Int. J. Neonatal Screen., Volume 7, Issue 3 (September 2021) – 29 articles

Although several countries have adopted severe combined immunodeficiency (SCID) into their newborn screening (NBS) program, other countries are still in the decision process of adding this disorder in their program and finding the appropriate screening strategy. This decision may be influenced by the cost(-effectiveness) of these screening strategies. In this study, the cost(-effectiveness) of different NBS strategies for SCID was estimated based on real-life data from a prospective implementation study in the Netherlands. The cost of testing per child for SCID was estimated at EUR 6.36. The cost of diagnostics after screen-positive results was assessed to vary between EUR 985 and 8561 per child dependent on final diagnosis. Cost-effectiveness ratios varied from EUR 41,300 per QALY for the screening strategy with T-cell receptor excision circle (TREC) ≤ 6 copies/punch to EUR 44,100 for the screening strategy with a cut-off value of TREC ≤ 10 copies/punch. The analysis based on real-life data resulted in higher costs, and consequently in less favorable cost-effectiveness estimates than analyses based on hypothetical data, indicating the need for verifying model assumptions with real-life data. The comparison of different screening strategies suggest that strategies with a lower number of referrals, e.g., by distinguishing between urgent and less urgent referrals, are favorable from an economic perspective. Full article

Screening for severe combined immunodeficiency (SCID) was introduced into the Swedish newborn screening program in August 2019 and here we report the results of the first year. T cell receptor excision circles (TRECs), kappa-deleting element excision circles (KRECs), and actin beta (ACTB) levels were quantitated by multiplex qPCR from dried blood spots (DBS) of 115,786 newborns and children up to two years of age, as an approximation of the number of recently formed T and B cells and sample quality, respectively. Based on low TREC levels, 73 children were referred for clinical assessment which led to the diagnosis of T cell lymphopenia in 21 children. Of these, three were diagnosed with SCID. The screening performance for SCID as the outcome was sensitivity 100%, specificity 99.94%, positive predictive value (PPV) 4.11%, and negative predictive value (NPV) 100%. For the outcome T cell lymphopenia, PPV was 28.77%, and specificity was 99.95%. Based on the first year of screening, the incidence of SCID in the Swedish population was estimated to be 1:38,500 newborns. Full article

We established a diagnostic system for adrenoleukodystrophy (ALD) and peroxisomal disorders (PD) over 35 years ago in Japan, and have diagnosed 237 families with ALD and more than 100 cases of PD other than ALD using biochemical and molecular analyses. In particular, since the only treatment for the cerebral form of ALD is hematopoietic stem cell transplantation at an early stage of onset, we have developed a protocol for the rapid diagnosis of ALD that can provide the measurements of the levels of very-long-chain fatty acids in the serum and genetic analysis within a few days. In addition, to improve the prognosis of patients with ALD, we are working on the detection of pre-symptomatic patients by familial analysis from the proband, and the introduction of newborn screening. In this review, we introduce the diagnostic and newborn screening approaches for ALD and PD in Japan. Full article

Krabbe disease is an autosomal recessive leukodystrophy caused by pathogenic variants in the galactocerebrosidase (GALC) gene. GALC activity is needed for the lysosomal hydrolysis of galactosylceramide, an important component of myelin. While most patients are infants, older patients are also diagnosed. Starting in 1970, a diagnosis could be made by measuring GALC activity in leukocytes and cultured cells. After the purification of GALC in 1993, the cDNA and genes were cloned. Over 260 disease-causing variants as well as activity lowering benign variants have been identified. While some pathogenic variants can be considered “severe,” others can be considered “mild.” The combination of alleles determines the type of Krabbe disease a person will have. To identify patients earlier, newborn screening (NBS) has been implemented in several states. Low GALC activity in this screening test may indicate a diagnosis of Krabbe disease. Second tier testing as well as neuro-diagnostic studies may be required to identify those individuals needing immediate treatment. Treatment of pre-symptomatic or mildly symptomatic patients at this time is limited to hematopoietic stem cell transplantation. Treatment studies using the mouse and dog models have shown that combining bone marrow transplantation with intra-venous gene therapy provides the best outcomes in terms of survival, behavior, and preservation of normal myelination in the central and peripheral nervous systems. With earlier diagnosis of patients through newborn screening and advances in treatment, it is hoped that more patients will have a much better quality of life. Full article

