Screening For Duchenne Muscular Dystrophy Research Articles

Newborn screening for Duchenne muscular dystrophy: the perspectives of stakeholders

The rapidly evolving clinical landscape of Duchenne muscular dystrophy (DMD) is driving innovative approaches for early diagnosis through genomic newborn bloodspot screening (NBS). However, the potential impact of these programs on families and healthcare systems remains unexplored. This study assessed the perceived benefits, harms, barriers, and enablers for DMD NBS amongst primary caregivers of children with DMD and healthcare professionals (HCPs). This Australian multi-centre cross-sectional study used a mixed-methods convergent methodology. Participants completed a codeveloped questionnaire and their perceptions on the utility, model of care, and processes of DMD NBS were thematically analysed. Participants included 50 caregivers and 26 HCPs (68.5% and 53.1% response rate respectively). Most caregivers (40/50, 80%) perceived net benefits of DMD NBS and highlighted an early diagnosis as actionable knowledge, even with the current paucity of disease modifying therapies. This knowledge was valued to enable access to multidisciplinary supportive care (29/50, 58%), clinical trials (27/50, 54%), psychological support (28/50, 56%), inform reproductive planning (27/50, 54%), and facilitate financial planning based on the future needs of their child (27/50, 54%). Whilst HCPs acknowledged these opportunities, only 16/26 (61.5%) believed there were definite net benefits, with notable concerns over the psychological harms of diagnostic knowledge without a recourse to disease modifying therapeutic intervention early in life. Caregivers and HCPs perceived a range of potential benefits of DMD NBS. Health system readiness will be founded on developing an integrated model of care that not only supports the psychosocial and information needs of families receiving a newborn diagnosis of DMD, but also provides care and clinical surveillance for individuals for whom a diagnosis may remain uncertain. Medical Research Futures fund (GNT2017165, MRF2015965).

Screening for Duchenne muscular dystrophy in newborns in the Ningxia region

To evaluate the incidence rate of Duchenne muscular dystrophy (DMD) in the male newborns in the Ningxia region and establish a critical threshold for screening DMD in newborns to distinguish between the normal population and affected individuals. A total of 10 000 male newborns were screened using immunofluorescence analysis of creatine kinase isoenzyme concentrations in heel spot dried blood specimens. Newborns with the concentrations higher than the critical threshold were recalled for serum creatine kinase measurements. Genetic testing was performed to confirm diagnosis in cases showing abnormalities. Among the screened 10 000 male newborns, two were confirmed to have DMD through genetic testing, resulting in a preliminary estimated incidence rate of 1/5 000 for male newborns in the Ningxia region. The critical threshold for creatine kinase isoenzyme concentration in newborns in this region was determined to be 468.57 ng/mL. Screening for DMD in newborns is feasible in the Ningxia region. Early screening, diagnosis, and treatment of DMD can improve the quality of life for affected individuals and help families make informed decisions regarding further pregnancies.

Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina

PurposeCurrent and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. MethodsWe performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. ResultsWe screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. ConclusionPopulation-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.

Creatine kinase in neonatal screening for Duchenne Muscular Dystrophy: an acceptability assessment

Objective: The present study evaluated the acceptance among parents of newborns to the creatine kinase (CK) test in the neonatal screening of Duchenne Muscular Dystrophy-DMD and raised possible barriers and elements that facilitate the acceptance of the test. Methods: The assessment of acceptance of the CK test for DMD screening was carried out through interviews, guided by a semi-structured script, with parents of newborns in the state of Mato Grosso, Brazil. Results: Six hundred and four parents participated in the research, only five being excluded for not meeting the eligibility criteria. The acceptance of screening among respondents was high (94.5%), surpassing that described in the retrieved literature. Long journeys to the collection site and the absence of information about the disease and the CK test can negatively influence parents regarding the performance of the test. The reduction in diagnostic delay seems to be a positive factor in the acceptance of screening. Conclusions: Non-mandatory neonatal screening for DMD using the CK test demonstrated high acceptance by the interviewed population; however, research has identified factors that can both motivate and discourage screening.

