IAGSA 2006-2007

2nd  “gathering for families" in Alassio (Savona, Italy) in March 2006
 
Conference at the Pavia’s University (Italy) “New advances in Aicardi-Goutières sindrome – 2nd International Meeting”  9-10 giugno 2006
Over the past year, the association has carried out some valuable work on the scientific front, and we refer, in particular, to the II International Meeting on Aicardi-Goutières Syndrome (9-10 June, 2006) and to Dr Crow’s three-day visit to the Department of Child Neurology and Psychiatry at the C. Mondino Foundation in Pavia in September 2006, during which the Italian patients affected by the syndrome were examined and reassessed.
From a scientific point of view, the most significant data to emerge from the June meeting were  those on the new genetic discoveries presented by Dr Crow and Dr Jackson. These data have made an important contribution both to the diagnosis of this disease and to our understanding of its pathogenesis. 
In particular, it is now clear that this is a genetically heterogeneous syndrome (i.e., that there are a number of genes that, if mutated, can give rise to the disease) and, to date, 4 distinct genes have been identified (but there will certainly be others, too):
AGS1 on chromosome 3, known as TREX1
AGS2 on chromosome 13 known as RNaseH2B/FLJ11712
AGS3 on chromosome 11 known as RNaseH2C/AYP1
AGS4 on chromosome 19 known as RNaseH2A
The first of these genes, TREX1, codes for an enzyme (DNase)  involved in breaking down DNA, and mutations of this gene are found in around 25% of AGS patients known to have a mutation. Most patients with this mutation are from Northern Europe.
The other three genes, AGS2,3 and 4 instead encode three separate proteins that function as a single enzyme complex (each protein is a subunit of the enzyme) called RNaseH2 which, instead, is involved in breaking down RNA. AGS2 is the gene most frequently mutated in European families (accounting for around 55% of families with mutations), whereas AGS3 has been found to be mutated in families from Pakistan; mutations of AGS4 are very rare (<5% of families with mutations).
We do not yet understand exactly how the genetic mutations and the resulting alteration of the proteins they encode cause the disease, although one hypothesis is related to the role of the TREX1 and RNaseH2 enzymes in digesting their own organism’s nucleic acids (DNA and RNA): when cells naturally die in organisms the nucleic acids they contain have to be broken down and the job of these enzymes is to get rid of these endogenous (‘self’) nucleic acids; however, if they do not work properly, the DNA and RNA will accumulate and could be mistaken by the organism for DNA and RNA of viral origin, thereby triggering an immune response similar to that which protects the organism against viruses; in this case, however, since there are no viruses present, the target of the response is the organism itself. Further studies will have to be conducted to clarify and confirm this hypothesis and also to explain why this pathological response, at a certain point, is interrupted. It is still too soon to derive any practical benefit (e.g. therapeutic opportunities) from these discoveries, but they are nevertheless very important because they have opened up broad avenues for future research.
One practical consequence of the possibility of having a genetic diagnosis, beyond that of allowing definitive confirmation of the diagnosis, is that it makes it possible, in families found to have a mutation in one of the 4 known genes, to carry out prenatal diagnosis in the event of future pregnancies from the same two parents of an already affected child. 
 
Collaboration with Dr Crow:
Dr Crow is currently analysing blood samples taken from the children seen in Pavia during his three-day visit in September 2006. Many of the patients have already been analysed and most of them found to have a mutation in one of the 4 examined genes, confirming the accuracy of the earlier clinical diagnoses. The analyses of a few of these cases are still ongoing. Currently, IAGSA has 21 Italian AGS cases, two of whom have now died. Twenty subjects have undergone genetic testing, which gave positive results in 12 cases (11 AGS2 and 1 AGS4); two cases were found to carry heterozygotic mutations and the significance of this finding remains to be clarified. Six cases were negative for mutations on the known genes and are thus “candidates” to show mutations in other genes probably involved in the pathogenesis of AGS.
Dr Crow is continuing his study of these cases in the attempt to identify new genes involved in the pathogenesis of the disease. On the basis of the data he has gathered, Dr Crow is currently writing an article on genotype-phenotype correlations, which will provide an update on these aspects.
There have also emerged some atypical cases, which are still being investigated not only by Dr Crow, but also in collaboration with our colleagues from the Gaslini Institute in Genoa.       
An atypical case will be presented in an oral communication at the 7th Congress of the European Paediatric Neurology Society, which will be held in Turkey in September 2007; this meeting is to include a session devoted to Aicardi-Goutières syndrome.
 
Collaboration with Dr Jackson:
Last September,  IAGSA sent Dr Jackson  blood samples from some of the children examined. Dr Jackson plans shortly to conduct studies on these samples, measuring the enzymatic activity of RNAse and exonuclease (the enzymes encoded by the mutated genes) and correlating it with the mutations present; another aim is to create lymphoblastoid cell lines with a view to conducting future studies investigating how the enzymatic abnormality might cause the inflammatory process associated with the syndrome.
 
Collaboration with Prof. Izzotti 
Prof. Izzotti has completed his study, presented at the meeting, which  brings together the results of the research project on cDNA microarray of CSF. The future lines of research and collaboration in this field are currently in the process of being defined in the light of the recent genetic discoveries.
 
Neuroradiological aspects
Dr Uggetti is currently reviewing the neuroradiological documentation of the known cases, which will form the basis of a neuroradiological follow-up study, focusing in particular on the white matter abnormality found in AGS.
 
CSF neurotransmitters
In Pavia, data were gathered on alterations of CSF neurotransmitter metabolites (analysis carried out by Prof. Blau in Zurich) in subjects affected by AGS. The profile of CSF neurotransmitters described by Blau does seem to be characteristic of the syndrome in its early stages, as a consequence of raised interferon-alpha: when the level of interferon-alpha falls, the profile of CSF neopterins and biopterins in the CSF becomes less significant. 
IAGSA has 8 children who have undergone this measurement, and who thus constitute a larger sample than the one analysed by Blau in his previous study. An initial resumé of these findings was presented as a poster at the  35th  SENP congress recently held in Pavia. 
 
Future projects
A research project entitled “AICARDI GOUTIERES SYNDROME: a paradigmatic example of a rare disease with onset in the first year of life” has been proposed for inclusion in the 2007 Italian Ministry of Health funded research conducted at the  IRCCS “C. Mondino Institute of Neurology” Foundation. In view of the rarity of this disease, the relative lack of studies on its long-term clinical progression and the need to define its clinical spectrum and diagnostic criteria, the study aims, in collaboration with IAGSA,  to describe the long-term clinical and neuroradiological evolution of the syndrome and to lay the foundations for the creation of a protocol for the follow up of AGS patients and an international AGS database.
These same topics will also be the subject of a degree thesis which is being written in the current academic year.
 
Development of therapeutic strategies
In the month of October 2007 IAGSA has commissioned the Department of Health Sciences of Genoa University to carry out a research programme for the development of AGS therapeutic treatments by experimental pre-clinical models.