BackgroundSpinocerebellar ataxia 27A (SCA27A) is a rare neurodegenerative disorder characterized by childhood‐onset tremor and progressive cerebellar dysfunction. SCA27A is usually caused by loss‐of‐function FGF14 variants.ObjectivesWe report the identification of a novel FGF14 variant in a five‐generation family with autosomal dominant ataxia and describe the clinical phenotype and response to subthalamic nucleus deep brain stimulation (STN‐DBS) and 4‐aminopyridine (4‐AP).MethodsWhole genome sequencing was performed on the proband, two affected sisters (Patients 2 and 3), and one unaffected sister (III5). Sanger sequencing was performed to confirm the variant and sequence additional family members.ResultsA novel heterozygous in‐frame deletion (p.Val119del) in FGF14 was identified in this family affected by childhood‐onset tremor followed by late‐onset progressive ataxia. Two patients showed significant tremor reduction following STN‐DBS and balance improvement with 4‐AP.ConclusionsWe identified a novel likely pathogenic FGF14 variant segregating in a family with SCA27A. Additionally, we suggest STN‐DBS and 4‐AP as promising treatment options for this condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundSpinocerebellar ataxia type 2 (SCA2) is a rare, inherited neurodegenerative disease characterized by progressive deterioration in both motor coordination and cognitive function. Atrophy of the cerebellum, brainstem, and spinal cord are core features of SCA2; however, the evolution and pattern of whole‐brain atrophy in SCA2 remain unclear.ObjectiveWe undertook a multisite, structural magnetic resonance imaging (MRI) study to comprehensively characterize the neurodegeneration profile of SCA2.MethodsVoxel‐based morphometry analyses of 110 participants with SCA2 and 128 controls were undertaken to assess groupwise differences in whole‐brain volume. Correlations with clinical severity and genotype, and cross‐sectional profiling of atrophy patterns at different disease stages, were also performed.ResultsAtrophy in SCA2 versus controls was greatest (Cohen's d >2.5) in the cerebellar white matter (WM), middle cerebellar peduncle, pons, and corticospinal tract. Very large effects (d >1.5) were also evident in the superior cerebellar, inferior cerebellar, and cerebral peduncles. In the cerebellar gray matter (GM), large effects (d >0.8) were observed in areas related to both motor coordination and cognitive tasks. Strong correlations (|r| > 0.4) between volume and disease severity largely mirrored these groupwise outcomes. Stratification by disease severity exhibited a degeneration pattern beginning in the cerebellar and pontine WM in preclinical subjects; spreading to the cerebellar GM and cerebro‐cerebellar/corticospinal WM tracts; and then finally involving the thalamus, striatum, and cortex in severe stages.ConclusionThe magnitude and pattern of brain atrophy evolve over the course of SCA2, with widespread, nonuniform involvement across the brainstem, cerebellar tracts, and cerebellar cortex; and late involvement of the cerebral cortex and striatum. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundDysregulated leukotriene signaling is proposed to be involved in pathogenesis of Parkinson's disease (PD).ObjectiveThe objective was to examine the safety and tolerability of montelukast, a cysteinyl‐leukotriene receptor1 and GPR17 antagonist, in patients with PD. Secondary outcomes were target engagement, effects on PD signs/symptoms, and central neuroinflammation.MethodsFifteen PD patients were recruited to a 12‐week open‐label trial of 20 mg bi‐daily montelukast treatment. Patients underwent ratings with the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS‐UPDRS), the Montreal Cognitive Assessment (MoCA), Beck's Depression Inventory (BDI), Parkinson's Disease Questionnaire‐39 (PDQ‐39), [11C]PBR28‐PET, and lumbar punctures before and during montelukast treatment.ResultsAll patients completed the study. Three patients reported loose stool. No serious adverse events related to treatment were reported. MDS‐UPDRS‐Total scores improved by 6.9 points. Very low levels of montelukast were detected in all cerebrospinal fluid (CSF) samples and resulted in a reduction in inflammation/metabolism markers. [11C]PBR28 binding was lowered in high, but not mixed, affinity binders after montelukast.ConclusionsMontelukast crosses the blood–brain barrier at very low levels and is well tolerated and safe in PD patients. Preliminary effects on neuroinflammation and clinical scores motivate a future randomized controlled trial (RCT) in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundThe Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS‐UPDRS), Part III, is the gold standard for assessing motor symptoms in