AIM OF THE STUDY:This study aimed to analyze the most established genetic causes of Parkinson's disease (PD) in a cohort of patients from Czechia. CLINICAL RATIONALE FOR THE STUDY:PD is the second most common neurodegenerative disorder, with both genetic and environmental factors contributing to its pathogenesis. MATERIAL AND METHODS:We examined 214 patients with PD and 186 controls. Each patient underwent an examination using the Montreal Cognitive Assessment to assess the severity of cognitive impairment. Genetic analysis was performed using next- -generation sequencing and multiplex ligation-dependent probe amplification, focusing on mutations in GBA1, LRRK2, PINK1, PRKN, and SNCA genes. RESULTS:Clinically relevant mutations in GBA1 (pathogenic/likely pathogenic or severe/mild/risk variants) were the most frequently observed variants (n = 30; 14.0% of the PD cohort in total), including both known pathogenic mutations and the mild risk allele p.Glu365Lys (n = 12; 5.6% of cases), which was associated with earlier disease onset. Pathogenic mutations were also detected in LRRK2 (n = 2; 0.9%), SNCA (n = 1; 0.5%), and compound heterozygous mutations in PRKN (n = 2; 0.9%). Carriers of heterozygous mutations in PRKN were equally represented in patients and controls. No pathogenic PINK1 mutations were identified. Cognitive impairment was not significantly more frequent in GBA1 mutation carriers (p = 0.320). A positive family history of PD was more common in patients than in healthy controls (n = 51; 24% vs. n = 6; 3%, p < 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS:Our findings highlight notable genetic variability in Czech PD patients, particularly involving GBA1 mutations. However, these variants were not associated with early cognitive decline. The study underscores the value of genetic screening in PD and the need for further research into genotype-phenotype correlations.

BACKGROUND:Although de novo causation in dystonia is widely acknowledged, there have been only a few trio-sequencing analyses in this field. We sought to prioritise de novo variants in dystonia and characterise the clinical and molecular features associated with the top gene candidate identified after genomic matchmaking. METHODS:We (re)assessed exome-sequencing data for de novo variants in genes with strong mutational constraint in a sample of 257 dystonia trios. Via data sharing, we collected information on individuals with variants in KLC1, encoding a subunit of the axonal-transport motor protein kinesin-1. Biophysical, biochemical, and functional studies, including differential scanning fluorimetry, X-ray crystallography, fluorescence-polarisation measurements, and immunoprecipitation from cells were performed for representative KLC1 variants. FINDINGS:Missense and loss-of-function de novo variants in constrained genes without implication in autosomal dominant or X-linked conditions were found in 11.7% (30/257) of cases with dystonia. We then ascertained 7 unrelated patients with movement and neurodevelopmental disorders who harboured distinct, predicted deleterious de novo KLC1 missense variants. These variants clustered within the cargo adaptor-binding tetratricopeptide repeat domain and 3 variants mapped to an identical amino-acid position. Highly similar infantile-onset dystonic-spastic phenotypes were observed in the subjects with the recurrently affected residue. For all functionally tested variants, we observed changes in KLC1 stability and/or altered binding behaviour to known kinesin-1 interactors, such as JIP3, previously associated with dystonia and neurodevelopmental impairment. INTERPRETATION:Our research supports the existence of a kinesinopathy linked to KLC1, featuring phenotypic overlap with diseases related to mutational defects of key interactors of KLC1. The full dystonia de-novo variant compendium is reported as a resource for additional disease-gene discovery. FUNDING:Else Kröner-Fresenius-Stiftung, German Federal Ministry of Education and Research, Technical University of Munich-Institute for Advanced Study, EU Renewal and Resilience Plan, Czech Ministry of Health, European Union-Next Generation EU, Italian Ministry for Universities and Research.

Magnetic resonance imaging (MRI) is a valuable clinical and research tool for patients managed using deep brain stimulation (DBS). Unfortunately, MRI under these conditions is associated with substantial risks, necessitating stringent regulations that limit its clinical and research utility. In addition, magnetic susceptibility differences between DBS hardware and surrounding tissues significantly compromise spatial encoding mechanisms of conventional MRI sequences, resulting in image signal loss and geometric distortions. The impact on gradient-recalled echo echo-planar imaging sequences commonly utilised for functional MRI in DBS settings is particularly severe. This review presents a range of mitigation strategies aimed at both safety and enhanced image quality, spanning innovations in DBS hardware design to advanced MRI sequences capable of addressing issues inherent to the presence of DBS hardware, such as electrode heating and susceptibility artefacts. Additionally, we highlight approaches incorporating the discussed novel postprocessing techniques and functional MRI acquisition protocols, along with their limitations and associated challenges to enable their wider dissemination, with the overarching objective of improving the quality of life of DBS patients.

