Search Results (432)

In this retrospective study, we aimed to evaluate the performance of dried-blood-spot (DBS) testing as a diagnostic method for the congenital cytomegalovirus (cCMV). We reviewed the medical records and DBS test results of 89 patients who had also undergone diagnostic cCMV testing within the first 21 days of life. The DBS test had a sensitivity of 83.9%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 73%. Patients with a true-positive DBS had a higher median level of CMV in blood according to PCR than those with a false-negative result. Additionally, all patients with cCMV and hearing loss had a positive DBS test, with higher median viremia levels observed in those with hearing loss compared to those without a CMV PCR blood test. These results suggest that DBS-based testing is useful in the diagnosis of cCMV, and its performance may be related to levels of CMV viremia. DBS testing accurately identified those patients with congenital/early onset hearing loss and those at risk of developing late-onset hearing loss. Full article

To investigate COVID-19 surveillance among pregnant women, the California Genetic Disease Screening Program conducted a screening performance and seroprevalence evaluation of maternal SARS-CoV-2 antibodies detected in banked newborn dried blood spots (DBS). We obtained seropositive results for 2890 newborn DBS from cohorts in 2020 and 2021 using Enable Bioscience’s Antibody Detection by Agglutination-PCR (ADAP) assay for SARS-CoV-2 antibodies. To infer maternal infection, we linked 312 women with a known laboratory-confirmed COVID-19 episode with their newborn’s DBS SARS-CoV02 antibody result. Among 2890 newborns, we detected 453 (15.7%) with SARS-CoV-2 antibodies in their DBS. Monthly snapshot statewide seroprevalence among neonates was 12.2% (95% CI 10.3–14.1%, n =1156) in December 2020 and 33.3% (95% CI 29.1–37.4%, n = 26) in March 2021. The longest time recorded from COVID-19 infection to a seropositive neonatal result was 11.7 months among the 312 mothers who had an available SARS-CoV-2 PCR test result. Approximately 94% (153/163) of DBS were seropositive when a known maternal infection occurred earlier than 19 days before birth. The estimated relative sensitivity of DBS to identify prevalent maternal infection was 85.1%, specificity 98.5% and PPV 99.2% (n = 312); the sensitivity was lowest during the December 2021 surge when many infections occurred within 19 days of birth. Fifty pre-pandemic specimens (100% seronegative) and 23 twin-pair results (100% concordant) support an intrinsic specificity and PPV of ADAP approaching 100%. Maternal infection surveillance is limited by a time lag prior to delivery, especially during pandemic surges. Full article

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by biallelic pathogenic/likely pathogenic variants of the survival motor neuron 1 (SMN1) gene. Early diagnosis via newborn screening (NBS) and pre-symptomatic treatment are essential to optimize health outcomes for affected individuals. We developed a multiplex quantitative polymerase chain reaction (qPCR) assay using dried blood spot (DBS) samples for the detection of homozygous absence of exon 7 of the SMN1 gene. Newborns who screened positive were seen urgently for clinical evaluation. Confirmatory testing by multiplex ligation-dependent probe amplification (MLPA) revealed SMN1 and SMN2 gene copy numbers. Six newborns had abnormal screen results among 47,005 newborns screened during the first year and five were subsequently confirmed to have SMA. Four of the infants received SMN1 gene replacement therapy under 30 days of age. One infant received an SMN2 splicing modulator due to high maternally transferred AAV9 neutralizing antibodies (NAb), followed by gene therapy at 3 months of age when the NAb returned negative in the infant. Early data show that all five infants made excellent developmental progress. Based on one year of data, the incidence of SMA in Alberta was estimated to be 1 per 9401 live births. Full article

The sweat test (ST) is the current diagnostic gold standard for cystic fibrosis (CF). Many CF centres have switched from the Gibson–Cooke method to the Macroduct system-based method. We used these methods simultaneously to compare CF screening outcomes. STs using both methods were performed simultaneously between March and December 2022 at CF Centre in Florence. We included newborns who underwent newborn bloodspot screening (NBS), newborns undergoing transfusion immediately after birth, and children with CF screen-positive, inconclusive diagnosis (CFSPID). We assessed 72 subjects (median age 4.4 months; range 0–76.7): 30 (41.7%) NBS-positive, 18 (25.0%) newborns who underwent transfusion, and 24 (33.3%) children with CFSPID. No significant differences were found between valid sample numbers, by patient ages and groups (p = 0.10) and between chloride concentrations (p = 0.13), except for sweat chloride (SC) measured by the Gibson–Cooke and Macroduct methods in CFSPID group (29.0, IQR: 20.0–48.0 and 22.5, IQR: 15.5–30.8, respectively; p = 0.01). The Macroduct and Gibson–Cooke methods showed substantial agreement with the SC values, except for CFSPID, whose result may depend on the method of sweat collection. In case of invalid values with Macroduct, the test should be repeated with Gibson–Cooke method. Full article

