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    Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys

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    Author
    Dang, UJ; Ziemba, M; Clemens, PR; Hathout, Y; Conklin, LS; Hoffman, EP; Smith, EC; Mah, JK; Guglieri, M; Nevo, Y; ...
    Date
    2020-08-01
    Source Title
    Human Molecular Genetics
    Publisher
    OXFORD UNIV PRESS
    University of Melbourne Author/s
    Ryan, Monique
    Affiliation
    Paediatrics (RCH)
    Metadata
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    Document Type
    Journal Article
    Citations
    Dang, U. J., Ziemba, M., Clemens, P. R., Hathout, Y., Conklin, L. S., Hoffman, E. P., Smith, E. C., Mah, J. K., Guglieri, M., Nevo, Y., Kuntz, N., McDonald, C. M., Tulinius, M., Ryan, M. M., Webster, R., Castro, D. & Finkel, R. S. (2020). Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys. HUMAN MOLECULAR GENETICS, 29 (15), pp.2481-2495. https://doi.org/10.1093/hmg/ddaa132.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251781
    DOI
    10.1093/hmg/ddaa132
    Abstract
    Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFβ and fibrosis pathways in muscle.

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