reliability. Abnormal cortical modulation in both disorders converges on a shared cerebellar-cortical pathway, with basal ganglia influences in MxMD-ADCY5 transmitted via the cerebellum to the cortex, and cerebellar contributions in MYC/DYT-SGCE directly influencing the cortex. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) neurogenerative disorder that results from CAG trinucleotide repeat expansions in the ATXN3 gene, leading to toxic protein aggregate formation and cellular pathway dysfunction. The dysfunction of cellular pathways also correlates with stress responses, such as the formation of stress granules (SG). Recent research suggests that SG and their components contribute to polyglutamine disease pathogenesis. We combined the analysis of two mouse models for SCA3, data from RNA sequencing, and postmortem brain tissue samples. This study intended to clarify the role of the SG component, calcium-regulated heat-stable protein 1 (CARHSP1), in SCA3. Among several SG components, CARHSP1 was found to be upregulated genetically in SCA3. The downregulation of Carhsp1 reduced the density of mutant protein aggregates, while enhancing motor function and alleviating neuropathological defects in SCA3 mouse models. The findings indicate that modulating CARHSP1 and possible other SG components may provide a molecular target for therapeutics in SCA3, emphasizing the role of SG in polyQ disorders. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited disorders characterized by iron accumulation in the basal ganglia. Although the prevalence is estimated at 0.1-0.3 per 100,000,000 individuals, epidemiological data remain limited. To determine the carrier frequency and lifetime risk ratios of autosomal recessive NBIA disorders within a Middle Eastern cohort by screening eight established NBIA genes in a large regional exome cohort. Variants in NBIA-associated genes were analyzed in 16,769 individuals using whole-exome sequencing, clinical-exome sequencing, and TruSight One panels. The lifetime risk of autosomal recessive NBIA disorders was estimated at 3.43 per 1,000,000 individuals (95% CI 1.43-6.46). PLA2G6 contributed the largest proportion of the estimated disease burden, followed by PANK2 and C19orf12. This is the first systematic analysis of lifetime risk and carrier frequencies of NBIA in Middle Eastern populations. The findings suggest a notable carrier frequency and highlight the need for region-specific genetic screening. © 2026 International Parkinson and Movement Disorder Society.
Spastic paresis, resulting from central nervous system lesions, significantly impairs functional performance. In the framework of the International Classification of Functioning, Disability, and Health, functional performance was defined as functioning at the activity level in relation to the impairment of body functions and structures, that is, symptoms of spastic paresis syndrome. Reliable clinical outcome assessments (COAs) for functional performance evaluation are needed. This systematic review evaluates the clinimetric properties of functional performance COAs in spastic paresis and provides recommendations for their use. A literature search identified relevant COAs, which were systematically assessed by an international expert panel and classified as "recommended," "recommended with caveats," "suggested," or "listed" following the Movement Disorder Society-COA methodology. Seventy-one COAs were identified, and 14 COAs used in over 2% of studies were reviewed. Five COAs assessing lower limb functional performance met the "recommended" criteria, whereas none of the upper limb COAs met the criteria for "recommended." Two upper-limb COAs were evaluated as "recommended with caveats." Two variants of the 10-Meter Walk Test, along with the 2-Minute or 6-Minute Walk Test (to account for fatigability), are recommended for assessing lower limb functional performance in patients with spastic paresis. The Wisconsin Gait Scale is recommended, although its clinical feasibility is limited. For the upper limb, the 13-item Arm Motor Ability Test and the Modified Frenchay Scale are classified as "recommended with caveats" because of identified limitations. Establishing consistent scoring guidelines and standardized protocols will be essential to enhance their clinical applicability and diffusion. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
