Progettazione dello screening neonatale allargato per le malattie metaboliche ereditarie: impatto nella popolazione e nei servizi

Each inborn metabolic disease represents a rare pathology. But, the whole group of inborn metabolic diseases should be considered in its complexity, heterogeneity and relevance. Since the sixties several countries developed screening programs, and from the nineties, with the use of tandem mass spectrometry, the possibility to analyze simultaneously a huge number of metabolites have allowed the screening of about forty metabolic diseases. In the present work, the planning of newborn screening for inborn metabolic disease in the Veneto Region, where a new regional law has been taken into force, is studied. The above cited law provides for the improvement of the already existing centres in the Region: Padua and Verona for the first level test and the regional referral centre of expertise for inborn metabolic disease of Padua Teaching Hospital for the second level test. The regional law provides for a panel of diseases including inborn errors involving the metabolism of organic acids (5 disorders), amino acid (6), mitochondrial (9) and lisosomial (3) defects. At a national level, Italy still has not a regulated planning for inborn metabolic disease screening in newborns. Besides, in many countries such as Australia, United States of America, Germany, and Portugal, newborn screening has been activated since several years. This has allowed us to refer to the experience of other countries on screening implementation in order to get a consistent data source leading to a better understanding of the prevalence of diseases explored and the proportions of newborns positive to the screening test and who needs second level test. Exploring the available literature on neonatal newborn screening with tandem mass spectrometry for Pompe and Fabry disease, included in our diseases panel, no evidence has been found except of two pilot studies performed in Austria even though no data considering mucopolysaccharidoses. On the basis of the experience of other countries, we estimated in our region an annual number of cases ranging from 6 to 24, excluding Fabry disease. For this pathology, the number of cases estimated is 8-20. In 2009, the total number of births in the region was 47,367. Among the remaining pathologies, phenylketonuria and MCAD (medium chain acyl-CoA dehydrogenase deficiency) are the most frequent inborn metabolic diseases with an annual number of cases ranging from 1 to 5 and from 2 to 5 respectively. Looking at international literature there is not a worldwide consent metabolites and cut-off for first level test. Usually cut-off are computed on the basis of statistics of healthy at term newborns and reviewed afterwards when a bigger number of newborn will be screened. The planning needs also a functional fitting of first and second level centres in order to: minimize the time between the birth and the second level visit, and newborn harm avoiding. From the data gathered from the other countries, the estimated number of newborns in Veneto Region who requires a second level visit in one year ranges 285-393. This planning question has been approached with a dynamic simulation model that enables to compare different allocation choice and to choose those reducing newborns risks and wasting resources. This created simulation model could be implemented in order to answer to different questions: a new attribution of resources to fulfil changes in care requests even though the inclusion in the screening program of other or newly discovered pathologies. In this context, the role of the birth centre is essential, not only for samples collection, but also because it will inform the family about screening results and, in case of positive results, it addresses the family to the second level centre, gives all the information needed, performs the eventually required second blood samples. In this thesis we have also studied a database to collect all information on neonatal newborn screening from birth to the final test results. In this data collection, the birth centre, the screening centre and the second level centre are involved. The diagnosis process required all the available medical history of the newborn and family. The birth centre is already involved in the data collection of the delivery assistance certificate which is a web system and the second level centre is part of the rare disease registry network. The newborn screening will connect these two data flows and, in addition to be an essential communication tool among centres, will allow the monitoring of the screening procedure efficacy. As effectiveness measure, it could be possible to gather the false positive rates, the positive predictive values but also to allow the false negative monitoring that is newborns with screening negative results showing a late disease onset "re-catching" them with the Rare Diseases Register System. The planned screening program could be implemented in order to be updated with clinical and therapeutical advancements and discoveries on diagnosable pathologies, with new available technologies, with the efficacy outcomes achieved in time, with cultural changes in the population and also in the available resources.