AicardiGoutières

Aicardi–Goutières syndrome (AGS) is a rare autosomal recessive genetic disorder characterized by early-onset neuroinflammation and impaired brain development. It typically presents in infancy with irritability, fever, poor feeding, and vomiting, followed by hypotonia that may evolve into spasticity or dystonia, seizures, and global developmental delay. Growth retardation is common, and some patients have microcephaly.

Neuropathology and imaging features are notable for intracranial calcifications, especially in the basal ganglia and dentate nuclei, as well as white matter abnormalities and brain atrophy. Cerebrospinal fluid often shows elevated levels of interferon-α and other signs of innate immune activation. A robust interferon-stimulated gene signature in peripheral blood or CSF supports the diagnosis.

Genetically, AGS is caused by mutations in several genes involved in nucleic acid metabolism and innate immune sensing. The most common associated genes include TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1 (also known as MDA5). Inheritance is autosomal recessive, though additional genes have been linked to AGS forms as research advances.

Diagnosis relies on a combination of clinical presentation, characteristic MRI and CT findings, CSF interferon signature, and confirmation by genetic testing. Differential diagnosis includes congenital infections and other leukodystrophies.

Management is supportive and multidisciplinary, focusing on neurodevelopmental therapies, seizure control, and management of feeding or respiratory issues. There is no curative therapy; however, suppression of type I interferon signaling with targeted therapies like Janus kinase inhibitors has been explored in some cases. Prognosis is variable, but many affected individuals experience significant neurodevelopmental impairment. AGS is considered part of the broader class of type I interferonopathies.