[18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) represents an endorsed neurodegeneration biomarker in neuronal α-synucleinopathies. Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents a prodromal stage of such disorders. To assess [18F]FDG PET as a neurodegeneration biomarker, using published brain metabolic disease-related patterns, and a regional-based approach, across the prodromal to overt α-synucleinopathy continuum. We included 83 prodromal subjects with iRBD, comprising non-converters (n = 56) and converters (n = 27) to an overt α-synucleinopathy (either Parkinson's disease [PD] or dementia with Lewy bodies [DLB]) according to the last available follow-up, and 85 subjects with PD (n = 40) and DLB (n = 45). For comparison, we enrolled a group of healthy subjects (n = 41). Participants underwent brain [18F]FDG PET at baseline. Analysis of covariance was used to test the ability of previously published [18F]FDG PET disease-related patterns in characterizing neurodegeneration levels along the prodromal to overt α-synucleinopathy continuum, and across the motor-predominant (parkinsonism-first) and the cognitive-predominant (dementia-first) clinical trajectories. We further assessed metabolic changes using a regional-based approach. All disease-related patterns effectively discriminated clinical stages, from prodromal to overt α-synucleinopathies, with comparable performance. [18F]FDG PET significantly distinguished all groups along the cognitive-predominant pathway; whereas in the motor-predominant pathway, converter patients were not significantly discriminated from non-converters. Regionally, the inferior parietal, precuneus, and middle frontal areas exhibited the most prominent decrease in [18F]FDG uptake with progression, alongside relative parallel progressive increases in the cerebellum, pons, parahippocampal areas, putamen, and pallidum. [18F]FDG PET disease-related patterns efficiently characterize neurodegeneration from prodromal to overt α-synucleinopathy, best assessing the cognitive-predominant (dementia-first) pathway. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disease with distinctive neuroendocrine manifestations, with dystonia being the most common. No clear guidelines are available for the treatment of dystonia in WSS. The aim was to analyze the impact of deep brain stimulation (DBS) on WSS-associated dystonia. Patients with genetically confirmed WSS who underwent globus pallidus internus (GPi) DBS for dystonia were analyzed retrospectively. The participants were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and were videotaped pre- and post-surgery at multiple follow-up points. The primary outcome was the BFMDRS score at 1 year post-surgery, compared with baseline. The primary outcome was correlated with preoperative factors, including age at onset, disease duration at surgery, proportion of life lived with dystonia, and severity rate. Five patients with severe progressive generalized dystonia secondary to clinically and genetically confirmed WSS underwent bilateral GPi DBS from February 2011 through September 2023. The mean age at disease onset and at the time of DBS was 11.3 and 18.6, respectively. All patients' BFMDRS total scores improved from baseline to 12 months post-DBS. The mean pre-DBS BFMDRS score was 71.1, and the mean post-DBS BFMDRS score was 43.6. The percentage improvement in the BFMDRS mean score from pre- to post-DBS was approximately 39%. Our case series showed clinical improvement in patients who underwent bilateral GPi DBS as an advanced therapy for generalized dystonia secondary to WSS. We recommend further research on DBS in a larger sample of WSS patients to obtain significant results. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
L-DOPA-induced dyskinesia is attributed to opposite activity changes mediated by D1 and D2 dopamine receptors in the two striatal output pathways. Whereas the causal role of direct-pathway D1 receptors is well established, the specific involvement of indirect-pathway D2 receptors in dopaminergic dyskinesias has remained elusive. We used conditional knockout approaches in mice to determine whether indirect-pathway D2 receptors causally contribute to dyskinetic and dystonic responses to dopaminergic agents. Studies were conducted in mice with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway receiving subchronic treatments with L-DOPA or D2/D1-selective agonists. A conditional knockout of indirect-pathway D2 receptors was produced either through the entire striatum (double-transgenic Adora2a-Cre/Drd2loxP/loxP mice) or selectively in the dopamine-denervated dorsal striatum (proenkephalin promoter-driven Cre vector delivery to Drd2loxP/loxP mice). The severity of L-DOPA-induced abnormal involuntary movements and dystonia was halved in both knockout models compared with control mice, whereas the treatment effect on normal motor behaviors was either not reduced or improved. All dyskinetic and dystonic features induced by the D2-selective receptor agonist sumanirole were completely abolished, whereas those induced by the D1-class agonist SKF38393 were largely unaffected. Using phosphorylated ribosomal protein S6 as an activity marker, we detected a treatment-induced recruitment of prototypical parvalbumin-positive neurons in the external globus pallidus (a target of indirect-pathway projections). This effect was inhibited in both knockout models. We provide experimental evidence that indirect-pathway D2 receptors significantly contribute to the expression of dyskinesia during L-DOPA treatment and mediate D2 agonist-dependent dystonic features. