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

Clin Chem. 2019 Oct;65(10):1295-1306. doi: 10.1373/clinchem.2019.305391. Epub 2019 Aug 2.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Dietary Supplements
  • Drug Monitoring / methods*
  • Dystroglycans
  • Female
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies / blood*
  • Muscular Dystrophies / drug therapy*
  • Muscular Dystrophies / pathology
  • Mutation
  • Nucleoside Diphosphate Sugars / analysis
  • Nucleoside Diphosphate Sugars / blood*
  • Nucleotidyltransferases / genetics
  • Ribitol / pharmacology
  • Ribose / pharmacology


  • Nucleoside Diphosphate Sugars
  • Dystroglycans
  • cytidine diphosphate ribitol
  • Ribitol
  • Ribose
  • Nucleotidyltransferases
  • CRPPA protein, human

Associated data

  • PDB/4CVH