{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:11:45Z","timestamp":1781788305742,"version":"3.54.5"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Natural\u2010history datasets have become pivotal for drug development and for shaping clinical\u2010practice 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\u2010outcome, and regulatory advances into a practical framework for capturing and interpreting natural\u2010history data, using Gaucher disease (GD) as a paradigm. We reviewed more than 300 peer\u2010reviewed articles (2005\u20132025), FDA guidance documents, and output from large real\u2010world registries. Particular attention was paid to long\u2010read GBA sequencing, biomarkers such as lyso\u2010Gb1, emerging newborn screening programs, and preliminary observational work that points toward multi\u2010state disease modeling. Key observations include: (i) Whole\u2010gene sequencing has expanded genotype\u2013phenotype maps, revealing more than 70 recombinant GBA alleles that confound panel tests; (ii) registry trajectories suggest that formal multi\u2010state models could capture treatment\u2010modified courses and silent endpoints\u2014monoclonal gammopathy, malignancy, Parkinson's disease, pulmonary arterial hypertension\u2014better than current summary statistics; (iii) lyso\u2010Gb1 outperforms legacy biomarkers and now serves as a second\u2010tier newborn\u2010screening marker; (iv) Robust natural\u2010history evidence has already underpinned regulatory approvals across several lysosomal disorders\u2014including olipudase alfa for ASMD, cerliponase alfa for CLN2, vestronidase alfa for MPS VII, and sebelipase alfa for infantile\u2010onset LAL\u2010D\u2014demonstrating that well\u2010curated registries can serve as viable external controls for future LSD submissions. The convergence of deep phenotyping, genotype\u2010aware analytics, and systematic biomarker capture promises to transform natural\u2010history 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\u2010generation therapeutics.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    identifier: NCT00358943, NCT03291223.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70128","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:33:54Z","timestamp":1768293234000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Natural\u2010History Mapping of Lysosomal Storage Disorders (\n                    <scp>LSDs<\/scp>\n                    ): Gaucher Disease as a Model for Precision Care"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5099-1410","authenticated-orcid":false,"given":"Noor Ul","family":"Ain","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Vaishnaw","sequence":"additional","affiliation":[{"name":"Genetic Counseling Class of \u203225 University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod. 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