Creatine kinase‐MM concentration in dried blood spots from newborns and implications for newborn screening for Duchenne muscular dystrophy

Abstract

Introduction/Aims: Creatine kinase-MM (CK-MM) is a marker of skeletal muscle damage. Detection of elevated levels of CK-MM in newborns can enable an early suspicion of the diagnosis of Duchenne muscular dystrophy (DMD) before symptom onset. Our aim was to investigate CK-MM levels in DMD-affected and unaffected newborns using an immunoassay that measures CK-MM concentration in dried blood spots collected for routine newborn screening.Methods: To validate the assay in our laboratory, CK-MM measurements and newborn demographic information were collected for 8584 de-identified specimens and 15 confirmed DMD patients. After analyzing validation data, CK-MM normal ranges were determined based on age of newborn at specimen collection. Subsequently, the assay was used to measure CK-MM concentration in 26 135 newborns as part of a consented pilot study to screen for DMD in New York State. Mean and median levels of CK-MM based on age of collection, in addition to the 2.5th, 50th, 97.5th, and 99.5th percentiles, were recalculated using the validation and screening data sets.Results: Median CK-MM within 1 hour of birth was 109 ng/mL, rose to a high of 499 ng/mL at 25 hours of age, and then declined to 200 ng/mL at 2 days of life. The median continued to decline more slowly and then stabilized at approximately 40 ng/mL at 1 week of life.Discussion: Because of the marked variability and elevated CK-MM levels observed within the first days of life, it is important to set multiple CK-MM age-related cut-offs when screening for DMD in newborns.

Newborn Screening for Duchenne Muscular Dystrophy: First Year Results of a Population-Based Pilot

“…During validation studies for the GSP Neonatal CK-MM kit, it was apparent that CK-MM values were high at birth, especially within the first three days of life, and decreased with age. The NYS NBS program, therefore, selected four different referral cut-offs for four categories of newborns based on the age at specimen collection: (1) 0–47 h, (2) 48–71 h, (3) 72 to 167 h, and (4) ≥168 h. The referral cut-offs decreased with age at collection [ 16 ]. No other variables (e.g., sex, gestation age, race, etc.)…”

Duchenne expert physician perspectives on Duchenne newborn screening and early Duchenne care

“…We partnered with an expert working group of health care providers to inform the development of a physician survey on perspectives and predicted practices for follow‐up after DMD NBS. The workgroup was affiliated with a completed NBS pilot (Park, Maloney, Caggana, & Tavakoli, 2022 ) and composed of neurologists, geneticists, and genetic counselors with considerable experience with DMD and early diagnosis and treatment. The workgroup reviewed draft versions of the survey and provided input on preferred word choice, participant population, response options, and question inclusion.…”

Multi-Laboratory Evaluation of Prototype Dried Blood Spot Quality Control Materials for Creatine Kinase-MM Newborn Screening Assays

“…The 27 CK-MM results from each pool were evaluated based on both the multiple cutoffs used by NYS depending on post-natal age [ 7 , 8 ], and on a single preliminary provisional cutoff and a subsequent refined cutoff used by RTI for newborns less than 72 h old. By both NYS and RTI criteria, all CK-MM levels in Pools B and C measured in all three laboratories were screen-negative (that is, in the expected range for DMD-unaffected newborns).…”

“…Along with these advances in treatment, a fluoroimmunometric assay specific for the MM isoform of CK has recently been developed using instrumentation designed for NBS; it received authorization by the U.S. Food and Drug Administration in December 2019 [ 5 , 6 ]. This assay has been used in several recent DMD-NBS pilot studies [ 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Globally, at least one newborn screening program has included DMD in its routine NBS panel using this assay [ 13 ], and DMD has recently been nominated for inclusion in the U.S.…”