Simone Zittel

The objective was to characterize pain and evaluate quality of life (QoL) in cervical dystonia (CD) by comparing pain profiles with patients affected by orthopedic cervical conditions (OCC) and evaluating differences between CD patients with and without head tremor (HT). Additionally, longitudinal changes after botulinum toxin (BoNT) treatment in CD were assessed. Pain is the most prevalent non-motor symptom in CD. However, its clinical characteristics and underlying mechanisms are incompletely understood. Isolated CD and OCC patients were evaluated regarding pain characteristics and QoL using self-report questionnaires. CD patients additionally underwent blinded motor assessment and were stratified according to the presence of HT. A subset of CD patients was reevaluated 4–6 weeks after BoNT treatment. 49 CD patients and 49 OCC patients were investigated. The overall pain profile was comparable between CD and OCC; only nociceptive pain perception was higher in OCC than in CD. HT in CD patients was associated with increased nociceptive pain and greater QoL impairment. Following BoNT injection in CD, pain and QoL improved significantly. The marked similarities of pain profiles in CD and OCC together with the increased nociceptive pain in CD patients with HT suggest that musculoskeletal mechanisms contribute to pain in CD. Improvement of pain and QoL in CD patients with long disease duration after BoNT treatment indicates the relevant effect on non-motor symptoms. Further studies are needed to clarify the underlying pathophysiology of pain in CD.

Spinocerebellar ataxia type 27B is a recently described autosomal dominant, late-onset cerebellar ataxia caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 ( FGF14 ) gene. Despite being recognized as a frequent adult-onset ataxia, its full clinical spectrum remains incompletely understood. To characterize the neurological, cognitive, and paraclinical phenotype of patients with heterozygous FGF14 repeat expansions (>200) and expand the currently known motor and non-motor features, as well as to assess the co-occurrence of other repeat expansions. In this cross-sectional single-center study, patients with heterozygous FGF14 repeat expansions underwent standardized neurological examination and cognitive screening. Paraclinical data were reviewed when available. 18 patients were included in the study (mean age at onset: 64 [37–79], at examination: 76 [61–94]). They all presented with gait ataxia, most commonly a lateral veering gait with corrective sidesteps. In addition to the core known cerebellar phenotype, we identified other movement-disorder manifestations, including myokymia, myoclonus, dystonia, and parkinsonism, with nigrostriatal degeneration confirmed in one patient. Cognitive impairment was common, with two-thirds of patients fulfilling criteria for cerebellar cognitive–affective syndrome (mean MoCA: 25 [21–29], CCAS: 86.9/120 [62–108]). Worse CCAS and MoCA performance was associated with increasing ataxia severity. FGF14 repeat expansions ranged from 210 to 520, and co-occurrence with heterozygous expansions in RFC1 or ATXN8/ATXN8OS were identified in three patients. Earlier diagnostic misclassification as transient ischemic attack was reported in 33%. These findings expand the known phenotype of spinocerebellar ataxia type 27B, emphasizing it as a multisystem movement disorder.

Pathogenic variants in leucine-rich repeat kinase 2 ( LRRK2 ) ¹ are among the most frequent monogenic causes of Parkinson’s disease (PD) ² and act through a gain-of-function mechanism of increased kinase activity. LRRK2 -targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC–COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.

Impaired cerebellar influence on motor cortical excitability and plasticity has been reported in cervical dystonia (CD) patients, accompanied by the absence of cerebellar brain inhibition (CBI). Polarity-specific modulation of CBI in healthy individuals using cerebellar transcranial direct current stimulation (ctDCS) suggested that ctDCS could normalize abnormal cerebellar output and improve clinical symptom severity in CD. The objective of this study was to determine whether anodal or cathodal ctDCS can modulate neurophysiological parameters of cortico-cortical, cerebello-cortical or afferent inhibition and improve motor symptom severity in CD patients. Fifteen patients with isolated CD participated in a randomized, double-blinded crossover study consisting of three sessions of anodal, cathodal, or sham ctDCS. Before and after each intervention, motor symptom severity and inhibitory circuits of the sensorimotor network were investigated using transcranial magnetic stimulation (TMS), including short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI) and CBI. Baseline TMS measurements showed inhibitory influence of SICI (p < 0.001) and SAI (p < 0.001) in CD patients, whereas CBI had no inhibitory effect (p = 0.281). The different ctDCS interventions caused no significant modulation in any of the inhibitory TMS paradigms investigated. Similarly, motor symptom severity remained unchanged after the ctDCS interventions. A single session of ctDCS was not effective to modulate inhibitory circuits of the sensorimotor network in isolated CD patients. Future studies focusing on repetitive ctDCS interventions or multifocal stimulation protocols are needed to assess the influence on network excitability and connectivity as well as on motor symptoms.

