Aicardi–Goutières syndrome

Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, 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. Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, 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. 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 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. 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 is a genetically heterogeneous disease resulting from mutations in any of seven genes encoding: a 3' repair exonuclease with preferential activity on single stranded DNA (TREX1); any of the three components of the ribonuclease H2 endonuclease complex acting on ribonucleotides in RNA:DNA hybrids (RNASEH2A, RNASEH2B, RNASEH2C); a SAM domain and HD domain containing protein which functions as a deoxynucleoside triphosphate triphosphohydrolase (SAMHD1); an enzyme catalysing the hydrolytic deamination of adenosine to inosine in double-stranded RNA (ADAR1); and the cytosolic double-stranded RNA receptor (MDA5, also known as IFIH1). 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 most cases, except for IFIH1- and rare cases of TREX1- and ADAR1-related disease, these mutations follow an autosomal recessive inheritance pattern (and thus the parents of an affected child face a 1 in 4 risk of having a further child similarly affected at every conception). AGS can be divided into subtypes based on the gene in which the causative mutation occurs. A survey of 374 patients with an AGS diagnosis reported that the most frequent mutations occurred in RNASEH2B. AGS-associated mutations have been found to show incomplete penetrance in some cases, with children in the same family with the same mutations showing markedly different neurological and developmental outcomes. Clinical features and disease course vary somewhat by genotype, with TREX1 associated with likely in utero onset and high mortality rate, and RNASEH2B mutations associated with slightly milder neurological impairments, lower interferon activity, and longer lifespan. Type I interferon activity was originally described over 50 years ago as a soluble factor produced by cells treated with inactivated, non-replicating viruses that blocked subsequent infection with live virus. Although the rapid induction and amplification of the type I interferon system is highly adaptive in terms of virus eradication, aberrant stimulation or unregulated control of the system could lead to inappropriate and / or excessive interferon output.