Closing the gap: An urgent need for newborn screening of organic acid disorders in developing countries.

Organic acid disorders are rare inherited metabolic disorders of key metabolic pathways. For the identification of specific organic acids, investigation of urinary metabolites and genetic testing are required through newborn screening programmes. Delayed diagnosis leads to complications, such as cardiac attacks, respiratory problems, neuro-developmental disorders, intellectual disability, and even premature death. The burden of such inherited disorders is quite high in developing countries of South Asia due to high rate of consanguinity in the region. Unfortunately, such disorders are left untreated due to the lack of screening facilities in such countries. The current narrative review was planned to highlight the urgent need for closing this gap and implementing effective newborn screening programmes for organic acid disorders in developing countries. The implementation of effective programmes is crucial for reducing morbidity and mortality, and for improving the quality of life for the affected children and of their families, thus promoting global health equity.

Informing parents of newborns with sickle cell trait detected at neonatal screening: A northern France experience.

Neonatal screening for sickle cell disease (SCD) in France, targeted since 1995, indirectly detects newborns with sickle cell trait (SCT). Information about carrier status must be communicated to families in accordance with the 2006 National Consultative Ethics Committee recommendations; however, no national protocol for this exists. In the departments of Nord and Pas-de-Calais, the Regional Neonatal Screening Center transmits this information through a general practitioner (GP). This study aimed to assess the success rate of local practices in transmitting SCT information to parents. The secondary objectives included explaining transmission failures, evaluating post-information couple screening rates, and conducting a nationwide evaluation of SCT information dissemination. In this retrospective, multicenter study, family doctors were surveyed regarding newborns screened for SCT between January 1 and December 31, 2020, in the Nord and Pas-de-Calais departments. Among the 260 screened newborns, 197 were eligible for analysis. Results showed that 31.2% of newborns with SCT had their GP definitively sharing information with their parents. Based on this information, subsequent parental screening accounted for 13.6% of cases. The reasons cited by the GP for failing to convey information included elusive families (52.5%), unfamiliarity or refusal of the role (35%), limited SCD knowledge (25%), and ethical considerations (12.5%). This study highlights the difficulty and heterogeneity in transmitting carrier status information to parents of newborns with SCT. Our findings could serve as a foundation for the development of new methods for information transmission, given the generalization of neonatal screening for SCD by the French National Authority for Health.

Screening primary carnitine deficiency in 10 million Chinese newborns: a systematic review and meta-analysis.

BACKGROUND: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants. METHODS: PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns. RESULTS: After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05‰ [95%CI, (0.04‰, 0.06‰)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07‰, 95%CI, (0.05‰, 0.08‰)] than in northern China [0.02‰, 95%CI, (0.02‰, 0.03‰)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79‰, 95%CI, (47‰, 135‰)] (P < 0.05). CONCLUSIONS: This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns.

Positive impacts of universal newborn screening on the outcome of children with sickle cell disease in the province of Quebec: A retrospective cohort study.

A universal newborn screening program for sickle cell disease (uNS-SCD) was implemented in the province of Québec (Qc) in November 2013, close in time to the recommendation of early initiation of hydroxyurea (HU) therapy for children. This retrospective cohort study evaluated the impact of such a program on children first seen between January 2000 and December 2019. Cohorts pre-SCD-uNS in Qc (pre-QcNS) (n = 253) and post-QcNS (n = 157) for patients seen prior to or after Nov 2013 were compared. Kaplan-Meier curves, Poisson regression, and logistic regressions were used for statistical analysis, using Software R version 4.2.1. Median age at first visit decreased significantly from 14.4 [interquartile range: 2.4-72.0] to 1.2 months [1.2-57.6] (p < 0.001). The percentage of children born in Qc undiagnosed at birth and referred after a first SCD-related complication dropped from 42.6% to 0.0% (p < 0.0001). The median age of HU introduction for patients with SS/Sß°-thalassemia decreased from 56.4 [31.2-96.0] to 9.0 months post-QcNS [8.0-12.1] (p < 0.001). Event-free survival improved significantly for any type of hospitalization as well as for vaso-occlusive crisis (VOC) (140-257 days (p < 0.001) and 1320 vs. 573 days (p < 0.002), respectively), resulting in a reduction from 2 [interquartile range: 1.0-3.0] to 1.0 hospitalizations/patient-year [0.6-1.4] (p < 0.001). Children with SS/Sß°-thalassemia referred post-QcNS also had fewer emergency department visits for VOC (RR: 0.69, 95% confidence interval: 0.54-0.88). The Universal NS program allows early detection and referral of children with SCD to comprehensive care centers. Earlier access ensures that children benefit from essential preventive interventions, reducing disease burden. This cohort study highlights that uNS-SCD is an essential public health measure.

