Abstract
Background and Objectives The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in 3 muscle-enriched biomarkers in serum of patients with BMD over 4-year time and studied associations with disease severity, disease progression, and dystrophin levels in BMD.
Methods We quantitatively measured creatine kinase (CK) using the International Federation of Clinical Chemistry reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography–tandem mass spectrometry, and myostatin with ELISA in serum and assessed functional performance using the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMRv), 6-Minute Walking Test (6MWT), and forced vital capacity in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance was analyzed using linear mixed models.
Results Thirty-four patients with 106 visits were included. Eight patients were nonambulant at baseline. Cr/Crn and myostatin were highly patient specific (intraclass correlation coefficient for both = 0.960). Cr/Crn was strongly negatively correlated, whereas myostatin was strongly positively correlated with the NSAA, TMRv, and 6MWT (Cr/Crn rho = −0.869 to −0.801 and myostatin rho = 0.792 to 0.842, all p < 0.001). CK showed a negative association with age (p = 0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with the average annual change of the 6MWT (rho = −0.532 and 0.555, p = 0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin, and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv, and 6MWT.
Discussion Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD, as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers.
Glossary
- 6MWT=
- 6-Minute Walking Test;
- ADP=
- adenosine diphosphate;
- ATP=
- adenosine triphosphate;
- BMD=
- Becker muscular dystrophy;
- CK=
- creatine kinase;
- Cr/Crn=
- creatine/creatinineratio;
- CV=
- coefficient of variation;
- DMD=
- Duchenne muscular dystrophy;
- FVC=
- forced vital capacity;
- ICC=
- intraclass correlation coefficient;
- NSAA=
- North Star Ambulatory Assessment;
- TA=
- tibialis anterior;
- TMRv=
- 10-meter run velocity
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
The Article Processing Charge was funded by Leiden University Medical Center.
↵* These authors contributed equally as co-senior authors.
Submitted and externally peer reviewed. The handling editor was Renee Shellhaas, MD, MS.
- Received January 26, 2022.
- Accepted in final form October 11, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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