Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy.

BACKGROUND: Advances in treatment for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) hold promise for children with these disorders. Accurate genetic diagnosis, early in the disease process, will allow these treatments to be most effective. Newborn screening (NBS) for SMA has been recommended in the United States, and a pilot DMD NBS program is underway in Hangzhou, China. DATA SOURCES: A PubMed search, limited to the past 5 years, was conducted to identify: (1) therapeutic advancements for DMD/SMA approved by the United States Food and Drug Administration or the European Medicine Agency and (2) The status of NBS for DMD/SMA. RESULTS: We review the current state of approved treatments for DMD/SMA. We present recommendations regarding the future of NBS for these diseases, with a focus on the outcomes and challenges of SMA NBS in New York, USA, and the DMD NBS pilot program in Hangzhou, China. CONCLUSIONS: Approved treatments for DMD and SMA may change the natural history of these diseases. Long-term studies of these treatments are underway. To avoid the known diagnostic delay associated with these disorders and provide optimal effectiveness of these treatments, early identification of patients through NBS will be necessary. Establishing comprehensive follow-up plans for positively identified patients will need to be in place for NBS programs to be successful.

Duchenne Muscular Dystrophy Newborn Screening: Evaluation of a New GSP® Neonatal Creatine Kinase-MM Kit in a US and Danish Population.

Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked disease and is the most common pediatric-onset form of muscular dystrophy, affecting approximately 1:5000 live male births. DNA testing for mutations in the dystrophin gene confirms the diagnosis of this disorder. This study involves assessment of screening newborns for DMD using an immunoassay for muscle-type (MM) creatine kinase (CK) isoform-the GSP Neonatal CK-MM kit. Comparisons were made with CK activity determination by fluorescence measurement. In addition, the study evaluated the effect of gestational age, age of infant at time of sampling and how stable the CK-MM was over time. This assay discriminates well between normal, unaffected and Duchenne affected populations and is suitable for Duchenne newborn screening.

Characterization of a Blood Spot Creatine Kinase Skeletal Muscle Isoform Immunoassay for High-Throughput Newborn Screening of Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive, lethal X-linked neuromuscular disorder with an average worldwide incidence of 1:5000. Blood spot creatine kinase (CK) enzyme assays previously used in newborn screening programs for DMD are nonspecific because measured CK enzyme activity is attributable to 3 isoenzyme forms of CK (CK-MM, CK-MB, and CK-BB) and it is the CK-MM isoform that is found predominantly in skeletal muscle. CK-MM is increased in boys with DMD owing to muscle damage. We describe a sensitive and specific automated immunoassay for CK-MM to screen for DMD in blood spots. METHODS: The prototype assay was developed on the PerkinElmer GSP® analyzer to enable high-throughput screening. CK-MM was assayed using a solid phase, 2-site immunofluorometric system. Purified human CK-MM was used to create calibrators and controls. RESULTS: The limit of blank (LOB), detection (LOD), and quantification (LOQ) values were <1, 3, and 8 ng/mL, respectively. The analytical measurement range was 4-8840 ng/mL. Interassay (n = 40) imprecision was <7% across the analytical range. Cross-reactivity was <5% for CK-MB and 0% for CK-BB. The mean recovery of CK-MM was 101% (range 87%-111%). Blood spots from newborn infants (n = 277) had a mean CK-MM concentration of 155 ng/mL and a 99th centile of 563 ng/mL. The mean blood spot CK-MM concentration from 10 cases of DMD was 5458 ng/mL (range 1217-9917 ng/mL). CONCLUSIONS: CK-MM can be reliably quantified in blood spots. The development of this CK-MM assay on a commercial immunoassay analyzer would enable standardized and high-throughput newborn blood spot screening of DMD.