Aicardi-Goutieres syndrome (AGS) is an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical handicap. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly reminiscent of congenital infection. Otherwise, most affected infants present at variable times after the first few days of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. As many as 40% have chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, milder cases of AGS exist and thus the true extent of the phenotype associated with mutations in the AGS-related genes is not yet known.
The diagnosis can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), and identifiable mutations in one of the five known related genes. Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 are identified in approximately 90% of individuals with characteristic clinical and radiologic findings of AGS; such testing is clinically available. At least one other gene in which mutations are disease causing is postulated but remains unknown.
Most AGS is inherited in an autosomal recessive manner; in a few instances, AGS can result from de novo autosomal dominant mutations in TREX1. At conception, each sib of an affected individual with autosomal recessive AGS has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Most individuals with AGS do not reproduce. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation(s) in the family have been identified.