TY - JOUR
T1 - Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications
AU - Ligezka, Anna N.
AU - Radenkovic, Silvia
AU - Saraswat, Mayank
AU - Garapati, Kishore
AU - Ranatunga, Wasantha
AU - Krzysciak, Wirginia
AU - Yanaihara, Hitoshi
AU - Preston, Graeme
AU - Brucker, William
AU - McGovern, Renee M.
AU - Reid, Joel M.
AU - Cassiman, David
AU - Muthusamy, Karthik
AU - Johnsen, Christin
AU - Mercimek-Andrews, Saadet
AU - Larson, Austin
AU - Lam, Christina
AU - Edmondson, Andrew C.
AU - Ghesquière, Bart
AU - Witters, Peter
AU - Raymond, Kimiyo
AU - Oglesbee, Devin
AU - Pandey, Akhilesh
AU - Perlstein, Ethan O.
AU - Kozicz, Tamas
AU - Morava, Eva
N1 - Publisher Copyright:
© 2021 American Neurological Association.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118126540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85118126540&partnerID=8YFLogxK
U2 - 10.1002/ana.26245
DO - 10.1002/ana.26245
M3 - Article
C2 - 34652821
AN - SCOPUS:85118126540
SN - 0364-5134
VL - 90
SP - 887
EP - 900
JO - Annals of neurology
JF - Annals of neurology
IS - 6
ER -