Genotyping in patients with congenital adrenal hyperplasia by sequencing of newborn bloodspot samples.

OBJECTIVES: Genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency ranges from 45 to 97 %. We performed massively parallel sequencing of CYP21A2 on stored newborn bloodspot samples to catalogue the genotypes present in our patients with CAH and enable genotype-phenotype comparison. METHODS: Participants ≤15 years old with clinically diagnosed CAH were recruited from The Sydney Children's Hospitals Network. Phenotype was classified from clinical and biochemical details in the medical record as salt wasting (SW), simple virilising (SV), non-classic (NC) or an intermediate phenotype (SW/SV; SV/NC). Amplicon-based sequencing for CYP21A2 was performed on stored newborn bloodspot samples by the New South Wales Newborn Bloodspot Screening Laboratory on MiSeq™Dx (Illumina, California). Available genetic test results were also obtained from the medical records. RESULTS: Samples from 67 participants (43 % female, age 0.3-15 years) were sequenced, including 9 sibships. SW phenotype was present in 33/67 participants (49 %), SV in 9 (13 %) and NC in 16 (24 %). Intermediate phenotypes included SW/SV in seven participants (10 %) and SV/NC in two (3 %). Variants were identified in 90/116 alleles (78 %). A complete genotype was available in 47/67 participants (70 %). The most common genotype was homozygous c.293-13A/C>G (I2G) in 7/47 participants (15 %). Genotype correlated with the most commonly reported phenotype in 36/44 cases (82 %). Correlation was higher in SW and NC phenotypes. CONCLUSIONS: This study uses genetic testing of newborn bloodspots to identify and characterise the genotypes present in an ethnically diverse Australian population with CAH. It further strengthens our knowledge of genotype-phenotype correlations in CAH.

Outcomes of lowered newborn screening thresholds for congenital hypothyroidism.

BACKGROUND: Newborn screening (NBS) has largely eliminated the physical and neurodevelopmental effects of untreated congenital hypothyroidism (CH). Many countries, including Australia, have progressively lowered NBS bloodspot thyroid-stimulating hormone (b-TSH) thresholds. The impact of these changes is still unclear. OBJECTIVES: To evaluate the performance of CH NBS following the reduction of b-TSH thresholds in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia, from 15 to 8 mIU/L, and to determine the clinical outcomes of cases detected by these thresholds. METHODS: NBS data of 346 849 infants born in NSW/ACT, Australia from 1 November, 2016-1 March, 2020 inclusive were analysed. A clinical audit was conducted on infants with a preliminary diagnosis of CH born between 1 January, 2016-1 December, 2020 inclusive. RESULTS: The lowered b-TSH threshold (≥8 mIU/L, ~99.5th centile) detected 1668 infants (0.48%), representing an eight-fold increase in recall rate, of whom 212 of 1668 (12.7%) commenced thyroxine treatment. Of these 212 infants, 62 (29.2%) (including eight cases with a preliminary diagnosis of thyroid dysgenesis) had an initial b-TSH 8-14.9 mIU/L. The positive predictive value for a preliminary diagnosis of CH decreased from 74.3% to 12.8% with the lowered threshold. Proportionally, more pre-term infants received a preliminary CH diagnosis on screening with the lower threshold (16.1% of 62) than with the higher threshold (8.0% of 150). CONCLUSION: Clinically relevant CH was detected using the lowered threshold, albeit at the cost of an eight-fold increase in recall rate. Further clinical and economic studies are required to determine whether benefits of lowered screening thresholds outweigh potential harms from false-positive results on infants, their families and NBS programs.

Expanding the Australian Newborn Blood Spot Screening Program using genomic sequencing: do we want it and are we ready?

