This article includes discussion of Aicardi-Goutieres syndrome, familial encephalopathy with chronic CSF lymphocytosis, familial chilblain lupus, pseudo-TORCH, and Cree Indian encephalitis, all manifestations of a spectrum of inherited disorders based on inappropriate chronic production and attack on brain tissue by interferon alpha, which simulates chronic viral infection. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Aicardi-Goutieres syndrome is a rare, genetically determined encephalopathy. The main features 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 is elevated in cerebrospinal fluid and blood. There are 2 main clinical presentations: an early-onset neonatal form highly reminiscent of congenital infection and a later-onset presentation, occurring several months after 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 decade has seen the discovery of 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.
• 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.
• 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.
• 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.
• Other phenotypes: disseminated lupus erythematodes, childhood chilblain lupus, and leukodystrophy and retinopathy are expressed by mutations of the same genes.
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 (Aicardi and Goutieres 1984). 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 in these patients as well as in another possibly affected family reported by Babbitt and colleagues in 1969 (Babbitt et al 1969). Following the publication by Aicardi and Goutieres, and prior to the finding of its associated gene defects, similar cases were reported (Troost et al 1984; Tolmie et al 1995; Kato et al 1998; Ostergaard et al 1999; Lanzi et al 2002; Lanzi et al 2005; Rasmussen et al 2005).
Barth and colleagues reported widespread cerebral microangiopathy and infarctions in an autopsied case (Barth et al 1999). This finding was confirmed by Rasmussen and associates (Rasmussen et al 2005).
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 (Lebon et al 1985), acquired herpetic encephalitis and other viral diseases of the CNS (Dussaix et al 1985). 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 (Lebon et al 1988). 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 as pseudo-TORCH, also belong to the Aicardi-Goutieres syndrome complex (Reardon et al 1994; Sanchis et al 2005).
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 (Aicardi and Goutieres 1984), 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 (Goutieres et al 1998), and by Lanzi and colleagues, who reviewed 21 cases (Lanzi 2002). In 2004 more than 100 cases, including patients from new studies, were registered by Lebon and colleagues (Lebon 2002).
Crow's group in the UK identified the first gene associated with Aicardi-Goutieres syndrome, the 3'-5' exonuclease encoding TREX1 (Crow et al 2006a). This and subsequent studies so far identified mutations in 7 genes causing Aicardi-Goutieres syndrome. Overlap was also reported with disseminated lupus erythematosus (Crow and Rehwinkel 2009). A most telling story is provided by Cree encephalitis, an apparent infectious disease present in Cree Indian families (Black et al 1988), subsequently proved to be allelic to AGS1, making Aicardi-Goutieres syndrome the ultimate diagnosis (Crow et al 2000).
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