Newborn Screening For Phenylketonuria Research Articles

Perspectives and Insights Into Phenylketonuria: Patient Narratives About the Early Years Following Newborn Screening.

Newborn screening for Phenylketonuria (PKU) began in 1963, and since then knowledge and treatment recommendations have evolved. In the decades following newborn screening for PKU, individual and family experiences varied widely. We present narratives by people living with PKU during these years, including individuals actively following in PKU clinic and those who have been out of PKU clinic for many years. These stories describe different individual experiences, including diet discontinuation in childhood, changing treatment guidelines, and new treatments that have become available.

Delays in Newborn Screening for Phenylketonuria from Birth to Diagnosis and Factors Affecting This.

This study aims to evaluate the process of neonatal phenylketonuria (PKU) screening from birth to admission to the pediatric metabolism polyclinic, determining delays in the screening program and the factors influencing them. This study was conducted during 2021-2023. Blood collection dates, results, and probable parameters causing delays in the screening program were recorded. This study included 118 infants. Admission time to the polyclinic was (mean ± SD) 25.2 ± 12.6 days (min-max: 3.4-78.9 days). Admission time was significantly high for refugees, those whose parents were consanguineous, and those who had more heel-prick blood samples taken (p < 0.001, p = 0.005, and p < 0.001, respectively). The first heel-prick blood phenylalanine (phe) level was significantly negatively correlated with the admission time (p < 0.001). Patients' admission time whose first blood phe level < 240 μmol/L was statistically significantly higher than in those with ≥240 μmol/L (p < 0.001). We determined that there were delays in PKU screening from birth to admission to the polyclinic. Being a refugee, the presence of consanguineous marriages, the increase in the number of heel-prick tests, and blood phe levels at a range of 120-240 μmol/L were the factors that played a role in this delay. Taking steps to reduce the impact of these parameters can prevent delays in newborn PKU screening and increase the success of the screening program.

Comparison of Tandem Mass Spectrometry and the Fluorometric Method-Parallel Phenylalanine Measurement on a Large Fresh Sample Series and Implications for Newborn Screening for Phenylketonuria.

Phenylketonuria (PKU) was the first disease to be identified by the newborn screening (NBS) program. Currently, there are various methods for determining phenylalanine (Phe) values, with tandem mass spectrometry (MS/MS) being the most widely used method worldwide. We aimed to compare the MS/MS method with the fluorometric method (FM) for measuring Phe in the dried blood spot (DBS) and the efficacy of both methods in the NBS program. The FM was performed using a neonatal phenylalanine kit and a VICTOR2TM D fluorometer. The MS/MS method was performed using a NeoBaseTM 2 kit and a Waters Xevo TQD mass spectrometer. The Phe values measured with the MS/MS method were compared to those determined by the FM. The cut-off value for the NBS program was set at 120 µmol/L for FM and 85 µmol/L for MS/MS. We analyzed 54,934 DBS. The measured Phe values varied from 12 to 664 µmol/L, with a median of 46 µmol/L for the MS/MS method and from 10 to 710 µmol/L, with a median of 70 µmol/L for the FM. The Bland-Altman analysis indicated a bias of -38.9% (-23.61 µmol/L) with an SD of 21.3% (13.89 µmol/L) when comparing the MS/MS method to the FM. The Phe value exceeded the cut-off in 187 samples measured with FM and 112 samples measured with MS/MS. The FM had 181 false positives, while the MS/MS method had 106 false positives. Our study showed that the MS/MS method gives lower results compared to the FM. Despite that, none of the true positives would be missed, and the number of false-positive results would be significantly lower compared to the FM.

