Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy
| Autor: | Moniek Riemersma, Dirk Lefeber, Erik-Jan Kamsteeg, Else Kragt, Nicol C. Voermans, Michèl A.A.P. Willemsen, Monique van Scherpenzeel, Ellen van Beusekom, Esther Hermans, Jeroen R Vermeulen, Maartje Pennings, Mohammad Alsady, Walinka van Tol, Angel Ashikov, Giorgio Tasca, Hans van Bokhoven |
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| Přispěvatelé: | Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Pediatric surgery |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Glycosylation D-RIBOSE Ribose Clinical Biochemistry Pharmacology POSTTRANSLATIONAL MODIFICATION THERAPY Mass Spectrometry Muscular Dystrophies Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] chemistry.chemical_compound Mice 0302 clinical medicine ISPD Medicine Muscular dystrophy Dystroglycans Cytidine diphosphate Nucleoside Diphosphate Sugars Middle Aged Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Nucleotidyltransferases medicine.anatomical_structure Female lipids (amino acids peptides and proteins) medicine.symptom Drug Monitoring GLYCOPROTEIN COMPLEX ALPHA-DYSTROGLYCAN FKRP Mice Transgenic METABOLISM Ribitol complex mixtures 03 medical and health sciences Animals Humans Disorders of movement Radboud Institute for Molecular Life Sciences [Radboudumc 3] Myopathy Muscle Skeletal Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] business.industry MUTATIONS Biochemistry (medical) Skeletal muscle medicine.disease Fukutin carbohydrates (lipids) 030104 developmental biology HEK293 Cells chemistry Dietary Supplements Mutation DEFECTIVE GLYCOSYLATION business 030217 neurology & neurosurgery Ex vivo Chromatography Liquid |
| Zdroj: | Clinical Chemistry, 65, 1295-1306 Clinical Chemistry, 65, 10, pp. 1295-1306 Clinical Chemistry, 65(10), 1295-1306. American Association for Clinical Chemistry van Tol, W, van Scherpenzeel, M, Alsady, M, Riemersma, M, Hermans, E, Kragt, E, Tasca, G, Kamsteeg, E-J, Pennings, M, van Beusekom, E, Vermeulen, J R, van Bokhoven, H, Voermans, N C, Willemsen, M A, Ashikov, A & Lefeber, D J 2019, ' Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy ', Clinical Chemistry, vol. 65, no. 10, pp. 1295-1306 . https://doi.org/10.1373/clinchem.2019.305391 Clinical Chemistry, 65(10), 1295-1306 |
| ISSN: | 0009-9147 |
| Popis: | BACKGROUND Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required. METHODS An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues. RESULTS CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker–Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of α-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD. CONCLUSIONS Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner. |
| Databáze: | OpenAIRE |
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