Evaluation of Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Siblings with Gaucher Disease Discordant for Parkinsonism.

Background: In Gaucher disease (GD), glucocerebrosidase (GCase) deficiency results from biallelic pathogenic GBA1 variants. While GBA1 variants are a major risk factor for Parkinson's disease (PD), most patients with GD never develop parkinsonism.

Objectives: To understand factors impacting PD penetrance in patients with GD by comparing induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DANs) from GD siblings discordant for PD.

Consensus Guidance for Genetic Counseling in GBA1 Variants: A Focus on Parkinson's Disease.

Glucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving.

Phenotypic consequences of GBA1 pathological variant R463C (p.R502C).

Gaucher disease (GD) is an autosomal recessively inherited lysosomal storage disorder caused by biallelic pathological variants in the GBA1 gene. Patients present along a broad clinical spectrum, and phenotypes are often difficult to predict based on genotype alone. The variant R463C (p.

Comparative study of enriched dopaminergic neurons from siblings with Gaucher disease discordant for parkinsonism.

Inducible pluripotent stem cells (iPSCs) derived from patient samples have significantly enhanced our ability to model neurological diseases. Comparative studies of dopaminergic (DA) neurons differentiated from iPSCs derived from siblings with Gaucher disease discordant for parkinsonism provides a valuable avenue to explore genetic modifiers contributing to -associated parkinsonism in disease-relevant cells. However, such studies are often complicated by the inherent heterogeneity in differentiation efficiency among iPSC lines derived from different individuals.

Factors Related to the Development of Infective Endocarditis in Hemodialysis Patients in a Third-Level Hospital in Panama.

Introduction: Venous access for hemodialysis (HD) makes patients more susceptible to transient bacteremia, predisposing them to the development of infective endocarditis (IE). Among the risk factors observed in this population are temporary access to HD, hypoalbuminemia, diabetes mellitus, female gender, anemia, and colonization by methicillin-resistant (MRSA).

Methodology: A retrospective case-control study with a one-to-two ratio was carried out on patients with chronic kidney disease (CKD) undergoing renal replacement therapy with at least one vascular access for HD at Complejo Hospitalario Dr.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

Background: In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system.

Revisiting the diagnosis of Gaucher disease in a family with multiple GBA1 variants.

Our ability to identify different variants in GBA1, the gene mutated in the lysosomal storage disorder Gaucher disease (GD), has greatly improved. We describe a multigenerational family with type 1 GD initially evaluated over three decades ago. Re-evaluating both the genotype and phenotype, we determined that one family member with genotype N370S/T369M (p.

Rapid-Onset Dystonia and Parkinsonism in a Patient With Gaucher Disease.

Biallelic mutations in GBA1 cause the lysosomal storage disorder Gaucher disease, and carriers of GBA1 variants have an increased risk of Parkinson's disease (PD). It is still unknown whether GBA1 variants are also associated with other movement disorders. We present the case of a woman with type 1 Gaucher disease who developed acute dystonia and parkinsonism at 35 years of age during a recombinant enzyme infusion treatment.

The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era.

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries.

Polygenic Parkinson's Disease Genetic Risk Score as Risk Modifier of Parkinsonism in Gaucher Disease.

Background: Biallelic pathogenic variants in GBA1 are the cause of Gaucher disease (GD) type 1 (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. Heterozygous GBA1 variants are also a common genetic risk factor for Parkinson's disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk for PD.

Longitudinal evaluation of olfactory function in individuals with Gaucher disease and mutation carriers with and without Parkinson's disease.

Objective: Biallelic mutations in , which encodes the lysosomal enzyme glucocerebrosidase, cause the lysosomal storage disorder Gaucher disease (GD). In addition, mutations in are the most common genetic risk factor for future development of Parkinson's disease (PD). However, most mutation carriers will never develop parkinsonism.

Neuropathological Features of Gaucher Disease and Gaucher Disease with Parkinsonism.

Deficient acid β-glucocerebrosidase activity due to biallelic mutations in results in Gaucher disease (GD). Patients with this lysosomal storage disorder exhibit a wide range of associated manifestations, spanning from virtually asymptomatic adults to infants with severe neurodegeneration. While type 1 GD (GD1) is considered non-neuronopathic, a small subset of patients develop parkinsonian features.

Imaging and genetics in Parkinson's disease: assessment of the GBA1 mutation.

Introduction: Several genetic variants are associated with an increased risk for developing Parkinson's Disease (PD) and limited genotype/phenotype correlation. Specifically, mutations in GBA1, the gene coding for the lysosomal enzyme glucocerebrosidase, are associated with an earlier age of onset and faster disease progression. Given these phenotypic differences associated with GBA1 variants, we explored whether cortical thickness and other biomarkers of neurodegeneration differed in healthy controls and PD patients with and without GBA1 variants.

Comparison of Transcranial Sonography and [ F]-Fluorodopa PET Imaging in GBA1 Mutation Carriers.

Background: Mutations in GBA1 are a common genetic risk factor for parkinsonism; however, penetrance is incomplete, and biomarkers of future progression to parkinsonism are needed. Both nigral sonography and striatal [ F]-FDOPA PET assay dopamine system health, but their utility and coherence in this context are unclear.

Objective: The aim of this study is to evaluate the utility and coherence of these modalities in GBA1-associated parkinsonism.

α-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease.

Background: Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported.

EEG abnormalities in patients with chronic neuronopathic Gaucher disease: A retrospective review.

The clinical phenotype of Gaucher disease type 3 (GD3), a neuronopathic lysosomal storage disorder, encompasses a wide array of neurological manifestations including neuro-ophthalmological findings, developmental delay, and seizures including progressive myoclonic epilepsy. Electroencephalography (EEG) is a widely available tool used to identify abnormalities in cerebral function, as well as epileptiform abnormalities indicating an increased risk of seizures. We characterized the EEG findings in GD3, reviewing 67 patients with 293 EEGs collected over nearly 50 years.

Parkinsonism in Patients with Neuronopathic (Type 3) Gaucher Disease: A Case Series.

Background: The link between Parkinson's disease (PD), the second most common neurodegenerative disorder, and nonneuronopathic Gaucher disease (GD) is well established. Currently, PD is primarily associated with nonneuronopathic GD; however, with currently available treatments, patients with chronic neuronopathic GD, who historically had a shortened life span, are now living well into their 50s and beyond.

Cases: We highlight 4 patients with chronic neuronopathic GD with parkinsonian features, describing their GD genotype and phenotype as well as the presentation and progression of their parkinsonism.

Pro-cathepsin D, Prosaposin, and Progranulin: Lysosomal Networks in Parkinsonism.

Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are a risk factor for parkinsonism. Pursuing the potential mechanisms underlying this risk in aging neurons, we propose a new network uniting three major lysosomal proteins: (i) cathepsin D (CTSD), which plays a major role in α-synuclein (SNCA) degradation and prosaposin (PSAP) cleavage; (ii) PSAP, essential for GCase activation and progranulin (PGRN) transport; and (iii) PGRN, impacting lysosomal biogenesis, PSAP trafficking, and CTSD maturation. We hypothesize that alterations to this network and associated receptors modify lysosomal function and subsequently impact both SNCA degradation and GCase activity.

The natural history of type 2 Gaucher disease in the 21st century: A retrospective study.

Objective: To gather natural history data to better understand the changing course of type 2 Gaucher disease (GD2) in order to guide future interventional protocols.

Methods: A structured interview was conducted with parents of living or deceased patients with GD2. Retrospective information obtained included disease presentation, progression, medical and surgical history, medications, family history, management, complications, and cause of death, as well as the impact of disease on families.