Cost-Effectiveness of Newborn Screening for Phenylketonuria and Congenital Hypothyroidism

To evaluate the long-term costs and health effects of the Swedish newborn screening program for classic phenylketonuria (PKU) alone and in combination with congenital hypothyroidism compared with no screening. A decision-analytic model was developed to estimate and compare the long-term (80years) costs and health effects of newborn screening for PKU and congenital hypothyroidism. Data were obtained from the literature and translated to Swedish conditions. A societal perspective was taken, including costs falling on health care providers, municipal care and services, as well as production loss due to morbidity. Screening 100 000 newborns for PKU resulted in 73 gained quality-adjusted life-years (QALYs) compared with no screening. When adding congenital hypothyroidism, the number of gained QALYs was 232 compared with PKU alone, adding up to a total of 305 QALYs gained. Corresponding cost estimates were $80.8, $70.3, and $10.05 million USD for no screening, PKU screening, and PKU plus congenital hypothyroidism screening, respectively, indicating that screening for PKU plus congenital hypothyroidism was more effective and less costly compared with the other strategies. The majority of cost savings with PKU plus congenital hypothyroidism screening was due to reductions in productivity losses and municipal care and services costs. The Swedish newborn screening program for PKU and congenital hypothyroidism saves substantial costs for society while generating additional QALYs, emphasizing the importance of public investments in early diagnosis and treatment.

Quantitation of Phenylalanine in Dried Blood Spot Using Liquid Chromatography Tandem Mass Spectrometry for Monitoring of Patients with Phenylketonuria (PKU).

Newborn screening for phenylketonuria (PKU) is performed by analysis of phenylalanine in dried blood spot (DBS). Once diagnosed by a definitive method, a patient's dietary control is performed by repeated analysis of phenylalanine in venous blood or DBS. Since venipuncture is time consuming, painful, and may often be difficult to achieve in newborns, the use of DBS for analysis of phenylalanine is becoming a preferred method for dietary monitoring of patients with PKU. Using a lancet, patients or their guardians collect finger capillary blood on an approved filter paper. Once collected, the filter paper with DBS is sent to the laboratory for phenylalanine analysis. In the laboratory, phenylalanine is extracted from the DBS using organic solvents. Here, we describe an LC-MS/MS method for the analysis of phenylalanine from DBS with an approximation to serum levels.

Louis Isaac Woolf (24 April 1919 – 7 February 2021)

Professor Emeritus Louis Woolf died aged 101 on Sunday, 7 February 2021, in Vancouver, British Columbia. He is best known for his pioneering work conceiving and developing the first dietary treatment for phenylketonuria (PKU) based on a phenylalanine – a depleted hydrolysate of milk protein. His idea came from a ‘light bulb’ moment at a biochemistry meeting.Louis joined the Biochemical Society in May 1949 and continued until his death. He was thereby one of the longest ever serving members of the Society.He was born in London, the third child of Jewish parents from northern Romania. In 1938 he gained scholarships to study for a degree in chemistry at University College London (UCL) achieving First Class Honours and then a PhD. In 1939, at the outbreak of World War II, he was evacuated to Aberystwyth in Wales, along with the rest of UCL, to complete his degrees. There he met his future wife Frances Mary Richards.In 1947 he secured a post at Great Ormond Street Hospital (GOSH) to research tyrosine metabolism in premature babies. His first publication in a 1950 issue of the Biochemical Journal described this. Included in his chromatography studies were patients with PKU, then considered ‘untreatable’. He had postulated that their severe learning difficulties arose either from their abnormally raised blood phenylalanine concentrations or its toxic metabolite phenylacetic acid. He presented his investigations on the latter at the 1951 Biochemical Society Annual General Meeting in London. He wondered, could PKU patients be treated by lowering their concentration of phenylalanine with an artificial, low phenylalanine diet with added nutrients to make it a complete food? A protein substitute of pure amino acids was then extremely expensive. Fortuitously he went to a Biochemical Society meeting at which an economical growth medium for the microbiological assay of amino acids in protein was described. Phenylalanine and aromatic amino acids were removed from an acid hydrolysate of protein by filtration through charcoal. Louis knew that an acid hydrolysate of the milk protein, casein, was available from Allen and Hanbury, where he had worked, and could provide the basis for his dietary concept. Louis was unable to persuade paediatricians at GOSH to trial this. More receptive was a German paediatrician, Horst Bickel, visiting from his post in Birmingham, who enquired whether Louis could think of a way to treat PKU. Whilst sceptical of Louis’ idea, Bickel successfully treated a 2-year-old girl with PKU in Birmingham utilizing Louis’ method for producing a liquid food low in phenylalanine content. This was a world first and a lasting legacy.Louis moved to Oxford in 1958 to continue research into PKU. It is less well known that, since his time at GOSH, Louis had been convinced that newborn screening for PKU would improve outcomes by enabling earlier dietary therapy. Urine testing was a simple and non-invasive way and he and Senior Medical Officer in Public Health, Dr Nancy Gibbs, trialled a urine screening programme aimed at detecting all cases of PKU in a cohort of babies in Cardiff, Wales, from 1958 to 1959 – another world first which was partially successful. By 1968, with experience from other trials in other UK countries, it was apparent that urine detection in new-borns was insufficiently reliable and blood analysis became the recommendation with the heel prick test we are now so familiar with.Louis’ published work and presentations had become known internationally. In 1968 Dr William Gibson offered him a post as associate professor at the University of British Columbia (UBC). He was promoted to professor 6 years later in 1974. He published extensively, with over 120 papers to his name, a book on renal tubular dysfunction and contributions to books, conferences and supervision of many research students. He retired in 1984 after a 16-year teaching and research career at UBC.A shy and modest man, he was devoted to his family. His wife Frances died in 1991 and Louis is survived by his only daughter Lesley, grandsons Benjamin and Oliver, two great-grandchildren, Graham and Willow, and his youngest brother, Henry. He was beautifully spoken in a refined, old-fashioned British way with an astonishing memory to the end. Generous to people who criticized him, he quietly stood his ground, recognizing that valid debate is integral to scientific discovery. And – like many another innovative scientist – it is in this way that he triumphed over sceptical adversity to leave a legacy in pioneering the successful treatment of PKU.

