Annals of neurology | 2021
Sorbitol is a severity biomarker for PMM2-CDG with therapeutic implications.
Abstract
OBJECTIVE\nEpalrestat, an aldose reductase inhibitor increases PMM enzyme activity in a PMM2-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, urine polyol levels and fibroblast glycoproteomics in PMM2-CDG patients.\n\n\nMETHODS\nWe performed PMM enzyme measurements, multiplexed proteomics and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months.\n\n\nRESULTS\nPMM enzyme activity increased post-epalrestat treatment. Compared to 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 towards the control fibroblasts glycosylation profile. Sorbitol levels were increased in the urine of 74% of PMM2-CDG patients 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.\n\n\nINTERPRETATION\nEpalrestat 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 PMM2-CDG pediatric patient 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. This article is protected by copyright. All rights reserved.