Introduction Newborn bloodspot screening (NBS) is freely and universally available to babies born in Australia, with nearly 300 000 newborns screened each year. The NBS programme screens for approximately 30 conditions; however, there are hundreds of childhood conditions that could be treated if identified earlier and asymptomatically. Contemporary screening platforms have relied on mass spectrometry-based technologies, limiting surveillance to conditions with validated biomarkers detectable within the neonatal period. Advancements in metabolic techniques and genomics have expanded the range of conditions that could be detected. The NewbornsInSA research study will develop, validate and evaluate a novel multi-omic model of newborn screening, integrating metabolomic and genomic newborn screening as complementary methodologies.Methods Parents can opt in to additional NBS through NewbornsInSA during pregnancy or shortly after birth. One thousand prospectively recruited families will be offered genomic NBS by whole-genome sequencing, including analysis of a virtual gene panel of over 600 genes, and concurrent metabolomic screening. Clinically actionable pathogenic or likely pathogenic genetic variants will be reported to parents and whole genome sequencing data will be available on request for diagnostic reanalysis, if required later in life.Acceptability of the NewbornsInSA programme will be evaluated through stakeholder engagement activities with healthcare professionals, members of the public and patient advocacy groups. Family experiences will be assessed using online surveys. The diagnostic yield, accuracy and the costs and consequences of the multi-omic NBS model will be assessed by comparison to standard-of-care NBS.NewbornsInSA will investigate the acceptability, feasibility and cost-effectiveness of a multi-omic newborn screening model in a prospectively recruited South Australian population. We hypothesise that this approach will increase the number of conditions identified, reduce the time to diagnosis and facilitate earlier care with better outcomes for newborns with genetic conditions.Ethics and dissemination This research study has been ethically approved by the Women’s and Children’s Health Network Human Research Ethics Committee (2022/HRE00258 and 2023/HRE00236). Findings will be disseminated through peer-reviewed publication and conferences.

PURPOSE:To report interim results from the ongoing, open-label, phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria. METHODS:Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs). RESULTS:As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at week 26 (least-squares mean change [SE]: 36.4 [2.8] mg/kg/day from baseline) (P < .0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths. CONCLUSION:Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria. CLINICALTRIALS: GOV IDENTIFIER:NCT05166161 (https://www. CLINICALTRIALS:gov/study/NCT05166161; date of registration, December 8, 2021).

Newborn screening programs are instrumental in the early detection of treatable conditions in the first days of life. By integrating genomic approaches, there is potential to expand the range of conditions included in these programs. As part of a research study, NewbornsInSA, we validated a genomic newborn screening workflow. Analysis of whole-genome sequencing data was restricted to a virtual panel of 613 genes, selected through engagement with local clinical teams. We assessed the workflow’s performance using retrospective samples with known variant status. To reduce manual curation time, bioinformatics scripts were developed to auto-classify cases into those with no findings and those requiring manual review. We report on early findings from applying this workflow to a prospectively recruited cohort in which five reportable findings have been made to date. We discuss reporting challenges encountered in genes associated with multiple conditions, with incomplete penetrance, or variants associated with only mild phenotypes.

Data from a phase 2/3, randomized, controlled, open-label, multicenter trial in children with neuronopathic mucopolysaccharidosis II (MPS II; Hunter syndrome) older than 3 years suggested a benefit of intrathecal idursulfase-IT on cognitive functioning in some patients. We describe a separate, parallel, open-label, single-arm, 52-week substudy of the same trial (NCT02055118) that investigated idursulfase-IT in children with MPS II younger than 3 years at enrollment and Bayley Scales of Infant and Toddler Development (BSID-III) quotient 55-85. This report describes a prespecified analysis of nine patients (aged 1.4-3.0 years) who had received 3-years' treatment with idursulfase-IT. BSID-III cognitive composite scores generally remained relatively stable over time. At the last available assessment, scores were "high average" (110; n = 1), "average" (100-90; n = 4), and "low average" (85-80; n = 4). Eight patients transitioned to the Differential Ability Scales (DAS-II) after ages ≥42 months, and scores decreased for all patients when the instrument for assessing cognitive function changed. However, DAS-II General Conceptual Ability scores were relatively stable for the remainder of the follow-up. At the last available assessment, scores were "average" (106; n = 1), "low average" (85-80; n = 3), and "very low" (69-43; n = 4). Cerebrospinal fluid concentrations of total glycosaminoglycans were markedly reduced from baseline levels (mean [range] 1278 [429-2660] ng/mL) by week 16 and remained low thereafter. Data suggest early enzyme replacement therapy may stabilize cognitive development or slow the progression of cognitive impairment in young patients with neuronopathic MPS II.