Newborn Screening and Treatment of Phenylketonuria: Projected Health Outcomes and Cost-Effectiveness.

The objective of this study was to evaluate the cost-effectiveness of newborn screening and treatment for phenylketonuria (PKU) in the context of new data on adherence to recommended diet treatment and a newly available drug treatment (sapropterin dihydrochloride). A computer simulation model was developed to project outcomes for a hypothetical cohort of newborns with PKU. Four strategies were compared: (1) clinical identification (CI) with diet treatment; (2) newborn screening (NBS) with diet treatment; (3) CI with diet and medication (sapropterin dihydrochloride); and (4) NBS with diet and medication. Data sources included published literature, primary data, and expert opinion. From a societal perspective, newborn screening with diet treatment had an incremental cost-effectiveness ratio of $6400/QALY compared to clinical identification with diet treatment. Adding medication to NBS with diet treatment resulted in an incremental cost-effectiveness ratio of more than $16,000,000/QALY. Uncertainty analyses did not substantially alter the cost-effectiveness results. Newborn screening for PKU with diet treatment yields a cost-effectiveness ratio lower than many other recommended childhood prevention programs even if adherence is lower than previously assumed. Adding medication yields cost-effectiveness results unlikely to be considered favorable. Future research should consider conditions under which sapropterin dihydrochloride would be more economically attractive.

Robert Guthrie and the Trials and Tribulations of Newborn Screening.

Routine newborn screening for many disorders is now so ingrained in newborn care that there is no question about whether it should be done. However, acceptance of newborn screening was not guaranteed when Robert Guthrie introduced it for phenylketonuria (PKU). This article describes the professional and personal story of Guthrie, a physician and microbiologist, who veered from cancer research to a commitment to prevent intellectual disability from PKU. It recounts how Guthrie was able to overcome strong opposition to mandatory screening from prominent physicians and medical societies, so that newborn screening for PKU would be routinely performed throughout the developed world, and would eventually form the basis for the (much more) comprehensive screening conducted today.

Self-Reported Anxiety, Depression and Coping in Parents of Children with Phenylketonuria

