Oral ribose supplementation in dystroglycanopathy: A single case study

Abstract

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.

Keywords: CDP‐ribitol; FKRP; alpha‐dystroglycan; muscular dystrophy; ribose; trial.

FIGURE 1

α‐Dystroglycan (DG) glycosylation and extracellular matrix (ECM) binding. (A) In patients with a FKRP mutation, α‐dystroglycan is hypoglycosylated resulting in, among others, loss of binding to the ECM causing muscular dystrophy. Some symptoms that these patients present with are limb girdle muscular dystrophy type 2I and cardiomyopathy. In the cytoplasm isoprenoid synthase domain‐containing protein (ISPD) produces cytidine 5′‐diphosphate (CDP)‐ribitol. This in turn can be used by fukutin (FKTN) and fukutin‐related protein (FKRP) in the Golgi apparatus to elongate the O‐glycan with two ribitol‐5‐phosphate residues. After a β1,2‐xylose (Xyl) and a β1,4 glucuronic acid (GlcA) is added to allow the α1,3‐Xyl‐β1,3‐GlcA repeats to finalize its glycosylation, glycosylated α‐DG will bind to laminin α‐2 in the muscle sarcolemma as well as to other components of the ECM. (B) Hypothesis for ribose supplementation. When extracellular ribose is transported into the cell it can be converted to ribitol‐5‐phosphate via reduction and phosphorylation. Having an excess of ribose could result in an higher production of CDP‐ribitol by the myocytes which could compensate for the reduced function of FKRP. This in turn could improve the patients' (cardiac) muscle strength via restoring glycosylation of αDG and thus extra anchor points for laminin to improve the binding between ECM and muscle cell membrane.

FIGURE 2

Overview of the study set‐up. With V1–V4 being visit one to four at which the participant visited the Radboud UMC outpatient clinic for measurements of our main outcome parameters. Intermediate Questionnaires (IQ1 and IQ2) consisted of three questionnaires and a 3‐day dietary intake journal.

FIGURE 3

Strength measurements using the MicroFET hand‐held dynamometer. Results are shown as change in muscle force when compared to baseline (visit 1). NE = neck extension; NF = neck flexion; SEAR = serratus anterior right; SEAL = serratus anterior left; SAR = shoulder abduction right; SAL = shoulder abduction left; EFR = elbow flexion right; EFL = elbow flexion left; EER = elbow extensors right; EEL = elbow extensors left; HGR = handgrip right; HGL = handgrip left; HFR = hip flexion right; HFL = hip flexion left; HER = hip extension right; HEL = hip extension left; KFR = knee flexion right; KFL = knee flexion left; KER = knee extension right; KEL = knee extension left.

FIGURE 4

Biochemical levels of urate, glucose, and creatine kinase in blood. (A) Blood urate levels. (B) Blood glucose levels (fed state). (C) Blood creatine kinase levels. (D) Mean normalized area of CDP‐ribitol levels in erythrocytes. CDP, cytidine diphosphate.