Despite the remarkable success of deep brain stimulation (DBS) in alleviating Parkinson's disease (PD) symptoms, complexities arising from inherent inter-individual variability and the vast array of available methodologies for functional brain imaging data processing and interpretation have resulted in substantial heterogeneity across published reports. Within this context, advanced modelling approaches offer a promising conceptual framework. However, the optimal criteria and methodological strategies yielding reliable outputs remain to be established. Leveraging a substantial dataset of 104 PD patients managed with subthalamic nucleus DBS, the present study applied nine machine learning algorithms to distinguish between DBS ON and OFF states. The input features were derived from global and local connectivity metrics and BOLD fluctuation amplitudes obtained from resting-state functional magnetic resonance imaging (fMRI) data. Model performance was evaluated using a 5-fold cross-validation with hyperparameter optimization, and the efficacy of various feature maps was systematically compared. The generalizability of classification models was further tested through validation in an independently acquired cohort of 34 additional PD patients. Global connectivity measures when combined with linear modelling approaches-namely logistic regression and linear discriminant analysis-or with support vector classifiers employing nonlinear kernels demonstrated superior classification performance. These models achieved area under receiver operating characteristic curve values of up to 0.82, with comparable performances observed within the validation cohort. Overall, this investigation not only identifies the most promising fMRI metrics and machine learning algorithms for future DBS-fMRI research but also reinforces the prevailing view of network-wide modulation standing at the core of DBS effects.

OBJECTIVE:Genomic sequencing leaves >50% of dystonia-affected individuals without a diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) data from 167 patients with dystonia across a range of ages and presentations. METHODS:We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. The recruited patients had early-onset dystonia in 85.0%, non-focal dystonia in 92.2%, and coexisting features in 76.0%. Thirty-six patient samples with pre-identified variants (36/167, 21.6%) and 131 samples with no previously prioritized diagnostic candidates from genomic sequencing (131/167, 78.4%) were evaluated. RESULTS:We found that >80% of dystonia-associated genes were detected by fibroblast RNA-seq. Expression and splicing aberration analyses produced a manageable number of significant RNA defects affecting dystonia-associated genes. The approach was especially successful in validating pathogenic effects of loss-of-function variants, with disease-relevant RNA-underexpression detected for 66.7% (10/15). Studying aberrant expression and splicing in the context of other pre-identified variant types yielded relevant results in 28.6% (6/21 samples). We obtained a 6.9% (9/131) diagnostic uplift for patients without prior candidates, all of whom exhibited combined dystonia with autosomal recessive inheritance. The new diagnoses from RNA-seq and genomic reanalysis were based on previously neglected splice-region (3/9) and deep(er) intronic (6/9) variants. For the observed events, integration of new machine-learning scores predicted corresponding aberrant gene expression in the brain. INTERPRETATION:Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and offered a modest yield in patients without prior candidate variants. ANN NEUROL 2026;99:1363-1378.

BACKGROUND: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. OBJECTIVE:This systematic review evaluates the clinimetric properties of functional performance COAs in spastic paresis and provides recommendations for their use. METHODS: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. RESULTS: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." CONCLUSIONS: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.

Over the course of Parkinson’s disease (PD), there is considerable intersubject variability in gray matter (GM) loss across a wide range of subcortical structures and cortical areas, which is often predictive of the clinical trajectory of the disease. The biological or clinical factors underlying these individual differences are not well understood. Obstructive sleep apnea (OSA) is a sleep-disordered breathing that is associated with an increased risk of cognitive impairment and neurodegeneration. In this study, we investigated whether moderate-to-severe OSA in untreated de novo PD is linked to more severe GM atrophy compared to PD without OSA and a group of controls. High-resolution structural 3 T MRI T1 and T2-weighted scans were used to estimate subcortical GM volumes and hippocampal subfields, and to perform vertex-wise analyses of cortical thickness and cortical surface area. We found that the presence of OSA was associated with a significant bilateral reduction in hippocampal volume, particularly in the CA1, CA3, and subicular regions, an effect specifically observed in PD patients and not in the control group. These findings suggest that the co-occurrence of OSA and PD may be related to early structural brain changes, highlighting the importance of timely OSA diagnosis and management to potentially delay cognitive decline in PD.