Background:Multiple acyl-Coenzyme A dehydrogenase deficiency (MADD) is an inborn error of metabolism affecting fatty acid, amino acid and choline oxidation and is included in newborn screening in Australia. Recent reports describe adults with clinical and biochemical features of MADD, but negative genetic findings, associated with sertraline use. Aim:To describe a well newborn found to have a transient MADD-like biochemical pattern on newborn screen analysis, attributed to maternal sertraline use. Results:The newborn was delivered via semi elective C-section at term and was well at delivery, with age-appropriate growth percentiles. The mother had been taking sertraline throughout pregnancy and at delivery. Newborn screen analysis on day 2 showed elevation in multiple acylcarnitines (C5DC, C6, C8, C10 and C14:1), suggestive of MADD. The neonate remained well post-delivery and blood glucose and lactate levels at 1 and 4 h of age were normal.Repeat acylcarnitine profile on day 5 of life showed improving values. Urine organic acids showed mild elevation of 2-hydroxyglutarate, supporting the MADD-like biochemical pattern. By day 12 of life, the acylcarnitines had normalised. Extensive gene panel analysis, including ETFA, ETFB, and ETFDH, identified no variants of clinical significance. Conclusion:Maternal sertraline use is a potential cause of a transient neonatal MADD-like biochemical pattern. Such medication-related effects should be considered when reviewing the possible aetiology of newborn screen results suggestive of MADD.

**Background:** Late-onset Pompe disease (LOPD) is a rare, autosomal recessive metabolic disorder that is heterogeneous in disease presentation and progression. People with LOPD report a significantly lower physical, psychological, and social quality of life (QoL) than the general population. **Objectives:** This study investigated how individuals’ self-reported LOPD status (improving, stable, declining) relates to their QoL. Participant experiences such as use of mobility or ventilation aids, caregivers, symptomology, and daily life impacts were also characterized. **Methods:** A 2-part observational study was conducted online between October and December 2023 using the 36-item short-form tool (SF-36) and a survey. Adults with LOPD (N=41) from Australia, France, Italy, and the Netherlands were recruited. **Results:** Participants reporting “declining” LOPD status (56%) had lower physical functioning SF-36 scores than those reporting as “stable” or “improving.” Those self-reporting as stable or improving often described an acceptance of declining health in their responses. Physical functioning scores were generally stable in respondents who had been receiving enzyme replacement therapy (ERT) for 1-15 years, but those who had received ERT for >15 years had lower scores. Requiring ventilation and mobility aids had additive negative impacts on physical functioning. Difficulty swallowing, speaking, and scoliosis were the most burdensome symptoms reported by those on ERT for >15–25 years. **Discussion:** These results demonstrate the humanistic burden of LOPD; through declining physical functioning SF-36 scores over increasing time and increased use of aids, and also through factors related to self-reported LOPD status (where declining status was associated with lower scores) and symptomology variances. Taken holistically, these areas are valuable to explore when informing optimized care. Among a largely declining cohort, even those not self-reporting decline often assumed future deterioration, highlighting the need for improved therapies and the potential to initiate or switch ERT based on evolving symptomology and daily life impacts. **Conclusion:** Our results indicate that progressing LOPD leads to loss of QoL in ways that relate to time, use of aids, evolving symptomology, and the patient’s own perspective. A holistic approach to assessing the individual can help ensure relevant factors are investigated and held in balance, supporting optimized care.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced ( n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2–6 years ( n = 11) and ≥ 7 years ( n = 6)]), one ERT-naïve cohort ( n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL − 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; − 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number : NCT02675465 January 26, 2016.