Since the introduction of genome sequencing in medicine, the factors involved in deciding how to integrate this technology into population screening programs such as Newborn Screening (NBS) have been widely debated. In Australia, participation in NBS is not mandatory, but over 99.9% of parents elect to uptake this screening. Gauging stakeholder attitudes towards potential changes to NBS is vital in maintaining this high participation rate. The current study aimed to determine the knowledge and attitudes of Australian parents and health professionals to the incorporation of genomic sequencing into NBS programs. Participants were surveyed online in 2016 using surveys adapted from previous studies. The majority of parents (90%) self-reported some knowledge of NBS, with 77% expressing an interest in NBS using the new technology. This was significantly lower than those who would utilise NBS using current technologies (99%). Although, many health professionals (62%) felt that new technologies should currently not be used as an adjunct to NBS, 79% foresaw the use of genomic sequencing in NBS by 2026. However, for genomic sequencing to be considered, practical and technical challenges as well as parent information needs were identified including the need for accurate interpretation of data; pre-and post-test counselling; and appropriate parental consent and opt-out process. Therefore, although some support for implementing genomic sequencing into Australian NBS does exist, there is a need for further investigation into the ethical, social, legal and practical implications of introducing this new technology as a replacement to current NBS methods.

Newborn screening for spinal muscular atrophy in Australia: a non-randomised cohort study.

BACKGROUND: In light of a new therapeutic era for spinal muscular atrophy (SMA), newborn screening has been proposed as a gateway to facilitate expedient diagnosis and access to therapeutics. However, there is paucity of evidence on health outcomes outside the homogenous populations in clinical trials to justify broader implementation of newborn screening for SMA. In this real-world study, we aimed to investigate the effectiveness of newborn screening coupled with access to disease-modifying therapeutics, as an intervention for SMA. METHODS: In this prospective, non-randomised cohort study done at Sydney Children's Hospital Network (NSW, Australia), we included children younger than 16 years with homozygous exon 7 deletions of survival motor neuron 1 gene (SMN1) mutations, non-selectively assigned to a screening group (incident population diagnosed by newborn screening) from Aug 1, 2018, to Aug 1, 2020, or a comparator group (incident population diagnosed by clinical referral) from Aug 1, 2016, to July 31, 2018. We excluded infants with compound heterozygous SMN1 mutations and those participating in ongoing and unpublished clinical trials. Effectiveness of newborn screening for SMA was compared using motor development milestone attainment defined by WHO Multicentre Growth Reference Study at 2 years post diagnosis. Secondary outcome measures included mortality and change in Hammersmith Infant Neurological Examination-2 (HINE-2) score, ventilation requirements, and enteral requirements 2 years from the time of diagnosis. FINDINGS: 34 children met the study inclusion criteria, but 33 children were included in the study population after one neonate was excluded due to participation in an ongoing unpublished clinical trial. 15 children were included in the screening group (seven [47%] male and eight [53%] female; median age 2·1 weeks [IQR 1·9-2·7]) and 18 children (nine [50%] male and nine [50%] female) were included in the comparator group (median age 47·8 weeks [13·0-99·9]). The 2-year survival rate was 93% (14 of 15 children) in the screening group and 89% (16 of 18) in the comparator group. Among survivors, 11 (79%) of 14 walked independently or with assistance in the screening group, compared with one (6%) of 16 children in the comparator group (χ2=16·27; p<0·0001). A significantly greater change in motor function was observed in the screening group compared with the comparator group over 2 years (HINE-2 score group difference, 12·32; p<0·0001). The requirement for non-intensive ventilation or feeding support at follow-up was higher in the comparator group than in the screening group (odds ratio 7·1 [95% CI 0·7-70·2]). Significant predictors of functional motor outcomes as determined by HINE-2 score at 2 years post diagnosis were HINE-2 score (p=0·0022), CHOP-INTEND (p=0·0001), compound muscle action potential (CMAP; p=0·0006), and disease status (p=0·023) at diagnosis. INTERPRETATION: Newborn screening for SMA, coupled with early access to disease-modifying therapies, effectively ameliorates the functional burden and associated comorbidities for affected children. For children diagnosed through newborn screening, motor score, CMAP, and disease status at diagnosis has clinical utility to determine functional independence. FUNDING: Brain Foundation and National Health and Medical Research Council.

Newborn Screening for the Diagnosis and Treatment of Duchenne Muscular Dystrophy.

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.

Fifty years of newborn screening for congenital hypothyroidism: current status in Australasia and the case for harmonisation.

