2nd International Meeting 2006

AICARDI-GOUTIERES SYNDROME – 2nd International Meeting



Pavia, June 9-10, 2006



The meeting was divided into two sessions: the first, held at the IRCCS "C. Mondino Institute of Neurology" Foundation, of the University Pavia, on the afternoon of Friday, June 9, was chaired by Prof. E. Fazzi and devoted to an examination of the work conducted to date and to an exchange of ideas for the definition of new avenues of research.

Prof. Fazzi opened the meeting with a thought for Prof. Aicardi, who was unable to attend for health reasons, extending to him, in his absence, the best wishes of all those present and recalling that he is, of course, the eminent teacher whose clinical observations, together with those of Françoise Goutières, first made it possible to describe this disease that takes his name: the same disease that IAGSA is concerned with, and that was the focus of reflection and study of this second international meeting.

Prof. Fazzi illustrated the work carried out at the Department of Child Neurology and Psychiatry at the IRCCS C. Mondino Foundation, where 23 Italian patients have been examined and where the staff frequently receive, via e-mail, requests for clinical opinions from medical doctors and families from all over the world (Brazil, Algeria, USA, UK, Belgium, Japan, Colombia, Argentina, etc.)

The centre is currently involved in research projects and has contacts with Prof. P. Lebon, in Paris, for the measurement of interferon-alpha (INF-alpha) in the cerebrospinal fluid (CSF), with Prof. Y. Crow from Leeds, who is conducting genetic research, with Prof. T. Kuijpers from Amsterdam with whom a therapeutic trial has been set up and carried out, and with Prof. A. Izzotti from Genoa, for the study of gene expression in the CSF by means of microarray analysis. Finally, CSF samples of six patients have been sent to Prof. N. Blau in Zurich for analysis of pterins and neurotransmitters, following a report by Prof. Blau regarding neurotransmitter alterations in subjects with Aicardi-Goutières syndrome.

The frequent e-mail exchanges between the various parties over the past few years have ensured that everyone has kept abreast of the ongoing projects.

Prof. Fazzi then handed over to Prof. Y. Crow who spoke about the rapid advances in the genetic field, to Prof. A. Jackson, from Edinburgh, who has worked closely with Prof. Crow, to Prof. Izzotti from Genoa who spoke about the study of gene expression using the microarray analysis technique, to Prof. D. N. Black from Canada, who raised the therapeutic hypothesis of the use of anti-immune drugs, such as steroids, and to Prof. T. Kuijpers from Amsterdam, who talked about recent advances in the immunological field.

Finally, Dr R. Oriano, representing the families of affected children, asked the experts about the current and future prospects for a gene therapy, possibly involving substitution of the missing protein, if not to cure the affected children, then at least to improve their quality of life. Prof. Crow replied, explaining that in the likely hypothesis of the pathogenic event having occurred in the prenatal period, the possibility of interrupting its effect is very remote.


In the second session, which took place on Saturday June 10 in the "Aula del ‘400" at the University of Pavia and was chaired by Prof. F. Guzzetta from Rome and by Prof. E. Fazzi from Pavia, the various speakers presented, in detail, the data from their studies.

The proceedings were opened Prof. P. Lebon from Paris, who has been involved, from the start, in research into the production of INF-alpha in the CSF of children with Aicardi-Goutières syndrome. At the meeting, recent advances on the production of interferon during foetal life were presented, data that are fundamental for the possible prenatal diagnosis of the syndrome.

Next in the spotlight were the important results of the genetic research carried out by Prof. Y. Crow. Over the past 9 months or so, work in the genetic field has made rapid progress with the identification of 4 genes responsible for Aicardi-Goutières syndrome.

According to the studies conducted, the genes responsible for the syndrome number at least four and the clinical picture is probably broader than was initially thought; for example, it is possible that the progression of the disease may not be constant.

The responsible genes identified to date (Crow repeatedly underlined that there are at least 4 of these, and possibly more) are the following: TREX1 mapped on the AGS1 locus (chr 3) in 13 families, showing a pan-ethnic diffusion; FLJ11712 mapped on the AGS2 locus (chr 13) in 29 families, again with a pan-ethnic diffusion; AYP1, mapped on the AGS3 locus (chr 11) in 10 families originating from Pakistan and Bangladesh; and finally RNASEH2A identified in a Spanish family.

The fact that these genes have been identified will have important implications for diagnosis, also in the pre-natal period, and for the detection of carriers.

From a clinical perspective, these discoveries induce us to reflect not only on the need to define, starting now, a genotype-phenotype correlation, but also on the progressivity, or otherwise, of the disease and, above all, on the clinical criteria for its diagnosis. Crow, for example, wonders whether the presence of leukodystrophy is fundamental to the diagnosis and also raises the question of the age of the patient at assessment and diagnosis, given that the presence or absence of certain clinical signs or symptoms could be related to this.

