2. Academic Validation
  3. Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy

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.
Walinka van Tol 1 2,  Monique van Scherpenzeel 2,  Mohammad Alsady 1,  Moniek Riemersma 1,  Esther Hermans 1,  Else Kragt 2,  Giorgio Tasca 3,  Erik-Jan Kamsteeg 4,  Maartje Pennings 4,  Ellen van Beusekom 4,  Jeroen R Vermeulen 5,  Hans van Bokhoven 4,  Nicol C Voermans 1,  Michèl A Willemsen 6,  Angel Ashikov 1,  Dirk J Lefeber 7 2
Affiliations

Affiliations

  • 1 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 2 Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 3 Unità Operativa Complessa di Neurologia, Dipartimento di Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy.
  • 4 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5 Department of Child Neurology, VUmc, Amsterdam, the Netherlands.
  • 6 Department of Pediatric Neurology, Amalia Children's Hospital, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 7 Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; [email protected].
PMID: 31375477 DOI: 10.1373/clinchem.2019.305391
Abstract

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.

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