Factors influencing creatine kinase-MM concentrations in newborns and implications for newborn screening for Duchenne muscular dystrophy

IntroductionNewborn screening for Duchenne muscular dystrophy can be performed via a first-tier creatine kinase-MM measurement followed by reflex testing to second-tier molecular analysis of the DMD gene. In order to establish appropriate cut-offs for the creatine kinase-MM screen, factors that influence creatine kinase-MM in newborns were investigated. Materials and methodsCreatine kinase-MM data from a consented pilot study in New York State were collected over a two-year period and combined with de-identified validation data and analyzed. Univariate analysis and multiple linear regression analysis were performed. ResultsThe analysis indicated that age of newborn at specimen collection, gestational age and birth weight were significant influencers of CK-MM levels in newborns. In addition, to a lesser extent, sex, race/ethnicity and seasonal temperature also affect CK-MM levels in newborns. ConclusionsTo reduce false positive and false negative cases, newborn screening programs should be cognizant of factors that influence CK-MM when determining cut-offs for the assay. Variability based on age at specimen collection and birth weight are primarily observed within the first week of life. Therefore, particularly during this time period, multi-tiered cut-offs based on age of collection and lower cut-offs for premature and low birth weight babies are recommended. Other cut-off determinants may include sex, race/ethnicity and seasonal temperature.

Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.

Duchenne muscular dystrophy (DMD) is an X-linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre-symptomatic diagnosis. At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first-tier screen measured creatine kinase-MM (CK-MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK-MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next-generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene. In the two-year pilot study, 36,781 newborns were screened with CK-MM. Forty-two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified. This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.

P497: Two years of newborn screening for Duchenne Muscular Dystrophy in North Carolina: Results from Early Check*

P497: Two years of newborn screening for Duchenne Muscular Dystrophy in North Carolina: Results from Early Check*

A pilot study of newborn screening for Duchenne muscular dystrophy in Guangzhou

BackgroundTo estimate the overall situation of Duchenne muscular dystrophy (DMD) screening in newborns in Guangzhou, China. MethodA total of 62553 newborns including 44268 males and 18285 females were screened for DMD by measuring muscle specific creatine kinase isoform (CK-MM) concentrations using the GSP® Neonatal CK-MM kit based on time-resolved immunofluorescence. We recalled positive cases and recollected dried blood spots (DBS) for retest of CK-MM. The newborns with retest positive result were recalled again for serum creatine kinase (CK) and multiplex ligation-dependent probe amplification (MLPA) test. Whole exon sequencing was performed when MLPA test was negative. ResultsFour males were diagnosed with DMD. The incidence of males was 1/11067. No DMD patient was found in female. There were significant differences of CK-MM concentration between male and female newborns. Among gestational age (GA), birth weight (BW) and age at sampling, linear regression analysis showed that CK-MM concentration was much more closely correlated with GA and age at sampling. ConclusionsCK-MM concentration is affected by gender, GA, BW and age at sampling. The efficiency of DMD screening might be improved by adjusting a multitier cut-off value according to GA and age at sampling. DMD newborn screening should be male priority.

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

Advancements in therapies for Duchenne muscular dystrophy (DMD) have made diagnosis within the newborn period a high priority. We undertook a consortia approach to advance DMD newborn screening in the United States. This manuscript describes the formation of the Duchenne Newborn Screening Consortium, the development of the pilot protocols, data collection tools including parent surveys, and findings from the first year of a two-year pilot. The DMD pilot design is population-based recruitment of infants born in New York State. Data tools were developed to document the analytical and clinical validity of DMD NBS, capture parental attitudes, and collect longitudinal health information for diagnosed newborns. Data visualizations were updated monthly to inform the consortium on enrollment. After 12 months, 15,754 newborns were screened for DMD by the New York State Newborn Screening (NYS NBS) Program. One hundred and forty screened infants had borderline screening results, and sixteen infants were referred for molecular testing. Three male infants were diagnosed with dystrophinopathy. Data from the first year of a two-year NBS pilot for DMD demonstrate the feasibility of NBS for DMD. The consortia approach was found to be a useful model, and the Newborn Screening Translational Research Network’s data tools played a key role in describing the NBS pilot findings and engaging stakeholders.

Large scale population screening for Duchenne muscular dystrophy-Predictable and unpredictable challenges.

ObjectiveLarge deletions and duplications account for 65%–80% of pathogenic Duchenne muscular dystrophy (DMD) variants. A nationwide carrier screening for DMD was initiated in Israel in 2020. We assessed the carrier rate and spectrum of variants detected in a cohort of women screened for DMD carrier status and analyzed screening efficacy and challenges related to DMD population screening.MethodsA cohort of 12,362 women were tested at a single institute using multiplex ligation‐dependent probe amplification based copy number analysis of the 79 DMD exons. Consecutive sequencing of the primer region was performed when a single exon deletion was suspected.ResultsDeletions involving multiple exons were detected in seven cases and duplications involving multiple exons were found in four. Of these, nine were pathogenic based on previous reports and familial segregation testing, translating to a carrier rate of 1:1374. A family history was reported in three cases. Single exon deletions were suspected in 81 cases; further sequencing detected a single nucleotide variant affecting probe hybridization. These cases clustered according to ethnic origin.DiscussionPopulation screening for DMD has a significant yield. Most carriers did not report a family history of dystrophinopathies. Screening should be adjusted for methodological limitations. Some cases may require extensive genetic counseling and work‐up.

