ゴーシェ病

Gaucher disease is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency of acid beta-glucocerebrosidase (Enzyme Commission 3.2.1.45). Its clinical presentation is polymorphic, dominated by hepatosplenomegaly and cytopenias, and may mimic a malignant hematologic disorder or a chronic infection. This is a clinical case report compiled in the pediatrics department of the Yalgado Ouédraogo University Hospital Center. The patient was a four-year-old boy with a history of chronic malnutrition and multiple hospitalizations in various hospitals across the country. He was admitted for abdominal distension that had been present for two years, associated with recurrent epistaxis and severe bicytopenia. Clinical signs on admission included good general condition, pallor of the skin and mucous membranes, and hepatosplenomegaly. Laboratory findings revealed bicytopenia on the complete blood count and hyperproteinemia. The progression to pancytopenia led to the performance of a myelogram, which revealed numerous foam cells resembling Gaucher cells, raising suspicion of a constitutional lysosomal storage disorder. Enzyme assay confirmed a glucocerebrosidase deficiency, leading to a diagnosis of Gaucher disease type 1. Treatment was symptomatic, and the patient died the day before the enzyme assay results were received, eighty-four days after his initial admission to our hospital. This case illustrates the difficulties and consequences of delayed diagnosis in countries with limited resources and technical capabilities.

Endothelial dysfunction underlies many cardiovascular and metabolic diseases. Lysosomal storage disorders, particularly sphingolipidoses, cause intracellular accumulation of specific sphingolipids due to inherited enzyme defects. This review focuses on Gaucher, Niemann-Pick (types A, B, A/B) and Fabry diseases, selected because they exhibit clinically significant cardiovascular manifestations and each accumulates a distinct sphingolipid-glucocerebroside, sphingomyelin, or globotriaosylceramide-allowing comparative analysis of how different metabolic defects converge on similar endothelial phenotypes. We summarize current knowledge on how substrate accumulation disrupts the ceramide/sphingosine-1-phosphate (S1P) rheostat, affecting NO synthase, vascular permeability, inflammation, angiogenesis, autophagy and cell death. Common and disease-specific changes in endothelial morphology and barrier function are discussed. Importantly, direct experimental evidence for endothelial involvement in Gaucher and Niemann-Pick diseases remains scarce; most mechanistic insights derive from non-endothelial cell models, highlighting a significant gap that underscores the need for targeted endothelial studies. Deficiencies of GBA1, SMPD1, and GLA each modulate S1P and ceramide production through distinct pathways, yet all three conditions share similar functional endothelial alterations driven by disrupted sphingolipid homeostasis. Understanding these common mechanisms opens new perspectives for diagnostic biomarkers and therapeutic strategies aimed at restoring sphingolipid balance in the endothelium, though further research is required to validate these findings in endothelial-specific contexts.

Adeno-associated virus (AAV) delivery of lysosomal enzymes to the brain is currently being tested in several clinical trials. However, publicly available non-human primate (NHP) studies comprehensively reporting biodistribution, transgene expression, and safety across the central nervous system (CNS) remain limited. Here, we examined AAV9-GBA1 (encoding glucocerebrosidase [GCase]) delivery to mice and NHPs. Loss-of-function GBA1 mutations cause Gaucher's disease and are risk factors for Parkinson's disease and dementia with Lewy bodies. In mice, early postnatal intracerebroventricular administration produced appreciable transgene expression and increased GCase activity in the brain without adverse findings. Two independent adult NHP studies evaluated AAV9-GBA1 brain delivery via intracisterna magna (ICM) and intraparenchymal (IPa) administration. ICM delivery produced considerable transgene expression in the spinal cord and dorsal root ganglia (DRG) neurons along with adverse microscopic findings, but limited brain expression and activity. In contrast, IPa delivery into the thalamus and/or putamen produced substantial transgene expression and GCase activity in injected and connected brain regions, with limited effects in distal regions, including the spinal cord. While no AAV-related DRG toxicity was detected with IPa, procedure- and AAV9-GBA1-related adverse microscopic brain findings were observed and associated with clinical outcomes. Further technological advances are needed to achieve safe and therapeutic AAV transgene expression in NHP brain.