Parkinson's disease (PD). However, motor symptoms fluctuate significantly from day to day, potentially limiting the sensitivity of this scale for trials with short duration and crossover designs. This study investigated whether day‐to‐day variability in motor symptoms exceeds the minimal clinically important difference (MCID) in the MDS‐UPDRS, Part III.MethodsTwenty PD participants (Hoehn & Yahr stages 1.5–3) underwent 10 weekly off‐medication assessments by one assessor on the same morning. Several determinants of day‐to‐day variability were explored.ResultsSymptom variability often exceeded the MCID for worsening and improvement. Current mental stress and fatigue did not correlate with worse scores, nor did physical activity and sleep quality in the previous week.ConclusionsThese findings suggest that day‐to‐day symptom variability impacts MDS‐UPDRS scores in smaller and shorter‐duration trials of symptomatic interventions. Continuous monitoring using wearable sensors may offer more accurate and reliable measures for evaluating PD motor symptoms in clinical studies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundIsolated rapid‐eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha‐synucleinopathies. Resting‐state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra‐ and inter‐network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear.ObjectiveTo characterize intra‐ and inter‐network rsFC in iRBD patients using a data‐driven approach and to assess its associations with clinical features and cognitive functioning.MethodsForty‐two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting‐state networks were characterized using independent component analyses. Group differences in intra‐ and inter‐network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses.ResultsiRBD patients displayed lower intra‐network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non‐motor symptoms in iRBD patients. Reduced inter‐network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status.ConclusionsiRBD is characterized by both reductions in intra‐network rsFC in cortical and subcortical networks and inter‐network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra‐ and inter‐network rsFC are associated with cognitive performance and non‐motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha‐synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundPerry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin (DCTN1). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin.ObjectivesLittle is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains.MethodsWe evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology.ResultsInsoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs (ACTL6B, CAMK2B, STMN2, UNC13A, KCNQ2, ATG4B, GPSM2, and HDGFL2) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A, reached significance in the substantia nigra despite similar pTDP‐43 levels.ConclusionWe detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background and ObjectiveRecently, RAB32 has been identified as possibly linked to Parkinson's disease. We studied the prevalence and clinical correlates of the p.Ser71Arg variant in the RAB32 gene in a large case series of Italian patients with Parkinson's disease or atypical parkinsonism.MethodsA single‐center cohort with a case‐control component (consecutively collected at the Parkinson Institute of Milan between 2002 and 2023) was screened for the RAB32 p.Ser71Arg variant. Detailed clinical characteristics of carriers were reviewed. Healthy control subjects were partners or unrelated caregivers. The variant was detected by a TaqMan polymerase chain reaction assay.ResultsA total of 4600 patients (3762 with PD and 838 with atypical parkinsonisms) and 1722 healthy control subjects were consecutively included in the study. We identified 20 new variant carriers that, together with the 8 previously identified, had younger age at onset than noncarriers (51.0 ± 10.7 vs. 58.3 ± 11.0 years, respectively; P = 0.01). All carriers had a good response to dopaminergic therapy and device‐aided therapies. Carriers had mild or no cognitive decline and mild or no depressive symptoms; six had impulse control disorders and one a REM behavior disorder. Family history was positive in 55.5% of cases versus 22.0% of patients without the variant (P < 0.001) and was compatible with a dominant pattern of inheritance. The variant was not identified in patients with atypical parkinsonisms.ConclusionsThis study confirms that RAB32 is associated with a relatively young adult‐onset PD with a favorable therapeutic response. This variant should be included in genetic panels used for the diagnosis of familial and/or relatively young‐onset PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.