Prof. Crow dwelt, in particular, on the importance of the skin lesions, citing systemic lupus erythematosus as a borderline pathology.

According to the geneticist, the pathogenic indications emerging from the results obtained to date concern the relationship between TREX1 and the RNAse H complex; the timing of the pathogenic event; and the importance of the role of environmental factors and of INF-alpha.

Prof. Crow’s lecture was followed by that of Prof. Andrew Jackson from Edinburgh, who has worked particularly closely with Crow in recent months. Jackson explained further the role of the mutations in the RNASEH2A gene, which are the cause of the reduction of enzymatic activity. He also added that the mutated amino acid is often constant in the different families, and referred to the murine model with alteration of the TREX1 gene in which, conversely, there is a total loss of enzymatic activity and in which the disease expression does not include neurological signs, but a cardiomegaly that has an inflammatory basis.

These discoveries are the fruit of years of research in the field that has depended on collaboration between clinicians and geneticists, and, as one might easily imagine, they allow new hopes for diagnosis of the condition and for the pursuit of new research directions, one of which, as Prof. Jackson hypothesised, may be a project to create an animal model of the syndrome.

The proceedings continued with the intervention of Prof. Izzotti from Genoa, who described his group’s work on the study of gene expression using the microarray analysis technique. In the wake of purely laboratory-based studies, the group has recently embarked on an attempt to establish correlations between gene expression and the clinical symptoms presented by affected children, work that will see the team from Genoa availing itself of the clinical experience of Prof. Fazzi and her group in Pavia.

Prof. Izzotti declared his support for the pathogenic theories set out by Crow on the basis of recent discoveries; indeed, also in the studies conducted in Genoa, the down-regulation of RNase emerges as an important pathogenic factor. Izzotti also underlined the fact that the double strand RNA is the major inducer of INF-alpha production.

Prof. Izzotti again recalled the importance, on a pathogenic level, of microangiopathy and reduced angioproliferation.

A final reflection from Dr Black concerned the analogies between cutaneous microangiopathy and cerebral microangiopathy, which are still being clarified.

The morning’s proceedings closed with Prof. T. Kuijpers from Amsterdam who reported on recent acquisitions by his group in the immunological field, in particular with regard to the role played by INF-alpha in the immune systems of affected subjects. These studies have important practical implications with regard to the therapeutic avenues, both those attempted, in part, in the past and, especially, those foreseen for the future.

The afternoon session, chaired by Prof. Lebon and by Prof. Izzotti, was devoted to the more clinical aspects, beginning with the report by Prof. Black, who has discovered a form of encephalitis, within the Cree Indian community, that shows considerable similarities with Aicardi-Goutières syndrome. The report was an opportunity, for those present, to see how clinical observation can lead to the identification of a hitherto unknown disease.

The afternoon continued with a clinical case description, by Dr D’Amico, of a patient seen by the neurologists at the Bambino Gesù hospital in Rome, and concerning a suspected diagnosis of Aicardi-Goutières syndrome in a 32-year-old woman. This case aroused considerable interest, in view of its possible contribution to an extension of the clinical spectrum of the syndrome.

The meeting moved from clinical to neuroradiogical aspects with the contribution of Dr Uggetti from Pavia, who spoke about the many diseases in which it is possible to find intracranial calcifications. Her report underlined the importance of diagnostic imaging techniques in the diagnosis of Aicardi-Goutières syndrome.

Dr S. Orcesi, from Pavia, then presented a report and discussion of three as yet unresolved clinical cases, seen at the Department of Child Neurology and Psychiatry at the IRCCS C. Mondino Institute of Neurology, which is the IAGSA clinical reference centre.

Plenty of time was then allotted to the discussion between the speakers and the families, who were present in force and who showed a particular interest in the future therapeutic prospects, in the recent genetic discoveries, and in the management of their children’s various problems.

For example, the speakers were asked whether it is possible and opportune to treat some of the more severe consequences of the disease, such as the epileptic seizures and the hypertrophy.

The speakers pointed out that there do exist therapies that can give good results even though the extreme rarity of the disease means that a careful assessment is mandatory in order to avoid possible side effects.

There were many questions about the possibility of undergoing antenatal diagnostic testing for Aicardi-Goutières syndrome.

The discussion was certainly useful both for the families, who were able to obtain in-depth information, and for the experts, who were made aware of which issues are most pressing for the parents of children affected by Aicardi-Goutières syndrome.


The meeting was recognised, by the Italian and the medical press, as an extremely important event in view of the unusual nature of the disease and the international attention focused on it, given that it attracted the world-leading experts, from Europe, the United States and Canada, involved in scientific research into the syndrome.