The purpose of neonatal screening is the early detection of congenital metabolic and endocrine disorders that, if untreated, could lead to fatal crises or other long-term adverse sequelae. In Germany, neonatal screening is legally regulated. Quality-assurance reports ("DGNS reports") are created and published annually by the German Society for Neonatal Screening (Deutsche Gesellschaft für Neugeborenen-Screening). Data from the DGNS reports for the years 2006-2018 serve as the basis of the present publication. For the years 2006-2018, prevalences were calculated and data on process quality were evaluated. Among 9 218 538 births, 6917 neonates were identified who had one of the target diseases. The overall prevalence was 75 per 100 000 neonates; the disorders most commonly found were congenital hypothyroidism (30 per 100 000) followed by phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCAD) (10 per 100 000 each). Of the 272 205 follow-up screenings requested, 80% were received. The rate of positive screening findings (recall rate) declined over the observation period, from 0.90% in 2006 to 0.37% in 2018. For every five positive screening findings, one case of a target disorder was confirmed. 79% of the children for whom treatment was indicated began to receive treatment within two weeks. The low recall rate and the early initiation of treatment in 79% of the affected children indicate that neonatal screening for metabolic and endocrine disorders in Germany is effective. The incorporation of tracking structures and the introduction of a registry could further improve the quality of the program.

Newborn screening (NBS) programs for treatable metabolic disorders have been enormously successful, but molecular-based screening has not been broadly implemented so far. This prospective pilot study was performed within the German NBS framework. DNA, extracted from dried blood cards was collected as part of the regular NBS program. As cystinosis has a prevalence of only 1:100,000-1:200,000, a molecular genetic assay for detection of the SMN1 gene mutation with a higher prevalence was also included in the screening process, a genetic defect that leads to spinal muscular atrophy (SMA). First tier multiplex PCR was employed for both diseases. The cystinosis screening employed assays for the three most common CTNS mutations covering 75% of German patients; in case of heterozygosity for one of these mutations, samples were screened by next generation sequencing (NGS) of the CTNS exons for 101 CTNS mutations. A detection rate of 98.5% is predicted using this approach. Between January 15, 2018 and May 31, 2019, 257,734 newborns were screened in Germany for cystinosis. One neonate was diagnosed with cystinosis, consistent with the known incidence of the disease. No false positive or false negatives were detected so far. Screening, communication of findings to parents, and confirmation of diagnosis were accomplished in a multi-disciplinary setting. This program was accomplished with the cooperation of hospitals, physicians, and parents. In the neonate diagnosed with cystinosis, oral cysteamine treatment began on day 18. After 16 months of treatment the child has no clinical signs of renal tubular Fanconi syndrome. This pilot study demonstrates the efficacy of a molecular-based neonatal screening program for cystinosis using an existing national screening framework.

Newborn screening using dried blood spots (NBS) is widely acknowledged as a highly successful procedure in secondary prevention. For a number of congenital disorders, severe disability or death are impressively prevented by early detection and early treatment through NBS. However, as with any other screening, NBS can also cause harm, and the principle that “the overall benefits of screening should outweigh the harms” must be considered when introducing and implementing NBS programmes. This publication compiles the results of a systematic literature research on requirements for NBS infrastructure and procedures which was conducted as part of a research project on the quality and shortcomings of the NBS pathway in Germany. The compilation contains the requirements and recommendations for realising the principle of “maximise benefits and minimise harms” in relevant NBS pathway components such as parental education and information, coverage, timeliness, laboratory quality assurance, follow-up of abnormal results, confirmatory diagnostics, documentation, and evaluation. The results reflect the complexity of NBS infrastructure, and thus, they illustrate the importance of considering and implementing NBS as a well-coordinated public health programme with continuous quality management. Special attention should be paid to the perspectives of parents and families. Some NBS issues can substantially benefit from digital instruments or international cooperation. The literature review presented here has contributed to a concept of proposals for the advancement of NBS in Germany, and despite different settings, it may as well be of interest for other countries to achieve the best possible course and outcome of NBS for each child.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial β-oxidation of fatty acids resulting in hypoketotic hypoglycemia, hepatopathy, and often fatal outcome in undiagnosed children. Introduction of tandem mass spectrometry–based newborn screening programs in the late 1990s has significantly reduced morbidity and mortality in MCAD deficiency; however, neonatal death in individuals with early disease manifestation and severe hypoglycemia may still occur. We describe the fatal disease course in eight newborns with MCAD deficiency, aiming to raise awareness for early clinical symptoms and the life-saving treatment, and promote systematic post-mortem protocols for biochemical and genetic testing, necessary for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.Conclusion: Early newborn screening and awareness for clinical symptoms is lifesaving in MCAD deficiency, which may present with fatal neonatal crisis. Systematic post-mortem diagnostic protocols are needed for sudden neonatal deaths. What is Known:• Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency identified by newborn screening has an excellent outcome.• Fatal neonatal crises occur in the first days prior to screening. What is New:• Poor feeding, no monitoring of blood glucose, and homozygosity of the common gene variant (c.985A > G) are major risk factors for fatal neonatal crisis in MCAD deficiency.• Post-mortem diagnostic protocols are indispensable for correct diagnosis and counselling of the family if unexpected death occurred in the neonatal period.