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Taruscio D.,Centro Nazionale Malattie Rare | Pierannunzio D.,Centro Nazionale Epidemiologia
BMC Neurology

Background: This paper provides a strategy to obtain a reliable estimate of the incidence rate for Amyotrophic lateral sclerosis based on data from the National Registry of Rare Diseases (NRRD). In fact, unobserved cases may be due to the fact that " a long time" may intercour between the suspect of having the disease (onset) and the date the disease is diagnosed. Potential factors that may influence the probability of experiencing the event (diagnosis) conditionally on the onset (suspected) are investigated. Since we are treating rare diseases, the role of social and economic factors is not that obvious; latent as well as observed factors may influence the delay to diagnosis.Methods: We use a semiparametric estimator based on the distribution of delay to diagnosis to account for potential underreporting. In particular, we propose to adopt an Horvitz-Thompson based estimator to correct the incidence figure that can be derived for the period 2007-2009 from the NRRD, Italy.Results: The incidence estimates obtained by adopting the proposed approach are about 1 case per 100000 inhabitants and despite they let recovering a good part of underreporting, they are still far from ALS incidence international ranges between 1.5 and 2.5. However, by looking only at northern Italy, the incidence estimates we can derive are coherent with those known internationally.Conclusions: These results confirm the existence of substantial differences in reporting accuracy, and point out where the system of data collection must be improved. In particular, when reliable individual characteristics will be available, they could be employed to refine the proposed estimator. © 2012 Rocchetti et al.; licensee BioMed Central Ltd. Source

Morciano C.,Centro Nazionale Malattie Rare | Laricchiuta P.,Centro Nazionale Malattie Rare | Taruscio D.,Centro Nazionale Malattie Rare | Schunemann H.,McMaster University
Public Health Genomics

Background: The Directive 2011/24/EU [OJEU 2011, L88/45] on the application of patient rights in cross-border health care requires the European Commission to support Member States in the development of European reference networks (ERNs). These ERNs are meant to ease the access of patients to highly specialized health care and to facilitate the cooperation at the European Union level in particular medical domains where expertise is scarce, especially in the rare disease area. Methods: The Directive 2011/24/EU [OJEU 2011, L88/45] and the recent Commission Delegated Decision [OJEU 2014, L147/71] as well as the Implementing Decision [OJEU 2014, L147/79] require ERNs and health care providers wishing to join ERNs to have the capacity of developing good practices guidelines. Results: This provision results in a number of challenges but also opportunities for Member States with respect to guideline production. Member States could consider the importance of devoting resources to build efficient systems and capacities for the development and implementation of trustworthy guidelines. Furthermore, they could adopt a cooperative approach to optimize guideline production across countries. Finally, they could promote the establishment of new research governance based on systematically identified research gaps and prioritized as well as communicated research recommendations. Conclusion: Member States are at a decisive point in establishing the details to ensure the transparent and effective functioning of ERNs. Producing explicit plans for the development and use of trustworthy guidelines should be an essential part of this effort. © 2015 S. Karger AG, Basel. Source

Nardozza A.P.,University of Rome Tor Vergata | Sabetta G.,University of Rome Tor Vergata | Torreri P.,Centro Nazionale Malattie Rare | Bocchinfuso G.,University of Rome Tor Vergata | And 5 more authors.
Journal of Biological Chemistry

Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr 63exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide-binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Ferrelli R.M.,Uifficio Relazioni Esterne | De Santis M.,Centro Nazionale Malattie Rare | Gentile A.E.,Centro Nazionale Malattie Rare | Taruscio D.,Centro Nazionale Malattie Rare
Annali dell'Istituto Superiore di Sanita

In the context of the Community Programme in the field of Health, the European Commission financed a series of initiatives to support the development and use of indicators for planning health services for Rare Diseases (RDs). The European Project for Rare Disease National Plans Development (EUROPLAN) elaborated a set of 59 process and outcome indicators, for monitoring the implementation and for evaluating the impact of the National Plans on RDs. Due to the high number and difficulty in handling the indicators, the subsequent Joint Action "Working for RDs" planned to derive a selection of 21 core indicators that were adopted by the European Union Committee of Experts on RDs in June 2013. The descriptive study carried out in the framework of the Joint Action to select the key indicators to orient policies for RDs shows that core indicators represent an excellent opportunity to share knowledge and comparability among Member States. Source

Taruscio D.,Centro Nazionale Malattie Rare | Capozzoli F.,Centro Nazionale Malattie Rare | Frank C.,Centro Nazionale Malattie Rare
Annali dell'Istituto Superiore di Sanita

According to the Regulation (EC) N. 141/2000 of the European Parliament and of the Council, rare diseases are life-threatening or chronically debilitating conditions, affecting no more than 5 in 10 000 persons in the European Community. It is estimated that between 6000 to 8000 distinct rare diseases affect up to 6% of the total EU population. Therefore, these conditions can be considered rare if taken individually but they affect a significant proportion of the European population when considered as a single group. Several initiatives have been undertaken at international, European and national level to tackle public health as well as research issues related to the prevention, diagnosis, treatment and surveillance of these diseases. The development of innovative and effective medical products for their diagnosis and treatment is frequently hampered by several factors, including the limited knowledge of their natural history, the difficulties in setting up clinical studies due to the limited numbers of patients affected by a specific disease, the weak interest of sponsors due to the restricted market opportunities. Therefore, incentives and other facilitations have been adopted in many parts of the world, including in the EU, in order to facilitate the development and commercialization of diagnostic tools and treatments devoted to rare diseases. This paper illustrates mainly the European initiatives and will discuss the problematic and controversial aspects surrounding orphan drugs. Finally, activities and measures adopted in Italy are presented. Source

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