{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T23:09:13Z","timestamp":1773184153586,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T00:00:00Z","timestamp":1591056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sylvia Toth Charity Foundation"},{"name":"Bartim\u00e9us Foundation"},{"name":"Friends of the Wilhelmina Children's Hospital Foundation"},{"name":"Beat Batten Foundation"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JIMD Reports"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The CLN3 disease spectrum ranges from a childhood\u2010onset neurodegenerative disorder to a retina\u2010only disease. Given the lack of metabolic disease severity markers, it may be difficult to provide adequate counseling, particularly when novel genetic variants are identified. In this study, we assessed whether lymphocyte vacuolization, a well\u2010known yet poorly explored characteristic of CLN3 disease, could serve as a measure of disease severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Peripheral blood obtained from healthy controls and CLN3 disease patients was used to assess lymphocyte vacuolization by (a) calculating the degree of vacuolization using light microscopy and (b) quantifying expression of lysosomal\u2010associated membrane protein 1 (LAMP\u20101), using flow cytometry in lymphocyte subsets as well as a qualitative analysis using electron microscopy and ImageStream analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Quantifying lymphocyte vacuolization allowed to differentiate between CLN3 disease phenotypes (<jats:italic>P<\/jats:italic> = .0001). On immunofluorescence, classical CLN3 disease lymphocytes exhibited abundant vacuole\u2010shaped LAMP\u20101 expression, suggesting the use of LAMP\u20101 as a proxy for lymphocyte vacuolization. Using flow cytometry in lymphocyte subsets, quantifying intracellular LAMP\u20101 expression additionally allowed to differentiate between infection and storage and to differentiate between CLN3 phenotypes even more in\u2010depth revealing that intracellular LAMP\u20101 expression was most pronounced in T\u2010cells of classical\u2010protracted CLN3 disease while it was most pronounced in B\u2010cells of \u201cretina\u2010only\u201d CLN3 disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Lymphocyte vacuolization serves as a proxy for CLN3 disease severity. Quantifying vacuolization may help interpretation of novel genetic variants and provide an individualized readout for upcoming therapies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jmd2.12128","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T06:19:07Z","timestamp":1591165147000},"page":"87-97","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Quantifying lymphocyte vacuolization serves as a measure of <scp>CLN3<\/scp> disease severity"],"prefix":"10.1002","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-6759","authenticated-orcid":false,"given":"Willemijn F. E.","family":"Kuper","sequence":"first","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlies","family":"Oostendorp","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry University Medical Center Utrecht  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte T. 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S.","family":"Nieuwenhuis","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine A.","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tineke","family":"Veenendaal","sequence":"additional","affiliation":[{"name":"Section Cell Biology, Center for Molecular Medicine University Medical Center Utrecht, Utrecht University  Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Klumperman","sequence":"additional","affiliation":[{"name":"Section Cell Biology, Center for Molecular Medicine University Medical Center 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