Aminotransferase and creatine kinase: Promising screening biomarkers for duchenne muscular dystrophy in chinese children
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Creatine kinase
A pilot newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) study proposes to assess the feasibility of the screening procedure, temporal course of the various steps of screening, and the public acceptability of the program. This is particularly vital to ascertain as DMD is considered a ‘non-treatable’ disease and thus does not fit the traditional criteria for newborn screening. However, modern perspectives of NBS for DMD are changing and point to possible net benefits for children and their families undertaking NBS for DMD. The aim of this workshop was to establish pathways for the successful implementation and evaluation of a pilot NBS for DMD program in Australia. Consensus was reached as to the rationale for, potential benefits, risks, barriers and facilitators of screening, alongside the establishment of screening protocols and clinical referral pathways.
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Screening test
Dried blood
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Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy, with an estimated frequency of 1:5000 live births. The impact of the disease presents as early as infancy with significant developmental delays, and ultimately loss of ambulation and respiratory insufficiency. Glucocorticoids are the only pharmacological agents known to alter the natural progression of the disease by prolonging ambulation, reducing scoliosis, and assisted ventilation. Introduction of therapy at an early age may halt the muscle pathology in DMD. In anticipation of the potentially disease-modifying products that are reaching regulatory review, Parent Project Muscular Dystrophy (PPMD) formally initiated a national Duchenne Newborn Screening (DNBS) effort in December 2014 to build public health infrastructure for newborn screening (NBS) for Duchenne in the United States. The effort includes a formalized national Duchenne Newborn Screening Steering Committee, six related Working Groups, a Duchenne Screening Test Development Project led by PerkinElmer, a program with the American College of Medical Genetic and Genomics' Newborn Screening Translation Research Network (NBSTRN), and collaborations with other Duchenne partners and federal agencies involved in NBS. We herein review the organization and effort of the U.S. DNBS program to develop the evidence supporting the implementation of NBS for DMD.
Anticipation (artificial intelligence)
Neuromuscular disease
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The hind leg muscle of normal mice and mice with hereditary muscular dystrophy was taken for individual analyses of the creatine-phosphorylating enzyme, creatine kinase. Creatine kinase activity was always found to be higher in the muscle of normal mice than in that of dystrophic mice, and the values in each group decreased with increasing age of the mice. The difference was greatest in mice of 2 weeks of age, and in the light of these findings some suggestions are made about the pathogenesis of muscular dystrophy.
Creatine kinase
Creatine
Pathogenesis
Dystrophy
Hindlimb
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The hind leg muscle of normal mice and mice with hereditary muscular dystrophy was taken for individual analyses of the creatine-phosphorylating enzyme, creatine kinase. Creatine kinase activity was always found to be higher in the muscle of normal mice than in that of dystrophic mice, and the values in each group decreased with increasing age of the mice. The difference was greatest in mice of 2 weeks of age, and in the light of these findings some suggestions are made about the pathogenesis of muscular dystrophy.
Creatine kinase
Creatine
Pathogenesis
Dystrophy
Hindlimb
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Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked muscular disease with an overall incidence of 1:5,000 live male births. Recent availability in treatment for DMD raised the need of early diagnosis, and DMD became as a selective item of newborn screening (NBS) since Feb. 2021 in our center.Dried blood spots (DBS) muscle-type creatine kinase (CK) isoform was measured with a commercialized kit with age-adjusted cutoffs. Subjects with an elevation of CK in the first screen were requested for a re-screen 2 weeks later. A DBS whole-exome sequencing (WES) panel for dystrophin and other neuromuscular-related genes was applied to confirm the diagnosis for subjects with persistent hyperCKemia.During a 1-year period, 50,572 newborns (male 26,130) received DMD screening at a mean age of 2 days (SD 1 day). Among them, 632 (1.2%) had an elevated CK value. A re-screen at a mean age of 14 days (SD 8 days) revealed 14 subjects with persistent hyperCKemia, and DMD was confirmed in 3 of them. The incidence of DMD in Taiwan was 1:8,710 (95% CI 1 in 2,963 to 1 in 25,610) live birth males. Results of DMD DBS also assisted in Pompe newborn screening.NBS for DMD enables earlier management of the disease. The high re-screening rate could potentially be waived by moving the DBS WES assay to a second-tier test. The long-term benefit and the impact of newborn screening on the prognosis of DMD, however, remain further elucidated.
Neuromuscular disease
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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.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).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.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.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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Serum creatine kinase isoenzymes were studied in 41 patients suffering from Duchenne type muscular dystrophy and 20 mothers of patients (carriers) by cellulose acetate electrophoresis. Both the MM and MB types were found in all cases of Duchenne type dystrophy patients, and in carriers with highly elevated total creatine kinase activity BB was not observed above the detection limits of the methods used. However, a so‐called atypical CK‐BB band has been demonstrated.
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Serum creatine kinase activity is the most useful test for Duchenne muscular dystrophy carrier detection, but only in 50-80% the carriers do have increased serum creatine kinase activity. To evaluate the diagnostic accuracy of post-exercise serum creatine kinase activity in identifying Duchenne muscular dystrophy carriers we did determine it in normal and possible Duchenne muscular distrophy carrier women. Creatine kinase activity was determined in basal conditions and at predetermined time intervals up to 10 hours after a constant exercise on a cycloergometer. Statistical analysis included: Fisher test on basal values; percent increase, difference between maximum and minimum values, absolute value after 8 hours and b coefficient of linear regression. Accuracy and sensitivity were evaluated for some of the data. Our results suggest that the activity of serum creatine kinase 8 hours after a quantified exercise can be useful to detect Duchenne muscular dystrophy carriers when basal activity is normal.
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Exertion
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This report summarizes the progress made in newborn screening for Duchenne muscular dystrophy (DMD). This subject was discussed fully at a symposium held on September 11-12, 2012, in Bethesda, Maryland, by a group of experts from multiple disciplines. The meeting was triggered by the simultaneous combination of improvements in methods for newborn screening for DMD and greater potential for treatment. On the screening side, a two-tier system of newborn screening was introduced that enabled creatine kinase levels and DMD gene analysis to be done on the same dried blood spots obtained at birth. Treatment improvements included promising results from exon skipping as well as multiple studies showing long-term benefits of glucocorticoids and data indicating that early intervention of both forms of therapy was the most beneficial. Conclusions from this symposium with supportive data could have a significant impact on propelling efforts for approval of newborn screening for DMD.
Muscle disease
Neuromuscular disease
Exon skipping
mdx mouse
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