Dystrophin Protein Quantification as a Duchenne Muscular Dystrophy Diagnostic Biomarker in Dried Blood Spots Using Multiple Reaction Monitoring Tandem Mass Spectrometry: A Preliminary Study.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle loss, leading to difficulties in movement. Mutations in the DMD gene that code for the protein dystrophin are responsible for the development of DMD disorder, where the synthesis of this protein is completely halted. Therefore, circulating dystrophin protein could be a promising biomarker of DMD disease. Current methods for diagnosing DMD have sensitivity, specificity, and reproducibility limitations. Herein, a quantitative liquid chromatography–tandem spectrometry (LC–MS/MS) technique in multiple reaction monitoring (MRM) mode was designed and validated for accurate dystrophin protein measurement in a dried blood spot (DBS). The method was successfully validated on the basis of international guidelines regarding calibration curves, precision, and accuracy. In addition, patients and healthy controls were used to test the amount of dystrophin protein circulating in DBS samples as a potential biomarker for DMD disorders. DMD patients were found to have considerably lower levels than controls. To the best of our knowledge, this is the first study to report dystrophin levels in DBS through LC–MS/MS as a diagnostic marker for DMD to the proposed MRM method, providing a highly specific and sensitive approach to dystrophin quantification in a DBS that can be applied in DMD screening.

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

Introduction/AimsCreatine 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.MethodsTo 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.ResultsMedian 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.DiscussionBecause 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.

Evaluation of the GSP Creatine Kinase-MM Assay and Assessment of CK-MM Stability in Newborn, Patient, and Contrived Dried Blood Spots for Newborn Screening for Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked disorder with a birth prevalence of 19.8:100,000 males worldwide. Elevated concentration of the muscle enzyme creatine kinase-MM (CK-MM) allows for presymptomatic screening of newborns using Dried Blood Spots (DBS). We evaluated imprecision and carryover of the FDA-approved PerkinElmer GSP Neonatal CK-MM kit over multiple runs, days, and operators, followed by quantification of CK-MM loss in stored newborn, contrived, and non-newborn patient DBS resulting from exposure to ambient versus low humidity (50-day trial), and high humidity and high temperature (8-day trial). Imprecision %CV was ≤14% for all verification comparisons and over 6 months of testing. On average, the mean CK-MM recovery after 50 days was >80% of initial concentration for all sample types stored in low humidity and <80% in ambient humidity. After 8 days of storage in high humidity and high temperature, the mean recovery for newborn samples was <80%. Verification results for the GSP Neonatal CK-MM assay were concordant with kit parameters and the assay performed consistently over 6 months. CK-MM degradation in ambient storage can be mitigated by reducing exposure to humidity. Assessment of DBS shipping and storage conditions is recommended prior to implementing DMD screening.

Large scale population screening for Duchenne muscular dystrophy – Preliminary results

Duchenne and Becker muscular dystrophies (DMD, BMD) are X linked dystrophinopathies caused by DMD gene mutations. Large deletions and duplications account for 65-80% of pathogenic DMD variants. The reported incidence is 1:3500 males. Two thirds of cases are inherited from a female carrier, but the actual carrier rate is currently unknown. In Israel, large-scale carrier screening for DMD was initiated in 2020. We aimed to assess the carrier rate and the spectrum of mutations in a large cohort of females tested for DMD carrier status, to evaluate the efficacy of DMD population screening, and to analyze specific challenges related to such screening.