Targeted screening for congenital CMV infection (cCMV), which entails CMV testing of infants who fail newborn hearing screening (NBHS), has become common practice. However, this strategy misses nearly all infected infants with normal hearing at birth who are nonetheless at high risk of subsequent hearing loss and would benefit from timely cCMV diagnosis. The objective of this study was to identify expanded criteria predictive of cCMV to increase the scope and utility of targeted newborn CMV screening. In this retrospective study, 465 newborns were tested for cCMV at a single tertiary care center with a targeted screening program between 2014 and 2018. Twenty-two infants were diagnosed with cCMV, representing 0.2% of the 12,189 births over this period and 4.7% of the infants tested. The highest prevalence of cCMV infection was among infants tested because of primary maternal CMV infection (8/42, 19%), followed by failed initial NBHS (10/88, 11.4%), maternal HIV infection (3/137, 2.2%), and clinical suspicion alone (5/232, 2.2%). The symptoms with the highest prevalence of infection among all infants tested included an enlarged liver and/or spleen (33.3%) (3/9), followed by petechiae (33.3%), microcephaly (9.4%), direct hyperbilirubinemia (7.7%), thrombocytopenia (6%), and growth impairment (4.3%). In addition to CMV screening of newborns who fail the NBHS, these data suggest that certain clinical signs of cCMV—in particular: thrombocytopenia, growth impairment, and HIV exposure in pregnancy—should be additional criteria for expanded targeted newborn CMV screening, where universal screening is not yet the standard of care. Full article

Whether or not conditions should be included in publicly funded newborn screening (NBS) programs should be discussed according to objective and transparent criteria. Certain criteria have been developed for the introduction of NBS programs in the context of individual countries; however, there are no standard selection criteria for NBS programs in Japan. This study aimed to develop a quantitative scoring model to assess newborn screening that incorporates the views of a variety of stakeholders in Japan. The five recommended eligibility criteria for NBS were stratified based on previous studies and expert opinions, using the analytic hierarchy process. We conducted a cross-sectional, web-based questionnaire targeting a wide range of people involved in NBS to investigate pairwise comparisons of the evaluation items between February and April of 2022. There were 143 respondents. Most of our respondents (44.1%) were physicians. Fifty-eight respondents (40.6%) had been engaged in NBS-related research or work for more than 10 years. The distribution of allocation points was the highest for ‘intervention’, ‘screening test’, ‘follow-up setting’, ’economic evaluation’, and ’disease/condition’, in that order. The algorithm in this study will guide decision makers in collecting and evaluating objective data, thus enabling transparent discussions to occur. Full article

The assumption of this study is strictly connected to the need to focus and to know more about the impact on the psychological state of the parents whose newborn babies get a positive result at Expanded Newborn Screening (ENS). As clinical experience shows us, this aspect seems to have a potentially lasting resonance on the way the disease will be managed and handled in the family, leading to potential negative effects and repercussions on the child’s wellbeing and on the quality of life within the family. On the basis of this and on the evidence emerging from a review of the literature, this study aims to investigate and objectify possible distress indicators elicited at the moment of the communication of a positive result at ENS. Questionnaires containing the Beck Depression Inventory-II, the State-Trait Anxiety Inventory-Y, and the Short Form 36 Health Survey tests were administered to the parents of 87 newborns who received positive results at ENS. The parents of 32 babies expressed the presence of discomfort potentially related to the communication of a positive result at ENS. Full article