Background: Significant number of patients with Parkinson’s disease (PD) gradually progress to Parkinson’s disease dementia (PDD). Recent proposal for updating current diagnostic criteria for PDD recommends alternative screening tests and broader functional assessments. Objective: To evaluate the diagnostic concordance among algorithms for PDD based on Level I (i.e., screening) criteria and to assess their predictive validity for Level II (i.e., neuropsychological battery) diagnosis. Methods: A cross-sectional retrospective analysis of 190 patients with PD who underwent a comprehensive neuropsychological assessment. A total of 68 diagnostic algorithms were operationalized using combinations of scores derived from the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Functional impairment was based either on the Functional Assessment Questionnaire (FAQ) item 9 or the FAQ total score. Diagnostic concordance was evaluated using Cohen’s κ. Predictive validity for Level II classification was assessed using projection predictive variable selection. Results: Estimated PDD rates ranged from 2.1% up to 16.8%. Concordance was moderate to high among algorithms using the same functional impairment definition (κ FAQ total = 0.75, κ FAQ 9 = 0.86) but substantially lower when functional impairment definitions differed (κ = 0.43). A parsimonious screening model combining MoCA Five Words and MMSE Sevens adequately approximated Level II classification and yielded a prevalence-adjustable heuristic decision rule. Conclusions: Diagnostic outcomes for PDD are sensitive to the choice of cognitive and functional instruments suggesting that different algorithms may capture partially distinct constructs. Minimal screening using selected items can approximate Level II PDD diagnosis, but this simplification entails a trade-off between sensitivity and specificity.

Assessing muscle activity is essential for diagnosis and treatment of movement disorders such as dystonia and spasticity. While task-based muscle functional magnetic resonance imaging (m-fMRI) enables non-invasive imaging of muscle activation, conventional methods rely on comparisons between rest and activity, which are unsuitable for patients with sustained muscle contractions. This pilot study introduces a resting-state muscle fMRI (rs-m-fMRI) approach based on regional homogeneity (ReHo) to evaluate muscle activity from spontaneous BOLD fluctuations during sustained isometric contraction without block-design contrasts. Eight healthy male participants performed separate isometric plantar and dorsal foot flexion tasks during 3 T MRI scanning. rs-m-fMRI data were analyzed using ReHo to assess local synchronization of BOLD signal. Calf muscle activation was quantified as the percentage of suprathreshold z-transformed ReHo voxels within each segmented muscle and activation thresholds were derived via ROC analysis. ROC analysis demonstrated moderate discrimination between expected active and inactive muscle regions (AUC = 0.63), with sensitivity of 0.57 and specificity of 0.61 at the selected threshold. Consistent condition-related differences were observed between active and inactive muscles during both conditions, with a higher percentage of suprathreshold zReHo voxels in voluntarily contracted muscles. This pilot study demonstrates the feasibility of detecting contraction-related ReHo differences using rs-m-fMRI from a single continuous acquisition. The activation threshold was internally calibrated using expected agonist and antagonist muscle groups and therefore does not represent an externally validated classifier. Further studies incorporating independent physiological validation, reproducibility assessment and larger patient cohorts are required before clinical translation.

Background:Mixed movement disorder due to pathogenic variants in the ADCY5 gene (MxMD-ADCY5) is a rare condition characterized predominantly by paroxysmal involuntary choreiform movements involving the limbs, face, and neck, often accompanied by dystonia and myoclonus. Speech disturbances, delayed motor development, cognitive impairment, axial hypotonia, and episodic exacerbations of dyskinesia are also common features. Currently, treatment strategies remain limited; however, several studies indicate a beneficial effect of caffeine in the management of dyskinesia. Objective:This clinical report aims to present a case of MxMD-ADCY5 showing a high therapeutic response to caffeine. To our knowledge, this is the first reported Ukrainian patient with this condition demonstrating dramatic improvement in paroxysmal dyskinesia after treatment with high-dose caffeine. Conclusions:In our clinical observation, administration of caffeine at a total daily dose of 600 mg resulted in significant clinical improvement in an adult patient with MxMD-ADCY5 over a follow-up period of at least 6 months. No adverse events or side effects were reported.

