Ruth Helen Walker

Background: VPS13A disease is a very rare neurodegenerative disorder caused by mutations in the VPS13A gene. Its prevalence appears to be relatively high in Puerto Ricans, although limited genetic information has been available. Objectives: To describe the genetics of VPS13A disease (chorea‐acanthocytosis) in Puerto Rico. Methods: Data were obtained from Puerto Rican patients with genetically confirmed VPS13A disease. Results: Eighteen cases were identified, all carrying at least one of four mutations, c.1400_1401del, c.3556_3557dup, c.3889C>T, and c.2825‐253_2905‐374del (exon_27‐deletion); six additional single variants were detected. Seizures were the presenting symptom in 53% of patients. Conclusion: The presence of these probable founder mutations could explain the apparently increased prevalence in Puerto Rico; half of the described variants are newly described mutations and half have been previously reported. Enhanced clinical awareness of the spectrum of presenting symptoms and diagnostic clues, and improved access to genetic testing are essential for timely diagnosis in this population.

Introduction: Black and Hispanic people are underrepresented in parkinsonism research leading to critical knowledge gaps and reduced quality of care. Methods: We 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. Results: During 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. Conclusions: Using 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.

The 12th International Meeting on Neuroacanthocytosis, Cohen Syndrome, and other VPS13-related Disorders was held on September 12th–14th, 2025, at the Jules Gonin Eye Hospital in Lausanne, Switzerland. This long-standing series of international symposia has traditionally focused on neuroacanthocytosis syndromes and associated disorders. The program further broadened its scope to include Cohen syndrome, reflecting the growing recognition of shared molecular features and common unsolved questions across VPS13-related disorders. The aim of the meeting was to present the latest updates in the field, from both clinical and basic science perspectives, and to facilitate collaboration and exchange of ideas among researchers, clinicians, and the patient community. An important aspect of these meetings is the active involvement of patients, their relatives and caregivers, who were invited to attend scientific sessions, in addition to participating in parallel patient-oriented sessions. A total of 20 oral communications were presented in eight scientific sessions accompanied by two keynote lectures, short talks by selected poster presenters, and the 2025 “Glenn Irvine Prize” award lecture.

Progressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimer’s disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau (“tauopathies”) by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified six independent PSP susceptibility loci with genome-wide significant ( p < 5×10 ^-8 ) associations including five known ( MAPT , MOBP , STX6 , RUNX2 , SLCO1A2 ) and one novel locus ( C4A ). Integration with cell type-specific epigenomic annotations revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinson’s disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation in MOBP , STX6 , RUNX2 , SLCO1A2 , and C4A in the pathogenesis of PSP.

Background: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea‐acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease‐specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation.Objective: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea‐acanthocytosis).Methods: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case.Results: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62‐ and ubiquitin‐positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one.Conclusions: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.

Chorea is a hyperkinetic movement disorder with a multitude of potential etiologies, both acquired and inherited. Although the differential diagnosis for new-onset chorea is extensive, there are often clues in the history, exam, and basic testing that can help to narrow the options. Evaluation for treatable or reversible causes should take priority, as rapid diagnosis can lead to more favorable outcomes. While Huntington's disease is most common genetic cause of chorea, multiple phenocopies also exist and should be considered if Huntington gene testing is negative. The decision of what additional genetic testing to pursue should be based on both clinical and epidemiological factors. The following review provides an overview of the many possible etiologies as well as a practical approach for a patient presenting with new-onset chorea. Article published online: 07 March 2023 © 2023. Thieme. All rights reserved. Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These are phenotypically similar disorders that affect primarily the basal ganglia and hence result in involuntary abnormal movements as well as neuropsychiatric and cognitive alterations. There are other shared features such as abnormalities of red cell membranes which result in acanthocytes, whose relationship to neurodegeneration is not yet known. Recent insights into the functions of these two proteins suggest dysfunction of lipid processing and trafficking at the subcellular level and may provide a mechanism for neuronal dysfunction and death, and potentially a target for therapeutic interventions.