神経有棘赤血球症

IntroductionBlack and Hispanic people are underrepresented in parkinsonism research leading to critical knowledge gaps and reduced quality of care.MethodsWe developed a novel, comprehensive clinical registry in which research eligibility, interest, and participation are actively tracked for all patients at our site to reduce selection bias and streamline recruitment. We also implemented targeted approaches to reduce psychosocial and sociocultural barriers to research participation of Black and Hispanic people. We then performed a retrospective chart review to test the hypothesis that these combined strategies would be associated with racially/ethnically unbiased research recruitment. All follow-up patients with degenerative parkinsonism seen at the Bronx Veterans Affairs Medical Center over a 19-month period were included in the analysis. Primary outcome measures were the approach and acceptance rates for CANPARK, a single-center prospective observational cohort study of American military veterans with parkinsonism.ResultsDuring the study window, 197 parkinsonism patients were seen, 192 were eligible for CANPARK [ages 53-91; 96.4% male; 29.7% Hoehn and Yahr ≥4; 25.0% atypical parkinsonism], 167 (87.0% of eligible patients) were invited to participate (similar in all racial/ethnic groups), and 128 of 159 patients who made a decision whether to participate (80.5%) agreed to enroll. Acceptance rates were comparable in Black (79.4%; p = 0.92) or Hispanic (87.5%; p = 0.43) versus White (80.2%) patients.ConclusionsUsing a novel, real-time clinical registry and targeted approaches, we achieved unbiased recruitment and high participation of Black and Hispanic patients in parkinsonism research. Future studies are needed to evaluate these approaches in other clinical settings.

BACKGROUND: Chorein, the VPS13A gene product whose loss causes chorea-acanthocytosis (ChAc, VPS13A disease), has been implicated in ferroptosis-related vulnerability, but the organellar basis of this phenotype remains unclear. Using VPS13A knockdown (VPS13A-KD) human embryonic kidney 293 (HEK293) cells, we previously found that chorein reduction is associated with impaired ferrous iron (Fe(II)) efflux, increased lipid peroxidation, reduced glutathione peroxidase 4 (GPX4) levels in the cytosolic fraction, and ferrostatin-1-suppressible cell death. METHODS AND RESULTS: In this study, we found that VPS13A-KD cells exhibited significantly elevated lipid peroxidation following treatment with the oxidant tert-butyl hydroperoxide (tBHP), and this increase was markedly suppressed by the iron chelator deferasirox (DFX) or the antioxidant vitamin E (α-tocopherol). DFX treatment induced enlarged vesicular structures in VPS13A-KD cells, showing spatial overlap of Fe(II), lipid peroxidation, and lysosomal signals, suggesting altered vesicular responses to oxidative stress. These enlarged vesicles showed partial spatial overlap with the late endosomal marker RAB7A, consistent with involvement of the late endosomal-lysosomal system. VPS13A-KD cells also exhibited mitochondrial morphological abnormalities, and a subset of enlarged vesicles overlapped with the mitochondrial outer membrane protein TOMM20, suggesting altered interactions between mitochondria and endolysosomal compartments. CONCLUSIONS: These findings suggest that lysosome-associated vesicular changes in VPS13A-KD cells may be associated with altered iron handling, consistent with our previous finding of impaired Fe(II) efflux. Although DFX reduced lipid peroxidation, it was also associated with prominent vesicular alterations, the significance of which remains to be clarified. In contrast, α-tocopherol attenuated oxidative injury without prominent vesicular accumulation in this model.

Chorea-acanthocytosis (ChAc), also referred to as VPS13A-related disease, is a rare autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in VPS13A. Peripheral acanthocytosis, historically considered a diagnostic hallmark, is increasingly recognized as variable and inconsistent. We describe a 47-year-old Moroccan man presenting with progressive gait instability, orolingual chorea, dysarthria, dysphagia, elevated serum creatine kinase, and axonal sensorimotor neuropathy. Repeated peripheral blood smears failed to demonstrate acanthocytosis. Brain MRI showed bilateral caudate and lentiform nucleus atrophy associated with mild non-specific midbrain atrophy. Exome sequencing identified a homozygous pathogenic VPS13A variant: NM_033305.3.3164dupT (p.Leu1055PhefsTer4). The variant was confirmed by Sanger sequencing and classified as pathogenic according to ACMG criteria (Class 5). This report expands the mutational spectrum of VPS13A-related disease and highlights the importance of integrating molecular genetics with clinical and neuroradiological findings for accurate diagnosis, particularly in the absence of peripheral acanthocytosis.

A 29-year-old woman with a novel homozygous VPS13A frameshift variant presented with drug-resistant temporal-lobe epilepsy and severe sensory neuronopathy, but no acanthocytes on repeated blood smears-expanding the phenotypic spectrum of chorea-acanthocytosis beyond its defining haematological feature.