dépistage néonatal

Objective
Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long‐ter

Since 1972, eighteen patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal‐onset Maple Syrup Urine Disease (MSUD) in Ireland. Patients were stratifie

The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversia…

Screening for rare diseases first began more than 50 years ago with neonatal bloodspot screening (NBS) for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and β-thalassaemia. NBS’s primary aim is health gain for children, while carrier screening enables autonomous reproductive choice. While screening can be beneficial, it also has the potential to cause harm and thus decisions are needed on whether a specific screening is worthwhile. These decisions are usually based on screening principles and criteria. Technological developments, both treatment driven and test driven, have led to expansions in neonatal screening and carrier screening. This article demonstrates how the dynamics and expansions in NBS and carrier screening have challenged four well-known screening criteria (treatment, test, target population and programme evaluation), and the decision-making based on them. We show that shifting perspectives on screening criteria for NBS as well as carrier screening lead to converging debates in these separate fields. For example, the child is traditionally considered to be the beneficiary in NBS, but the family and society can also benefit. Vice versa, carrier screening may be driven by disease prevention, rather than reproductive autonomy, raising cross-disciplinary questions regarding potential beneficiaries and which diseases to include. In addition, the stakeholders from these separate fields vary: Globally NBS is often governed as a public health programme while carrier screening is usually available via medical professionals. The article concludes with a call for an exchange of vision and knowledge among all stakeholders of both fields to attune the dynamics of screening.

Generalizing about the cost-effectiveness of newborn screening (NBS) is difficult due to the heterogeneity of disorders included in NBS panels, along with data limitations. Furthermore, it is unclear to what extent evidence about cost-effectiveness should influence decisions to screen for specific disorders. Screening newborns for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can serve as a useful test case, since there is no global consensus on whether CAH should be part of NBS panels. Published and unpublished cost-effectiveness analyses of CAH screening have yielded mixed findings, largely due to differences in methods and data sources for estimating health outcomes and associated costs of early versus late diagnosis as well as between-country differences. Understanding these methodological challenges can help inform future analyses and could also help interested policymakers interpret the results of economic evaluations.

Pyruvate dehydrogenase complex deficiencies (PDCDs) and other mitochondrial disorders (MtDs) can (a) result in congenital lactic acidosis with elevations of blood alanine (Ala) and proline (Pro)

Fatty acid oxidation disorders (FAODs) are potentially fatal inherited disorders for which management focuses on early disease detection and dietary intervention to reduce the impact of metabolic crises and associated spectrum of clinical symptoms. They can be divided functionally into long-chain (LC-FAODs) and medium-chain disorders (almost exclusively deficiency of medium-chain acyl–coenzyme A dehydrogenase). Newborn screening (NBS) allows prompt identification and management. FAOD detection rates have increased following the addition of FAODs to NBS programs in the United States and many developed countries. NBS-identified neonates with FAODs may remain asymptomatic with dietary management. Evidence from numerous studies suggests that NBS-identified patients have improved outcomes compared with clinically diagnosed patients, including reduced rates of symptomatic manifestations, neurodevelopmental impairment, and death. The limitations of NBS include the potential for false-negative and false-positive results, and the need for confirmatory testing. Although NBS alone does not predict the consequences of disease, outcomes, or management needs, subsequent genetic analyses may have predictive value. Genotyping can provide valuable information on the nature and frequency of pathogenic variants involved with FAODs and their association with specific phenotypes. Long-term follow-up to fully understand the clinical spectrum of NBS-identified patients and the effect of different management strategies is needed.

Newborn screening disorders increasingly require genetic variant analysis as part of second-tier or confirmatory testing. Sanger sequencing and gene-specific next-generation sequencing (NGS)-based tests, the current methods of choice, are costly and lack scalability when expanding to new conditions. We describe a scalable, exome sequencing–based NGS pipeline with a priori analysis restriction that can be universally applied to any NBS disorder. De-identified abnormal newborn screening specimens representing severe combined immune deficiency (SCID), cystic fibrosis (CF), VLCAD deficiency, metachromatic leukodystrophy (MLD), and in silico sequence read data sets were used to validate the pipeline. To support interpretation and clinical decision-making within the bioinformatics pipeline, variants from multiple databases were curated and validated. CFTR variant panel analysis correctly identified all variants. Concordance compared with diagnostic testing results for targeted gene analysis was between 78.6% and 100%. Validation of the bioinformatics pipeline with in silico data sets revealed a 100% detection rate. Varying degrees of overlap were observed between ClinVar and other databases ranging from 3% to 65%. Data normalization revealed that 11% of variants across the databases required manual curation. This pipeline allows for restriction of analysis to variants within a single gene or multiple genes, and can be readily expanded to full exome analysis if clinically indicated and parental consent is granted.

The potential for genomic screening of the newborn, specifically adding genomic screening to current newborn screening (NBS), raises very significant ethical issues. Regardless of whether NBS of this type would include entire genomes or only the coding region of the genome (exome screening) or even sequencing specific genes, the ethical issues raised would be enormous. These issues include the limitations of bioinformatic interpretation of identified variants in terms of pathogenicity and accurate prognosis, the potential for substantial uncertainty about appropriate diagnosis, therapy, and follow-up, the possibility of much anxiety among providers and parents, the potential for unnecessary treatment and “medicalizing” normal children, the possibility of adding large medical costs for otherwise unnecessary follow-up and testing, the potential for negatively impacting medical and life insurance, and the almost impossible task of obtaining truly-informed consent. Moreover, the potentially-negative consequences of adding genomic sequencing to NBS might jeopardize all of NBS which has been and continues to be so beneficial for thousands of children and their families throughout the world.

Background
Among boys with X‐Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplan

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glyco…

To estimate health and economic outcomes associated with newborn screening (NBS) for infantile-onset Pompe disease in the United States. A decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared with clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course. Universal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared with clinical detection. The ICER was $379,000/QALY from a societal perspective and $408,000/QALY from the health-care perspective. Results were sensitive to the cost of enzyme replacement therapy. Newborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns. To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives. A total of 27,335 newborns were screened using this two-tier algorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote. Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.