Learning about Aicardi-Goutieres Syndrome !

Written by: G.Lanzi, E.Fazzi, S.Orcesi
Child  Neuropsychiatry Dept. - University of Pavia – Italia


Learning about Aicardi-Goutières  Syndrome



International Aicardi-Goutières Syndrome Association










What Is Aicardi Goutières Syndrome?

Aicardi Goutières syndrome (AGS) is an early-onset (in the first year of life) progressive encephalopathy that shows an autosomal recessive pattern of inheritance and is characterised by acquired microcephaly, basal ganglia calcification, white matter alterations, chronic cerebrospinal fluid (CSF) lymphocytosis and raised levels of interferon-a in the CSF.

Since the first description of 8 cases by Aicardi and Goutières in 1984, other reports appearing in the literature have highlighted a certain heterogeneity in the clinical picture of the syndrome, with less severe courses and later onsets emerging even within single families.

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The diagnosis of AGS is based on a clinical picture characterised by:

  • the development of microcephaly in the course of the first year of life;
  • the appearance of encephalopathy with severe developmental delay, spasticity and extrapyramidal signs;
  • the presence of bilateral and symmetrical basal ganglia calcification (in particular at the level of the putamen, pallidus and thalamus) visible on brain CT scan;
  • the presence of white matter alterations, visible as hypodensities on CT scan and as a hypersignalon MRI T2-weighted images, particularly at periventricular level, and sometimes also at brainstem level and in pyramidal tracts;
  • the presence of progressive periventricular and peripheral brain atrophy (evidenced by CT scan and MRI);
  • the detection, through CSF analysis, of chronic lymphocytosis ( > 5 cells/mm3, persisting for years), in the absence of other signs of infectious processes.
  • Most cases also present raised CSF, and sometimes serum, levels of interferon-α which, however, tend to decrease as the child gets older.
  • There have also been descriptions of tuborecticular inclusions in the endothelial cells of the skin, particularly in subjects with high systemic interferon-α levels.

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AGS is an extremely rare pathology and its true incidence is not known.

To date, around 50 cases have been described worldwide. Many of these are familial cases.

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Other Clinical Aspects

 Following a normal pregnancy and neonatal period, onset usually occurs in the first year of life, between the ages of 3 and 6 months.

Sometimes, however, the symptoms are already evident at birth.

Affected subjects present feeding difficulties, irritability, abnormal eye movements and recurrent bouts of fever which have no apparent cause and occur in the presence of negative serological investigations.

Microcephaly soon becomes apparent, as does the loss of previously acquired mental and motor skills, with the appearance of truncal hypotonia, limb spasticity and dystonic movements; eye contact is absent, and subjects develop opisthotonic postures and oral-facial dyskinesias.

They may present epileptic seizures, although these are not frequent.

There are no ocular abnormalities, nor is there involvement of the peripheral nervous system (nerves, muscles).

Many subjects present acrocyanosis and erythematous periungueal-like cutaneous lesions distally, mainly affecting the fingers, toes and ears. The children present severe neurological and cognitive impairment, even though cases have been described (with different degrees of involvement emerging even within single families) characterised by a less severe course, no marked deterioration, and some capacity for contact with other people and for the acquisition of minor milestone.

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Differential Diagnosis

A distinction must be drawn between AGS and other early-onset pathologies in which there is basal ganglia calcification, in particular, the static encephalopathies caused by prenatal infections (cytomegalovirus, rubella, HIV, etc..), and other progressive disorders that have a metabolic and/or mitochondrial underlying cause.

There are also some rare familial-type syndromes that have many features in common with AGS, but these are characterised by a more complex symptomatology (for example, the presence of growth hormone deficiency, of thrombocytopenia and hepatic or immunological  dysfunctions), and their relationship with AGS has yet to be clarified.

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AGS has a genetic basis. From the earliest reports, which described families with more than one affected child (often families showing parental consanguinity), an autosomal recessive mode of transmission of the disorder was established. If both parents of an affected child are found to be carriers of the syndrome, then there is a 25% risk of it appearing in subsequent pregnancies.

To date, in spite of continuous advances, the gene responsible for the syndrome has still not been identified.

The most recent studies point to the possibility of a genetic heterogeneity, i.e., the involvement, in the regulation of a single pathogenic mechanism, of a number of genes whose abnormalities could prompt onset of the disease.