[Sickle cell disease in French Guiana: assessing 30 years of neonatal screening (1992-2021)]. / La drépanocytose en Guyane : bilan de 30 années de dépistage néonatal (1992-2021).

Background: Sickle cell disease is one of the most common genetic diseases in France. In French Guiana, neonatal screening was introduced in 1992, at the same time as other screening programs for childhood diseases. The aim of this study is to describe the organization of newborn screening for sickle cell disease in French Guiana. Materials and methods: We used several data sources: data collected from hospital records since 2005, activity reports from the national neonatal screening program and data from screening campaigns organized by the Drepaguyane association between 2010 and 2021 on 1,300 subjects. Blood samples from newborns are collected by capillary or venous sampling and absorbed on blotting paper (Guthrie) at the same time as those for other neonatal screenings. The dried papers are sent to the inter-regional laboratory in Lille, for further processing. In Saint-Laurent-du-Maroni, in order to reduce the proportion of people lost to follow-up, a double screening is carried out and the results are returned before discharge from the maternity hospital. All data were entered into an anonymous Excel file. The data were analyzed using STATA software. Results: Among the 175,593 screened neonates between 1992 and 2021, screening detected 823 infants with sickle cell disease and 17,950 heterozygotes. Sickle cell genotypes include 493 SS (60%), 302 SC (37%) and 28 S-Beta-thalassemia (3%). The incidence of sickle cell disease was 1/213, 95% CI [1/236-1/204], and that of heterozygotes 1/10, IC 95% [1/12-1/8]. The majority of these children (52%) were from the Maroni region. The delay between screening and test results was 7 days. Only pathological results (homozygous, heterozygous) were communicated to parents and/or the attending physician by post. These data confirm the upward trend in the number of children screened for sickle cell disease in French Guiana. Data from screening campaigns organized by the Drepaguyane association have enabled to describe the distribution of the various abnormal hemoglobin fractions, and to confirm that HbS is more frequent in Western French Guiana. In Cayenne, in 2021, the active file comprised 699 patients, including 266 children under 18 years old. Discussion and conclusion: This study provides valuable data on 30 years of neonatal screening for sickle cell disease in French Guiana, and on the evolution of sickle cell disease patients. It confirms that French Guiana is the French territory with the highest incidence of sickle cell disease. This incidence continues to rise over time. The study reveals the improvement in the organization of sickle cell disease management in French Guiana between 1992, when screening was introduced, and the present day. It highlights the role of patient associations in the fight against this disease, by organizing awareness and screening campaigns. These data will be used to guide public health policies in the pursuit of improved care and primary prevention.

Investigating the Pregnancy and Post-Partum Health Experiences of Women Living with HIV.

INTRODUCTION: Pregnancy and the postpartum period is a difficult time for women living with HIV (WLWH) and postpartum engagement with HIV care is often reduced, with implications for health and well-being. We aimed to explore the postpartum health experiences of WLWH in relation to engagement in HIV care. METHODS: The NESTOR (iNvESTigating the pregnancy and pOst-paRtum health experience of women living with HIV) study was a UK based qualitative semi-structured interview study. 61 eligible women were identified. We used a purposive sampling technique to recruit women with differing levels of engagement in HIV care. Interviews were conducted via telephone or video call. Interviews were audio recorded and fully transcribed. We used a thematic approach for data analysis, and two researchers independently coded the data and established the key themes. RESULTS: 11 of 61 (18%) eligible women participated in the interviews, and the three main themes were 'infant feeding decisions', 'managing the risk of mother to child transmission', and 'managing the knowledge of their HIV status'. These themes offer detailed insights into the significant psychological and emotional challenges these women had experienced, and the practical support from healthcare professionals in both HIV and maternity services that had enabled them to navigate those challenges. DISCUSSION: There have been life-changing developments in the treatment and care for people living with HIV. However, even in the U = U (undetectable = untransmittable) era, traditional concerns about breastfeeding, risk of transmission to the infant and stigma continue to shape the postpartum experience of WLWH. As these impact on their emotional and psychological wellbeing, support in these areas needs to be prioritised.

The knowledge level of the healthcare professionals responsible for newborns' heel prick tests.