Kuwait is a small Arabian Gulf country with a high rate of consanguinity and where a national newborn screening program was expanded in October 2014 to include a wide range of endocrine and metabolic disorders. A retrospective study conducted between January 2015 and December 2020 revealed a total of 304,086 newborns have been screened in Kuwait. Six newborns were diagnosed with classic homocystinuria with an incidence of 1:50,000, which is not as high as in Qatar but higher than the global incidence. Molecular testing for five of them has revealed three previously reported pathogenic variants in the CBS gene, c.969G>A, p.(Trp323Ter); c.982G>A, p.(Asp328Asn); and the Qatari founder variant c.1006C>T, p.(Arg336Cys). This is the first study to review the screening of newborns in Kuwait for classic homocystinuria, starting with the detection of elevated blood methionine and providing a follow-up strategy for positive results, including plasma total homocysteine and amino acid analyses. Further, we have demonstrated an increase in the specificity of the current newborn screening test for classic homocystinuria by including the methionine to phenylalanine ratio along with the elevated methionine blood levels in first-tier testing. Here, we provide evidence that the newborn screening in Kuwait has led to the early detection of classic homocystinuria cases and enabled the affected individuals to lead active and productive lives. Full article

Early-onset carnitine palmitoyltransferase II deficiency (CPT II deficiency) (OMIM 600650) can result in severe outcomes, which are often fatal in the neonatal to infantile period. CPT II deficiency is a primary target in the Maritime Newborn Screening Program. We report a case of neonatal-onset CPT II deficiency identified through expanded newborn screening with tandem mass spectrometry. Identification through newborn screening led to early treatment interventions, avoidance of metabolic decompensation, and a better clinical outcome. Newborn screening for CPT II deficiency is highly sensitive and specific with no false positives identified. The only screen positive case detected identified a true positive case. This experience illustrates the importance of newborn screening for CPT II deficiency and demonstrates why reconsideration should be taken to add this disease as a primary newborn screening target. Full article

Since the approval of modifying therapies for Spinal Muscular Atrophy (SMA), several protocols aiming to screen SMN1 homozygous deletion in a neonatal context have been published. However, no work has compared different methodologies along with detailed implementation costs for centers where the neonatal screening of SMA has not yet been implemented. Therefore, our work compared different qualitative real-time PCR approaches for SMA screening and the estimated costs of test implementation. Using Brazilian blood samples, the presence and absence (P/A) and melt curve protocols were analyzed. MLPA was used as a confirmatory test. The costs were calculated for the simplex and multiplex tests plus equipment. The test workflow was based on the present experience and literature report. The accuracy of the P/A protocol was 1 (95% CI 0.8677−1) using dried blood spots (DBS). The melt curve protocol also achieved 100% concordance. The consumable costs ranged from USD 1.68 to 4.42 and from USD 2.04 to 12.76 per reaction, for the simplex and multiplex tests, respectively. The equipment acquisition costs ranged from USD 44,817.07 to 467,253.10, with several factors influencing this value presented. Our work presents a framework for decision-making, with a project demonstration of the different assays that will be useful in dealing with the issues of cost and availability of reagents. Moreover, we present a literature review and discussion of important concerns regarding treatment policies. We take the first step towards a future SMA NBS pilot program where it is not yet a reality. Full article

During the ISNS meeting “Newborn Screening for SCID ‘State of the Art’” on 26 and 27 January 2021, the topic of case definitions and related issues were discussed. There is currently a lack of uniform definitions and therefore a lack of uniform registration of screen-positive cases. This severely hampers the comparison of outcomes of different screening programs and the exchange of experiences gained by the different countries performing SCID screening, which is essential to improve screening programs. In this letter, I outline the current situation and indicate the need for uniform definitions and classification, which in my view needs to be a joined effort of screeners and immunologists. Full article