Cytomegalovirus (CMV) infection during pregnancy may result in long-term health problems for children with congenital CMV (cCMV). Currently, no prevention or treatment interventions are approved by the Food and Drug Administration for a cCMV indication. Healthcare provider and public awareness is low, and formal clinical practice guidelines and local practice patterns vary. A pilot study of eight cCMV experts was performed using qualitative semi-structured interviews to better understand clinical practice guidelines and patterns in the United States. Results from participant interviews highlighted the need for better prenatal diagnostic techniques, broader neonatal screening opportunities, and more robust evidence supporting intervention strategies. Healthcare provider and public partnerships are essential for advancing cCMV guidelines and improving care delivery. Our results provide a preliminary knowledge base and framework for developing a consensus cCMV research agenda to address evidence gaps that limit the revision of clinical practice guidelines. The changes in clinical practice patterns that may arise as a result of further research have the potential to reduce risk during pregnancy and improve care for children with cCMV infection. Full article

Genomic sequencing offers an unprecedented opportunity to detect inherited variants that are implicated in rare Mendelian disorders, yet there are many challenges to overcome before this technology can routinely be applied in the healthy population. The age-based genomic screening (ABGS) approach is a novel alternative to genome-scale sequencing at birth that aims to provide highly actionable genetic information to parents over the course of their child’s routine health care. ABGS utilizes an established metric to identify conditions with high clinical actionability and incorporates information about the age of onset and age of intervention to determine the optimal time to screen for any given condition. Ongoing partnerships with parents and providers are instrumental to the co-creation of educational resources and strategies to address potential implementation barriers. Implementation science frameworks and informative empirical data are used to evaluate strategies to establish this unique clinical application of targeted genomic sequencing. Ultimately, a pilot project conducted in primary care pediatrics clinics will assess patient and implementation outcomes, parent and provider perspectives, and the feasibility of ABGS. A validated, stakeholder-informed, and practical ABGS program will include hundreds of conditions that are actionable during infancy and childhood, setting the stage for a longitudinal implementation that can assess clinical and health economic outcomes. Full article

Newborn screening using dried blood spots (NBS) is widely acknowledged as a highly successful procedure in secondary prevention. For a number of congenital disorders, severe disability or death are impressively prevented by early detection and early treatment through NBS. However, as with any other screening, NBS can also cause harm, and the principle that “the overall benefits of screening should outweigh the harms” must be considered when introducing and implementing NBS programmes. This publication compiles the results of a systematic literature research on requirements for NBS infrastructure and procedures which was conducted as part of a research project on the quality and shortcomings of the NBS pathway in Germany. The compilation contains the requirements and recommendations for realising the principle of “maximise benefits and minimise harms” in relevant NBS pathway components such as parental education and information, coverage, timeliness, laboratory quality assurance, follow-up of abnormal results, confirmatory diagnostics, documentation, and evaluation. The results reflect the complexity of NBS infrastructure, and thus, they illustrate the importance of considering and implementing NBS as a well-coordinated public health programme with continuous quality management. Special attention should be paid to the perspectives of parents and families. Some NBS issues can substantially benefit from digital instruments or international cooperation. The literature review presented here has contributed to a concept of proposals for the advancement of NBS in Germany, and despite different settings, it may as well be of interest for other countries to achieve the best possible course and outcome of NBS for each child. Full article

Residual heel prick Dried Blood Spots (DBS) are valuable samples for retrospective investigation of inborn metabolic diseases (IMD) and biomarker analyses. Because many metabolites suffer time-dependent decay, we investigated the five-year stability of amino acids (AA) in residual heel prick DBS. In 2019/2020, we analyzed 23 AAs in 2170 residual heel prick DBS from the Dutch neonatal screening program, stored from 2013–2017 (one year at +4 °C and four years at room temperature), using liquid chromatography mass-spectrometry. Stability was assessed by AA changes over the five years. Hydroxyproline could not be measured accurately and was not further assessed. Concentrations of 19 out of the remaining 22 AAs degraded significantly, ranked from most to least stable: aspartate, isoleucine, proline, valine, leucine, tyrosine, alanine, phenylalanine, threonine, citrulline, glutamate, serine, ornithine, glycine, asparagine, lysine, taurine, tryptophan and glutamine. Arginine, histidine and methionine concentrations were below the limit of detection and were likely to have been degraded within the first year of storage. AAs in residual heel prick DBS stored at room temperature are subject to substantial degradation, which may cause incorrect interpretation of test results for retrospective biomarker studies and IMD diagnostics. Therefore, retrospective analysis of heel prick blood should be done in comparison to similarly stored heel prick blood from controls. Full article