PURPOSE: This study was conducted to determine the level of knowledge of healthcare professionals involved in newborn heel prick tests. METHODS: The study was conducted between 10.02.2021-10.03.2021 with 147 healthcare workers working in heel prick screening in health institutions where heel prick blood samples were collected in a province and districts in the Central Anatolia region of Turkey. As a data collection tool, a questionnaire prepared by the researcher in line with the literature was used. The data were evaluated by number, percentage, mean and standard deviation analysis and chi-square analysis was performed in IBM SPSS for Windows 29.0v programme. RESULTS: The majority of healthcare professionals gave correct answers to the questions regarding the collection, storage and transfer of heel prick. It has been observed that healthcare professionals do not have sufficient information regarding the definition of Congenital Metabolic Diseases, their findings and where to refer patients whose results are suspicious.The most significance was found in the distribution of answers regarding the symptoms of the screened diseases according to occupational groups. CONCLUSION: In diseases that can be controlled with treatment and nutrition if detected early, errors in the collection, storage and transport of the sample can affect the test result and delay the diagnosis. Healthcare professionals have important responsibilities issues from genetic counseling before marriage, taking heel blood, from informing the family to caring for the diagnosed baby. PRACTICE IMPLICATIONS: This study will provide valuable information to health professionals involved in newborn screening and to future studies in this field.

Early Screening for Long QT Syndrome and Cardiac Anomalies in Infants: A Comprehensive Study.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents sudden and unexplained deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for a prolonged QTc interval, a marker for Long QT Syndrome (LQTS), should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiograms (ECGs) could identify congenital heart defects (CHDs) early, especially those not detected at birth. Infants with prolonged QTc intervals typically undergo genetic analysis for Long QT Syndrome. (2) Methods: The study involved infants aged 20-40 days, born with no apparent clinical signs of heart disease, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHDs identified immediately after birth, as well as infants who had previously had an ECG or echocardiogram for other medical reasons, were excluded from the study. We used statistical software (SPSS version 22.0) to analyze the data. (3) Results: Of the 42,200 infants involved, 2245 were enrolled, with 39.9% being males. Following this initial screening, 164 children (37.8% males) with prolonged QTc intervals underwent further evaluation. Out of these 164 children, 27 children were confirmed to have LQTS. However, only 18 children were finally investigated for genetic mutations, and mutations were identified in 11 tests. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Treatment options included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%. (4) Conclusions: This screening approach has demonstrated effectiveness in the early identification of LQTS and other cardiac rhythm anomalies, with additional identification of mutations and/or prolonged QTc intervals in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

Prevalência e fatores associados à realização dos exames de triagem neonatal no Brasil: comparação da PNS 2013 e 2019 / Prevalence of neonatal screening and associated factors in Brazil: a comparison of the 2013 and 2019 National Health Surveys

Resumo Analisou-se a prevalência e fatores associados à realização da Triagem Neonatal Completa (TNC) entre crianças (<2 anos de idade) no Brasil incluídas na Pesquisa Nacional Saúde 2013 (n=4.442) e 2019 (n=5.643). Estudo transversal comparou as estimativas de prevalência e intervalos de confiança de 95% (IC95%) da TNC (testes do olhinho, orelhinha e pezinho). Diferenças foram consideradas estatisticamente significante ao nível de 5%. Regressões de Poisson bruta e ajustada foram realizadas para estimar Razões de Prevalência (RP) e IC95% para a associação das variáveis socioeconômicas, demográficas e de saúde com a TNC. Verificou-se aumento estatisticamente significante da TNC: 67,4% (IC95%: 65,5-69,3) em 2019, ante 49,2% (IC95%: 47,1-51,3) em 2013. Porém, ainda existem desigualdades e defasagens entre os estados da federação e variáveis sociodemográficas. Entre os anos, a TNC foi menor nas crianças de cor/raça parda e preta, dos três piores quintis de renda, sem plano de saúde, cadastradas na Estratégia de Saúde da Família, da região norte, de cidades do interior e da zona rural do Brasil. Apesar de o aumento da prevalência de TNC, desigualdades e defasagens individuais e contextuais permaneceram, indicando os desafios das políticas de saúde.