Newborn screening (NBS) for congenital hypothyroidism (CH) started in the 1970s, with the introduction of radioimmuno assays (RIA) for the measurement of thyroxine (T4), and thyroid stimulating hormone (TSH). With the development of sensitive enzyme immune assays (EIA, FIA, FEIA), RIAs were replaced in the newborn screening laboratories. With the increasing number of analytes and centralization of NBS, there is a growing demand of total automation. In the course of method validation, two fully automated platforms for the determination of TSH in dried blood samples (DBS) were compared. The GSP from PerkinElmer (PE), and the NS2400 from Labsystems (LDx), together with the recommended test kits from both manufacturers. Both systems showed good performance, with recoveries, of 103.0% (LDx) and 98.5% (PE), and CVs for intra and interassay variations at various concentrations, between 4.3 and 15.7. Both assays had a good correlation (r² = 0.8814). With LDx/NS2400 platform, TSH values were in the mean 2.09 mU/L higher; however, the difference of both results from the mean was within ±2 SD, up to 30 mU/L, and only for values above 50 mU/L did the difference become bigger. However, this has no influence on the clinical interpretation. No false negative results were observed with either of the two platforms. TSH results obtained with the LDx/NS2400 were slightly higher than those obtained with the PE/GSP; however, the recall rate was lower: 0.059% compared to 0.063%. This can be explained by the much narrower distribution of TSH values. In conclusion, both platforms are equally suitable for medium and large NBS laboratories. However, due to the more open structure the LDx/NS2400 platform has a lot of advantages compared to the totally closed PE/GSP platform. Full article

Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme. Full article

Newborn screening (NBS) follow-up programs in the United States are managed at the state level, leaving limited opportunities for collaboration across programs and coordinated resource sharing. The Newborn Screening Technical assistance and Evaluation Program (NewSTEPs), a program of the Association of Public Health Laboratories (APHL), has established a national community of practice for NBS follow-up by creating a network of follow-up staff and stakeholders through education and engagement opportunities. The activities of NewSTEPs in support of NBS follow-up have strengthened information dissemination, collaboration, data collection and technical assistance-driven mentorship across the national system. Full article

Homocystinuria, caused by cystathionine β-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria. The 14-month-old boy had normal newborn screening. The 7-year-old boy initially had an abnormal newborn screen for homocystinuria but second tier test that consisted of total homocysteine was normal, so his newborn screen was reported as normal. With the advent of expanded newborn screening many treatable metabolic disorders are detected before affected infants and children become symptomatic. Methionine is the primary target in newborn screening for homocystinuria and total homocysteine is a secondary target. Screening is usually performed after 24–48 h of life in most states in the US and some states perform a second screen as a policy on all tested newborns or based on when the initial newborn screen was performed. This is done in hopes of detecting infants who may have been missed on their first screen. In the United Kingdom, NBS using dried blood spot is performed at 5 to 8 days after birth. It is universally known that methionine is a poor target and newborn screening laboratories have used different cutoffs for a positive screen. Reducing the methionine cutoff increases the sensitivity but not necessarily the specificity of the test and increasing the cutoff will miss babies who may have HCU whose levels may not be high enough to be detected at their age of ascertainment. It is not clear whether adjusting methionine level to decrease the false negative rates combined with total homocysteine as a second-tier test can be used effectively and feasibly to detect newborns with HCU. Between December 2005 and December 2020, 827,083 newborns were screened in Kentucky by MS/MS. Kentucky NBS program uses the postanalytical tools offered by the Collaborative Laboratory Integrated Reports (CLIR) project which considers gestational age and birthweight. One case of classical homocystinuria was detected and two were missed on first and second tier tests respectively. The newborn that had confirmed classical homocystinuria was one of twenty-three newborns that were referred for second tier test because of elevated methionine (cutoff is >60 µmol/L) and/or Met/Phe ratio (cutoff is >1.0); all 23 dried blood spots had elevated total homocysteine. One of the subjects of this case report had a normal methionine on initial screen and the other had a normal second-tier total homocysteine level. The performance of methionine and total homocysteine as screening analytes for homocystinuria suggest that it may be time for newborn screening programs to consider adopting next generation sequencing (NGS) platforms as alternate modality of metabolic newborn screening. Because of cost considerations, newborn screening programs may not want to adopt NGS, but the downstream healthcare cost incurred due to missed cases and the associated morbidity of affected persons far exceed costs to newborn screen programs. Since NGS is becoming more widely available and inexpensive, it may be feasible to change testing algorithms to use Newborn Metabolic NGS as the primary mode of testing on dry blood specimens with confirmation with biochemical testing. Some commercial laboratories have Newborn Screening Metabolic gene panel that includes all metabolic disorders on the most comprehensive newborn screening panel in addition to many other conditions that are not on the panel. A more targeted NGS panel can be designed that may not cost much and eventually help avoid the pitfalls associated with delayed diagnosis and cost of screening. Full article

