Christine Klein

Background and Objectives: X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder caused by a retrotransposon insertion with a polymorphic hexanucleotide repeat expansion in the TAF1 gene. While the disease predominantly affects males, female carriers may exhibit a variable phenotypic expression. Neurobiological alterations in asymptomatic female mutation carriers (fMC) remain largely unexplored. We aimed to investigate whether fMC exhibit neurodegenerative changes despite the absence of overt clinical manifestations and to assess their clinical, genetic, and longitudinal correlates using multimodal MRI. Methods: In this cross-sectional and longitudinal multimodal study, 103 female relatives of XDP patients underwent clinical, genetic, and MRI assessments. Forty-two were identified as fMC and 61 as healthy controls (HC). Structural T1-weighted MRI was analyzed using voxel-based morphometry and subcortical volumetry, while susceptibility-weighted imaging assessed iron deposition. Clinical evaluation included standardized motor and cognitive testing. Longitudinal follow-up MRI was available for a subset of participants (20 fMC, 13 HC). Results: fMC exhibited significant striatal atrophy compared to HC, with volume reductions in the caudate (-19.4%), putamen (-18.6%), and pallidum (-28.6%) (all p<0.001), despite the absence of overt movement disorders or cognitive deficits, accompanied by relative cerebellar hypertrophy. In fMC striatal volumes decreased with increasing age (putamen: rho=−0.382, p=0.012; caudate: rho=−0.631, p<0.001) and virtual time from genetically determined estimated age at onset (putamen: rho=−0.406, p=0.008; caudate: rho=−0.660, p<0.001). Susceptibility-weighted imaging revealed increased iron deposition in the caudate in fMC, which increased with greater local atrophy (rho=0.718, p<0.001). No significant longitudinal progression was detected over follow-up intervals of up to 25.5 months. Discussion: Asymptomatic female carriers of the XDP-associated TAF1 variant exhibit significant striatal neurodegeneration and iron accumulation, indicating a dominant-negative effect despite X-linked inheritance. Future longitudinal studies should focus on non-motor features and integrate genetic, imaging, and clinical markers to improve risk stratification and identify the subset of female carriers most likely to benefit from future disease-modifying therapies.

Background Scalable models for Parkinson's disease (PD) genetics in underrepresented populations are needed, as most studies have focused on individuals of European-ancestry, limiting generalisability across ancestral and environmental contexts. Kyrgyzstan has been largely absent from global PD research. Using Kyrgyzstan as a case study, we aimed to develop and evaluate a scalable PD genetics model integrating research and local capacity building. Methods We implemented a stepwise capacity-building framework within a multi-site prospective PD genetics cohort that included participants with PD and controls, with longitudinal follow-up. The framework integrated community engagement, workforce development, specialist clinical services, data governance, clinical phenotyping, biobanking, and genetic data generation. Participants were recruited through a university-affiliated movement disorders clinic and mobile outreach clinics, using a secure electronic data-capture system and Global Parkinson's Genetics Program (GP2)-aligned standards. Feasibility endpoints included recruitment, participation, assessment completeness, and genetic quality-control metrics. Findings Within 20 months, specialist clinical services and a PD registry with biobanking and secure data infrastructure were established, and 1240 participants were enrolled, representing multiple Central Asian ethnicities, including Kyrgyz, Uzbek, Uyghur, Tatar, Kalmyk, and Dungan, and the country's rural-urban distribution. High participation coincided with community engagement and recruitment through mobile clinics and community outreach. Interpretation Embedding capacity building within active research enabled rapid development of neurogenetic and specialist clinical infrastructure in a resource-limited setting. This programme provides a potentially transferable model for equitable inclusion of underrepresented populations in PD genetics and related neurogenetic research in low- and middle-income countries. Funding This project was supported by the Global Parkinson's Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (MJFF).