Abstract This study analyzed the prevalence of complete neonatal screening (CNS) of children aged under 2 years in Brazil and associated factors using data from the 2013 (n=4,442) and 2019 (n=5,643) national health surveys. We conducted a cross-sectional study to compare prevalence of CNS (eye, ear and heel prick tests) adopting 95% confidence intervals (95%CI) and a 5% significance level. Crude and adjusted Poisson regression was performed to estimate prevalence ratios (PR) and 95%CI to assess the association between socioeconomic, demographic and health variables and CNS. There was a statistically significant increase in CNS prevalence, from 49.2% (95%CI: 47.1-51.3) in 2013 to 67.4% (95%CI: 65.5-69.3) in 2019. However, large disparities persist across states and between sociodemographic groups. In both years, CNS prevalence was lowest among brown and black children, those from families in the three lowest income quintiles, children without health insurance, those from families registered in the Family Health Strategy and children living in the North, cities outside the state capital/metropolitan regions and rural areas. Despite the increase in prevalence of CNS, deep individual and contextual inequalities persist, posing challenges for health policies.

Impact of national health insurance and socioeconomic disparities on newborn hearing screening performance in South Korea: A nationwide population-based evaluation.

OBJECTIVES: This study aimed to assess the impact of national health insurance coverage on newborn hearing screening (NHS) outcomes by analyzing hearing questionnaires from the National Infant Health Check-up Program (NIHCP) in South Korea. METHODS: This study evaluated the performance and referral rates of NHS using nationwide data from 814,875 infants enrolled in the 4-month NIHCP from January 2017 to December 2019. This period encompasses the periods before and after the National Health Insurance in South Korea began covering NHS expenses in October 2018. The study also investigated household income levels to determine their relationship with participation in the NIHCP and NHS outcomes. RESULTS: The performance of NIHCP increased year-on-year, with NHS performance rates increasing from 88.5 % in 2017 to 91.5 % in 2019. Analysis by household income level revealed that the medical benefit recipients' group had the lowest NHS performance rate of 81.9 % in 2019, whereas that of the higher income level group exceeded 90 %. The NHS referral rate remained consistent at 0.9 % nationally during the study period. CONCLUSION: The inclusion of NHS in national insurance coverage positively influenced its performance rates across South Korea. Nevertheless, the data indicate the need for more focused and customized support for low-income families to enhance early hearing detection and interventions in newborns and infants.

Genetic Screening-Emerging Issues.

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit-harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems.

Neonatal screening of ABO/RhD blood group and direct antiglobulin Coombs test. Experience of a single institution.

BACKGROUND: Evaluating the ABO/RhD blood group and the direct antiglobulin Coombs test (DAT) at birth is recommended good practice, but there is variability in its universal implementation. This study aims to show the comparative results in various variables of clinical impact during the hospital stay of neonates with positive DAT compared with those with negative DAT, based on the systematic detection of the ABO/RhD group and DAT at birth. METHODS: Newborns between 2017 and 2020 in a high-risk pregnancy care hospital were included. The ABO/RhD and DAT group was determined in umbilical cord samples or the first 24 hours of life. Demographic, maternal, and neonatal variables were recorded. The association between the variables was estimated using the odds ratio (OR). RESULTS: 8721 pairs were included. The DAT was positive in 239 newborns (2.7%), with the variables associated with positive PDC being maternal age > 40 years (OR: 1.5; 95% CI: 1.0 to 2.3), birth by cesarean section (1.4; 1.1-2.0), mother group O (6.4; 3.8-11.8), prematurity (3.6; 2.6-5.0), birth weight < 2500 g (2.1; 1.6-2.8), newborn group A (15.7; 10.7-23.1) and group B (17.6; 11.4-27.2), hemoglobin at birth < 13.5 g/dl (4.5; 2.8-7.1) and reticulocytosis > 9% (1.9; 1.2 to 3.1). DISCUSSION: The frequency of neonatal positive PDC was 2.7%, with a significant association with maternal/neonatal incompatibility to the ABO and RhD group, with a substantial impact on various neonatal variables. These results support the policy of universal implementation at the birth of the ABO/RhD and DAT determination.

