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Objective: Eating disorders are complex illnesses with high morbidity and mortality. Yet, there is promising evidence to support the effects of nutrition on the brain and behaviour. One proposed example is the use of tyrosine as an adjunct treatment in anorexia nervosa (AN). However, recruitment and retention in eating disorder clinical trials has posed difficulties for researchers. The aim of this study was to pilot test a parallel randomised controlled trial (RCT) of tyrosine supplementation to explore the feasibility of recruitment and retention, intervention adherence and data collection methods from the perspective of participants and researchers., Method: Feasibility was assessed using numbers participating, questionnaire completion in patients and parent/carers completing and declining participation, a researcher implementation record and clinical measures. Subjects included adolescents aged 12-17 years with AN. The study was conducted over a 12-week period, with the intervention group receiving 5 mg of L-tyrosine supplement and the control group receiving a placebo., Results: Recruitment targets were not met and recruitment to a full RCT based on the current study protocol and recruitment sites did not prove feasible. Of the 39 approached for RCT participation, seven were recruited to the RCT (18% response rate) despite extending recruitment periods, with 100% retained and analysed. Patients or parents/carers identified barriers to study participation including burden, the need to consume tyrosine as tablets, and the use of blood, urine and psychological testing. Blood tyrosine rose markedly for subjects in the intervention group. No side effects were reported or measured., Conclusions: This study offers a unique exploration of the feasibility of a tyrosine trial in anorexia nervosa and is of relevance to assist the success of future nutrition trials. Exploring the suitability of future study designs for nutrition intervention research is warranted., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Hunter New England Health (reference number 06/05/24/3.06) and University of Newcastle (approval number H-385-0207) Human Research Ethics Committees. Written, informed consent was obtained from all participants involved in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Clinical Trial Registration The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000007235)., (© 2024. Crown.)

Aspartylglucosaminuria (AGU) (OMIM #208400) is a recessively inherited disorder of glycoprotein catabolism, a subset of the lysosomal storage disorders (LSDs). Deficiency of the enzyme glycosylasparaginase (E.C. 3.5.1.26) leads to accumulation of aspartylglucosamine in various organs and its excretion in the urine. The disease is characterized by an initial period of normal development in infancy, a plateau in childhood, and subsequent regression in adolescence and adulthood. No curative treatments are currently available, leading to a protracted period of significant disability prior to early death. Hematopoietic stem cell transplantation (HSCT) has demonstrated efficacy in other LSDs, by providing enzyme replacement therapy in somatic viscera and decreasing substrate accumulation. Moreover, donor-derived monocytes cross the blood-brain barrier, differentiate into microglia, and secrete enzyme in the central nervous system (CNS). This has been shown to improve neurocognitive outcomes in other LSDs. The evidence to date for HSCT in AGU is varied, with marked improvement in glycosylasparaginase enzyme activity in the CNS in mice models, but varying neurocognitive outcomes in humans. We present a case series of four children with AGU who underwent HSCT at different ages (9 years, 5 years, 5 months, and 7 months of age), with long-term follow-up post-transplant (over 10 years). These cases demonstrate similar neurodevelopmental heterogeneity based on formal developmental assessments. The third case, transplanted prior to the onset of neurocognitive involvement, is developing normally despite a severe phenotype in other family members. This suggests that further research should examine the role of early HSCT in management of AGU., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

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.

Sialuria is a rare autosomal dominant inborn error of metabolism characterized by cytoplasmic accumulation and urinary excretion of gram quantities of free sialic acid due to failure of feedback inhibition of the rate-limiting enzyme in the sialic acid synthesis pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). To date, eight cases had been published worldwide, all with heterozygous missense variants at the allosteric site, specifically at Arginine 294 (formerly 263) and Arginine 297 (formerly 266) of GNE. The described cases so far have rather homogeneous clinical features which include developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice. The apparent rarity of this disorder is hypothesized to be due to the variable and sometimes transient nature of the clinical features and to the absence of routine testing for urinary sialic acids. Here we present the ninth case of sialuria diagnosed in a child investigated because of clinical signs and symptoms and furthermore describe a novel pathogenic variant in the associated gene, GNE.

Newborn screening for several lysosomal disorders can now be accomplished successfully for case finding. However, many cases identified do not require immediate intervention and it is not yet clear, for some disorders, if there is a benefit in early diagnosis for those cases, or what should be called a benefit. Diagnosing adult-onset cases, especially when there are quite imperfect genotype-phenotype correlations, represents a significant expansion of what has heretofore been considered the aim of newborn screening. This mission creep should be carefully discussed, and certain aspects of newborn screening strengthened. We should all proceed with caution in this field., Competing Interests: Conflicts of InterestThe author declares no conflict of interest., (© 2018 by the author.)