Limited published research has evaluated mental health in parents of children with phenylketonuria (PKU) and their coping strategies. We aimed to assess anxiety, depression and coping in parents of Tunisian children treated for PKU. We conducted a cross-sectional study in the reference center for the management of inherited metabolic diseases in Tunisia. We used the Hospital Anxiety and Depression (HAD) scale and the Brief-COPE. Dependent variables were anxiety, depression, HAD Depression (HADD) and Anxiety (HADA) scores, and coping scores. Linear regression and logistic binary regression were used for multivariate analysis. Sixty-five parents from 42 families participated. 62% and 57% of them had anxiety and depression, respectively. Parental female gender (p = 0.049), rural origin (p = 0.005) and agitation in children with PKU (p = 0.031) were associated with anxiety. Parental age under 35 years (p = 0.043), agitation in children with PKU (p = 0.012) and behavioral disengagement (p = 0.003) were associated with higher HADA scores. Parents used problem focused (5.64 ± 1.34) more often than emotion focused coping (4.55 ± 0.90). Female gender was associated with emotion-focused coping (p = 0.042) and religion (p = 0.018). Motor disability in children with PKU was associated with humor (p = 0.047) and negatively associated with religion (p = 0.037). Psychological follow-up was associated with venting (p = 0.039). A low education level was negatively associated with self-blame (p = 0.024). Our study provided preliminary data which could be used to develop a targeted psychological support strategy for parents at risk for anxiety and depression not only in Tunisia but also in comparable populations where newborn screening for PKU is not available.

The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: A systematic review.

Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long-term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine-restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early-treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU-specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

Outcome of Patients With Inherited Neurotransmitter Disorders.

We report the outcome of 12 patients with inherited neurotransmitter disorders of monoamine, tetrahydrobiopterin and γ amino butyric acid metabolisms from a single Inherited Neurotransmitter Disorder Clinic including tyrosine hydroxylase (n=2), aromatic l-amino acid decarboxylase (n=1), 6-pyruvoyltetrahydropterin synthase, dihydropteridine reductase and succinic semialdehyde dehydrogenase deficiencies. Six patients (with 6-pyruvoyltetrahydropterin synthase, dihydropteridine reductase and tyrosine hydroxylase deficiencies) had normal neurodevelopmental outcome on treatment. Tetrahydrobiopterin loading test in newborns with positive newborn screening for phenylketonuria will identify patients with 6-pyruvoyltetrahydropterin synthase and dihydropteridine reductase deficiencies resulting in abnormal neurotransmitter synthesis in the central nervous system in the neonatal period to initiate disease-specific treatment to improve neurodevelopmental outcome.

The role of the clinician in the multi-omics era: are you ready?

Since Garrod’s first description of alkaptonuria in 1902, and newborn screening for phenylketonuria introduced in the 1960s, P4 medicine (preventive, predictive, personalized, and participatory) has been a reality for the clinician serving patients with inherited metabolic diseases. The era of high-throughput technologies promises to accelerate its scale dramatically. Genomics, transcriptomics, epigenomics, proteomics, glycomics, metabolomics, and lipidomics offer an amazing opportunity for holistic investigation and contextual pathophysiologic understanding of inherited metabolic diseases for precise diagnosis and tailored treatment. While each of the -omics technologies is important to systems biology, some are more mature than others. Exome sequencing is emerging as a reimbursed test in clinics around the world, and untargeted metabolomics has the potential to serve as a single biochemical testing platform. The challenge lies in the integration and cautious interpretation of these big data, with translation into clinically meaningful information and/or action for our patients. A daunting but exciting task for the clinician; we provide clinical cases to illustrate the importance of his/her role as the connector between physicians, laboratory experts and researchers in the basic, computer, and clinical sciences. Open collaborations, data sharing, functional assays, and model organisms play a key role in the validation of -omics discoveries. Having all the right expertise at the table when discussing the diagnostic approach and individualized management plan according to the information yielded by -omics investigations (e.g., actionable mutations, novel therapeutic interventions), is the stepping stone of P4 medicine. Patient participation and the adjustment of the medical team’s plan to his/her and the family’s wishes most certainly is the capstone. Are you ready?

DNAJC12 deficiency: A new strategy in the diagnosis of hyperphenylalaninemias.

Patients with hyperphenylalaninemia (HPA) are detected through newborn screening for phenylketonuria (PKU). HPA is known to be caused by deficiencies of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). Current guidelines for the differential diagnosis of HPA would, however, miss a recently described DNAJC12 deficiency. The co-chaperone DNAJC12 is, together with the 70kDa heat shock protein (HSP70), responsible for the proper folding of PAH. All DNAJC12-deficient patients investigated to date responded to a challenge with BH4 by lowering their blood phenylalanine levels. In addition, the patients presented with low levels of biogenic amine in CSF and responded to supplementation with BH4, L-dopa/carbidopa and 5-hydroxytryptophan. The phenotypic spectrum ranged from mild autistic features or hyperactivity to severe intellectual disability, dystonia and parkinsonism. Late diagnosis result in permanent neurological disability, while early diagnosed and treated patients develop normally. Molecular diagnostics for DNAJC12 variants are thus mandatory in all patients in which deficiencies of PAH and BH4 are genetically excluded.