INTRODUCCIÓN: La determinación del grupo sanguíneo ABO/RhD y la prueba directa de Coombs (PDC) al nacimiento son una práctica recomendada, pero existe variabilidad en su implementación universal. Se presentan los resultados de la determinación al nacimiento del grupo ABO/RhD y la PDC en una cohorte institucional. MÉTODOS: Se incluyeron los recién nacidos entre 2017 y 2020 en un hospital de atención a embarazos de alto riesgo. Se determinó el grupo ABO/RhD y se realizó la PDC en muestras de cordón umbilical o en las primeras 24 horas de vida. Se registraron las variables demográficas, maternas y neonatales. Se estimó la asociación entre las variables mediante la razón de probabilidad (OR). RESULTADOS: Se incluyeron 8721 binomios. La PDC fue positiva en 239 recién nacidos (2.7%), siendo las variables asociadas a la PDC positiva la edad materna > 40 años (OR: 1.5;IC95%: 1.0-2.3), el nacimiento por vía cesárea (1.4; 1.1-2.0), la madre del grupo O (6.4; 3.8-11.8), la prematuridad (3.6; 2.6-5.0); el peso al nacer < 2500 g (2.1; 1.6-2.8); el neonato del grupo A (15.7; 10.7-23.1) o del grupo B (17.6; 11.4-27.2), la hemoglobina al nacer < 13.5 g/dl (4.5; 2.8-7.1) y la reticulocitosis > 9% (1.9; 1.2 a 3.1). DISCUSIÓN: La frecuencia de PDC positiva neonatal es del 2.7%, con asociación significativa la incompatibilidad materna/neonatal al grupo ABO y RhD, con impacto significativo en diversas variables neonatales. Estos resultados apoyan la política de implementación universal al nacimiento de la determinación de ABO/RhD y PDC.

Evaluation of the first 5 years of a glutaric aciduria type I neonatal screening programme in Asturias.

INTRODUCTION: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community. MATERIAL: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L. RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life. CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.

Social determinants of gastrointestinal malformation mortality in Brazil: a national study.

Introduction: In Brazil, approximately 5% are born with a congenital disorder, potentially fatal without surgery. This study aims to evaluate the relationship between gastrointestinal congenital malformation (GICM) mortality, health indicators, and socioeconomic factors in Brazil. Methods: GICM admissions (Q39-Q45) between 2012 and 2019 were collected using national databases. Patient demographics, socioeconomic factors, clinical management, outcomes, and the healthcare workforce density were also accounted for. Pediatric Surgical Workforce density and the number of neonatal intensive care units in a region were extracted from national datasets and combined to create a clinical index termed 'NeoSurg'. Socioeconomic variables were combined to create a socioeconomic index termed 'SocEcon'. Simple linear regression was used to investigate if the temporal changes of both indexes were significant. The correlation between mortality and the different indicators in Brazil was evaluated using Pearson's correlation coefficient. Results: Over 8 years, Brazil recorded 12804 GICM admissions. The Southeast led with 6147 cases, followed by the Northeast (2660), South (1727), North (1427), and Midwest (843). The North and Northeast reported the highest mortality, lowest NeoSurg, and SocEcon Index rates. Nevertheless, mortality rates declined across regions from 7.7% (2012) to 3.9% (2019), a 51.7% drop. The North and Midwest experienced the most substantial reductions, at 63% and 75%, respectively. Mortality significantly correlated with the indexes in nearly all regions (p<0.05). Conclusion: Our study highlights the correlation between social determinants of health and GICM mortality in Brazil, using two novel indexes in the pediatric population. These findings provide an opportunity to rethink and discuss new indicators that could enhance our understanding of our country and could lead to the development of necessary solutions to tackle existing challenges in Brazil and globally.

Evaluation of the First Three Years of Treatment of Children with Congenital Hypothyroidism Identified through the Alberta Newborn Screening Program.

The effectiveness of newborn screening (NBS) for congenital hypothyroidism (CH) relies on timely screening, confirmation of diagnosis, and initiation and ongoing monitoring of treatment. The objective of this study was to ascertain the extent to which infants with CH have received timely and appropriate management within the first 3 years of life, following diagnosis through NBS in Alberta, Canada. Deidentified laboratory data were extracted between 1 April 2014 and 31 March 2019 from Alberta Health administrative databases for infants born in this time frame. Time to lab collection was anchored from date of birth. Timeliness was assessed as the frequency of monitoring of Thyroid Stimulating Hormone (TSH) and appropriateness as the frequency of children maintaining biochemical euthyroidism. Among 160 term infants, 95% had confirmation of diagnosis by 16 days of age. The cohort had a median of 2 (range 0-5) TSH measurements performed in the time interval from 0 to 1 month, 4 (0-12) from 1 to 6 months, 2 (0-10) from 6 to 12 months, and 7 (0-21) from 12 to 36 months. Approximately half were still biochemically hypothyroid (TSH > 7 mU/L) at 1 month of age. After becoming euthyroid, at least some period of hypo- (60%) or hyperthyroidism (TSH < 0.2 mU/L) (39%) was experienced. More work needs to be performed to discern factors contributing to prolonged periods of hypothyroidism or infrequent lab monitoring.

Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease.

BACKGROUND: Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective. METHODS: We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample. RESULTS: Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6-13.6 µmol/L [n = 45] vs 0.44; 0.24-0.99 µmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1-9.9 µmol/L [n = 8]) and neonatal controls (0.93; 0.4-1.8 µmol/L [n = 784]) (p < 0.05). CONCLUSIONS: We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.

Newborn screening in Colombia: The experience of a private program in Bogotá / Tamizaje neonatal en Colombia: la experiencia de un programa privado en Bogotá.

Introduction. The first neonatal screening program in Colombia ­ PREGEN ­ was set up in the medical private sector of Bogotá in 1988. We report the results from recent years that, given the scarcity of similar information in our country, may help estimate the frequency of the evaluated neonatal disorders and which ones should be included in the neonatal screening programs in our country. Objective. To describe the results of PREGEN´s newborn screening program between 2006 and 2019. Materials and methods. We analyzed databases and other informative documents preserved in PREGEN from the 2006-2019 period. Results. One in every 164 newborns screened in our program had an abnormal hemoglobin variant, and one in every 194 carried some hemoglobin S variant. Glucose-6- phosphate dehydrogenase deficiency and congenital hypothyroidism are next as the more common disorders. Conclusions. Abnormal hemoglobin causes the most frequent monogenic disorder in the world. Glucose-6-phosphate dehydrogenase deficiency is the most common enzymopathy affecting nearly 400 million individuals worldwide. Since both disorders are more common in people of African descent and confer some resistance to malaria, we believe that screening for both disorders may be more relevant in the areas with African ancestry in our country.

Introducción. En Colombia, el primer programa de tamizaje neonatal, PREGEN, inició labores en el sector privado de Bogotá en 1988. En este artículo se presentan los resultados obtenidos en los últimos años, que, dada la carencia de estos estudios en el país, pueden servir para evaluar la frecuencia de aparición de los trastornos congénitos evaluados y estimar cuáles de ellos deben ser objeto de tamizaje neonatal a nivel nacional. Objetivos. Reportar los resultados del programa de tamizaje PREGEN entre el 2006 y el 2019. Materiales y métodos. Para este análisis se examinaron las bases de datos y otros documentos informativos de PREGEN para el periodo 2006-2019. Resultados. Uno de cada 164 recién nacidos tamizados en el programa PREGEN en Bogotá presentó una variante anormal de la hemoglobina y uno de cada 194 es portador de hemoglobina S. Los siguientes dos trastornos más frecuentes encontrados fueron la deficiencia de la enzima glucosa-6-fosfato deshidrogenasa (frecuencia 1:2.231) y el hipotiroidismo congénito (frecuencia 1:3.915). Conclusiones. Las hemoglobinopatías mostraron ser uno de los desórdenes monogénicos más comunes, seguidos por la deficiencia de glucosa-6-fosfato deshidrogenasa y el hipotiroidismo congénito. Se calcula que cerca de 400 millones de personas en el mundo están afectadas por la deficiencia de glucosa-6-fosfato deshidrogenasa, por lo cual es la enzimopatía más común en el mundo. Como ambos desórdenes son más frecuentes en poblaciones de origen africano y confieren algún grado de resistencia a la malaria, es de prever que su tamizaje debe ser de mayor importancia en las zonas con ancestros africanos en Colombia.

Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias.

The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine ß-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-ß-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.

Diagnosing Cystic Fibrosis in the 21st Century-A Complex and Challenging Task.

Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of therapeutic interventions, thereby ameliorating pulmonary function, addressing nutritional deficits, averting complications, mitigating morbidity, and ultimately enhancing the quality of life and extending longevity. This review aims to amalgamate existing knowledge to provide a comprehensive appraisal of contemporary diagnostic modalities pertinent to CF in the 21st century. Deliberations encompass discrete delineations of each diagnostic modality and the elucidation of potential diagnostic quandaries encountered in select instances, as well as the delineation of genotype-phenotype correlations germane to genetic counseling endeavors. The synthesis underscores that, notwithstanding the availability and strides in diagnostic methodologies, including genetic assays, the sweat test (ST) retains its position as the preeminent diagnostic standard for CF, serving as a robust surrogate for CFTR functionality. Prospective clinical investigations in the realm of CF should be orchestrated with the objective of discerning novel diagnostic modalities endowed with heightened specificity and sensitivity.

Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis. CASE PRESENTATION: The male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby's parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child. CONCLUSIONS: CPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.