Syntesis of European NIMBL Project

Pavia,  19/10/2010

Dear family,

We are writing to you on behalf of IAGSA with some very important news: June 2010 saw the start of a major research project, named NIMBL (Nuclear Immune-Mediated Brain and Lupus-like conditions), which is being funded by the European Community and coordinated by Prof. Y. Crow of Manchester. Among the centres participating in this project is the C. Mondino National Institute of Neurology in Pavia, in particular the Child Neuropsychiatry Unit with the indispensable collaboration of IAGSA. The duration of the project is three years. The aim of this multicentre study, which will involve centres in Europe and the United States, is to gain a better understanding – clinical, molecular and genetic –  of several rare, difficult-to-diagnose inherited diseases all of which, in most cases, affect the central nervous system and are probably caused by an alteration of the normal immune response. Aicardi-Goutières syndrome is one of these diseases. We attach a brief summary of the premises on which this study is based, its purpose and objectives, and the means through which it aims to achieve these objectives.

We believe that this research project could offer a unique and crucial opportunity for international collaboration between physicians and researchers with different and complementary professional expertise, who will be able to share current knowledge of the disease and explore in more depth the mechanisms that underlie it, in a bid to improve understanding and early diagnosis of the condition and identify possible avenues for treatment.

We therefore wish to know whether you are interested in your son/daughter taking part in this research. If you are, please let us know by phone and/or e-mail (using the number and addresses below) or via IAGSA itself. You will then be contacted and given full details and further explanations. Please don’t hesitate to get in touch with any questions you may have prior to making a decision. We would also be pleased, if you wish, to inform your paediatrican/GP directly of the project and also give him/her any information required so that he/she may advise you.

We look forward to hearing from you and in the meantime send you our very best wishes.

 

           Nadia Cairati                                                                  Prof. E. Fazzi,  Dr S. Orcesi, Dr I. Olivieri

          President of IAGSA                                                                      IAGSA Doctors

 

E-mail - Dr S. Orcesi : simona.orcesi@mondino.it

IAGSA:  iagsa@libero.it

Phone : ++ 39 0382/380280 (Mrs E. Botta, between 11.30 and 13.00)

 

The aims of the European NIMBL project

The NIMBL study will focus on Aicardi-Goutières syndrome and several other clinical conditions, including a cutaneous form of systemic lupus erythematosus (familial chilblain lupus) and an adult-onset form of retinal vasculopathy with cerebral leukodystrophy (RVCL).  Aicardi-Goutières syndrome is known to be an inherited disease characterised by raised CSF levels of INF-α, an inflammatory mediator physiologically produced by the human organism in response to a normal infection. In Aicardi-Goutières syndrome, the over-production of INF-α that is responsible for the acute-phase symptoms could be an inflammatory response to the abnormal persistence of DNA fragments that are usually eliminated by certain protein-enzyme complexes.  Although the exact function of the TREX1 and RNaseH2 complexes is not known, it is suggested that they may be involved in this process of DNA elimination, and thus that their alteration may underlie the pathogenesis of the disease. However, abnormal INF-α levels often occur in other pathological conditions, too, from congenital infections to certain autoimmune diseases, such as systemic lupus erythematosus, a condition that has actually also been observed in individuals with Aicardi-Goutières syndrome. The finding of an overlapping of Aicardi-Goutières syndrome with other immune-mediated diseases has led to a growing realisation, among researchers and clinicians, of the need for greater knowledge of the pathogenetic, genetic and/or immunological bases and clinical characteristics of these conditions – to allow better interpretation of the clinical pictures encountered, more homogeneous diagnostic criteria, and research of possible drug treatments.

This research project will thus involve professionals of different kinds, who will work together at various levels (clinical, molecular-genetic, immunological), making use not only of genetic and immunological investigations, but also of experiments on animal models (rats). Indeed, the objective is, through the animal model, to reproduce the various clinical phenotypes so that they can be submitted to more in-depth molecular study. From a clinical point of view, a fundamental requirement is the creation of a register of patients with a definite diagnosis of Aicardi-Goutère’s syndrome – a database that will collect information on the greatest possible number of cases: details of examinations and investigations undertaken, patients’ state of health and clinical problems presented. This is the part of the project in which the collaboration of IAGSA and of the families of affected children will be fundamental, particularly with regard to the collecting of: updated patient data and documentation, details of examinations carried out and of the current state of health of each child, etc., as well as all other data useful for establishing more precisely the clinical characteristics of the disease, the criteria for its diagnosis and the nature of the genotype-phenotype correlation.  In addition, annual meetings will be held for families and patients in Europe (one in Pavia and the other in Manchester), while a single meeting will be organised in the United States (Washington DC). On these occasions, full details of the ongoing research and its possible developments will be provided. Above all, however, these meetings will provide an opportunity for a clinical re-assessment of the patients, the aim being to standardise, in the light of recent scientific discoveries, the protocol of examinations that each child should, over time, be submitted to, and to collect more detailed clinical information. At these meetings, families will also be informed of the possibility of creating a “blood bank” (plasma and CSF) for each patient, in order to allow more detailed analyses, useful for obtaining a better definition of the pathogenesis of the disease. For this purpose, parents will be asked to authorise the taking of a blood sample from their child. At these meetings, information will also be collected about the health of the child’s parents and of any siblings. Naturally participation in the study is entirely voluntary and each family is free to decide what kind of collaboration they feel able to offer.

Pavia 10 October 2010