Background: The VPS35 p.D620N variant causes autosomal dominant Parkinson’s disease (PD) and has been shown to activate the LRRK2 kinase pathway, resulting in increased Rab substrate phosphorylation in peripheral immune cells and elevated urinary bis(monoacylglycero)phosphate (BMP) levels. Recently, a VPS35 variant of unknown significance (c.959C>T; p.A320V) was described in two late-onset sporadic PD patients. Methods: We ascertained a family from the Canary Islands in which six siblings were chronically exposed to high doses of pesticides. Three siblings developed levodopa-responsive, akinetic-rigid PD, while the other three remained unaffected. Whole-exome sequencing was performed in the three affected siblings. The frequency of the resulting candidate variant was assessed in 23,327 PD patients and 9,235 controls from four independent cohorts. Members of this pedigree and unrelated controls were assessed for LRRK2 kinase activity in monocytes and neutrophils and BMP levels in urine. Results: The three affected siblings were all heterozygous for p.A320V, whereas the three unaffected siblings did not carry the variant. In the combined PD case-control cohort, p.A320V was identified in six patients and one control. However, unlike p.D620N, heterozygous carrier status for p.A320V was not associated with increased LRRK2 kinase activity or elevated urine BMP levels. Conclusions: While VPS35 p.A320V co-segregated with PD in this family, it did not exhibit the characteristic LRRK2-associated biomarker signature observed in VPS35 p.D620N carriers. It is possible that p.A320V exerts a subtle effect on VPS35 function that was not captured by the assays performed and that chronic pesticide exposure contributed to disease penetrance in this pedigree.

The genetics of Parkinson’s disease (PD) in underrepresented populations remain poorly characterized, potentially overlooking population-specific contributions. We analyzed 461 Chilean PD cases from a movement disorders center. Pathogenic, likely pathogenic, or GBA1 risk variants were identified in 58 individuals (12.6%), mainly in LRRK2 (50%) and GBA1 (44.8%), while PRKN, SNCA , and SQSTM1 collectively represented 5.2%. All LRRK2 variants were p.G2019S, with an overall frequency of 6.3%, the highest reported in South America, and enrichment of Ashkenazi Jewish ancestry at this locus. These findings characterize the genetic landscape of PD in Chile and support its relevance for LRRK2 -targeted studies.

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.

Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson’s disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry. Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci ( AR , ATXN1 , ATXN2 , ATXN3 , CACNA1A , HTT and THAP11 ), spanning seven ancestries. Among these, ATXN2 expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate ATXN2 repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with ≥32 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, >92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as ATXN3 and THAP11 , showed more ancestry-specific distributions. Clinically, individuals with pathogenic ATXN2 and ATXN3 expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD. This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for ATXN2 with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.

Pathogenic variants in ATP13A2 , which encodes an endolysosomal polyamine exporter, cause Kufor-Rakeb syndrome and are associated with early-onset parkinsonism and related neurodegenerative disorders; however, the mechanisms by which ATP13A2 dysfunction drives disease remain incompletely defined. In Atp13a2 knockout mice, we identified an early, transient reduction in brain polyamines that precedes overt gliosis and behavioural abnormalities. Pharmacological polyamine depletion exacerbates phenotypes, whereas oral supplementation of spermidine, but not spermine, rescues parkinsonian symptoms establishing metabolic polyamine deficiency as a pathogenic driver. Mechanistically, spermidine counteracts microglia lysosomal dysfunction in the brain and exerts mitochondrial antioxidant and anti-inflammatory effects in primary mouse microglia, thereby improving neuronal integrity. In the absence of Atp13a2, microglial spermidine import relies on the related polyamine transporter Atp13a3. Importantly, these findings translate to human systems, whereby spermidine attenuates inflammation in ATP13A2-deficient human differentiated microglia, while postmortem ATP13A2-deficient brain analysis confirms increased microglia reactivity. Spermidine also rescues motor deficits and dopaminergic neuron loss in ATP13A2-deficient Drosophila and other fly parkinsonism models. Together, these findings identify early polyamine dysregulation as a mechanistic contributor to ATP13A2-associated parkinsonism and nominate spermidine supplementation as a potential therapeutic strategy for ATP13A2-driven pathology and possibly a broader range of parkinsonian sub-types.

To better understand the earliest stages of alpha‐synucleinopathy, the Parkinson's Progression Markers Initiative (PPMI) has enrolled participants prior to the diagnosis of Parkinson's disease (PD) or dementia with Lewy Bodies (DLB). In this review, we describe lessons learned from prior enrollment and current strategies for PPMI eligibility. Severe hyposmia remains the strongest clinical predictor of aggregated synuclein as measured by a positive cerebrospinal fluid alpha‐synuclein seed amplification assay (CSF aSyn SAA). CSF aSyn SAA is positive before dopamine transporter binding decreases, as measured by dopamine imaging. PPMI's adaptive eligibility criteria have enabled efficient identification of people in the early stage of neuronal synuclein disease defined by biomarkers alone and can inform future therapeutic studies. ANN NEUROL 2026;100:S26–S35