Veronica Wiley

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.

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.

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.

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.

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.

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.

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.

The International Society for Neonatal Screening (ISNS) has met regularly at both international meetings and those of the various chapters

Fragile X syndrome (FXS) is the most prevalent heritable cause of cognitive impairment but is not yet included in a newborn screening (NBS) program within Australia. This paper aims to assess the feasibility and reliability of population screening for FXS using a pilot study in one hospital. A total of 1971 mothers consented for 2000 newborns to be tested using routine NBS dried blood spot samples. DNA was extracted and a modified PCR assay with a chimeric CGG primer was used to detect fragile X alleles in both males and females in the normal, premutation, and full mutation ranges. A routine PCR-based fragile X assay was run in parallel to validate the chimeric primer assay. Babies with CGG repeat number ≥59 were referred for family studies. One thousand nine hundred and ninety NBS samples had a CGG repeat number less than 55 (1986 < 50); 10 had premutation alleles >54 CGG repeats (1/123 females and 1/507 males). There was complete concordance between the two PCR-based assays. A recent review revealed no clinically identified cases in the cohort up to 5 years later. The cost per test was $AUD19. Fragile X status can be determined on routine NBS samples using the chimeric primer assay. However, whilst this assay may not be considered cost-effective for population screening, it could be considered as a second-tier assay to a developed immunoassay for fragile X mental retardation protein (FMRP).

The fragile X syndrome (FXS) results from mutation of the FMR1 gene that prevents expression of its gene product, FMRP. We previously characterized 215 dried blood spots (DBS) representing different FMR1 genotypes and ages with a Luminex-based immunoassay (qFMRP). We found variable FMRP levels in the normal samples and identified affected males by the drastic reduction of FMRP. Here, to establish the variability of expression of FMRP in a larger random population we quantified FMRP in 2,000 anonymous fresh newborn DBS. We also evaluated the effect of long term storage on qFMRP by retrospectively assaying 74 aged newborn DBS that had been stored for 7-84 months that included normal and full mutation individuals. These analyses were performed on 3 mm DBS disks. To identify the alleles associated with the lowest FMRP levels in the fresh DBS, we analyzed the DNA in the samples that were more than two standard deviations below the mean. Analysis of the fresh newborn DBS revealed a broad distribution of FMRP with a mean approximately 7-fold higher than that we previously reported for fresh DBS in normal adults and no samples whose FMRP level indicated FXS. DNA analysis of the lowest FMRP DBS showed that this was the low extreme of the normal range and included a female carrying a 165 CGG repeat premutation. In the retrospective study of aged newborn DBS, the FMRP mean of the normal samples was less than 30% of the mean of the fresh DBS. Despite the degraded signal from these aged DBS, qFMRP identified the FXS individuals. The assay showed that newborn DBS contain high levels of FMRP that will allow identification of males and potentially females, affected by FXS. The assay is also an effective screening tool for aged DBS stored for up to four years.