Promising treatments for spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, prompted calls for inclusion in newborn screening (NBS). In January 2018, the New England Newborn Screening Program (NENSP) began statewide screening for SMA using a tiered algorithm looking for the absence of SMN1 Exon 7. When results from the first and second tier needed reconciliation, we developed and validated a third tier DNA sequencing assay to ensure the presence or absence of SMN1 Exon 7. All nine infants referred to specialty centers through NBS showed single base substitution of c.840C>T, and were confirmed to have SMA. Further, a minor sequencing protocol modification allowed the estimation of SMN2 copy number in SMA affected patients; we developed and validated a copy-number assay yielding 100% match with seven previously characterized specimens of SMA patients. All nine SMA-affected infants found through NBS were also assayed for SMN2 copy number. Results were comparable but not 100% matched with those that were reported by independent diagnostic laboratories. In conclusion, a sequencing protocol confirms NBS findings from real-time qPCR, and its modified application allows NBS programs that have sequencing capabilities to provide SMN2 copy numbers without the need for additional instrumentation. Full article

Newborn screening (NBS) for severe combined immunodeficiency (SCID) started in Catalonia in January-2017, being the first Spanish and European region to universally include this testing. In Spain, a pilot study with 5000 samples was carried out in Seville in 2014; also, a research project with about 35,000 newborns will be carried out in 2021–2022 in the NBS laboratory of Eastern Andalusia. At present, the inclusion of SCID is being evaluated in Spain. The results obtained in the first three and a half years of experience in Catalonia are presented here. All babies born between January-2017 and June-2020 were screened through TREC-quantification in DBS with the Enlite Neonatal TREC-kit from PerkinElmer. A total of 222,857 newborns were screened, of which 48 tested positive. During the study period, three patients were diagnosed with SCID: an incidence of 1 in 74,187 newborns; 17 patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 13,109 newborns who also benefited from the NBS program. The results obtained provide further evidence of the benefits of early diagnosis and curative treatment to justify the inclusion of this disease in NBS programs. A national NBS program is needed, also to define the exact SCID incidence in Spain. Full article

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs—nusinersen and onasemnogene abeparvovec—improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000–40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture. Full article

To minimize false-positive cases in newborn screening by tandem mass spectrometry in Japan, practical second-tier liquid chromatography-tandem mass spectrometry analyses have been developed using a multimode ODS column with a single set of mobile phases and different gradient elution programs specific to the analysis of acylcarnitines, acylglycines, amino acids, and organic acids. Most analyses were performed using underivatized samples, except for analysis of methylcitric acid, and careful conditioning of the column was necessary for analyses of organic acids. Our second-tier tests enabled us to measure many metabolites useful for detection of target disorders, including allo-isoleucine, homocysteine, methylmalonic acid, and methylcitric acid. We found that accumulation of 3-hydroxyglutaric acid was specific to glutaric acidemia type I and that the ratio of 3-hydroxyisovaleric acid to 3-hydroxyisovalerylcarnitine was useful to detect newborns of mothers with 3-methylcrotonyl-CoA carboxylase deficiency. Data from the analysis of short-chain acylcarnitine and acylglycine were useful for differential diagnosis in cases positive for C5-OH-acylcarnitine or C5-acylcarnitine. Full article

All newborn screening programs screen for severe combined immunodeficiency by measurement of T-cell receptor excision circles (TRECs). Herein, we report our experience of reporting TREC assay results as multiple of the median (MoM) rather than using conventional copy numbers. This modification simplifies the assay by eliminating the need for standards with known TREC copy numbers. Furthermore, since MoM is a measure of how far an individual test result deviates from the median, it allows normalization of TREC assay data from different laboratories, so that individual test results can be compared regardless of the particular method, assay, or reagents used. Full article

