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Identifying Non–Duchenne Muscular Dystrophy–Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs A Review

Michele A. Gatheridge, MD1; Jennifer M. Kwon, MD1,2; Jerry M. Mendell, MD3; Günter Scheuerbrandt, PhD4; Stuart J. Moat, PhD5; François Eyskens, MD, PhD6; Cheryl Rockman-Greenberg, MD, CM7,8; Anthi Drousiotou, PhD9; Robert C. Griggs, MD1
[+] Author Affiliations
1Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York
2Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
3Department of Pediatric Neurology, Nationwide Children’s Hospital and Ohio State University, Columbus, Ohio
4private practice in Breitnau, Germany
5Wales Newborn Screening Laboratory, Department of Medical Biochemistry and Immunology, University Hospital of Wales and School of Medicine, Cardiff University, Cardiff, Wales
6PCMA (Provincial Centre for Metabolic Disorders)–Newborn Screening and Genetic Biochemistry Laboratory, University Hospital of Antwerp, Antwerp, Belgium
7Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
8Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
9Department of Biochemical Genetics, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
JAMA Neurol. 2016;73(1):111-116. doi:10.1001/jamaneurol.2015.3537.
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Importance  Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients.

Objectives  To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings).

Evidence Review  Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015.

Findings  The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD.

Conclusions and Relevance  Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false-negative results are a possibility.

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