Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications
Anna N. Ligezka MSc
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
These authors contributed equally to this work.
Search for more papers by this authorSilvia Radenkovic PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Laboratory of Hepatology, Department of CHROMETA, KU Leuven, Leuven, Belgium
Department of Oncology, KU Leuven, Leuven, Belgium
Metabolomics Expertise Center, VIB-KU Leuven, Leuven, Belgium
These authors contributed equally to this work.
Search for more papers by this authorMayank Saraswat PhD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Institute of Bioinformatics, Bangalore, India
Manipal Academy of Higher Education (MAHE), Manipal, India
These authors contributed equally to this work.
Search for more papers by this authorKishore Garapati MBBS
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Institute of Bioinformatics, Bangalore, India
Manipal Academy of Higher Education (MAHE), Manipal, India
Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Search for more papers by this authorWasantha Ranatunga PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorWirginia Krzysciak PhD
Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorHitoshi Yanaihara MD, PhD
Department of Urology, Saitama Medical University, Saitama, Japan
Search for more papers by this authorGraeme Preston PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorWilliam Brucker MD, PhD
Department of Pediatrics, Human Genetics, Rhode Island Hospital, Providence, RI
Search for more papers by this authorRenee M. McGovern BA
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN
Search for more papers by this authorJoel M. Reid PhD
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN
Search for more papers by this authorDavid Cassiman MD, PhD
Laboratory of Hepatology, Department of CHROMETA, KU Leuven, Leuven, Belgium
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Search for more papers by this authorKarthik Muthusamy MD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorChristin Johnsen MD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorSaadet Mercimek-Andrews MD, PhD
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
Department of Medical Genetics, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada
Search for more papers by this authorAustin Larson MD
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorChristina Lam MD
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA
Search for more papers by this authorAndrew C. Edmondson MD, PhD
Section of Biochemical Genetics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorBart Ghesquière PhD
Department of Oncology, KU Leuven, Leuven, Belgium
Metabolomics Expertise Center, VIB-KU Leuven, Leuven, Belgium
Search for more papers by this authorPeter Witters MD
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium
Search for more papers by this authorKimiyo Raymond MD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorDevin Oglesbee MD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorAkhilesh Pandey MD, PhD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorTamas Kozicz MD, PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorCorresponding Author
Eva Morava MD, PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Address correspondence to Dr Eva Morava, Department of Clinical Genomics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]
Search for more papers by this authorAnna N. Ligezka MSc
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
These authors contributed equally to this work.
Search for more papers by this authorSilvia Radenkovic PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Laboratory of Hepatology, Department of CHROMETA, KU Leuven, Leuven, Belgium
Department of Oncology, KU Leuven, Leuven, Belgium
Metabolomics Expertise Center, VIB-KU Leuven, Leuven, Belgium
These authors contributed equally to this work.
Search for more papers by this authorMayank Saraswat PhD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Institute of Bioinformatics, Bangalore, India
Manipal Academy of Higher Education (MAHE), Manipal, India
These authors contributed equally to this work.
Search for more papers by this authorKishore Garapati MBBS
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Institute of Bioinformatics, Bangalore, India
Manipal Academy of Higher Education (MAHE), Manipal, India
Center for Molecular Medicine, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
Search for more papers by this authorWasantha Ranatunga PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorWirginia Krzysciak PhD
Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
Search for more papers by this authorHitoshi Yanaihara MD, PhD
Department of Urology, Saitama Medical University, Saitama, Japan
Search for more papers by this authorGraeme Preston PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorWilliam Brucker MD, PhD
Department of Pediatrics, Human Genetics, Rhode Island Hospital, Providence, RI
Search for more papers by this authorRenee M. McGovern BA
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN
Search for more papers by this authorJoel M. Reid PhD
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN
Search for more papers by this authorDavid Cassiman MD, PhD
Laboratory of Hepatology, Department of CHROMETA, KU Leuven, Leuven, Belgium
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Search for more papers by this authorKarthik Muthusamy MD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorChristin Johnsen MD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Search for more papers by this authorSaadet Mercimek-Andrews MD, PhD
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
Department of Medical Genetics, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada
Search for more papers by this authorAustin Larson MD
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorChristina Lam MD
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA
Search for more papers by this authorAndrew C. Edmondson MD, PhD
Section of Biochemical Genetics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorBart Ghesquière PhD
Department of Oncology, KU Leuven, Leuven, Belgium
Metabolomics Expertise Center, VIB-KU Leuven, Leuven, Belgium
Search for more papers by this authorPeter Witters MD
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium
Search for more papers by this authorKimiyo Raymond MD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorDevin Oglesbee MD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorAkhilesh Pandey MD, PhD
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorTamas Kozicz MD, PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Search for more papers by this authorCorresponding Author
Eva Morava MD, PhD
Department of Clinical Genomics, Mayo Clinic, Rochester, MN
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Department of Paediatrics, Metabolic Disease Center, University Hospitals Leuven, Leuven, Belgium
Address correspondence to Dr Eva Morava, Department of Clinical Genomics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]
Search for more papers by this authorAbstract
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
Potential Conflicts of Interest
Mayo Clinic and Eva Morava have a financial interest related to this research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. Maggie's Pearl LLC and Ethan Perlstein have a financial interest related to this research. Eva Morava and Mayo Clinic has a “Know How” on epalrestat treatment development for future clinical trials entitled Clinical investigations on the safety and efficacy of using oral Epalrestat in Phosphomannomutase 2- congenital disorders of glycosylation. Ethan Perlstein is the CEO of Maggie's Pearl LLC, which is developing epalrestat for future clinical trials. Maggie's Pearl LLC holds an Orphan Drug Designation for epalrestat, which is in development for the treatment of PMM2-CDG. Ethan Perlstein is also CEO of Perlara PBC. <zbmrule>
Supporting Information
| Filename | Description |
|---|---|
| ana26245-sup-0001-TableS1.docxWord 2007 document , 31.3 KB | Table S1. General information for 24 individuals with PMM2-CDG. Data includes all patients enrolled for clinical data collection (P1–P24), polyols quantification (P1–P5 and P7–P24), included in the in vitro studies (P1–P6, P8, P10, P17, P19, and P24), and the evaluation of safety and efficacy of epalrestat and sorbitol and mannitol excretion investigation (P1). *Abnormal sorbitol and mannitol levels are bold (sorbitol: controls <5 mmol/mol creatinine; mannitol: controls <20 mmol/mol creatinine). P1 was reported by Qian et al 2020; twins P4 and P5 were reported by Jaeken et al 1980. |
| ana26245-sup-0002-TableS2.docxWord 2007 document , 16.7 KB | Table S2. Treatment with 3 different doses of epalrestat in fibroblast of PMM2-CDG individuals. |
| ana26245-sup-0003-TableS3.docxWord 2007 document , 14.9 KB | Table S3. Blood transferrin glycoform ratio analysis by mass spectrometry 12 months prior to therapy and during 12 months treatment with 0.8 mg/kg/day (15 mg/day) epalrestat (Ono Pharmaceuticals, Osaka, Japan) in a single patient with PMM2-CDG. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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