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

doi:10.1373/clinchem.2019.305391

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 journal › Article › Academic › peer-review

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 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 language	English
Pages (from-to)	1295-1306
Number of pages	12
Journal	Clinical Chemistry
Volume	65
Issue number	10
DOIs	https://doi.org/10.1373/clinchem.2019.305391
Publication status	Published - Oct 2019

Keywords

ALPHA-DYSTROGLYCAN
POSTTRANSLATIONAL MODIFICATION
DEFECTIVE GLYCOSYLATION
GLYCOPROTEIN COMPLEX
D-RIBOSE
ISPD
MUTATIONS
FKRP
METABOLISM
THERAPY

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10.1373/clinchem.2019.305391

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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, 65(10), 1295-1306. https://doi.org/10.1373/clinchem.2019.305391

@article{c6bd5d9ec81c42acb47f10635bf14a29,

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

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 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",

keywords = "ALPHA-DYSTROGLYCAN, POSTTRANSLATIONAL MODIFICATION, DEFECTIVE GLYCOSYLATION, GLYCOPROTEIN COMPLEX, D-RIBOSE, ISPD, MUTATIONS, FKRP, METABOLISM, THERAPY",

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

note = "Funding Information: Employment or Leadership: M. van Scherpenzeel, GlycoMScan B.V. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: The European Union{\textquoteright}s Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 (EUROCDG-2). H. van Bokhoven, the Prinses Beatrix Spierfonds (Grant W.OR17-15); D.J. Lefeber, The Netherlands Organization for Scientific Research (VIDI Grant 91713359), the Prinses Beatrix Spier- fonds (Grant W.OR17-15), ERA-NET Cofund action N° 643578 (EUROCDG-2). Expert Testimony: None declared. Patents: None declared. Publisher Copyright: {\textcopyright} 2019 American Association for Clinical Chemistry.",

year = "2019",

month = oct,

doi = "10.1373/clinchem.2019.305391",

language = "English",

volume = "65",

pages = "1295--1306",

journal = "Clinical Chemistry",

issn = "0009-9147",

publisher = "American Association for Clinical Chemistry",

number = "10",

}

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 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

TY - JOUR

T1 - Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-L-Ribitol Pyrophosphorylase A Muscular Dystrophy

AU - van Tol, Walinka

AU - van Scherpenzeel, Monique

AU - Alsady, Mohammad

AU - Riemersma, Moniek

AU - Hermans, Esther

AU - Kragt, Else

AU - Tasca, Giorgio

AU - Kamsteeg, Erik-Jan

AU - Pennings, Maartje

AU - van Beusekom, Ellen

AU - Vermeulen, Jeroen R.

AU - van Bokhoven, Hans

AU - Voermans, Nicol C.

AU - Willemsen, Michel A.

AU - Ashikov, Angel

AU - Lefeber, Dirk J.

N1 - Funding Information: Employment or Leadership: M. van Scherpenzeel, GlycoMScan B.V. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: The European Union’s Horizon 2020 research and innovation program under the ERA-NET Cofund action N° 643578 (EUROCDG-2). H. van Bokhoven, the Prinses Beatrix Spierfonds (Grant W.OR17-15); D.J. Lefeber, The Netherlands Organization for Scientific Research (VIDI Grant 91713359), the Prinses Beatrix Spier- fonds (Grant W.OR17-15), ERA-NET Cofund action N° 643578 (EUROCDG-2). Expert Testimony: None declared. Patents: None declared. Publisher Copyright: © 2019 American Association for Clinical Chemistry.

PY - 2019/10

Y1 - 2019/10

N2 - 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

AB - 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

KW - ALPHA-DYSTROGLYCAN

KW - POSTTRANSLATIONAL MODIFICATION

KW - DEFECTIVE GLYCOSYLATION

KW - GLYCOPROTEIN COMPLEX

KW - D-RIBOSE

KW - ISPD

KW - MUTATIONS

KW - FKRP

KW - METABOLISM

KW - THERAPY

U2 - 10.1373/clinchem.2019.305391

DO - 10.1373/clinchem.2019.305391

M3 - Article

C2 - 31375477

SN - 0009-9147

VL - 65

SP - 1295

EP - 1306

JO - Clinical Chemistry

JF - Clinical Chemistry

IS - 10

ER -