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)., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2018 by the authors.)

Objectives: To evaluate children with cystic fibrosis (CF) who had a late diagnosis of CF (LD-CF) despite newborn screening (NBS) and compare their clinical outcomes with children diagnosed after a positive NBS (NBS-CF)., Study Design: A retrospective review of patients with LD-CF in New South Wales, Australia, from 1988 to 2010 was performed. LD-CF was defined as NBS-negative (negative immunoreactive trypsinogen or no F508del) or NBS-positive but discharged following sweat chloride < 60 mmol/L. Cases of LD-CF were each matched 1:2 with patients with NBS-CF for age, sex, hospital, and exocrine pancreatic status., Results: A total of 45 LD-CF cases were identified (39 NBS-negative and 6 NBS-positive) with 90 NBS-CF matched controls. Median age (IQR) of diagnosis for LD-CF and NBS-CF was 1.35 (0.4-2.8) and 0.12 (0.03-0.2) years, respectively (P <.0001). Estimated incidence of LD-CF was 1 in 45 000 live births. Compared with NBS-CF, LD-CF had more respiratory manifestations at time of diagnosis (66% vs 4%; P <.0001), a higher rate of hospital admission per year for respiratory illness (0.49 vs 0.2; P = .0004), worse lung function (forced expiratory volume in 1 second percentage of predicted, 0.88 vs 0.97; P = .007), and higher rates of chronic colonization with Pseudomonas aeruginosa (47% vs 24%; P = .01). The LD-CF cohort also appeared to be shorter than NBS-CF controls (mean height z-score -0.65 vs -0.03; P = .02)., Conclusions: LD-CF, despite NBS, seems to be associated with worse health before diagnosis and worse later growth and respiratory outcomes, thus providing further support for NBS programs for CF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening., Methods: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy., Results: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly., Conclusion: The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.