Fourteen years of newborn screening for phenylketonuria in Vojvodina

Introduction. Phenylketonuria is an inborn disorder of metabolism, a rare, hereditary disease caused by deficiency of phenylalanine hydroxylase enzyme necessary for conversion of phenylalanine into tyrosine. The aim of this study is to determine the incidence of hyperphenylalaninemia and classical phenylketonuria in population of the Autonomous Province of Vojvodina. Material and Methods. We performed retrospective analysis at Medical Genetics Service, the Institute for Youth and Health Care of Vojvodina and examined the clinical material of the previous fourteen years, during the interval from 2003-2016. The analysis of the obtained results was carried out using descriptive statistics. Results. During fourteen years, from 01.01.2003 to 31.12.2016, 27 newborns with hyperphenylalaninemia were detected, and the incidence of hyperphenylalaninemia in the Autonomous Province of Vojvodina was 1: 9.525. Classical phenylketonuria was detected in 15 persons during indicated period, and the incidence was 1:17.143. Conclusion. Phenylketonuria is a hereditary disease whose adverse effects can be avoided, if it is recognized in time, and if recommended treatment measures are adequately applied, thereby improving the quality of life of persons affected by the disease as well as the whole family, that is facilitated by the introduction and implementation of neonatal screening.

Newborn Screening in Slovenia.

IntroductionNewborn screening in whole Slovenia started in 1979 with screening for phenylketonuria (PKU). Congenital hypothyroidism (CH) was added into the programme in 1981. The aim of this study was to analyse the data of neonatal screening in Slovenia from 1993 to 2012 for PKU, and from 1991 to 2012 for CH.MethodsBlood samples were collected from the heels of newborns between the third and the fifth day after birth. Fluorometric method was used for screening for PKU, CH screening was done by dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA).ResultsFrom 1993 to 2012, from 385,831 newborns 57 were identified with PKU. 184 newborns out of 427,396 screened from 1991 to 2012, were confirmed for CH. Incidences of PKU and CH in the periods stated are 1:6769 and 1:2323, respectively.ConclusionsSuccessful implementation of newborn screening for PKU and CH has helped in preventing serious disabilities of the affected children. Adding screening for new metabolic diseases in the future would be beneficial.

Conversion of a laboratory-based test for phenylalanine detection to a simple paper-based format and implications for PKU screening in low-resource settings.

Laboratory-based testing does not reach many individuals in lower-resource settings who could benefit from access to appropriate tests for diagnosis and therapy. A critical issue is laboratory-based testing often requires an environment with a high level of resources and supporting infrastructure that is not available in many areas of the world. The current report describes the conversion of a laboratory-based test for phenylalanine detection to a simple paper-based test appropriate for use in low-resource settings. The paper-based test is easy to operate, with all reagents stored dry on the card, is compatible with visible detection for clinically relevant concentrations of phenylalanine, and has a time to result of 10 minutes. Next steps for test development are discussed in the context of the potential for the paper-based Phe test to be used as a newborn PKU screening test in settings that are not well served by existing screening approaches.

PO-0904 Describing The Knowledge Of Parents About Newborn Screening

Screeningis generally consider part of the routine care for newborns. Newborn screening for phenylketonuria (PKU) has been available since the early 1960s. The fist newborn screening for PKU started in Ankara in Turkey in 1986 and extended country wide in 1993. PKU rate in Turkey occurs 1 in 4000 newborns because of consanguineous marriage. Consanguineous marriage rat in Turkey is 21%. This research was planned to describe the knowledge of parents about newborn PKU screening. A questionnaire was used to gather the data. To determine the effects data were evaulated by using chi square test and percentage analysis on the SPSS 11.0 program package. The study was performed during the period of January 2005 and March 2005 in a University Hospital and 150 mothers in postpartum period were included in the research. The questionnaire was obtained by face to face technique. Results The mean age of mothers was 26.49% of mother were graduated basic school. 74.7%of mother were house wife. 68% of mothers were primipara. 47% of mothers statedthat the test was ‘a IQ test’. Sixty-four percent of mothers didn’t know how toexecute the test. 69.3% of mothers didn’t know how long to continue the test.61.3% of mothers didn’t know how to learn the results of the test. Although99.3% of newborns were seem to be physically healthy, it was stated thatpostpartum screening tests should be applied. Considering this results, inorder to inform the mothers about the obtained results, a PKU educationbrochure was prepared and given to the unit. Conclusions Nurses who understand the pathophysiology and management of PKU in pregnancycan provide the care necessary for maternal and neonatal health. Healthcare providersare responsible for informing parents about the implications of newbornscreening to improve awareness and understanding.

