Anna N Ligezka1,2, Silvia Radenkovic1,3,4,5, Mayank Saraswat6,7,8, Kishore Garapati6,7,8,9, Wasantha Ranatunga1, Wirginia Krzysciak2, Hitoshi Yanaihara10, Graeme Preston1, William Brucker11, Renee M McGovern12, Joel M Reid12, David Cassiman3,13, Karthik Muthusamy1, Christin Johnsen1, Saadet Mercimek-Andrews14,15, Austin Larson16, Christina Lam17,18, Andrew C Edmondson19, Bart Ghesquière4,5, Peter Witters13,20, Kimiyo Raymond6, Devin Oglesbee6, Akhilesh Pandey6, Ethan O Perlstein21, Tamas Kozicz1,6, Eva Morava1,6,13. 1. Department of Clinical Genomics, Mayo Clinic, Rochester, MN. 2. Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. 3. Laboratory of Hepatology, Department of CHROMETA, KU Leuven, Leuven, Belgium. 4. Department of Oncology, KU Leuven, Leuven, Belgium. 5. Metabolomics Expertise Center, VIB-KU Leuven, Leuven, Belgium. 6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 7. Institute of Bioinformatics, Bangalore, India. 8. Manipal Academy of Higher Education (MAHE), Manipal, India. 9. Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. 10. Department of Urology, Saitama Medical University, Saitama, Japan. 11. Department of Pediatrics, Human Genetics, Rhode Island Hospital, Providence, RI. 12. Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN. 13. Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium. 14. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. 15. Department of Medical Genetics, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada. 16. Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO. 17. Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA. 18. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA. 19. Section of Biochemical Genetics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA. 20. Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium. 21. Maggie's Pearl LLC, Sturgis, MI.
Abstract
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.
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.
Authors: P Trouillas; T Takayanagi; M Hallett; R D Currier; S H Subramony; K Wessel; A Bryer; H C Diener; S Massaquoi; C M Gomez; P Coutinho; M Ben Hamida; G Campanella; A Filla; L Schut; D Timann; J Honnorat; N Nighoghossian; B Manyam Journal: J Neurol Sci Date: 1997-02-12 Impact factor: 3.181
Authors: Andrea Cortese; Yi Zhu; Adriana P Rebelo; Sara Negri; Steve Courel; Lisa Abreu; Chelsea J Bacon; Yunhong Bai; Dana M Bis-Brewer; Enrico Bugiardini; Elena Buglo; Matt C Danzi; Shawna M E Feely; Alkyoni Athanasiou-Fragkouli; Nourelhoda A Haridy; Rosario Isasi; Alaa Khan; Matilde Laurà; Stefania Magri; Menelaos Pipis; Chiara Pisciotta; Eric Powell; Alexander M Rossor; Paola Saveri; Janet E Sowden; Stefano Tozza; Jana Vandrovcova; Julia Dallman; Elena Grignani; Enrico Marchioni; Steven S Scherer; Beisha Tang; Zhiqiang Lin; Abdullah Al-Ajmi; Rebecca Schüle; Matthis Synofzik; Thierry Maisonobe; Tanya Stojkovic; Michaela Auer-Grumbach; Mohamed A Abdelhamed; Sherifa A Hamed; Ruxu Zhang; Fiore Manganelli; Lucio Santoro; Franco Taroni; Davide Pareyson; Henry Houlden; David N Herrmann; Mary M Reilly; Michael E Shy; R Grace Zhai; Stephan Zuchner Journal: Nat Genet Date: 2020-05-04 Impact factor: 41.307
Authors: Daniel Medina-Cano; Ekin Ucuncu; Lam Son Nguyen; Michael Nicouleau; Joanna Lipecka; Jean-Charles Bizot; Christian Thiel; François Foulquier; Nathalie Lefort; Catherine Faivre-Sarrailh; Laurence Colleaux; Ida Chiara Guerrera; Vincent Cantagrel Journal: Elife Date: 2018-10-12 Impact factor: 8.140
Authors: Rita Francisco; Sandra Brasil; Carlota Pascoal; Andrew C Edmondson; Jaak Jaeken; Paula A Videira; Cláudia de Freitas; Vanessa Dos Reis Ferreira; Dorinda Marques-da-Silva Journal: Int J Environ Res Public Health Date: 2022-06-02 Impact factor: 4.614
Authors: Sandra Brasil; Mariateresa Allocca; Salvador C M Magrinho; Inês Santos; Madalena Raposo; Rita Francisco; Carlota Pascoal; Tiago Martins; Paula A Videira; Florbela Pereira; Giuseppina Andreotti; Jaak Jaeken; Kristin A Kantautas; Ethan O Perlstein; Vanessa Dos Reis Ferreira Journal: Int J Mol Sci Date: 2022-08-05 Impact factor: 6.208