ゴーシェ病

Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.

PURPOSE: To establish a standardized, clinically relevant nomenclature for myopic traction maculopathy (MTM) that prioritizes lesions based on visual impact and potential prognostic significance. DESIGN: International consensus meeting PARTICIPANTS: Panel of myopia and retinal imaging experts selected by the Myopia Society. METHODS: An international group of experts from the Myopia Society systematically evaluated existing MTM classification systems and their limitations. The panel integrated recent OCT findings to develop a hierarchical nomenclature reflecting disease severity and visual prognosis. The proposed system underwent validation through multi-observer agreement testing to ensure clinical reliability and reproducibility. MAIN OUTCOME MEASURES: Development of a validated nomenclature that accurately describes MTM pathology, predicts visual outcomes, guides clinical management decisions, and facilitates standardized research reporting. RESULTS: The consensus panel identified four primary MTM manifestations arranged in descending order of severity: (1) macular detachment (2) full-thickness macular hole (3) lamellar macular hole (4) retinoschisis. When reporting MTM, the term "myopic" precedes the most severe lesion, followed by any associated lesions in the order of severity (e.g., "myopic macular detachment with full-thickness hole and schisis"). The panel also established specific OCT imaging protocols to standardize diagnosis and progression monitoring. CONCLUSIONS: This new OCT-based anatomical nomenclature for MTM complements existing classification systems by emphasizing clinically relevant, founded in up-to-date imaging-based evidence, and intended to standardize lesion descriptions. By providing a standardized framework for describing complex MTM lesions, the system may help clinicians monitor disease progression and may enable more consistent outcomes reporting in clinical research. Its adoption in future studies should enhance research comparability and support ongoing efforts to improve patient care.

BACKGROUND Gaucher disease (GD) is the most common lysosomal storage disorder caused by glucocerebrosidase deficiency. Type 1 GD (GD1) often presents with nonspecific manifestations, including splenomegaly, cytopenias, growth impairment, and skeletal involvement, leading to delayed diagnosis and irreversible complications. This report highlights the delayed diagnosis of GD1 in a patient with longstanding mild manifestations and emphasizes the importance of considering GD in patients with unexplained cytopenias and splenomegaly. CASE REPORT We describe a male patient with GD1 whose first manifestations appeared in infancy and included splenomegaly. During childhood, persistent cytopenias, hepatosplenomegaly, and growth deceleration were observed; however, the diagnosis remained unrecognized. At age 14, the patient developed severe skeletal pain accompanied by fever, prompting further diagnostic evaluation. Imaging studies revealed bone marrow abnormalities, and bone biopsy demonstrated foamy macrophages but did not establish a definitive diagnosis. At age 15, GD1 was suspected and subsequently confirmed by enzymatic testing, biomarker assessment, and genetic analysis. Enzyme replacement therapy with imiglucerase resulted in clinical improvement, reduced organomegaly, and stabilization of laboratory parameters. The patient subsequently underwent a structured transition from pediatric to adult care without treatment interruption. CONCLUSIONS GD should be considered in patients with unexplained splenomegaly and persistent cytopenias, even when early manifestations are mild and nonspecific. Early recognition and disease-specific diagnostic testing may reduce diagnostic delay, facilitate timely treatment initiation, and help prevent irreversible complications. This case also highlights the importance of a structured transition from pediatric to adult care in maintaining long-term treatment continuity.

BACKGROUND: Neuronopathic Gaucher disease (GD types II and III) represents rare and severe phenotypes of glucocerebrosidase deficiency, characterized by neurological involvement and variable systemic manifestations. Data on clinical presentation and genotype-phenotype patterns in Eastern European populations remain limited. METHODS: We conducted a retrospective cohort study of 92 patients with confirmed Gaucher disease followed at the National Children's Specialized Hospital "Okhmatdyt" (Kyiv, Ukraine) between 2001 and 2024. Among them, 4 patients had type II and 6 had type III GD. Diagnosis was established by measurement of leukocyte β-glucocerebrosidase activity and molecular analysis of the GBA1 gene. Clinical, laboratory, and imaging data were analyzed descriptively. RESULTS: Type II GD presented in early infancy, with symptom onset from birth to 5 months of age (mean age at onset 2.8 ± 2.6 months) and was diagnosed between 5 and 9 months of age (mean 7.0 ± 2.3 months). Initial manifestations included cytopenias, splenomegaly, failure to thrive, and ichthyosiform dermatitis. Hepatomegaly was uncommon at onset, but hepatosplenomegaly was documented in all patients at diagnosis, followed by rapid neurological regression and death by 14 months of age. Type III GD had a mean age at onset of 2.3 ± 1.66 years and a mean age at diagnosis of 13.8 ± 16.87 years, reflecting substantial diagnostic delay. Oculomotor abnormalities were the most frequent presenting manifestations (83%). At diagnosis, all patients exhibited hepatosplenomegaly, cytopenias, and neurological involvement, while liver function remained preserved. Across both phenotypes, GBA1 variant combinations included genotypes predicted to result in very low or absent residual glucocerebrosidase activity, as well as genotypes predicted to retain some residual activity. Severe clinical courses were observed even in patients whose genotypes were predicted to retain residual enzyme activity, suggesting that predicted residual activity alone does not reliably explain clinical severity. CONCLUSIONS: In this Ukrainian cohort, neuronopathic GD demonstrated distinct clinical trajectories, with rapidly progressive infantile disease in type II and heterogeneous presentation with marked diagnostic delay in type III. Hepatosplenomegaly was a common systemic feature during disease progression, but should not be interpreted as an isolated stratifying sign. Its presence, particularly in combination with early or progressive neurological manifestations, should raise suspicion of neuronopathic GD.