INTRODUCTION/AIMS:The randomized, double-blind PROPEL study (NCT03729362) suggested benefits for cipaglucosidase alfa plus miglustat (cipa+mig) versus alglucosidase alfa plus placebo (alg+pbo) in enzyme replacement therapy (ERT)-experienced adults with late-onset Pompe disease (LOPD). To further assess treatment response and the effect of switching treatment from alg to cipa+mig, we conducted a within-group effect size analysis in ERT-experienced patients. METHODS:In this post hoc analysis, standardized within-group effect sizes (Cohen's d for correlated measurements from baseline to week 52) were calculated by dividing the mean change from baseline by the corresponding standard deviation for motor function, lung function, and muscle strength outcomes; patient-reported outcomes/quality of life; and biomarker levels (creatine kinase and hexose tetrasaccharide). RESULTS:In PROPEL, 77% of patients received ERT with alg before study entry (median ERT duration 7.4 years). ERT-experienced patients remaining on alg+pbo (n = 30) generally showed within-group worsening (d ≤ -0.2) or stability (-0.2 < d < 0.2) across most outcomes, while those switched to cipa+mig (n = 65) mostly showed improvement (d ≥ 0.2) or stability. Patients remaining on alg+pbo demonstrated statistically significant worsening for several lung function outcomes, biomarker levels, and significant improvement for Patient-Reported Outcomes Measurement Information System (PROMIS)-Dyspnea. Patients switched to cipa+mig did not demonstrate significant worsening for any outcomes and showed significant improvements for 6-min walk distance (absolute and % predicted); upper, lower, and overall manual muscle testing; PROMIS-Fatigue; Physician (overall score) and Subject Global Impression of Change (5/8 subdomains); and biomarker levels. DISCUSSION:ERT-experienced patients with LOPD who switched from alg to cipa+mig treatment achieved improvements or stability in most outcomes. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT03729362.

Background Phenylketonuria is an inherited condition characterised by neurotoxic accumulation of phenylalanine (Phe). APHENITY assessed the efficacy and safety of orally administered synthetic sepiapterin in children and adults with phenylketonuria. Methods APHENITY was a phase 3, randomised, double-blind, placebo-controlled study performed at 34 clinics, hospitals, and university sites in 13 countries. Individuals of all ages with a clinical diagnosis of phenylketonuria were eligible for inclusion if they had a blood Phe concentration of 360 mu mol/L or higher at study entry, whereas individuals with hyperphenylalaninaemia due to pathogenic variants in GCH1, PTS, QDPR, SPR, and PCBD1, consistent with a diagnosis of primary BH 4 deficiency, were excluded. Part 1 was a 14-day open-label assessment of blood Phe concentration response to sepiapterin. In part 2, sepiapterin-responsive participants were randomly assigned (1:1) by a web-response system based on a block randomisation schedule (permuted block size of 2 and 4) to 6 weeks of sepiapterin ( forced-dose escalation: 20, 40, and 60 mg/kg per day per consecutive 2-week period) or placebo. The investigational drug and placebo were identical in their appearance and delivery. Dried blood samples were collected for analysis of Phe concentration on days -1, 1 (before dose was administered), 5, 10, 14, 19, 24, 28, 33, 38, and 42 in part 2, either in-clinic or at home. The primary endpoint for part 2, mean change from baseline in blood Phe after 6 weeks, was assessed in the primary analysis set of participants with at least a 30% reduction in blood Phe concentration in part 1, who took at least one dose in part 2. Safety was evaluated in all participants receiving at least one dose of treatment. The completed study is registered at EudraCT (2021-000474-29) and ClinicalTrials.gov (NCT05099640). Findings APHENITY was conducted between Sept 30, 2021, and April 3, 2023. 187 people were assessed for eligibility, of whom 157 were enrolled. In part 1, 156 participants were assessed or evaluated, of whom 114 (73%) were sepiapterin-responsive (ie, >= 15% reduction in blood Phe from baseline). In part 2, 98 participants (49 in the placebo group and 49 in the sepiapterin group) were in the primary analysis set. There was a significant reduction of blood Phe concentration after 6 weeks of sepiapterin (-63%, SD 20) compared with placebo (1%, 29; least squares mean change -395 center dot 9 mu mol/L, SE 33 center dot 8; p<0 center dot 0001). Treatment-emergent adverse events were reported in 33 (59%) of 56 participants who received sepiapterin and 18 (33%) of 54 participants who received placebo. Most treatment-emergent adverse events were mild gastrointestinal events (11 [20%] of 56 participants who received sepiapterin and ten [19%] of 54 participants who received placebo) that resolved quickly. There were no deaths and no serious or severe adverse events. Interpretation Sepiapterin is a promising oral therapy for individuals with phenylketonuria, was well tolerated, and resulted in significant and clinically meaningful reductions in blood Phe concentration in participants with varying disease severity. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.