After it was demonstrated in 2005 that T cell receptor excision circle (TREC) quantification for dried blood spot (DBS) samples on Guthrie cards is an effective means of SCID screening and following several pilot studies, the practice was formally recommended in the US in 2010. More and more countries have adopted it since then. In France, before the health authorities could recommend adding SCID to the list of five diseases that were routinely screened for, feasibility and cost-effectiveness studies had to be conducted with a sufficiently large cohort of neonates. We carried out three such studies: The first sought to verify the effectiveness of the assay. The second, DEPISTREC, evaluated the feasibility of universal SCID screening in France and assessed the clinical benefit and economic advantage it would provide. Through the third study, NeoSKID, still under way and to continue until recommendations are issued, we have been offering SCID screening in the Pays de la Loire region of France. This review briefly describes routine newborn screening (NBS) and management of primary immunodeficiency diseases (PIDs) in France, and then considers the lessons from our studies and the status of SCID screening implementation within the country. Full article

Surveys are used to gather a range of data on newborn screening (NBS) processes. We describe the development of a survey about parents’ NBS experiences, in the United States, informed by cognitive pretest interviews among parents with varying NBS test results (true-positive, false-positive, normal). Cognitive pretest interviews were conducted following a semi-structured script and notes were taken to identify problematic survey items. The study team met weekly to discuss pretest feedback, draft changes, and generate revised items. Pretests indicated that parent experiences with NBS are varied and NBS screening procedures are not well understood. Substantial modifications were made to survey questions concerning NBS testing and result communication. Pretesters often associated NBS with other tests/exams/scales—APGAR scores, Ages and Stages questionnaires, and genetic testing during pregnancy. Some pretesters recalled receiving NBS blood spot results during their hospital admission, an uncommon practice, and few recalled knowing results would be provided to them or their pediatrician in the first few weeks of life. Thorough explanations regarding NBS procedures and expectations were embedded within the survey to enhance and improve interpretation of survey questions. Future NBS experience surveys should utilize cognitive pretesting to capture divergent experiences and improve response validity. Full article

The Wisconsin Newborn Screening (NBS) Program began screening for severe combined immunodeficiency (SCID) in 2008, using real-time PCR to quantitate T-cell receptor excision circles (TRECs) in DNA isolated from dried blood NBS specimens. Prompted by the observation that there were disproportionately more screening-positive cases in premature infants, we performed a study to assess whether there is a difference in TRECs between full-term and preterm newborns. Based on de-identified SCID data from 1 January to 30 June 2008, we evaluated the TRECs from 2510 preterm newborns (gestational age, 23–36 weeks) whose specimens were collected ≤72 h after birth. The TRECs from 5020 full-term newborns were included as controls. The relationship between TRECs and gestational age in weeks was estimated using linear regression analysis. The estimated increase in TRECs for every additional week of gestation is 9.60%. The 95% confidence interval is 8.95% to 10.25% (p ≤ 0.0001). Our data suggest that TRECs increase at a steady rate as gestational age increases. These results provide rationale for Wisconsin’s existing premature infant screening procedure of recommending repeat NBS following an SCID screening positive in a premature infant instead of the flow cytometry confirmatory testing for SCID screening positives in full-term infants. Full article

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine β-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 μmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 μmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B₁₂ deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway. Full article

The onset of the COVID-19 pandemic caused significant changes in healthcare delivery. Telemedicine rapidly and unexpectedly became the primary vehicle for ambulatory management. As newborn screen (NBS) referrals require varying levels of acuity, whether telemedicine could be used as a safe and effective medium to return these results were unknown. We sent an online survey to metabolism providers internationally to investigate triage differences of abnormal NBS results during the COVID-19 pandemic. The survey compared personal practice for the periods of March–June 2019 and March–June 2020. Responses were received from 44 providers practicing in 8 countries. Nearly all (93%) practiced in areas of widespread SARS-COV-2 community transmission during spring 2020. There was a significant expansion of telemedicine use for NBS referrals at the onset of the COVID-19 pandemic (OR: 12, 95% CI: 3.66–39.3, p < 0.0001). Telehealth primarily replaced in-person ambulatory metabolism visits. The increased frequency of virtual care was similar across NBS analytes. Providers found telehealth for NBS referral equally efficacious to in-person care. Institutional patient surveys showed no difference in satisfaction with provider communication, provider empathy, or appointment logistics. Our survey was limited by unprecedented disruption in healthcare delivery, necessitating further validation of telegenetics for NBS in the post-pandemic era. Nevertheless, our findings demonstrate that telemedicine is potentially a viable and practical tool for triaging abnormal NBS results. Full article

