Evidence-based path to newborn screening for duchenne muscular dystrophy
Article first published online: 23 MAR 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 71, Issue 3, pages 304–313, March 2012
How to Cite
Mendell, J. R., Shilling, C., Leslie, N. D., Flanigan, K. M., al-Dahhak, R., Gastier-Foster, J., Kneile, K., Dunn, D. M., Duval, B., Aoyagi, A., Hamil, C., Mahmoud, M., Roush, K., Bird, L., Rankin, C., Lilly, H., Street, N., Chandrasekar, R. and Weiss, R. B. (2012), Evidence-based path to newborn screening for duchenne muscular dystrophy. Ann Neurol., 71: 304–313. doi: 10.1002/ana.23528
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 12 JAN 2012 11:16PM EST
- Manuscript Accepted: 5 JAN 2012
- Manuscript Revised: 31 DEC 2011
- Manuscript Received: 15 NOV 2011
- Centers for Disease Control and Prevention. Grant Numbers: 5U50DD000030, 1R18DD000344
- Research Institute at Nationwide Children's Hospital, Columbus, OH
- Paul D. Wellstone Cooperative Muscular Dystrophy Center, Nationwide Children's Hospital. Grant Number: 1U54HD066409-01;JRM
- Ohio Department of Health
Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing.
A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification.
DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels >2,000U/l. In 3 newborns with CK >2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP.
A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations. ANN NEUROL 2012;