Kailash P. Bhatia

Background: JAK2 variants are a hallmark of myeloproliferative neoplasms (MPNs), including polycythemia vera and essential thrombocythemia. These disorders are often associated with thrombotic and inflammatory complications. From a movement disorder perspective, chorea is a rare but well‐recognized neurological occurrence in this context, whereas parkinsonism has received limited attention. Objectives: To describe parkinsonian phenotypes in patients with JAK2 ‐mutated MPNs and explore possible pathophysiological links. Methods: We identified five patients with a JAK2 ‐mutated MPNs and parkinsonism and reviewed their demographic and clinical features, neuroimaging, and levodopa response. Results: Parkinsonian phenotypes were heterogeneous, including Parkinson's disease ( n = 2), atypical parkinsonism ( n = 1), motor neuron disease with parkinsonism ( n = 1), and chorea followed by parkinsonism ( n = 1). The latter patient developed parkinsonism approximately 22 months after onset of generalized chorea. When available ( n = 2), DaTscan was abnormal. Levodopa responsiveness was variable. Conclusion: Although JAK2 ‐mutated MPNs and parkinsonism may coexist coincidentally, recent evidence suggests plausible pathophysiological links, including vascular, inflammatory, immune‐mediated, and treatment‐related mechanisms.

Background Childhood neurodegenerative disorders are usually rare, genetic, and life-limiting. Whilst targeted approaches present huge potential, significant hurdles include disease rarity, geographical dispersion of patients, funding, clinical trial design, and execution. Crucially, the paucity of robust biomarkers and objective measures of disease progression hampers evaluation of efficacy, drug development and regulatory approval. To address this paradigm, we developed a Multimodal Multiomics Machine Learning (MMM) framework, integrating large-scale, multi-source patient datasets to generate quantitative metrics for disease stratification and longitudinal tracking. We applied MMM to PLA2G6-associated neurodegeneration (PLAN), an ultra-rare condition currently lacking validated biomarkers, where precision gene therapy approaches are at an advanced preclinical stage. Methods A large, single time-point international natural history study (n = 310) was conducted alongside development of a disease-specific rating scale (CoPLAN-DRS), prospective longitudinal neuroimaging, and multiomic biomarker discovery. Machine learning methods were applied to the integrated dataset. Results Kaplan-Meier analyses enabled estimates for survival and time to loss of ambulation. Multiple clinical, radiological, and biofluid biomarkers were identified, clearly correlating with disease progression. The CoPLAN-DRS and brain MRI Quantitative Susceptibility Mapping showed strong positive correlation with age (rho = 0.69, 0.96 respectively). Nicastrin, a critical structural component of the gamma-secretase complex in Amyloid Precursor Protein (APP) processing, was identified as a novel biomarker. Neurofilament light levels showed strong negative correlation with disease progression (rho = -0.74). The complex multi-dimensional dataset was distilled into a simplified, clinically intuitive Digital Disease Dashboard (DDD), enabling real-time visualisation of disease severity. Conclusions Our study highlights the clinical utility of MMM in integrating multi-dimensional data from rare disease cohorts, delivering an unbiased, data-driven, optimised biomarker set. Condensing this into the DDD provides a pragmatically useful tool for clinicians, facilitating longitudinal tracking of disease. The MMM and DDD have accelerated clinical-trial readiness for PLAN, and potentially applicable to a broad range of neurogenetic disorders.

Background: Sensory tricks (also termed “alleviating maneuvers”) are voluntary maneuvers that transiently alleviate dystonic postures or movements and represent a hallmark clinical feature of dystonia with diagnostic and mechanistic significance. Despite extensive phenomenological description, the evidence base has not been systematically synthesized. Objectives: To characterize the prevalence, phenomenology, clinical effects, predictors, neurobiological mechanisms, and translational relevance of alleviating maneuvers in dystonia, and to prospectively evaluate the feasibility of quantitative synthesis across predefined outcome domains. Methods: A systematic review with a prespecified nested quantitative synthesis was conducted using a preregistered PROSPERO protocol (CRD420251175065). The nested component was defined a priori as a domain‐restricted analytic strategy in which random‐effects meta‐analysis was planned where ≥ 3 conceptually comparable studies were available, and in which the feasibility of pooling was itself treated as a primary methodological outcome. PubMed, Scopus, and the Cochrane Library were searched from inception. Studies reporting original empirical data on alleviating maneuvers in human dystonia of any etiology were included. Qualitative synthesis examined phenomenology, clinical effects, predictors, mechanisms, and translational applications. Heterogeneity was examined separately along clinical, methodological, and outcome‐level dimensions. Results: Of 631 records, 53 studies met inclusion criteria; 31 contributed to qualitative synthesis and 26 to nested quantitative analyses, with 4 contributing to both. No eligible studies in functional or tardive dystonia were identified. Alleviating maneuvers were reported across dystonia subtypes, with prevalence ranging from 13% to 90%; the largest registry cohort (n = 1477) reported effective maneuvers in 68.7% of patients. Acute motor improvements of 30%–50% in head deviation were reported during trick execution, although effects were transient. Responsiveness was associated with shorter disease duration and better response to botulinum toxin. No domain met criteria for formal meta‐analysis; structural barriers were predominantly methodological and outcome‐level rather than clinical. Conclusions: Alleviating maneuvers are a clinically consistent and mechanistically informative feature of dystonia, but their magnitude, durability, and predictors remain inconsistently measured. Standardized paradigms and outcome reporting are required to enable quantitative synthesis and sham‐controlled evaluation of device‐based alleviating‐maneuver analogues.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson’s disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.

BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from 9 families with bi-allelic BORCS5 variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 KO in zebrafish resulted in microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients’ clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotent stem cell–derived forebrain neurons. However, PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.

IntroductionThe trajectory of Subjective well-being (SWB) in such as Parkinson’s disease (PD) and focal/segmental craniocervical dystonia (FSCD) is poorly understood. The aim of this study was to examine changes in SWB (subjective happiness, meaning in life, hope, life satisfaction) and loneliness in PD, FSPD, and healthy controls (HCs) one year after baseline assessment and to identify the most important aspects of change for each patient group.MethodsFifty three people with PD, 41 with dystonia, and 14 HCs completed questionnaires assessing various aspects of SWB and loneliness at baseline and one year later.ResultsSubjective happiness, life satisfaction and loneliness remained stable within each of the groups over the one year period. Over the one year period, group-specific changes were observed in hope and meaning in life. Hope agency declined in PD, increased in FSPD and remained stable in HCs, while hope pathways decreased in PD and remained stable in FSPD and HCs. Presence of meaning in life increased for FSPD, decreased in HCs and remained stable in PD. Search for meaning decreased in FSPD and remained stable for the two other groups.ConclusionsSWB is largely stable over one year, but people with PD show unique vulnerability in hope pathways and agency, likely due to progression of their illness. People with FSPD gained presence of meaning and hope agency over the follow-up period, suggesting their lives felt more purposeful and significant. Larger longitudinal studies over longer follow-up periods are needed.