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant neurological disease characterized by cortical myoclonic tremor and epileptic seizures. The proposed pathogenic (TTTCA) pentanucleotide repeat expansion (exp) insertion, flanking the polymorphic (TTTTA)exp, has been reported in seven distinct FCMTE causative genes/loci, and a repeat motif-specific phenotype correlation is claimed. However, the pathogenic mechanism of FCMTE is still poorly understood. We investigated how the (TTTCA)exp insertion causes the disease, mainly employing the FCMTE1 patients-induced pluripotent stem cell-derived neurons (iPSC-neurons), focusing on the formation of (UUUCA)exp RNA foci and their associated cellular toxicity. First, (TTTCA)exp insertion neither altered SAMD12 expression nor translates into repeat peptides. Second, (UUUCA)exp RNA foci were detected in both the constructed cell line and iPSC-neurons, and presented toxicity effects. Third, NOVA2, a neuron-specific splicing regulator, was identified as the key RNA-binding protein interacting with (UUUCA)exp RNA. The (UUUCA)exp RNA disrupted the nuclear distribution pattern of NOVA2, and reciprocally, knockdown of NOVA2 promoted the formation of (UUUCA)exp RNA foci. Shared synaptic-related pathways of alternative splicing events were observed in both FCMTE1-iPSC-neurons and NOVA target genes. These findings support a repeat motif-dependent mechanism involving (UUUCA)exp RNA foci and the functional disruption of the key RNA-binding protein NOVA2, providing valuable insights for future studies on FCMTE and other pentanucleotide repeat expansion diseases. © 2026 International Parkinson and Movement Disorder Society.
Leucine-rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian-prevalent LRRK2 p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2-targeted trials. The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying LRRK2 p.G2385R and/or p.R1628P variants and in patients with idiopathic PD (iPD). We recruited 242 participants: patients with PD carrying LRRK2 p.G2385R (PD-G2385R; n = 57), p.R1628P (PD-R1628P; n = 61), or both (n = 5); patients with iPD (n = 61); and healthy control subjects (HCs; n = 58). Monocyte LRRK2 activity markers (pRab10Thr73 and pLRRK2Ser935) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment. Compared with HCs, pRab10Thr73 was elevated (indicative of LRRK2 kinase hyperactivation) in PD-G2385R (~1.2-fold, P = 0.011) and in double-variant carriers (~2.8-fold, P = 0.008), but not in PD-R1628P or iPD. Inversely correlated with pRab10Thr73 (rs = -0.611, P < 0.001), pLRRK2Ser935 was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double-variant carriers). All double-variant carriers, the majority of single-variant carriers, and one-third of participants with iPD had pRab10Thr73 greater than the control median. Higher pRab10Thr73 correlated with better cognition. LRRK2 kinase activity is enhanced in patients with PD carrying LRRK2 p.G2385R, with further elevation observed in a small group of double-variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the need for biochemical stratification beyond genotyping in future LRRK2 trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically defined by three cardinal motor symptoms: bradykinesia, rigidity, and tremor. Although the natural history of bradykinesia and rigidity is well described, the evolution of tremor as the disease progresses remains controversial. The goal was to clinically characterize long-term trajectories of rest, postural, and action tremor in PD and examine their neural network correlates using longitudinal resting-state functional magnetic resonance imaging (rs-fMRI). In this retrospective longitudinal cohort study, we analyzed 93 tremor-positive PD patients (mean disease duration: 3.6 years), each with up to six clinical assessments over 4.2 years. Linear mixed-effects models assessed temporal change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Fahn-Tolosa-Marín Tremor Rating Scale (FTM-TRS) scores. Rs-fMRI data from 30 tremor-affected patients (mean interval, 3.35 years) were analyzed for seed-to-whole-brain connectivity and connectivity between predefined brain regions. Bradykinesia (β = +0.09, P < 0.001) and rigidity (β = +0.06, P < 0.001) worsened, whereas total FTM-TRS scores declined by 0.49 points/year (P = 0.037), driven by reductions in postural (P < 0.001) and action tremor (P = 0.033); resting tremor remained stable. Rs-fMRI revealed longitudinal changes in cerebellar- and thalamic-seed-to-whole-brain connectivity. Tremor in PD evolves along distinct clinical courses, often stabilizing or improving as other motor features worsen. These findings are consistent with partially adaptive reorganization within tremor-related networks and underscore the importance of identifying patient subtypes with divergent trajectories to inform prognosis and optimize therapy. