1,084,195 newborns screened in our centre correspond to about 1.6 times the annual birth rate in Germany. As far as we know this is the first prospective single centre evaluation of a NBS programme utilizing MS/MS. Numerous publications describe the epidemiology, technical aspects and clinical validity of MS/MS screening while there are only a few retrospective evaluations of NBS programmes. Only the Australian screening programme provides data on similar aspects of overall test performance for groups of disorders as well as of follow-up results [13
In our cohort 75% of all patients started treatment within the first 13 days of life. Out of 133 patients at risk for episodes of decompensation 11 (8%) presented clinically before the screening result was available. Even taking blood samples at 24 hrs after birth and optimal further processing of specimens would not have prevented most of these patients from early adverse events (Table ). Kaplan-Meier-analysis revealed disorder related patterns of early and late decompensations (Figure ). Urea cycle disorders, organic acid disorders, and amino acid disorders show the highest, earliest and continuous risk. Patients with medium-chain acyl-CoA dehydrogenase deficiency have a continuous but much lower risk for episodes of decompensation, and other fatty acid oxidation disorders an intermediate risk starting towards the end of the first year (with first intercurrent illness and/or missing feeds).
In medium-chain acyl-CoA dehydrogenase deficiency NBS leads to prevention of metabolic decompensations and neurological harm in nearly all patients [14
], compared to 40 to 74% presenting with severe illness, 16-26% with early death and 20% developing severe neurological impairment in unscreened populations [16
]. This benefit remains relevant although the number of MCADD cases detected is almost doubled by NBS. However, contemporary patients from unscreened cohorts surviving metabolic decompensations also showed normal neurological outcome, most probably due to improved awareness and emergency treatment [13
Our data correspond well to those of the Australian study [13
] for the common set of disorders as well as for medium-chain acyl-CoA dehydrogenase deficiency alone, except for the prevalence of symptomatic cases presenting during the first days of life (Table ). One patient showed normal intellectual and physical development, but slight myocloni on neurological examination. As the patient's mother showed similar symptoms, these are most probably unrelated to medium-chain acyl-CoA dehydrogenase deficiency. In his brother, also with medium-chain acyl-CoA dehydrogenase deficiency, mild muscular hypotonia without any practical consequences in everyday life was observed during the standardized examination. For comparison with the results of the Australian study both ratings were judged as "nil significant". In the present study 11 out of 1,084,195 children presented clinically before the screening result was available compared to 12 of 461,500 in the Australian screened cohort (OR: 0.39; 95% CI [0.17; 0.88]). Both studies document the value of extended newborn screening mainly on the basis of medium-chain acyl-CoA dehydrogenase deficiency, a disease of European origin.
Comparison of data across studies
Using phenylketonuria as a gold standard, patients with metabolic disorders included in the German 2005 screening panel achieved similarly good outcome data, whereas the outcome of the set of disorders screened additionally until 2005 was significantly worse than the outcome of the 2005 screening panel. Not including these disorders as a group into the screening panel could be defended as rational, although numbers are too small to draw conclusions for single disorders.
Evaluation of diseases with much lower frequencies can benefit from national and international collaboration, as could be shown for glutaric aciduria type I [19
], as well as from comparison with historical controls, well designed "n-of-1" trials and translational research [21
]. Systematic follow-up is also necessary to solve the question of mild phenotypes probably representing non-diseases.
Although unnecessary treatment of mild phenotypes of metabolic disorders is a serious problem [22
], it seems unjustified to attribute the issue exclusively to NBS. Considering screening as a programme there are multiple steps to identify mild variants and revise treatment decisions. Sampling time and cut-offs influence detection rates of mild variants and the same is true for methods and cut-offs of confirmatory procedures. Duarte galactosaemia needs no further investigation and no reporting [23
], but unfortunately this is not yet known for most other disorders. Therefore evaluation of the whole process including follow-up is necessary. Earlier sampling may allow earlier detection of some disorders e.g. maple syrup urine disease, but also increases the risk of missing others e.g. homocystinuria.
The principle that population screening requires a structured evaluation has been recently set in place by the US Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) instituting a permanent review panel in 2007 [24
]. Five criteria have been defined to add a condition to the NBS panel: sufficient information about the condition itself, evidence regarding appropriate screening tests, diagnostic methods, treatment and economic evaluations. In the European Union an evaluation process was recently initiated with the tender No. EAHC/2009/Health/09 'Evaluation of population newborn screening practices for rare disorders in Member States of the European Union' [25
]. Reports on NBS programmes from different parts of the world are necessary to allow a comprehensive assessment of benefits, harms and costs of NBS programs [26
]. As prevalences are likely to be different in populations of diverse ethnical background, pilot projects in individual countries will contribute important information [27
]. In the Arabic Gulf country Qatar the overall frequency of metabolic disorders detected by the particular NBS program is much higher (1:966) compared to the present study (1:2920), and prevalence in a Turkish pilot study was 1:839 [29
] illustrating a presumably likely high benefit of extended NBS in Turkey, Middle East and North African countries. In contrast the first comprehensive report from an East Asian country, Taiwan, revealed a prevalence of 1:6200 for all metabolic disorders, with an exceedingly low yield of fatty acid oxidation disorders, one of the main justifications for MS/MS screening in Caucasian populations [30
We have presented the data of a single centre longitudinal registry so that they can be compared with others. Aside from economic evaluation all the criteria set by the SACHDNC [24
] for extended NBS were addressed. We could demonstrate that physical and cognitive outcome of patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in patients with phenylketonuria. However, the specific evaluation of most of the rare disorders is still necessary and will require international registries and collaborative studies.