Natural‐history datasets have become pivotal for drug development and for shaping clinical‐practice guidelines in rare diseases, yet many lysosomal storage disorders would benefit from deep phenotyping and modern analytic methods. Our objective was to integrate the past decade of genomic, cellular, treatment‐outcome, and regulatory advances into a practical framework for capturing and interpreting natural‐history data, using Gaucher disease (GD) as a paradigm. We reviewed more than 300 peer‐reviewed articles (2005–2025), FDA guidance documents, and output from large real‐world registries. Particular attention was paid to long‐read GBA sequencing, biomarkers such as lyso‐Gb1, emerging newborn screening programs, and preliminary observational work that points toward multi‐state disease modeling. Key observations include: (i) Whole‐gene sequencing has expanded genotype–phenotype maps, revealing more than 70 recombinant GBA alleles that confound panel tests; (ii) registry trajectories suggest that formal multi‐state models could capture treatment‐modified courses and silent endpoints—monoclonal gammopathy, malignancy, Parkinson's disease, pulmonary arterial hypertension—better than current summary statistics; (iii) lyso‐Gb1 outperforms legacy biomarkers and now serves as a second‐tier newborn‐screening marker; (iv) Robust natural‐history evidence has already underpinned regulatory approvals across several lysosomal disorders—including olipudase alfa for ASMD, cerliponase alfa for CLN2, vestronidase alfa for MPS VII, and sebelipase alfa for infantile‐onset LAL‐D—demonstrating that well‐curated registries can serve as viable external controls for future LSD submissions. The convergence of deep phenotyping, genotype‐aware analytics, and systematic biomarker capture promises to transform natural‐history registries from descriptive archives into predictive engines. Gaucher disease offers a working template that, when extended across the LSD spectrum, can accelerate precision care and the development of next‐generation therapeutics. Trial Registration: ClinicalTrials.gov identifier: NCT00358943, NCT03291223.

Chronic antigenic stimulation is implicated in the pathogenesis of monoclonal gammopathy and multiple myeloma, yet longitudinal human evidence linking sustained antigen exposure to modifiable clonal plasma cell evolution remains limited. Gaucher disease (GD), caused by biallelic GBA1 pathogenic variants, is characterized by accumulation of glucosylsphingosine (LysoGL1), the direct antigenic target of GD‐associated clonal immunoglobulins and a pharmacologically suppressible stimulus. We conducted a longitudinal retrospective cohort study of 235 adults with GD (3628 person‐years; 2662 clinical visits), with incident‐only ascertainment from a confirmed gammopathy‐free baseline. Thirty‐one patients (13.2%) developed incident monoclonal gammopathy. GD conferred a ninefold excess risk relative to population expectations (SIR 9.04; 95% CI 5.79–13.45). Male sex independently increased hazard 3.3‐fold (HR 3.30; 95% CI 1.55–7.03; p < 0.01), mirroring the established male predominance of plasma cell dyscrasias. GD‐specific therapy, initiated solely for systemic disease indications, was associated with a dose‐dependent reduction in incident risk. In univariate Cox regression with age as the time scale, each additional therapy year conferred a 9% lower hazard (HR 0.91; 95% CI 0.88–0.94; p < 0.001), extending mean MGUS‐free time by 8.4 years between untreated and most‐treated quartiles. Cumulative therapy progressively suppressed circulating LysoGL1, with eliglustat achieving substantially deeper reduction than enzyme replacement therapy alone. Propensity score‐weighted analyses were directionally concordant (IPTW HR 0.19; 95% CI 0.11–0.30; p < 0.001). These findings establish GD as a tractable model of antigen‐driven oncogenesis—and provide a precedent for investigating whether therapeutic reduction of a defined antigenic stimulus can modify oncogenic trajectory in other chronic inflammatory states.

Background/Objectives: Gaucher disease (GD) is characterized by significant phenotypic heterogeneity, even among patients with identical GBA1 genotypes, suggesting the role of genetic and/or epigenetic modifiers. The enzymatic defect and pathological accumulation of glucosylceramide (GlcCer) lead to chronic metabolic inflammation, potentially interacting with other biological pathways to influence disease expression. Methods: This study leveraged one of the world’s most deeply phenotyped cohorts of GD patients, drawn from a major tertiary referral center, with prolonged longitudinal follow-up. Whole exome sequencing (WES) was conducted on 275 extensively characterized patients, focusing on those exhibiting complex phenotypes. Results: Eighteen patients (6.5%) presented with atypical manifestations not fully explained by GD. WES revealed additional genetic diagnoses, including hereditary hemochromatosis (n=5), Familial Mediterranean Fever (n=4), homozygous MSH6 mutation-associated hereditary cancer predisposition (n=2), and others. These concurrent genetic diseases can modify GD presentation and complicate clinical management. Conclusions: This work underscores the importance of recognizing complex phenotypes in GD, identifying modifier genes, and informing precision medicine strategies for improved patient outcomes.

Background: The gut-brain axis is a complex communication system between the gut microbiome, the trillions of bacteria that reside in our intestines, and the central nervous system. This two-way communication pathway is believed to play a significant role in human health and disease. Objectives: This study aims to unravel the microanatomy and functional significance of the human gut-brain axis. In other words, the researchers want to understand the exact anatomical structures and physiological mechanisms that underlie communication between the gut and the brain. Methods: The researchers are likely to employ a combination of techniques to investigate the gut-brain axis. These techniques might include: Histological analysis: This technique involves examining thin slices of tissue under a microscope to reveal the microscopic structure of the gut and brain tissues involved in gut-brain communication. Immunohistochemistry: This technique uses antibodies to identify and localize specific molecules in gut and brain tissues. This can help researchers pinpoint the molecules involved in signaling between the gut and the brain. Functional assays: These assays can be used to measure the activity of various cells and signaling pathways in the gut and brain in response to different stimuli. Results: The study is expected to shed light on the specific anatomical structures and signaling pathways that mediate gut-brain communication. This knowledge could improve our understanding of how the gut microbiome influences brain function and behavior. Conclusion: By elucidating the microanatomy and functional significance of the gut-brain axis, this research may pave the way for novel therapeutic strategies for gut-related disorders and neurological conditions. For example, understanding how gut bacteria influence mood could lead to the development of new probiotics or dietary interventions for treating anxiety or depression.