OBJECTIVES: Since its implementation 50 years ago in Quebec, Canada, newborn screening for congenital hypothyroidism has become one of the most successful public health measures worldwide. Screening programmes across Australia and New Zealand are characterised by significant commonalities in screening algorithms, and a high degree of regional cooperation in harmonisation efforts. We aimed to conduct a comprehensive survey of current performance and practices related to the total testing process for congenital hypothyroidism screening and provide recommendations for harmonisation priorities within our region. METHODS: A survey was conducted involving the six newborn screening laboratories which provide complete geographic coverage across Australasia. Approximately 360,000 newborns are screened annually. Survey questions incorporated pre-analytical, analytical, and post-analytical aspects of the screening programmes and an extensive 5-year (2016-2020) retrospective analysis of individual programme performance data. Responses from individual screening programmes were collated. RESULTS: The uptake of newborn screening was over 98% for the six major jurisdictions. All programmes have adopted a single-tier thyroid stimulating hormone (TSH) strategy using the Perkin Elmer GSP instrument. Significant similarities exist between programmes for recommended age of collection and recollection protocols for low birthweight newborns. The process for the determination of TSH cutoffs varies between programmes. TSH lower cut-offs for borderline-positive and positive notifications between 12-15 and 12-25 mIU/L blood, respectively. Recall rates vary between 0.08 and 0.20%. The case definition for congenital hypothyroidism generally includes biochemical and radiological parameters in addition to the commencement of thyroxine. All programmes reported collecting biochemical and clinical data on infants with positive screening tests, and positive predictive values vary between 23.6 and 77.3%. Variation in reported incidence (1:1,300-2,000) cannot be entirely explained by cutoff or recall rate (although one programme reporting fewer cases includes only permanent disease). CONCLUSIONS: Despite similarities between newborn screening algorithms for congenital hypothyroidism across Australia and New Zealand, differences in reported programme performance provide the basis for further harmonisation. Surveillance of a large population offers the potential for the ongoing development of evidence-based screening guidelines.

Economic Evaluation of Newborn Screening for Severe Combined Immunodeficiency.

Evidence on the cost-effectiveness of newborn screening (NBS) for severe combined immunodeficiency (SCID) in the Australian policy context is lacking. In this study, a pilot population-based screening program in Australia was used to model the cost-effectiveness of NBS for SCID from the government perspective. Markov cohort simulations were nested within a decision analytic model to compare the costs and quality-adjusted life-years (QALYs) over a time horizon of 5 and 60 years for two strategies: (1) NBS for SCID and treat with early hematopoietic stem cell transplantation (HSCT); (2) no NBS for SCID and treat with late HSCT. Incremental costs were compared to incremental QALYs to calculate the incremental cost-effectiveness ratios (ICER). Sensitivity analyses were performed to assess the model uncertainty and identify key parameters impacting on the ICER. In the long-term over 60 years, universal NBS for SCID would gain 10 QALYs at a cost of US $0.3 million, resulting in an ICER of US$33,600/QALY. Probabilistic sensitivity analysis showed that more than half of the simulated ICERs were considered cost-effective against the common willingness-to-pay threshold of A$50,000/QALY (US$35,000/QALY). In the Australian context, screening for SCID should be introduced into the current NBS program from both clinical and economic perspectives.

Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency.

Spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) are rare, inherited genetic disorders with severe mortality and morbidity. The benefits of early diagnosis and initiation of treatment are now increasingly recognized, with the most benefits in patients treated prior to symptom onset. The aim of the economic evaluation was to investigate the costs and outcomes associated with the introduction of universal newborn screening (NBS) for SCID and SMA, by generating measures of cost-effectiveness and budget impact. A stepwise approach to the cost-effectiveness analyses by decision analytical models nested with Markov simulations for SMA and SCID were conducted from the government perspective. Over a 60-year time horizon, screening every newborn in the population and treating diagnosed SCID by early hematopoietic stem cell transplantation and SMA by gene therapy, would result in 95 QALYs gained per 100,000 newborns, and result in cost savings of USD 8.6 million. Sensitivity analysis indicates 97% of simulated results are considered cost-effective against commonly used willingness-to-pay thresholds. The introduction of combined NBS for SCID and SMA is good value for money from the long-term clinical and economic perspectives, representing a cost saving to governments in the long-term, as well as improving and saving lives.

Integrating newborn screening for spinal muscular atrophy into health care systems: an Australian pilot programme.