The goal of newborn screening is to improve health outcomes by identifying and treating affected newborns. This manuscript provides an overview of a data tool to facilitate the longitudinal collection of health information on newborns diagnosed with a condition through NBS. The Newborn Screening Translational Research Network (NBSTRN) developed the Longitudinal Pediatric Data Resource (LPDR) to capture, store, analyze, visualize, and share genomic and phenotypic data over the lifespan of NBS identified newborns to facilitate understanding of genetic disease and to assess the impact of early identification and treatment. NBSTRN developed a consensus-based process using clinical care experts to create, maintain, and evolve question and answer sets organized into common data elements (CDEs). The LPDR contains 24,172 core and disease specific CDEs for 118 rare genetic diseases, and the CDEs are being made available through the NIH CDE Repository. The number of CDEs for each condition average of 2200 with a range from 69 to 7944. The LPDR is used by state NBS programs, clinical researchers, and community-based organizations. Case level, de-identified data sets are available for secondary research and data mining. The development of the LPDR for longitudinal data gathering, sharing, and analysis supports research and facilitates the translation of discoveries into clinical practice. Full article

Congenital adrenal hyperplasia (CAH) is an inherited disorder caused by the absence or severely impaired activity of steroidogenic enzymes involved in cortisol biosynthesis. More than 90% of cases result from 21-hydroxylase deficiency (21OHD). To prevent life-threatening adrenal crisis and to help perform appropriate sex assignments for affected female patients, newborn screening (NBS) programs for the classical form of CAH have been introduced in numerous countries. In Japan, the NBS for CAH was introduced in 1989, following the screenings for phenylketonuria and congenital hypothyroidism. In this review, we aim to summarize the experience of the past 30 years of the NBS for CAH in Japan, composed of four parts, 1: screening system in Japan, 2: the clinical outcomes for the patients with CAH, 3: various factors that would impact the NBS system, including timeline, false positive, and LC-MS/MS, 4: Database composition and improvement of the screening program. Full article

Propionic acidemia (PA) is a disorder of organic acid metabolism which typically presents with acute encephalopathy-like symptoms associated with metabolic acidosis and hyperammonemia during the neonatal period. The estimated incidence of symptomatic PA in Japan is 1/400,000. The introduction of neonatal screening using tandem mass spectrometry has revealed a far higher disease frequency of approximately 1/45,000 live births due to a prevalent variant of c.1304T>C (p.Y435C) in PCCB, which codes β-subunit of propionyl-CoA carboxylase. Our questionnaire-based follow-up study reveals that most of these patients remain asymptomatic. However, reports on symptomatic patients exhibiting cardiac complications such as cardiomyopathy and QT prolongation have been increasing. Moreover, there were even cases in which these cardiac complications were the only symptoms related to PA. A currently ongoing study is investigating the risk of cardiac complications in patients with neonatal screening-detected PA caused by this common variant. Full article

Congenital hypothyroidism (CH) is the most common preventable cause of intellectual impairment or failure to thrive by early identification and treatment. In Japan, newborn screening programs for CH were introduced in 1979, and the clinical guidelines for newborn screening of CH were developed in 1998, revised in 2014, and are currently undergoing further revision. Newborn screening strategies are designed to detect the elevated levels of thyroid stimulating hormone (TSH) in most areas of Japan, although TSH and free thyroxine (FT4) are often measured simultaneously in some areas. Since 1987, in order not to observe the delayed rise in TSH, additional rescreening of premature neonates and low birth weight infants (<2000 g) at four weeks of life or when their body weight reaches 2500 g has been recommended, despite a normal initial newborn screening. Recently, the actual incidence of CH has doubled to approximately 1:2500 in Japan as in other countries. This increasing incidence is speculated to be mainly due to an increase in the number of mildly affected patients detected by the generalized lowering of TSH screening cutoffs and an increase in the number of preterm or low birth weight neonates at a higher risk of having CH than term infants. Full article

Newborn screening (NBS) programs identify newborns at increased risk for genetic disorders, linking these newborns to timely intervention and potentially life-saving treatment. In the United States, the Health and Human Services (HHS) Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) recommends the disorders for state NBS programs to screen. ACHDNC updated the Recommended Uniform Screening Panel to include Spinal Muscular Atrophy (SMA) in July 2018. As of June 2021, 34 state NBS programs had fully implemented SMA newborn screening, and at least 8 programs were pursuing implementation. This article will review current SMA screening processes, considerations, challenges, and status. Full article