{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:38:02Z","timestamp":1791326282077,"version":"4.3.1"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["18B4322N"],"award-info":[{"award-number":["18B4322N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["1U54NS115198"],"award-info":[{"award-number":["1U54NS115198"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"Objective<\/jats:title>Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2\u2010congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2\u2010CDG.<\/jats:p><\/jats:sec>Methods<\/jats:title>We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2\u2010deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8\u2009mg\/kg\/day oral epalrestat were studied in a child with PMM2\u2010CDG for 12\u2009months.<\/jats:p><\/jats:sec>Results<\/jats:title>PMM enzyme activity increased post\u2010epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2\u2010deficient fibroblasts, 46% of which improved upon treatment. Total protein N\u2010glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts\u2019 glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2\u2010CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2\u2010CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3\u2009months and blood transferrin glycosylation normalized in 6\u2009months.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Epalrestat improved PMM enzyme activity, N\u2010glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems\u2010level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well\u2010tolerated and led to significant clinical improvements in the first pediatric patient with PMM2\u2010CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2\u2010CDG. ANN NEUROL 20219999:n\/a\u2013n\/a<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26245","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T12:26:07Z","timestamp":1634732767000},"page":"887-900","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Sorbitol Is a Severity Biomarker for PMM2\u2010CDG<\/scp> with Therapeutic Implications"],"prefix":"10.1002","volume":"90","author":[{"given":"Anna N.","family":"Ligezka","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Rochester MN"},{"name":"Department of Medical Diagnostics, Faculty of Pharmacy Jagiellonian University Medical College Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Radenkovic","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics Mayo Clinic Rochester MN"},{"name":"Laboratory of Hepatology, Department of CHROMETA 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