AIM: This study dynamically designed, evaluated, and implemented the components of an Australian newborn bloodspot screening (NBS) pilot programme for spinal muscular atrophy (SMA). METHOD: We used an implementation-effectiveness study design and continuous interdisciplinary review to measure SMA NBS test protocol performance, identify and overcome laboratory and clinical barriers to implementation, and describe progress during the 2-year pilot study. RESULTS: The NBS programme screened 252 081 newborn infants from 1st August 2018 to 31st January 2021. Using an NBS pilot test protocol, 21 infants were diagnostically confirmed with SMA. The NBS pilot test protocol had a sensitivity of 100%, specificity greater than 99.9%, false-positive rate less than 0.001%, a false-negative rate of 0%, and positive predictive value of 95.5%. A severe phenotype was predicted on the basis of two copies of SMN2 in 57.2% of newborn infants screening positive for SMA. Clinical signs consistent with SMA were evident in 6 out of 21 screen-positive newborn infants within the first 4 weeks of life. A multidisciplinary team establishing strong partnerships across clinical and laboratory staff was key to implementation. INTERPRETATION: This pilot programme suggests that NBS is essential for early identification of newborn infants at risk of SMA and can be effectively translated into clinical practice.

Immunoreactive Trypsinogen and Free Carnitine Changes on Newborn Screening after Birth in Patients Who Develop Type 1 Diabetes.

Are free carnitine concentrations on newborn screening (NBS) 48-72 h after birth lower in patients who develop type 1 diabetes than in controls? A retrospective case-control study of patients with type 1 diabetes was conducted. NBS results of patients from a Sydney hospital were compared against matched controls from the same hospital (1:5). Multiple imputation was performed for estimating missing data (gestational age) using gender and birthweight. Conditional logistic regression was used to control for confounding and to generate parameter estimates (α = 0.05). The Hommel approach was used for post-hoc analyses. Results are reported as medians and interquartile ranges. A total of 159 patients were eligible (80 females). Antibodies were detectable in 86. Median age at diagnosis was 8 years. Free carnitine concentrations were lower in patients than controls (25.50 µmol/L;18.98-33.61 vs. 27.26; 21.22-34.86 respectively) (p = 0.018). Immunoreactive trypsinogen was higher in this group (20.24 µg/L;16.15-29-52 vs. 18.71; 13.96-26.92) (p = 0.045), which did not persist in the post-hoc analysis. Carnitine levels are lower and immunoreactive trypsinogen might be higher, within 2-3 days of birth and years before development of type 1 diabetes as compared to controls, although the differences were well within reference ranges and provide insight into the pathogenesis into neonatal onset of type 1 diabetes development rather than use as a diagnostic tool. Given trypsinogen's use for evaluation of new-onset type 1 diabetes, larger studies are warranted.

Effect of Maternal Metformin Treatment in Pregnancy on Neonatal Metabolism: Evidence From Newborn Metabolic Screening.

OBJECTIVE: To investigate effects of maternal diabetes and metformin treatment on metabolic newborn screening (NBS) results of infants born to mothers with hyperglycemia during pregnancy. RESEARCH DESIGN AND METHODS: Retrospective case-control study. NBS results of infants born to mothers treated with metformin for hyperglycemia during pregnancy were compared with diet-treated subjects with diabetes and matched normal control subjects. EXCLUSIONS: maternal type 1 diabetes, major fetal anomalies, and incomplete infant data. Inclusions: maternal hyperglycemia in pregnancy treated with diet alone or diet plus metformin. Results from the New South Wales Newborn Screening Program (dried infant blood spot sample, 24-72 h after birth) for 25 routinely studied analytes were measured using mass spectrometry. Data from metformin-exposed and control infants were compared using nonparametric methods and multiples of the median for each analyte. RESULTS: A total of 574 case subjects were compared with 952 diet-treated case subjects with diabetes and 979 control subjects. Metformin-exposed infants had shorter gestational age (266 ± 7 vs. 272 ± 10 vs. 274 ± 9 days) (P < 0.001) and lower birth weights (3.28 ± 0.51 vs. 3.29 ± 0.49 vs. 3.33 ± 0.43 kg) (P = 0.008). Short-, medium-, and one long-chain acylcarntine (tetradecanoylcarnitine [C14]) concentrations were higher in the metformin-exposed group compared with normal control subjects. Comparison with diet-treated control subjects with diabetes (to eliminate confounding by hyperglycemia) continued to show raised butyrylcarnitine (C4), isovalerylcarnitine (C5), and glutarylcarnitine (C5D) in the metformin-exposed group. There was no evidence of vitamin B12 deficiency (low methionine and elevated propionylcarnitine [C3]) in metformin-exposed infants. All results were within normal population limits. CONCLUSIONS: We have identified subtle (nonpathological) changes in neonatal metabolism that represent a signature effect of fetal metformin exposure.

Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.

OBJECTIVE: To assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening. METHODS: Informed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses. RESULTS: By treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment. CONCLUSION: NBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.

Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning.

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the DBT gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.

"We needed this": perspectives of parents and healthcare professionals involved in a pilot newborn screening program for spinal muscular atrophy.

BACKGROUND: Newborn screening (NBS) for spinal muscular atrophy (SMA) is a recognised model through which health outcomes can be improved. However, perspectives of parents and healthcare professionals (HCPs) involved in such programs are largely unknown. METHODS: A pilot program for SMA ran from August 2018-July 2020. Using a mixed-methods convergent methodology, we used a self-administered questionnaire to understand parents' perceptions and psychological impact of the program from diagnosis to treatment. We thematically analysed successes/challenges encountered by HCPs and recommendations for service improvement from both participant groups. FINDINGS: 202,388 infants were screened for SMA and the perceptions of 44 parents and HCPs affected by a positive result in eighteen newborns was ascertained. Parents (n=29, 100%) were satisfied with NBS for SMA. Although screen-positive result was distressing for all parents, quality of life improved over time [CarerQoL-7D baseline median score 4 (SD=1.4) vs six-month median score 8 (SD=1.3), p<0.001)]. Challenges for HCPs included managing the time-critical nature of the pathway whilst remaining cognisant of limitations associated with the predictive screening test. INTERPRETATION: Interpretation: NBS for SMA fulfils criteria for population-wide screening. Net benefits are acknowledged by stakeholders to optimise lifelong outcomes. Harms including psychological distress associated with a screen-positive result may be managed by targeted psychosocial support, information provision and a personalised model of care together strengthening healthcare systems. FUNDING: The NSW Pilot NBS study was funded by Luminesce Alliance. Dr Kariyawasam received funding from the RTP Scholarship, University of New South Wales and The Freedman Family Foundation Scholarship, Sydney Children's Hospital Foundation.

Association of elevated neonatal thyroid-stimulating hormone levels with school performance and stimulant prescription for attention deficit hyperactivity disorder in childhood.

Untreated severe newborn thyroid deficiency causes neurocognitive impairment; however, the impact of mild thyroid deficiency is not known. This study aimed to examine whether mildly elevated neonatal thyroid-stimulating hormone (TSH) levels are associated with poor school performance or stimulant prescription for attention deficit hyperactivity disorder (ADHD). This record-linkage study included 232,790 term-born infants in Australia with a TSH level below newborn screening threshold (< 15 mIU/L). Among our cohort, as TSH levels increased, the proportion of infants born low birthweight via caesarean section and with disadvantaged socioeconomic status increased. Multivariable logistic regression analysis showed that, compared with infants with 'normal' neonatal TSH level (< 5 mIU/L), those with neonatal TSH 10-15 mIU/L had an increased risk of being exempt from school testing (aOR 1.63 (95% CI 1.06-2.69)) or prescribed a stimulant for ADHD (aOR 1.57 (95% CI 1.10-2.24)), adjusted for perinatal and sociodemographic factors. Among a nested analysis of 460 sibling pairs, siblings with 'mildly elevated' TSH levels were more likely to be exempt from school tests compared with siblings with normal TSH levels (aOR 2.53, 95% CI 1.01-6.33).Conclusion: In this population cohort and sibling analysis, mildly elevated neonatal TSH levels were associated with being exempt from school testing due to significant or complex disability. What is Known: • Newborn screening for severe thyroid hormone deficiency has virtually eliminated congenital hypothyroidism-associated intellectual disability in developed countries. • The impact of mild thyroid hormone deficiency in infants is unclear. What is New: • Children with a mildly elevated neonatal TSH level below current newborn screening cut-offs have an increased likelihood of being exempt from school testing due to significant or complex disability compared with siblings and peers. This study includes a population-based and nested sibling analysis.