BACKGROUND:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by a typical natural history, including early stagnation, rapid regression, a pseudostationary phase, and late motor deterioration. Seizures, autistic features, breathing abnormalities, stereotypies, and various movement disorders are often present. Currently, the diagnosis of atypical RTT requires a period of regression and fulfillment of at least two main criteria, and at least five of 11 supportive criteria. CASES:We describe five patients (aged 20-61 years), unexpectedly diagnosed with RTT, exhibiting a movement-disorder-predominant phenotype, most commonly dystonia. These patients lacked the typical natural course of RTT and, in most cases, showed preserved social functioning and an essentially normal life. As none of the patients fulfilled the diagnostic criteria for either typical or atypical RTT, we have labeled them as "atypical atypical" RTT. CONCLUSIONS:We recommend a revision of the current diagnostic criteria for RTT to include also more atypical presentations.

BACKGROUND:Deep brain stimulation (DBS) is an essential treatment option for disabling segmental or generalized dystonia. An underlying monogenic etiology is increasingly recognized as an important predictor of DBS outcomes. Moreover, the genetic background of dystonia is continuously expanding, posing new challenges in the tailored counseling of patients regarding advanced therapies. METHODS:To improve the quality of available evidence on the efficacy of DBS for treating monogenic dystonia, we conducted a systematic review in accordance with PRISMA guidelines. We applied a rigorous methodology and maximized the amount of information provided by including all patients, regardless of age or applied rating scale. RESULTS:Our findings confirm the high probability of a good DBS outcome in patients harboring TOR1A, SGCE, PANK2, and TAF1 variants. An intermediate response was associated with KMT2B and THAP1 variants. A particularly favorable outcome with > 80% improvement in dystonia symptoms was associated with a subset of DYT-TOR1A patients and few cases with SGCE-, KMT2B-, THAP1-, GNAO1-, and TAF1-related disease. Poor study quality, non-systematic assessment of DBS response, and pooling of patients with different genetic etiologies were among the encountered limitations. CONCLUSIONS:Based on the collected evidence, we formulated recommendations for applying DBS in monogenic dystonia. Our findings, together with the cumulative literature, advocate the introduction of genetic testing in the pre-DBS work-up. They furthermore highlight the need to implement and report on systematic assessments of DBS outcomes, including mandatory patient-reported outcomes. These steps will ensure optimal counseling and continuous improvement in the care of patients with monogenic dystonia.

Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated.To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations.By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays.This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia. Using whole-genome sequencing and proteomics, Zech et al. have shown that many patients with suspected monogenic dystonia carry mutations that are undetectable with exome analysis alone. Complementary approaches, such as RNA sequencing and functional studies, can improve rates of diagnosis.

Exome and genome sequencing leave >50% of dystonia-affected individuals without a molecular diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics methods and bioinformatics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) from a collection of 167 fibroblast samples from individuals affected with dystonic diseases. We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. We evaluated a “variant-positive” group of patient samples with preexisting information on variants (36/167, 21.6%), and a “variant-negative” group in which genomic sequencing alone had been unsuccessful in yielding a diagnostic candidate (78.4%). We found that at least 80% of dystonia-associated genes from databases were sufficiently detected by RNA-seq in fibroblasts, highlighting broad applicability. Expression and splicing aberration analyses then produced a manageable number of statistically significant RNA defects affecting dystonia-associated genes for effective case-by-case review. Our approach successfully detected RNA underexpression and mis-splicing for different types of pre-identified dystonia-related variants, providing both benchmarks and insights into mutational mechanisms. Applied to 131 samples from patients without candidate variants from exome and genome sequencing, RNA-seq aided the identification of previously unprioritized causative intronic alterations on reanalysis, providing an added diagnostic yield of 6.9% (9/131). For observed events, we also report the integration of new machine-learning scores predicting corresponding aberrant gene expression in the brain. Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and enabled diagnoses missed by genomic analysis alone, suggesting this framework could be generalized to other dystonias.