BackgroundNational newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.MethodsIn a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.ResultsOptimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.ConclusionsPhysical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.

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BACKGROUND: Although extended newborn screening (NBS) programs have been introduced more than 20 years ago, their impact on the long-term clinical outcome of individuals with inherited metabolic diseases (IMDs) is still rarely investigated. METHODS: We studied the clinical outcomes of individuals with IMDs identified by NBS between 1999 and 2016 in a prospective multicenter observational study. RESULTS: In total, 306 screened individuals with IMDs (115 with phenylketonuria and 191 with other IMDs with a lifelong risk for metabolic decompensation) were followed for a median time of 6.2 years. Although the risk for metabolic decompensation was disease-specific and NBS could not prevent decompensations in every individual at risk (n = 49), the majority did not develop permanent disease-specific signs (75.9%), showed normal development (95.6%) and normal cognitive outcome (87.7%; mean IQ: 100.4), and mostly attended regular kindergarten (95.2%) and primary school (95.2%). This demonstrates that not only individuals with phenylketonuria, serving as a benchmark, but also those with lifelong risk for metabolic decompensation had a favorable long-term outcome. High NBS process quality is the prerequisite of this favorable outcome. This is supported by 28 individuals presenting with first symptoms at a median age of 3.5 days before NBS results were available, by the absence of neonatal decompensations after the report of NBS results, and by the challenge of keeping relevant process parameters at a constantly high level. CONCLUSIONS: NBS for IMDs, although not completely preventing clinical presentations in all individuals, can be considered a highly successful program of secondary prevention.

We report the results of molecular neonatal screening for homocystinuria (cystathionine beta-synthase deficiency) in neonates of Qatari origin, developed in conjunction with a novel biochemical screening approach. DNA was extracted from dried blood spots (DBS); the prevalent Qatari CBS gene mutation p.R336C (c.1006C>T) and a second mutation were tested with specific TaqMan assays. Over a period of 2 years we screened 12,603 neonates and identified six affected neonates homozygous for p.R336C. There were 225 heterozygous carriers for p.R336C. One additional child with homocystinuria detected through biochemical screening was homozygous for a mutation not previously identified in Qatar. Homocystinuria in the Qatari population has an incidence of 1:1,800, the highest in the world and even higher than previously estimated. Allele frequency of the mutation p.R336C is approximately 1%, displaying a significant deviation from Hardy Weinberg equilibrium. In conclusion, first-line molecular neonatal screening is technically feasible and may be developed as an option for presymptomatic identification of genetic disorders caused by specific mutations or a limited number of prevalent mutations. However, sensitivity for the diagnosis of disorders caused by various mutations is limited even in a homogeneous population such as Qatar.

Background: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype.Methods: In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype.

Acute encephalopathic crisis in glutaric aciduria type I results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and reduced life expectancy. A conditio sine qua non for the prevention of irreversible brain damage is timely diagnosis and start of therapy, i.e. before the onset of neurological disease. As there are no specific clinical signs or symptoms that allow a reliable detection of these patients before the manifestation of encephalopathic crises, neonatal screening programmes for glutaric aciduria type I have been established in some countries using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. This article summarizes recent strategies, pitfalls and shortcomings of mass screening for glutaric aciduria type I, focusing on the relevant risk of missing patients with a mild biochemical phenotype (i.e. low excretors). Furthermore, it evaluates a binary strategy--using glutarylcarnitine as primary variable and glutarylcarnitine/acylcarnitine ratios as secondary variable--to improve the diagnostic sensitivity and specificity of neonatal screening for glutaric aciduria type I. An optimization of diagnostic as well as therapeutic procedures must be achieved before screening for glutaric aciduria type I can be regarded as reliable and beneficial for all patients.

The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B deficiency in the screening panel, while lowering the recall rate. An adapted second-tier strategy is presented for screening in Germany and will be prospectively evaluated over the next years in a pilot project named "Newborn Screening 2020".