Rare neurological diseases (RND) represent a growing but underrecognized global health burden, particularly in aging populations in whom clinical manifestations appear later in life, resulting in substantial morbidity, reduced quality of life, and increased mortality. Advances in understanding and treating these diseases have been hindered by low prevalence, phenotypic heterogeneity, and complex molecular mechanisms. Importantly, shared genetic and mechanistic links between rare and common neurodegenerative disorders, such as GBA1 (Glucosylceramidase Beta 1) gene variant-associated Gaucher disease (GD) and Parkinson's disease (PD), highlight convergent biological pathways that may be leveraged for biomarker discovery and therapeutic innovation. Notably, individuals heterozygous for pathogenic GBA1 variants, historically considered asymptomatic carriers, are now recognized to have an increased lifetime risk of developing PD and related synucleinopathies. This emerging evidence indicates that even single-allele variants can confer long-term neurological risk, reinforcing the continuum between rare monogenic disorders and more common neurodegenerative diseases. Extracellular Vesicles (EVs) have emerged as a promising, minimally invasive platform for advancing RND research, although translation remains limited by source specificity, vesicle heterogeneity, and incomplete clinical validation. By encapsulating proteins, lipids, and nucleic acids that reflect their cellular origin and disease state, EVs offer unique opportunities for early diagnosis, disease stratification, longitudinal monitoring, and assessment of treatment responses. In this review, we summarize fundamental aspects of EV biology and critically evaluate recent advances in EV-based biomarker discovery for RND, informed by translational insights from more prevalent neurodegenerative conditions. We further discuss the therapeutic potential of EVs, emphasizing their intrinsic biocompatibility, their reported capacity in selected preclinical settings to traverse biological barriers, including the blood-brain barrier, and their versatility as carriers for neuroprotective and gene-modifying cargo. Finally, we address key technical and translational challenges, including isolation, characterization, scalability, and regulatory considerations that currently limit clinical adoption. Collectively, this review highlights emerging opportunities and outlines an integrative translational perspective for EV-based diagnostic and therapeutic strategies into research and clinical paradigms for aging individuals affected by RND.

OBJECTIVES: To evaluate the short- and long-term clinical and laboratory outcomes of Enzyme Replacement Therapy (ERT) in Indian patients with Gaucher disease (GD) and to identify factors influencing the therapeutic response. METHODS: This retrospective, multicentre cohort study included 204 patients with confirmed GD across 13 Indian centres. Eligible participants had received at least one year of ERT and provided both baseline and follow-up data. Patients were stratified by splenectomy status. Longitudinal outcomes assessed over 1-5, 10, and 15 y included hemoglobin levels, platelet counts, liver and spleen volumes, chitotriosidase activity, bone pain, bone mineral density (BMD), and height/weight Z-scores. Subgroup analyses evaluated the impact of age at ERT initiation, GD subtype, genotype, and baseline disease severity. RESULTS: Of the 204 patients, 173 were non-splenectomised and 31 were post-splenectomy; notably, 136 (66.7%) presented with the GD3 phenotype. The median age at symptom onset, diagnosis, and ERT initiation was 1.5 y, 2.6 y, and 4.3 y respectively. The p.L483P allele was the predominant variant in the cohort. Within the first 1-5 y of ERT, non-splenectomised patients demonstrated marked improvements in hematological parameters, organomegaly, biomarker activity, growth metrics, and bone pain. These improvements were sustained through 10-15 y, characterized by stabilized visceral parameters, persistently low biomarker levels, steady growth, and a low incidence of new skeletal complications. Early initiation of ERT was associated with a greater magnitude of hematological response as early as 1 y. CONCLUSIONS: ERT facilitates rapid clinical and laboratory improvements within 1-5 y, with benefits sustained over 10-15 y in Indian GD patients. Despite significant diagnostic delays and the advanced stage of disease at presentation common in this population, long-term outcomes remain highly favourable. Early initiation of ERT is critical for optimizing treatment response and preventing irreversible sequelae.