{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:11:10Z","timestamp":1792455070137,"version":"4.5.0"},"reference-count":53,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T00:00:00Z","timestamp":1768003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agios Pharmaceuticals, Inc. \u00a9","award":["PI-19-013"],"award-info":[{"award-number":["PI-19-013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hereditary spherocytosis (HS) is the most common inherited red blood cell (RBC) membrane disorder and has traditionally been attributed to defects in cytoskeletal proteins such as spectrin, ankyrin, band 3, and protein 4.2. Growing evidence, however, shows that disturbances in ion transport also contribute to HS pathophysiology. This review summarizes current understanding of HS by integrating membrane structural defects with abnormalities in ion homeostasis and highlights the diagnostic value of osmotic gradient ektacytometry (OGE). Beyond membrane instability, HS erythrocytes exhibit increased cation permeability with abnormal Na+ influx and K+ loss, leading to cellular dehydration, elevated mean corpuscular hemoglobin concentration (MCHC), and reduced deformability. Dysregulation of mechanosensitive and Ca2+-activated K+ channels (PIEZO1, KCNN4) may modulate disease expression. OGE\u2014now the reference functional test for RBC deformability\u2014identifies reproducible phenotypes reflecting hydration status, including dehydrated (HS1) and partially hydrated (HS2) HS profiles. When combined with next-generation sequencing (NGS), OGE improves differentiation between HS and overlapping membranopathies such as hereditary xerocytosis or stomatocytosis. In conclusion, HS is a multifactorial disorder resulting from the interplay between cytoskeletal fragility, oxidative stress, and dysregulated ion transport. Integrated diagnostic strategies that combine hematologic indices, OGE, and targeted NGS enhance diagnostic accuracy, support genotype\u2013phenotype interpretation, and guide individualized clinical management. Future efforts should focus on ion-channel modulation and wider adoption of functional assays in precision hematology.<\/jats:p>","DOI":"10.3390\/ijms27020721","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T09:13:01Z","timestamp":1768209181000},"page":"721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hereditary Spherocytosis: Linking Ion Transport Defects to Osmotic Gradient Ektacytometry Profiles\u2014A Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Joan Llu\u00eds","family":"Vives-Corrons","sequence":"first","affiliation":[{"name":"Rare Anemias Ektacytometry Unit, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Krishnevskaya","sequence":"additional","affiliation":[{"name":"Rare Anemias Ektacytometry Unit, Josep Carreras Leukaemia Research Institute, 08916 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1016\/S0140-6736(08)61588-3","article-title":"Hereditary spherocytosis","volume":"372","author":"Perrotta","year":"2008","journal-title":"Lancet"},{"key":"ref_2","first-page":"12","article-title":"Clinical aspects and pathogenesis of hereditary spherocytosis","volume":"38","author":"Iolascon","year":"2016","journal-title":"Int. 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