Recessive mutations in PCBD1 cause a new type of early-onset diabetes.

Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 α), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.

Fifty years of phenylketonuria newborn screening — A great success for many, but what about the rest?

Guthrie's landmark discovery and the subsequent implementation of the first newborn screening programs for phenylketonuria (PKU) and other inherited errors of metabolism (IEM) could be – in a 50year retrospective – easily considered among the greatest advances in medicine. They have not just improved the quality of hundreds of thousands of lives, but also transformed our understanding and approach to PKU and IEM in general. However, according to the available albeit very scarce data, many countries and regions seem not to share the benefits of the last 50years of development. Many of them have not yet introduced the newborn screening for PKU or face significant problems in its implementation. In addition, the issue seems to be underrated by the relevant professional forums. Action to improve the current situation should urgently be taken.

50 years of newborn screening

Half a century ago Robert Guthrie published his seminal paper on newborn screening for phenylketonuria. Few of us will remember these early years and the difficulties encountered by Bob and his then few followers. The period was wonderfully summarized by him in the journal Screening in 1992 (volume 1, pages 5–15). From the 1960s to the end of the last century newborn screening progressed steadily with some technical advances and consolidated professional structures. Just before the turn of the century, highly sophisticated high-throughput multiple-analytes platforms (ELISAs, tandemMS, DNA, etc.) were developed and adapted for use in newborn screening. Particularly the applications of tandem mass spectrometry, paralleled by advances in molecular medicine, have now brought screening very much to center stage of scientific, medical and ethical issues. The Joint Meeting of the APHL Newborn Screening and Genetic Testing Symposium and the International Society for Neonatal Screening, held in Atlanta, Georgia, USA in May 2013, combined looking back and drawing from the experience of 50 years with a comprehensive coverage of today s hot topics. This issue of the journal draws on the material presented. The World Health Organisation and the European Community have both identified orphan diseases as a major future health challenge. Among these diseases, inborn errors of metabolism are especially important because of their high morbidity and mortality, high recurrence risk in affected families, and, most importantly, emerging therapeutic options, all leading to the need to identify asymptomatic newborns by newborn screening. The introduction of cost-effective programs is the main focus of developing and third-world countries, while in the developed countries an additional focus is on questions on acceptability, regulations, management, and suitability of individual diseases for newborn screening. The criteria for an acceptable screening program are hotly debated to date, with consolidated different results between most European countries, which in general only consider a limited number of disorders suitable for expanded MS/MS screening, and the USA with its basic recommendations of screening for 30+ conditions with an additional 25+ disorders some of which clearly do not meet the classical screening criteria. These discrepancies do not reflect major differences in genetic backgrounds of populations or estimated prevalences, but rather highlight different approaches to the estimation of risks and benefits for newborn screening, and just lack of evidence. We are still lacking detailed knowledge about the natural course ofmany diseases and their variants, information on middleand long-term outcome after early treatment initiation, and solid data on screening projects in non-Caucasian populations. In addition to the disease panel, the spectrum of metabolites analyzed, the organization of laboratories, analytical procedures, follow-up management, proficiency, and quality control all vary considerably among countries. In addition to state-run programs there is an increasing private, sometimes internationally operating sector with a hodgepodge of disorders and methods on sale. Conferences like that in Atlanta give us the opportunity to further develop international collaboration and to actively G. F. Hoffmann (*) :M. Lindner Department of General Pediatrics, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany e-mail: georg.hoffmann@med.uni-heidelberg.de