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Cytidine diphosphate-ribitol analysis for diagnostics and treatment monitoring of cytidine diphosphate-L-Ribitol pyrophosphorylase a muscular dystrophy

Lookup NU author(s): Professor Giorgio TascaORCiD


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© 2019 American Association for Clinical Chemistry.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 CDPribitol 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 mutationdependent 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 patientspecific manner.

Publication metadata

Author(s): 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 JR, Van Bokhoven H, Voermans NC, Willemsen MA, Ashikov A, Lefeber DJ

Publication type: Article

Publication status: Published

Journal: Clinical Chemistry

Year: 2019

Volume: 65

Issue: 10

Pages: 1295-1306

Print publication date: 01/10/2019

Acceptance date: 27/06/2019

ISSN (print): 0009-9147

ISSN (electronic): 1530-8561

Publisher: American Association for Clinical Chemistry Inc.


DOI: 10.1373/clinchem.2019.305391

PubMed id: 31375477


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