Background: Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis., Methods: We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60h. The patient received a 3-month trial of oral uridine for behavioural problems., Results: The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO., Conclusion: This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Congenital hypothyroidism causes intellectual delay unless identified and effectively treated soon after birth. Newborn screening has almost eliminated intellectual disability associated with congenital hypothyroidism. However, clinical uncertainty remains about infants with thyroid-stimulating hormone (TSH) concentrations less than the newborn screening cutoffs. We assessed the association between neonatal TSH concentrations and educational and developmental outcomes., Methods: We did a population-based record-linkage study of all liveborn infants undergoing newborn screening from 1994 to 2008 in New South Wales, Australia, with assessments of childhood development or school performance. Very-low-birthweight babies (<1500 g) were excluded. Developmental and educational outcomes were obtained and these were linked to individual records by the New South Wales Centre for Health Record Linkage. The primary educational outcome was the proportion of students with National Assessment Program Literacy and Numeracy (NAPLAN) results lower than the national minimum standard in reading or numeracy measured at all ages, and the primary developmental outcome was the proportion of children who were classified as being developmentally high risk (vulnerable in two or more of the five developmental domains assessed by the Australian Early Development Census) at age 4-6 years. The proportions of infants with each outcome were calculated per percentile (0-100) of TSH concentration. Multivariable logistic regression was used to account for potential confounding by maternal and fetal variables known to affect neonatal TSH concentrations or neurodevelopmental outcomes., Findings: 503 706 infants had a neonatal TSH result that linked to a developmental or educational outcome. 149 569 infants born between 2002 and 2008 were linked to an Australian Early Development Census developmental outcome and 354 137 were linked to a NAPLAN educational outcome. Median follow-up for educational outcome was 10 years (IQR 8-12) and for developmental outcome was 5 years (5-6). 5·5% (14 137 of 257 752) of infants scored less than the national minimum standard for numeracy in percentiles lower than the 75th percentile and this increased with each increase of percentile group to 11·3% (15 of 133) of infants with a TSH concentration between the 99·90th and 99·95th percentile. Infants with a neonatal TSH concentration in the 99·95th percentile or higher (above newborn screening cutoff) and likely to have diagnosed and treated congenital hypothyroidism had similar results to infants with a TSH concentration lower than the 75th percentile for both educational and developmental outcomes. Infants with a neonatal TSH concentration between the 99·5th and 99·9th percentile were more likely to have special needs (adjusted odds ratio [aOR] 1·68, 95% CI 1·23-2·30), poor numeracy performance (aOR 1·57, 1·29-1·90), and developmentally high risk (aOR 1·52, 1·20-1·93)., Interpretation: We found an association between neonatal TSH concentrations lower than the present newborn screening thresholds and poor educational and developmental outcomes. This association needs further investigation to assess whether assessment and treatment of these infants might improve their long-term cognitive outcomes., Funding: Australian National Health and Medical Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: Studies examining the relationship between maternal and infant thyroid parameters have shown conflicting results. Record linkage provides an opportunity to examine the association between maternal and infant thyroid-stimulating hormone (TSH) levels. Our aim was to demonstrate the feasibility of record linkage of newborn screening (NBS), laboratory and birth databases for research by investigating the association between maternal and newborn TSH levels., Methods: The records of 2802 women with first trimester serum TSH concentrations were linked with population-based birth data and NBS data containing infant TSH levels. Association between moderately high neonatal TSH levels (>5 mIU/L) and maternal and infant characteristics was evaluated. The correlation and association between maternal and infant TSH levels were assessed using Pearson's correlation coefficient and multivariable linear regression, respectively., Results: Of maternal and birth records, 99.3% linked with an NBS record. Mother's country of birth, gestational age (>41 weeks) and lower birthweight were associated with neonatal TSH levels >5 mIU/L. Neonatal and maternal first trimester TSH levels were not correlated, although statistically significant (r = 0.05, P = 0.008). The association between neonatal TSH and maternal TSH, after adjusting for maternal age, gestational age and age at NBS testing, was also small (b = 0.039, P = 0.009)., Conclusions: Record linkage is a feasible and cost-efficient way to investigate the association between maternal factors and neonatal hormone levels. First trimester maternal thyroid levels are not correlated with neonatal TSH levels. This method of outcome assessment can be used for future research examining long-term outcomes for infants with different NBS results., (© 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Classical homocystinuria is caused by mutations in the cystathionine β-synthase (CBS) gene. Previous experiments in bacterial and yeast cells showed that many mutant CBS enzymes misfold and that chemical chaperones enable proper folding of a number of mutations. In the present study, we tested the extent of misfolding of 27 CBS mutations previously tested in E. coli under the more folding-permissive conditions of mammalian CHO-K1 cells and the ability of chaperones to rescue the conformation of these mutations. Expression of mutations in mammalian cells increased the median activity 16-fold and the amount of tetramers 3.2-fold compared with expression in bacteria. Subsequently, we tested the responses of seven selected mutations to three compounds with chaperone-like activity. Aminooxyacetic acid and 4-phenylbutyric acid exhibited only a weak effect. In contrast, heme arginate substantially increased the formation of mutant CBS protein tetramers (up to sixfold) and rescued catalytic activity (up to ninefold) of five out of seven mutations (p.A114V, p.K102N, p.R125Q, p.R266K, and p.R369C). The greatest effect of heme arginate was observed for the mutation p.R125Q, which is non-responsive to in vivo treatment with vitamin B(6). Moreover, the heme responsiveness of the p.R125Q mutation was confirmed in fibroblasts derived from a patient homozygous for this genetic variant. Based on these data, we propose that a distinct group of heme-responsive CBS mutations may exist and that the heme pocket of CBS may become an important target for designing novel therapies for homocystinuria.

Newborn screening has evolved fast following recent advances in diagnosis and treatment of disease, particularly the development of multiplex testing and applications of molecular testing. Formal evidence of benefit from newborn screening has been largely lacking, due to the rarity of individual disorders. There are wide international differences in the choice of disorders screened, and ethical issues in both screening and not screening are apparent. More evidence is needed about benefit and harm of screening for specific disorders and renewed discussion about the basic aims of newborn screening must be undertaken., (© 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

There have been few reports of cases missed by expanded newborn screening. Tandem mass spectrometry was introduced in New South Wales, Australia in 1998 to screen for selected disorders of amino acid, organic acid and fatty acid metabolism. Of 1,500,000 babies screened by 2012, 1:2700 were diagnosed with a target disorder. Fifteen affected babies were missed by testing, and presented clinically or in family studies. In three cases (cobalamin C defect, very-long-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type 1), this led to modification of analyte cut-off values or protocols during the first 3 years. Two patients with intermittent MSUD, two with β-ketothiolase deficiency, two with citrin deficiency, two siblings with arginosuccinic aciduria, two siblings with homocystinuria, and one with cobalamin C defect had analyte values and ratios below the action limits which could not have been detected without unacceptable false-positive rates. A laboratory interpretation error led to missing one case of cobalamin C defect. Reference ranges, regularly reviewed, were not altered. For citrin deficiency, while relevant metabolites are detectable by tandem mass spectrometry, our cut-off values do not specifically screen for that disorder. Most of the missed cases are doing well and with no acute presentations although eight of 15 are likely to have been somewhat adversely affected by a late diagnosis. Analyte ratio and cut-off value optimisations are important, but for some disorders occasional missed cases may have to be tolerated to maintain an acceptable specificity, and avoid harm from screening.