Abstract | OBJECTIVE: 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.
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Authors | Anna N Ligezka, Silvia Radenkovic, Mayank Saraswat, Kishore Garapati, Wasantha Ranatunga, Wirginia Krzysciak, Hitoshi Yanaihara, Graeme Preston, William Brucker, Renee M McGovern, Joel M Reid, David Cassiman, Karthik Muthusamy, Christin Johnsen, Saadet Mercimek-Andrews, Austin Larson, Christina Lam, Andrew C Edmondson, Bart Ghesquière, Peter Witters, Kimiyo Raymond, Devin Oglesbee, Akhilesh Pandey, Ethan O Perlstein, Tamas Kozicz, Eva Morava |
Journal | Annals of neurology
(Ann Neurol)
Vol. 90
Issue 6
Pg. 887-900
(12 2021)
ISSN: 1531-8249 [Electronic] United States |
PMID | 34652821
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2021 American Neurological Association. |
Chemical References |
- Biomarkers
- Enzyme Inhibitors
- Thiazolidines
- epalrestat
- Sorbitol
- Rhodanine
- Phosphotransferases (Phosphomutases)
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Topics |
- Adolescent
- Adult
- Aged
- Biomarkers
(urine)
- Child
- Child, Preschool
- Congenital Disorders of Glycosylation
(diagnosis, drug therapy, urine)
- Enzyme Inhibitors
(therapeutic use)
- Female
- Glycosylation
- Humans
- Infant
- Male
- Middle Aged
- Patient Acuity
- Phosphotransferases (Phosphomutases)
(deficiency, urine)
- Prognosis
- Rhodanine
(analogs & derivatives, therapeutic use)
- Sorbitol
(urine)
- Thiazolidines
(therapeutic use)
- Young Adult
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