Some science behind the scenes

Aicardi-Goutieres syndrome

Aicardi–Goutières syndrome (AGS), is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodevelopmental disorder).

The majority of affected individuals experience significant intellectual and physical problems, although this is not always the case. The clinical features of AGS can mimic those of in utero acquired infection, and some characteristics of the condition also overlap with the autoimmune disease systemic lupus erythematosus (SLE).

Following an original description of eight cases in 1984, the condition was first referred to as 'Aicardi–Goutières syndrome' (AGS) in 1992, and the first international meeting on AGS was held in Pavia, Italy, in 2001.


In 1984, Jean Aicardi and Francoise Goutières described eight children from five families presenting with a severe early onset encephalopathy, which was characterized by calcification of the basal ganglia, abnormalities of the cerebral white matter and diffuse brain atrophy. An excess of white cells, chiefly lymphocytes, was found in the cerebrospinal fluid (CSF), thus indicating an inflammatory condition. During the first year of life, these children developed microcephaly, spasticity and dystonia. Some of the parents of the children were genetically related to each other, and the children were both male and female, which suggested that the disease was inherited as an autosomal recessive genetic trait.

In 1988, Pierre Lebon and his colleagues identified the additional feature of raised levels of interferon-alpha in patient CSF in the absence of infection. This observation supported the suggestion that AGS was an inflammatory disease, as did the later finding of increased levels of the inflammatory marker neopterin in CSF, and the demonstration that more than 90% of individuals with a genetic diagnosis of AGS, tested at any age, demonstrate an upregulation of interferon-induced gene transcripts - a so-called interferon signature.

All cases of Cree encephalitis (an early-onset progressive encephalopathy in a Cree Indian community in Canada), and many cases previously described as pseudo-TORCH syndrome, (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus), initially considered to be separate disorders, were later found to be the same as AGS (although other causes of, genetically distinct, ‘pseudo-TORCH’ phenotypes exist).


The initial description of AGS suggested that the disease was always severe, and was associated with unremitting neurological decline, resulting in death in childhood.

As more cases have been identified, it has become apparent that this is not necessarily the case, with many patients now considered to demonstrate an apparently stable clinical picture, alive in their 4th decade.

Moreover, rare individuals with pathogenic mutations in the AGS-related genes can be minimally affected (perhaps only with chilblains) and are in mainstream education, and even affected siblings within a family can show marked differences in severity.

In about ten percent of cases, AGS presents at or soon after birth (i.e. in the neonatal period). This presentation of the disease is characterized by microcephaly, neonatal seizures, poor feeding, jitteriness, cerebral calcifications (accumulation of calcium deposits in the brain), white matter abnormalities, and cerebral atrophy; thus indicating that the disease process became active before birth i.e. in utero. These infants can have hepatosplenomegaly and thrombocytopaenia, very much like cases of transplacental viral infection. About one third of such early presenting cases, most frequently in association with mutations in TREX1, die in early childhood.

Otherwise the majority of AGS cases present in early infancy, sometimes after an apparently normal period of development. During the first few months after birth, these children develop features of an encephalopathy with irritability, persistent crying, feeding difficulties, an intermittent fever (without obvious infection), and abnormal neurology with disturbed tone, dystonia, an exaggerated startle response, and sometimes seizures. Glaucoma can be present at birth, or develop later. Many children retain apparently normal vision, although a significant number are cortically blind. Hearing is almost invariably normal. Over time, up to 40% of patients develop so-called chilblain lesions, most typically on the toes and fingers and occasionally also involving the ears. They are usually worse in the winter.


AGS can occur due to mutations in any one of a number of different genes, of which seven have been identified to date, namely: TREX1, RNASEH2A, RNASEH2B, RNASEH2C (which together encode for the Ribonuclease H2 enzyme complex), SAMHD1, ADAR1, and IFIH1 (coding for MDA5). This neurological disease occurs in all populations worldwide, although it is almost certainly under-diagnosed. To date (2014) at least 400 cases of AGS are known.

AGS is a genetically heterogeneous disease resulting from mutations in any of seven genes encoding: TREX1

Viral infection triggers innate immune sensors to produce type I interferon. However, infection of T cells and macrophages with human immunodeficiency virus (HIV) does not trip those alarms. ….. Here we found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV.
 In …. cells and macrophages in which TREX1 was inhibited by RNA-mediated interference, cytosolic HIV DNA accumulated and HIV infection induced type I interferon that inhibited HIV replication and spreading. …. HIV-stimulated interferon production, in cells deficient in TREX1, did not involve known nucleic acid sensors. PMID: 20871604

Thus despite the dangers of the illness generated by AGS the mutation may confer some protective role against HIV to carriers.  What is not clear is what caused the mutation in the first place.

Although the cause of the various manifestations is a mutation in the gene, this is not in fact the actual cause, as we need to know what caused the mutation.

As the problem here is a generic one for all inheried diseases caused by mutation it is discussed in the section Inherited illness, please follow the link.