Study on newborn screening for Duchenne muscular dystrophy and diagnostic strategy

To establish a newborn screening system for Duchenne muscular dystrophy (DMD) through assessment of MM isoenzyme of creatine kinase (CK-MM) activity. The CK-MM level was detected using dry blood spot filter paper from 10 252 male newborns. The results were grouped based on their gestational age, sampling time and intervals between the experiments. The threshold value for CK-MM necessitating genetic testing was determined. Next-generation sequencing (NGS) was carried out for those with a CK-MM value over the threshold, and the result was verified by multiplex ligation-dependent probe amplification (MLPA). Based on the result of non-parametric rank sum test, the median CK-MM concentration has increased with the gestational age, and was inversely correlated with the age of the newborns among unaffected specimens. CK-MM on dry blood spot filter paper can be stable for 14 days at 2-8℃. Statistical analysis of CK-MM value of the 10 252 neonates suggested that the threshold may be set as 700 ng/mL. Exonic deletions were found in 2 confirmed cases, whose CK-MM level was greater than 2000 ng/mL. Detection of CK-MM in dry blood spot filter paper has provided an effective method for newborn screening of DMD. This simple and inexpensive method can be used for large-scale screening, which is of great value to the early intervention and treatment of the disease.

FDA authorizes first test to aid in newborn screening for Duchenne Muscular Dystrophy

FDA authorizes first test to aid in newborn screening for Duchenne Muscular Dystrophy

FDA authorizes first test to aid in newborn screening for Duchenne Muscular Dystrophy

FDA authorizes first test to aid in newborn screening for Duchenne Muscular Dystrophy

023 Genetic carrier screening for duchenne muscular dystrophy: the outcome of over twenty years of genetic counselling on disease epidemiology in a single-centre cohort study in new south wales (NSW), australia

IntroductionDuchenne Muscular Dystrophy (DMD), an X-linked recessive genetic disorder is maternally inherited in approximately two-thirds of affected boys. Female relatives have carrier risk. This study proposes that proactive genetic screening and counselling for patients’ relatives, contributes to reductions in preventable cases and ultimately disease incidence.MethodsA retrospective study of cases born in NSW from 1991–2013 was completed, using an electronic database of live male and prenatally diagnosed patients with DMD, referred to our tertiary service. Proband genotype/phenotype, pedigree, carrier-risk and extent of cascade screening were reviewed. Variance analysis (two-way ANOVA) was used to analyse changing trends in preventable cases.Results77 cases were identified. Mean age at presentation fell by 14-months over time. Probands were defined as ‘theoretically preventable’ when disease was identified in previous generations, or in males aged over 6 years, within the same generation. Fifteen (19%) cases were preventable, with a statistically significant decline in such cases over time.Cascade screening and prenatal testing of subsequent pregnancies was offered to all carrier mothers and female relatives in the mother’s generation. Fifteen women underwent prenatal testing. Three affected male foetuses were identified, with one live affected male being born, after parents proceeded with the pregnancy.ConclusionRigorous and expansive approaches to cascade-screening/counselling may account for decreases in preventable cases. Age of diagnosis has fallen, providing potential for more timely intervention, aided by newer diagnostic techniques that allow more accurate proband genotyping. Prenatal testing identified small numbers of affected males, facilitating parental decision-making in these select cases.

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

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. A PubMed search, limited to the past 5years, 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. 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. 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 - GENETICS: P.216Genetic carrier screening for Duchenne muscular dystrophy: the outcome of over forty years of genetic counselling on disease incidence in New South Wales Australia

Duchenne muscular dystrophy (DMD), an X-linked recessive genetic disorder results in progressive muscle weakness, causing significant morbidity and mortality. Its incidence is approximately 1 in 5000 live male births. DMD is caused by mutations in the dystrophin gene, maternally inherited in approximately two thirds of affected boys. Female relatives have carrier risk. Clinical genetics services offer carrier testing ('cascade screening') and genetic counselling for relatives of DMD patients, enabling identification of carrier status and provision of reproductive options. In selected countries, reduced disease incidence is observed, possibly due to genetic counselling, cascade testing and prenatal diagnosis. To estimate changes in DMD incidence in NSW over 40 years and determine whether cascade screening and genetic counselling has led to this change. A retrospective study of 'probands' (live male and prenatal genetically diagnosed DMD) cases born within NSW from 2002-2012 will be conducted. Female carriers/mosaic cases are excluded from analysis. A retrospective clinical review of confounding factors potentially associated with DMD diagnosis will also be conducted, using clinical data sourced from all the major NSW paediatric hospitals. Data will be collated with results from a previous study reporting DMD incidence over a 25-year period from 1975 to 2001 inclusive. The combined results of these studies will be presented in the final analysis. Birth rate statistics will be sourced from the Australian Bureau of Statistics. The denominator for incidence will be live male birth rates. Data analysis is pending. However, we hypothesize that DMD incidence in NSW has reduced over the last 40 years owing to improvements in the methodology of genetic screening. This study will demonstrate the impact of robust genetic screening and counselling services, thus serving as a model for other health care systems globally.