Screening newborns for congenital cytomegalovirus (cCMV) infection is critical for early detection and prompt diagnosis of related long-term consequences of infection, such as sensorineural hearing loss and neurodevelopmental delays. The objective of this study was to describe the validity of different newborn cCMV infection screening approaches and compare the expected number of cCMV cases detected across targeted and universal screening algorithms. The overall sensitivity (OSn) of targeted screening algorithms that required failure of auditory brain stem response and transient evoked otoacoustic emissions (TOAE; two-fail serial testing) or TOAE only (one-fail serial testing) before diagnostic CMV testing using saliva and urine PCR tests was 79% and 88%, respectively. The OSn for two-fail serial testing with diagnostic CMV testing using dried blood spot (DBS) was 75%. In contrast, OSn was 90% for universal screening (saliva and urine PCR tests) and 86% for universal screening with DBS testing alone. Overall, specificities were 100% across all algorithms. Universal screening using DBS testing and universal screening using saliva and urine testing can potentially detect 312 and 373 more cCMV cases per 100,000 live births, respectively, than two-fail serial testing. Overall, implementing universal cCMV newborn screening would improve cCMV detection, ultimately leading to better health outcomes. Full article

Mucopolysaccharidosis type II (MPS-II, Hunter syndrome, OMIM:30990) is a lysosomal storage disorder (LSD) that results in iduronate 2-sulphatase (I2S) enzyme deficiency. MPS-II was added to the Recommended Uniform Screening Panel (RUSP) in August 2022; thus, there is an increased demand for multiplexing I2S into existing LSD screening assays. After incubation with LSD synthetic substrates, extracts are cleaned using liquid–liquid extraction with ethyl acetate or protein precipitation using acetonitrile (ACN). We investigated cold-induced water ACN phase separation (CIPS) to improve the combination of 6-plex and I2S extracts to create a 7-plex assay, and compared it to room temperature ACN and ethyl acetate liquid–liquid extraction. The extracts were dried and resuspended in the mobile phase, and then analyzed using an optimized 1.9 min injection-to-injection liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS). The combination of ACN and CIPS improved the detection for I2S products without significant detriment to other analytes, which is attributable to a more complete coagulation and separation of heme, proteins, and extracted residual salts. Using CIPS for sample cleanup in dried blood spots (DBS) appears to represent a promising and straightforward way of achieving cleaner sample extracts in a new 7-plex LSD screening panel. Full article

Fabry disease is an X-linked progressive lysosomal disorder, due to α-galactosidase A deficiency. Patients with a classic phenotype usually present in childhood as a multisystemic disease. Patients presenting with the later onset subtypes have cardiac, renal and neurological involvements in adulthood. Unfortunately, the diagnosis is often delayed until the organ damage is already irreversibly severe, making specific treatments less efficacious. For this reason, in the last two decades, newborn screening has been implemented to allow early diagnosis and treatment. This became possible with the application of the standard enzymology fluorometric method to dried blood spots. Then, high-throughput multiplexable assays, such as digital microfluidics and tandem mass spectrometry, were developed. Recently DNA-based methods have been applied to newborn screening in some countries. Using these methods, several newborn screening pilot studies and programs have been implemented worldwide. However, several concerns persist, and newborn screening for Fabry disease is still not universally accepted. In particular, enzyme-based methods miss a relevant number of affected females. Moreover, ethical issues are due to the large number of infants with later onset forms or variants of uncertain significance. Long term follow-up of individuals detected by newborn screening will improve our knowledge about the natural history of the disease, the phenotype prediction and the patients’ management, allowing a better evaluation of risks and benefits of the newborn screening for Fabry disease. Full article

Caring for a child with congenital cytomegalovirus (cCMV) can be costly for families, not only in terms of out-of-pocket expenses, but also in terms of caregiver time, relationships, career trajectories, and mental health. These additional burdens are sometimes referred to as “spillover effects”. As parents of children with cCMV, we, the authors of this article, discuss the impact that cCMV has had on our families. While multiple studies have reported on the epidemiology, prevention, screening, diagnosis, and management of cCMV, there has been minimal research regarding the possible impact on the family unit. In this narrative review, we discuss the various areas of the lives of families and caregivers that may be impacted by raising a child with cCMV. Whether children are minimally or severely affected by the sequelae of cCMV, they and their families merit the progression of awareness of the virus and governmental policies to help end cCMV. As the existing cCMV-specific literature is limited, we correlate studies of other childhood disabilities and find the mutuality experienced by families affected by cCMV. Full article