Most patients with a rare movement disorder (MD) do not receive a molecular diagnosis, and the underlying genetic variants and mediating genes remain elusive. Here, we evaluate the diagnostic accuracy of conventional and next-generation sequencing-based genetic testing strategies in a cohort of 2,811 individuals with ataxia, spastic paraplegia and dystonia. Exome sequencing establishes genetic diagnoses in 19.3% of cases, and specificity of phenotypic features and age at testing are positive predictors. Genome analysis ‘beyond the exome’ increases the diagnostic yield by 7.5%, mostly due to the improved detection of structural variants and repeat expansions. Unsolved cases are included in the Solve-RD cohort and subjected to gene-burden analysis, providing evidence for loss-of-function variants in X-chromosomal CD99L2 causing spastic ataxia. Cellular studies show that the transmembrane protein CD99L2 occurs mainly in a ubiquitinated form and serves as an activating interactor of the calcium-dependent protease CAPN1. Ablation of cytoplasmic or extracellular domains of CD99L2 leads to its intracellular mislocalization and abrogation of its interplay with CAPN1. Transcriptome analysis in CD99L2 patient-derived fibroblasts reveals synaptic function-specific disturbances. Impaired CAPN1 activation and dysregulation of downstream neuronal pathways constitute the likely molecular cause for neurodegeneration.

Introduction: Parkinson's disease (PD) is a systems-level disorder, implicating basal ganglia–thalamo–cortical (BTC) and cerebello–thalamo–cortical (CTC) networks. While regional atrophy has been reported, network-wide volumetric profiles and their relevance for subtype classification and symptom association remain underexplored. Methods: We acquired T1-weighted MRI and quantitative susceptibility mapping (QSM) from 40 PD patients and 21 healthy control participants (HC). Volumes were extracted from 19 regions of interest (ROI) within the BTC and CTC networks using a multimodal pipeline. We assessed asymmetry, group differences, and symptom associations using regression models, and applied ridge regression models for PD vs. HC and motor subtype classification. Results: Network-level ROI volumes successfully classified PD vs. HC and PD motor subtypes, with the highest optimistic AUC of 0.88 for PD vs. HC (mean AUC of 0.63) and 0.95 for PD-TD vs. PD-PIGD (mean AUC reached 0.68). The thalamic nuclei and cerebellar lobules I–V, VIIIa, X were identified as key features. Atrophy in the dentate nucleus (DN), substantia nigra–subthalamic complex (SN–STN), and M1 predicted PD. Tremor severity correlated with the ventral lateral posterior thalamus (VLp), VIIb, and SN–STN volumes; bradykinesia severity with the thalamus; and postural instability and gait disturbance (PIGD) with lobule IV. No significant group-level differences for single volumes were found. Conclusion: Multiregional volumetric analysis within the BTC and CTC motor networks uncovered group differences between PD and HC that were not apparent when examining single ROIs alone. These findings highlight that PD-related alterations manifest as distributed volumetric patterns across interconnected motor circuits, supporting their role as imaging biomarkers.

Background: The RAB32 p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce. Objectives: Our aim was to clinically and biologically characterize individuals with PARK‐ RAB32 to gain insights into genotype–phenotype relationships, disease severity, and underlying pathology. Methods: We conducted a literature review following the MDSGene protocol, alongside detailed phenotyping of 11 PARK‐ RAB32 patients and one prodromal individual from the Rostock International PD (ROPAD) study. In addition to comprehensive scale‐based assessments, including olfactory testing, we obtained neuroimaging data and various biomaterials, and performed α‐synuclein seeding assays (SAA) in cerebrospinal fluid in a subset. Results: 83 patients (72 from the literature) were included in the analysis. The median age at onset was 54 (IQR: 46–61) years. Typical parkinsonism with a favorable dopaminergic response was observed in all patients. In our cohort, after a median disease duration of 11 years (IQR: 7–19.5), the mean Movement Disorders Society Modified Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) III score was 38.5 ± 21.8 points. Targeted testing revealed autonomic symptoms were present in all individuals, and 10 of 11 patients had hyposmia. Misfolded α‐synuclein was identified in 2 of 2 patients, but not in the prodromal individual. 123I‐FP‐CIT imaging was available for eight patients, revealing neurodegeneration in all of them. Conclusion: While PARK‐ RAB32 is clinically and likely pathologically similar to idiopathic PD, our study underscores the importance of carefully assessing non‐motor symptoms in this newly described form of PD. According to SynNeurGe criteria, PARK‐ RAB32 is classified as S ⁺ (evidence of synucleinopathy), N ⁺ (neurodegeneration supported by imaging data), and G _P ⁺ (presence of a genetic variant). © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Cervical dystonia (CD) has been recognized as a disorder of the brain’s sensorimotor network. Within this malfunctioning network, the cerebellum plays an important role that needs to be further characterized. Methods: To investigate the structural connectivity of the dentato-rubro-thalamic tract (DRTT), probabilistic tractography was performed in 18 CD patients and 18 matched healthy control (HC) subjects. Connectivity was quantified with fractional anisotropy (FA). Thirteen subjects in each group also participated in a neurophysiological double-blind experiment to investigate the effect of cathodal and sham cerebellar transcranial direct current stimulation (ctDCS) on sensorimotor associative plasticity, as evoked by paired associative stimulation (PAS). The association of FA of the DRTT and neurophysiological parameters was studied with linear models. Results: The FA of the DRTT was not different between the groups and not related to motor symptom severity in CD patients. In the HC group, there was a significant association between the structural connectivity of the DRTT and the effect that cathodal ctDCS had on the PAS effect. This association was not found in CD patients. Conclusions: The microstructural state of the DRTT is a potential biomarker for the efficacy of ctDCS in HC. The lack of this structure–function association in patients is further evidence of abnormal properties of the cerebellar motor network in CD.