Aicardi-Goutieres syndrome is a rare, genetically determined progressive encephalopathy. The main features of the earliest described, also the most common form, are progressive microcephaly associated with basal ganglia and white matter calcifications, leukodystrophy, cerebral atrophy, and variable increase of lymphocyte count in the cerebrospinal fluid. The cytokine interferon alpha usually present in viral infections is elevated in cerebrospinal fluid and blood without presence of infective agents. There are 2 main clinical presentations: an early-onset neonatal form highly reminiscent of congenital infection (pseudo-TORCH) and a later-onset presentation, occurring several months after apparently normal development. Recessive mutations in any of 7 genes involved in the removal of redundant endogenous or exogenous DNA, RNA, or DNA/RNA hybrids can cause Aicardi-Goutieres syndrome. Progress started with the pioneering work of Pierre Lebon, who discovered the increased interferon alpha in the cerebrospinal fluid of the patients. The last 2 decades have witnessed the discovery of 7 genes associated with Aicardi-Goutieres syndrome and the discovery of the basic pathogenic role of alpha-interferon by Yannick Crow, Gillian Rice, and many others.
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• Aicardi-Goutieres syndrome (AGS) is a progressive genetic encephalopathy, mimicking congenital infections like TORCH and congenital HIV.
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• Mutations in any of 7 genes involved in removal of endogenous or infectious nucleic acids cause Aicardi-Goutieres syndrome (AGS 1-7). Most, but not all, causative mutations are recessive.
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• Failure to remove intracellular remnants of nucleic acid leads to stimulation of the innate and adaptive immune responses by the cytokine interferon alpha. The resulting inflammation, predominantly in the central nervous system, causes its symptoms.
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• Increase of interferon alpha in the CSF in the absence of demonstrable infection is the principal laboratory finding linking the whole clinical spectrum and all known disease causing mutations in Aicardi-Goutieres syndrome.
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• Other phenotypes or shared expressions include disseminated lupus erythematodes, childhood chilblain lupus, and leukodystrophy and retinopathy.
Historical note and terminology
In 1984, Jean Aicardi and Francoise Goutieres reported 8 infants from 5 families who suffered from an early onset familial encephalopathy with chronic CSF lymphocytosis and basal ganglia calcifications mimicking an intrauterine infectious process but with negative TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes) investigations (03). Clinically, the patients showed bilateral spasticity, dystonia, ocular jerks, and acquired progressive microcephaly with a rapid course toward profound deterioration and death. In addition, CT scan showed diffuse and progressive brain atrophy, deep white matter hypodensities, and bilateral symmetric calcifications of the basal ganglia including the thalamus.
The authors suggested a probable genetic condition with autosomal recessive inheritance. In the literature, they identified 9 previously reported, possibly similar cases of unclassified leukodystrophy with calcifications. However, none of them had CT scan, and information on CSF was insufficient. Following the publication by Aicardi and Goutieres, and prior to the finding of its associated gene defects, similar cases were reported (83; 80; 38; 58; 43; 44; 64).
Barth and colleagues reported widespread cerebral microangiopathy and infarctions in an autopsied case (07). This finding was confirmed by Rasmussen and associates (64).
In 1988 the chronic CSF lymphocytosis and cerebral calcifications mimicking a congenital infection led Lebon and colleagues to search for interferon alpha, a cytokine previously shown to be elevated in congenital rubella (46), acquired herpetic encephalitis and other viral diseases of the CNS (31). The finding of elevated interferon alpha in patients reported by Lebon and associates in the absence of overt viral disease was the first evidence of an autoimmune process and introduced a valuable marker in clinical diagnosis that can be easily applied to CSF samples (45). In retrospect, this was a seminal paper because interferon alpha in later studies proved to be not an epiphenomenon, but a triggering factor in the whole disease process of Aicardi-Goutieres syndrome.
Similar cases with prenatal onset with microcephaly, increased cell count in the cerebrospinal fluid, increase of interferon alpha, absence of all known intrauterine infections and with cerebral calcifications manifest at birth, collectively known aspseudo-TORCH, also belong to the Aicardi-Goutieres syndrome complex (65; 75).
In 1988, the disorder was listed as Aicardi-Goutieres syndrome, an autosomal recessive disorder (OMIM 225750).
Thereafter, the clinical spectrum of the syndrome appeared broader than previously thought. Since the initial publication on 8 children (03), an update of the clinical and radiological presentation and results of interferon alpha studies was published by Goutieres and colleagues, who reviewed 27 cases from 19 families (32), and by Lanzi and colleagues, who reviewed 21 cases (43). In 2004 more than 100 cases, including patients from new studies, were registered by Lebon and colleagues (47).
Crow’s group in the UK identified the first gene associated with Aicardi-Goutieres syndrome, the 3’-5’ exonuclease encoding TREX1 (18). This and subsequent studies so far identified mutations in 7 genes causing Aicardi-Goutieres syndrome. Overlap was also reported with disseminated lupus erythematosus (23). A most telling story is provided by Cree encephalitis, an apparent infectious disease present in Cree Indian families (09), subsequently proved to be genetic and allelic to AGS1, making Aicardi-Goutieres syndrome the ultimate diagnosis (19).