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Sorbitol Is a Severity Biomarker for PMM2‐CDG with Therapeutic Implications
Author(s) -
Ligezka An.,
Radenkovic Silvia,
Saraswat Mayank,
Garapati Kishore,
Ranatunga Wasantha,
Krzysciak Wirginia,
Yanaihara Hitoshi,
Preston Graeme,
Brucker William,
McGovern Renee M.,
Reid Joel M.,
Cassiman David,
Muthusamy Karthik,
Johnsen Christin,
MercimekAndrews Saadet,
Larson Austin,
Lam Christina,
Edmondson Andrew C.,
Ghesquière Bart,
Witters Peter,
Raymond Kimiyo,
Oglesbee Devin,
Pandey Akhilesh,
Perlstein Ethan O.,
Kozicz Tamas,
Morava Eva
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26245
Subject(s) - sorbitol , medicine , glycosylation , endocrinology , chemistry , biochemistry
Objective Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2‐congenital 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‐CDG. Methods We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2‐deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2‐CDG for 12 months. Results PMM enzyme activity increased post‐epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2‐deficient fibroblasts, 46% of which improved upon treatment. Total protein N‐glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts’ glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2‐CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2‐CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. Interpretation Epalrestat improved PMM enzyme activity, N‐glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems‐level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well‐tolerated and led to significant clinical improvements in the first pediatric patient with PMM2‐CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2‐CDG. ANN NEUROL 20219999:n/a–n/a