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Although clinical markers (eg, motor and cognitive impairment) in isolated rapid eye movement sleep behavior disorder (iRBD) are associated with faster phenoconversion, their longitudinal trajectory patterns (linear or nonlinear) remain unclear. Additionally, evidence regarding the magnitude of neurodegenerative risk in iRBD compared to non-RBD individuals remains limited. The aim was to investigate longitudinal changes in clinical markers and assess the magnitude of neurodegenerative risk in iRBD versus non-RBD subjects. In this prospective matched cohort study, video-polysomnography-confirmed iRBD patients and age- and sex-matched non-RBD subjects were followed every 1.5-2 years to evaluate neurodegenerative outcomes and markers. Longitudinal marker changes and neurodegenerative risk between groups were compared. One-hundred thirty-three iRBD patients and 101 non-RBD subjects were followed for a mean of 6.9 ± 2.9 years. Parkinsonism-first converters were associated with motor dysfunction, whereas dementia-first converters were associated with cognitive, motor, olfactory, and color vision dysfunctions. Motor and global cognitive functions exhibited nonlinear progression in iRBD, with marked acceleration before parkinsonism or dementia diagnosis. Conversion rates in iRBD patients were 4.7% at 3 years, 30.1% at 7 years, and 79.5% at 13 years, exceeding those in non-RBD subjects (3% at 3 years and 16.1% at 13 years). iRBD patients had a higher neurodegeneration risk (hazard ratio [95% confidence interval [CI]: 9.6 [3.8, 23.8], P < 0.001). Motor and global cognition demonstrate nonlinear accelerating progressions during iRBD phenoconversion. iRBD carries a nearly 10-fold higher risk of future neurodegeneration than non-RBD subjects. These findings highlighted a critical window for risk stratification and early intervention before neurodegenerative disease onset in iRBD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Adaptive deep brain stimulation (aDBS) represents an important evolution in the treatment of Parkinson's disease (PD), building on conventional DBS (cDBS) by adjusting stimulation in response to real-time physiological signals. By enabling dynamic targeting of disease-related neural activity, aDBS offers the potential for more precise modulation of motor symptoms. Additional anticipated advantages include reduced stimulation-related side effects and improved energy efficiency, supporting long-term device performance. Although clinical uptake is still at an early stage, growing experience has highlighted both opportunities and areas requiring further refinement. Key challenges include inter-individual variability in biomarker expression, diversity in programming approaches, and ongoing debate regarding optimal thresholds and response latencies. The clinical significance of short-term local field potential (LFP) recordings continues to be actively investigated, particularly in the context of signal artifacts, physiological variability, and current hardware limitations. Beyond technical considerations, factors such as patient selection, ethical frameworks, and cost-effectiveness remain important determinants of broader implementation. Continued progress will depend on the development of robust and flexible control strategies that incorporate multimodal biomarkers, including wearable-derived motor metrics and patient-reported outcomes, to support personalized therapy. With an expanding evidence base and recent regulatory approvals, aDBS is increasingly transitioning from an experimental concept to a viable clinical tool. Future efforts should prioritize the translation of research paradigms into scalable clinical workflows that effectively balance automation with individualized patient care. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Large-scale sequencing initiatives have generated extensive genomic resources essential for variant interpretation, yet their effective use often requires bioinformatics expertise. To support identification of Parkinson's disease (PD) risk and disease-causing variants, we developed an open-access, summary-level genomic data browser. We performed uniform joint variant calling to harmonize whole-genome sequencing (WGS) data from AMP-PD Release 4, GP2 Data Releases, and additional controls from the Alzheimer's Disease Sequencing Project. Clinical-exome sequencing (CES) data from GP2 Release 8 were also included. The integrated dataset included 31,665 WGS and 9,559 CES samples, spanning 11 ancestries and over 300 million variants. The GP2 Genome Browser is a lightweight, flexible platform providing intuitive gene- and variant-level summaries with ancestry-stratified allele frequencies and functional annotations. It is open source and freely accessible at https://gp2.broadinstitute.org, enabling broad access to PD genomic data and supporting global research efforts. