Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-L-Ribitol Pyrophosphorylase A Muscular Dystrophy

Walinka van Tol, Monique van Scherpenzeel, Mohammad Alsady, Moniek Riemersma, Esther Hermans, Else Kragt, Giorgio Tasca, Erik-Jan Kamsteeg, Maartje Pennings, Ellen van Beusekom, Jeroen R. Vermeulen, Hans van Bokhoven, Nicol C. Voermans, Michel A. Willemsen, Angel Ashikov, Dirk J. Lefeber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 alpha-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. (C) 2019 American Association for Clinical Chemistry

Original languageEnglish
Pages (from-to)1295-1306
Number of pages12
JournalClinical Chemistry
Issue number10
Publication statusPublished - Oct 2019


  • ISPD
  • FKRP

Cite this