Differences in Newborn Screening Results Among Women with Gestational Diabetes Mellitus

Abstract Multiple studies undertaken on cord blood demonstrate analyte perturbations in infants exposed to gestational diabetes mellitus (GDM). Cord blood as a sample is influenced by maternal and placental metabolism. Newborn screening (NBS), performed after the first 24 hours of life reflects early neonatal metabolism. We compared NBS analytes between women with and without GDM with different management approaches in the Treatment of Booking of Gestational Diabetes (TOBOGM) pilot randomised controlled trial. Pregnant women with GDM risk factors were randomised to early or deferred GDM treatment following an oral glucose tolerance test (<20 weeks gestation). Women without GDM served as "decoys". From the decoy group 11 developed GDM (screened at 26-28 weeks), were analysed separately; their results were compared with the other groups. De-identified controls were chosen from NBS results from the same analytic run matched for sex, birthweight and gestational age. Results were available for 73/78 women participating in the pilot and 358 de-identified controls. Tyrosine levels (μmol/l; whole blood)were higher in the late GDM group vs early, deferred treatment, and decoy groups (medians:106.28; IQR: 96.73-151.11) (76.33; 64.64-97.90) (75.68; 66.59-110.88)(73.74; 58.32-90.36) (p=0.009) and remained elevated when compared to normal, age-matched controls (106.28; 96.73-151.11) (87.26; 68.55-111.26) (p value=0.01) Immunoreactive trypsinogen (μgm/l; whole blood)was highest in the early treatment group when compared with group-specific controls (22.30; 13.90-29.90 vs 14.00, 10.60-21.10) (p=0.02). These results provide evidence of biochemical perturbations detectable on NBS of in-utero exposure to hyperglycemia and treatment and provide data for hypothesis building.

Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme.

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.

Newborn Screening Samples for Diabetes Research: An Underused Resource.

Inborn errors of metabolism and diabetes share common derangements in analytes of metabolic networks that are tested for in newborn screening, usually performed 48-72 h after birth. There is limited research examining the metabolic imprint of diabetes on newborn screening results. This paper aims to demonstrate the links between diabetes, biochemical genetics and newborn screening in investigating disease pathophysiology in diabetes, provide possible reasons for the lack of research in diabetes in newborn screening and offer recommendations on potential research areas. We performed a systematic search of the available literature from 1 April 1998 to 31 December 2018 involving newborn screening and diabetes using OVID, MEDLINE, Cochrane and the PROSPERO register, utilizing a modified extraction tool adapted from Cochrane. Eight studies were included after screening 1312 records. Five studies reanalyzed dried blood spots (DBS) on filter paper cards, and three studies utilized pre-existing results. The results of these studies and how they relate to cord blood studies, the use of cord blood versus newborn screening dried blood spots as a sample and considerations on newborn screening and diabetes research is further discussed. The timing of sampling of newborn screening allows insight into neonatal physiology in a catabolic state with minimal maternal and placental influence. This, combined with the wide coverage of newborn screening worldwide, may aid in our understanding of the origins of diabetes.

The implementation of newborn screening for spinal muscular atrophy: the Australian experience.

PURPOSE: To evaluate the implementation of the first statewide newborn screening (NBS) program for spinal muscular atrophy (SMA) in Australia. Processes that hinder and support clinical development, translation, and sustainability of the first primary genetic screening program in Australia are appraised. METHODS: The study prospectively describes the course (timelines, health processes, and preliminary clinical outcomes) for SMA screen-positive newborns from 1 August 2018 to 31 July 2019 in New South Wales and Australian Capital Territory, Australia. RESULTS: In the first year of the program, 103,903 newborns were screened. Ten newborns screened positive for SMA. Genetic confirmation of SMA occurred in 9/10 (90%) of infants. Clinical signs of SMA evolved in 4/9 (44%) within 4 weeks of life, heralded by hypotonia and weakness initially recognized in the neck. Median time to implementing a care plan (including commencement of disease-modifying therapies) was 26.5 days (16-37 days) from birth. CONCLUSION: NBS is essential for early and equitable identification of patients with SMA. Expedient diagnosis and management are vital, as disease latency appears brief in some cases. NBS shows significant clinical utility to support early parental decision making, improve access to specialist neuromuscular expertise, and facilitate initiation of personalized therapeutic strategies.

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

BACKGROUND: 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. DATA SOURCES: A PubMed search, limited to the past 5 years, 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. RESULTS: 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. CONCLUSIONS: 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.