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Perinatal hypoxic-ischemic encephalopathy (HIE) is a severe condition resulting from impaired oxygen delivery to the developing brain, often leading to both motor deficits and dystonia-dyskinetic syndromes (DDS). In selected cases, deep brain stimulation of the globus pallidus internus (GPi-DBS) may provide a therapeutic option. However, predicting outcomes remains challenging because of clinical heterogeneity and variable responses. This retrospective study aims to identify preoperative imaging predictors of GPi-DBS efficacy in patients with DDS secondary to HIE, focusing on putaminal atrophy as a potential criterion. We retrospectively analyzed 73 patients with DDS secondary to HIE who underwent GPi-DBS at our institution from 2003 to 2023. Clinical outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Barry-Albright Dystonia Scale (BADS) at baseline and up to 15 years post-surgery. Preoperative magnetic resonance imaging scans were qualitatively and quantitatively evaluated to assess putaminal atrophy. Statistical analyses explored the relationships between imaging findings, clinical severity, and DBS outcomes. Patients with severe putaminal atrophy exhibited significantly higher preoperative BFMDRS motor and disability scores, correlating with a limited response to DBS at 1-year follow-up (P < 0.05). Volumetric analysis confirmed that greater putaminal atrophy was associated with poorer motor improvements post-surgery. The predictive value of putaminal volume for long-term outcomes remained significant at 5-year follow-up. Putaminal atrophy is a key predictor of suboptimal outcomes following GPi-DBS in patients with HIE-related DDS. These findings highlight the importance of preoperative imaging in candidate selection and underscore the need for alternative strategies in patients with severe post-anoxic basal ganglia damage. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Functional neurological disorders (FNDs) are common, disabling conditions that are genuinely experienced and arise from functional rather than structural abnormalities. Although theoretical frameworks implicate aberrant integration of prior expectations and sensory input, empirical evidence is limited, and it remains unclear whether such alterations reflect symptom-specific deficits or broader trait characteristics. To determine whether individuals with functional tremor exhibit altered integration of prior expectations and sensory input, by comparing their rate of adaptation to a split-belt gait perturbation with that of healthy controls. We examined split-belt treadmill adaptation-a paradigm inducing mismatch between predicted and actual sensory feedback-in patients with functional upper-limb tremor and age-matched healthy control subjects. Fifteen patients and 15 control subjects were recruited; three patients were excluded postenrolment because of the presence of functional gait features resulting in an inability to walk unsupported. Participants completed fast and slow tied-belt baseline walking, 7 minutes of split-belt adaptation, and 4 minutes of washout (ie, slow tied-belt walking). Adaptation and washout of step length asymmetry were quantified using single-exponential fits. Baseline spatiotemporal gait parameters did not differ between groups. Patients with functional tremor adapted step length asymmetry significantly faster than control subjects (26.7 ± 24.9 seconds vs. 100.6 ± 82.2 seconds; P = 0.006) and showed faster adaptation when returning to tied-belt modus (4.1 ± 5.9 seconds vs. 12.2 ± 11.3 seconds; P = 0.033). These findings indicate that individuals with functional tremor exhibit enhanced adaptation to novel sensorimotor contexts, contrasting with slowed adaptation reported in other neurological populations such as Parkinson's disease. Because this study included people with upper-limb functional tremor, accelerated adaptation may reflect a predisposing trait of FND rather than a symptom-specific or task-dependent phenomenon. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
The association between intronic variable number tandem repeat (VNTR) expansions in intron 10 of the HSF1 gene and essential tremor (ET) has not yet been validated in larger, more diverse populations. This study aimed to investigate the association between HSF1 gene VNTR expansions and ET in the population of Eastern China. We screened 324 patients and 197 healthy controls (HCs) using fluorescence amplicon length analysis polymerase chain reaction (PCR) then precisely identified and analyzed repeat expansions at this locus by combining repeat-primed PCR with long-read whole-genome sequencing. Despite identifying 18 patients (5.6%) carrying large HSF1 intronic VNTR expansions (>700 bp), our study found no significant difference in the overall distribution of repeat expansion lengths between the entire cohort of 324 ET patients and HCs, nor between familial and sporadic ET subgroups. The amplification of this repetitive sequence in intron 10 of the HSF1 gene does not constitute a universal, major, or reliable genetic risk factor for ET. © 2026 International Parkinson and Movement Disorder Society.