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).

[7] AGS can occur due to mutations in any one of a number of different genes, of which nine have been identified to date, namely: TREX1,[8] RNASEH2A, RNASEH2B, RNASEH2C (which together encode the ribonuclease H2 enzyme complex),[9] SAMHD1,[10] ADAR1,[11] and IFIH1 (coding for MDA5).

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

[citation needed] Otherwise the majority of AGS cases present in early infancy, sometimes after an apparently normal period of development.

[13] 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.

Mutations in the gene OCLN on chromosome 5q13.2, which is thought to cause band-like calcification in the brain, have been discovered in affected individuals and categorized as BLCPMG which often associated with AGS.

In mice, the loss of RNASEH2 activity causes neuroinflammation, atrophy of the cerebellum, and white matter defects that mirror AGS.

[27] Studies of the AGS-related proteins TREX1, the RNase H2 complex, SAMHD1 and ADAR1, suggest that an inappropriate accumulation of self-derived nucleic acids can induce type I interferon signaling.

[28][29][30] The findings of IFIH1 mutations in the similar context implicates the aberrant sensing of nucleic acids as a cause of immune upregulation.

[citation needed] 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.

[citation needed] 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.

[35] All cases of Cree encephalitis (an early-onset progressive encephalopathy in a Cree First Nations community in Canada),[39][40] 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).