The locus (the position that a gene occupies on a chromosome) of one of these genes was, in one group of families, recently identified on the short arm of chromosome 3, but it has not yet been possible to isolate the gene precisely, nor to understand how the disease is determined by its

Another possibility is that a small number of genes could be involved, determining a sort of "predisposition" to the disease which, in order to manifest itself, would require the intervention of environmental factors, such as aspecific infections (multifactorial inheritance).


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There is, to date, no cure for AGS, and the therapeutic interventions that have been tried in isolated cases have not been substantiated scientifically.

The care of the young AGS sufferer is thus undertaken with the aim of improving, as far as possible, his (or her) quality of life, and that of his family, through the provision of assistance, the treatment (pharmacological and otherwise) of intercurrent problems (bouts of fever, feeding difficulties, skin lesions, epileptic seizures), and the prevention of complications relating to the movement disorder and spasticity associated with the syndrome (muscle contractures, osteo-articular deformities).


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Unanswered Questions and Future Prospects

The importance of clarifying the aetiopathogenic mechanism underlying AGS, and in particular the significance of the presence of interferon-a in the CSF of affected subjects, is fundamental. Interferon-α is a cytokine that, in normal conditions, protects the cells against numerous viruses and has immunomodulating functions.

On the basis of the fact that, in mice, a prolonged presence of interferon-a in the CNS can lead to a progressive encephalopathy with cerebral calification, it has been hypothesised that interferon-a may play a role in the pathogenesis of AGS: that the syndrome may, for example, be due to a genetic alteration of the mechanism that controls the production of interferon-a and its response to various pathogens.

However, it is also possible that the increase in interferon-α is not the main cause of the disease, but rather a consequence of some other, as yet unknown, pathogenic mechanism.

It has also been hypothesised that the main cause of the syndrome could be a genetic angiopathy of the small vessels in the brain.

AGS is a rare pathology, but it needs to be understood fully so that it can be diagnosed with certainty.

It is only by establishing a clear distinction between the clinical picture of AGS and those of similar encephalopathies that the right approach to the problems of these children can be found, and accurate information given to parents on the risk of recurrence of the syndrome in subsequent pregnancies.

It is also very important that data is gathered relating to families in which there are subjects affected by the syndrome.

It is important to observe how the condition of these subjects evolves in the long term and to collect DNA from the families so that it can be sent to the highly specialised centres where efforts are under way to identify the genes responsible for the syndrome.

Once these have been identified, it will be possible to make prenatal diagnoses in affected families. An understanding of the genetic basis of AGS, and of its underlying pathogenic mechanism, will undoubtedly lead to the opening up of new therapeutic horizons.

It is crucial that any attempts to treat the syndrome involve a large enough number of subjects to guarantee the scientific reliability of the result.

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The Association


The International Aicardi Goutières Syndrome Association (IAGSA) was founded in Jun 2000 as a non profit-making organisation whose main aims are:

  • to raise awareness and spread knowledge of AGS;
  • to provide sufferers from this disease, and their families, with support through contacts with doctors and health organisations internationally;
  • to promote and support research in areas linked with AGS.


I.A.G.S.A.  Board

Honorary President Prof. Jean François Aicardi
President Fiammetta Boni Longo
Scientific director Prof. Giovanni Lanzi, M.D.
General secretary Prof. Elisa Fazzi, M.D.
Member Dr. Simona Orcesi, M.D.
Family representatives Dr. Roberto Oriano
 Mustafa Özer

Operational headquarters:
Via Vittadini, 1
27100 Pavia, Italy
Tel. and fax: 0039-382-33342
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Scientific headquarters:

Division of Child Neuropsychiatry - IRCCS
Fondazione C. Mondino - Via Palestro, 3
27100 Pavia, Italy
Tel. : 0039-382-380236 - Fax : 0039-382-380286
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Website: www.aicardi-goutieres.com

Post office account number: 17091240
Bank account number: 370813/79
Cassa Rurale ed Artigiana di Binasco
ABI 08386 - CAB 11300 - Swift: ICRAITMM386
Viale Matteotti, 50 - 27100 Pavia, Italy
Payments should be made out to:
Associazione Internazionale
Sindrome Aicardi-Goutières – IAGSA
Via Vittadini, 1 - 27100 Pavia - Italy

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Written by: G.Lanzi, E.Fazzi, S.Orcesi
Child  Neuropsychiatry Dept. - University of Pavia – Italia