General description

Aicardi-Goutières syndrome (AGS) is a rare genetic immune-mediated disorder characterized by aberrant activation of the innate immune system, particularly the type I interferon pathway. The syndrome is caused by mutations in any of nine genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1. These genes are involved in nucleic acid metabolism or sensing, and when mutated, lead to accumulation of endogenous nucleic acids or aberrant sensing of self-nucleic acids in the cytoplasm. This accumulation triggers an innate immune response similar to that seen in viral infections, resulting in overproduction of type I interferons, particularly interferon-alpha (IFN-α).

The excessive interferon production leads to a destructive inflammatory process primarily affecting the brain, causing characteristic neurological damage. Recent research has identified the brain microvasculature as a primary mediator of interferon-α neurotoxicity in AGS, with the brain itself being the primary source of neurotoxic IFN-α. The cerebral endothelial cells are particularly vulnerable to IFN-α-activated receptor signaling, resulting in a distinctive cerebral small vessel disease.

Clinical manifestations

Aicardi-Goutières syndrome (AGS) is typically classified into two forms based on the age of onset and severity: the early-onset (classic) form and the later-onset form.

The early-onset form appears within the first few months of life and is associated with more severe symptoms and a poorer prognosis. Infants with this form may exhibit severe encephalopathy accompanied by irritability and inconsolable crying, feeding difficulties, and failure to thrive. They often develop rapid myoclonus that affects the arms, legs, and face, as well as progressive microcephaly, which is characterized by an abnormally small head size. Developmental regression or profound developmental delays are common, along with spastic-dystonic tetraplegia, which involves muscle stiffness and involuntary contractions. Seizures, inflammation of the liver, brain, and spinal cord, chilblain-like skin lesions (especially on the extremities), and recurrent episodes of aseptic fever may also occur.

In contrast, the later-onset form begins after several weeks or months of normal development. Children with this form typically experience a loss of previously acquired motor and social skills, along with muscle weakness or stiffness (spasticity) and involuntary muscle contractions (dystonia). Neurological impairments in the later-onset form are generally less severe compared to the early-onset form.

Additionally, both forms may be accompanied by extraneurological manifestations. These can include chilblain-like skin lesions, glaucoma and other ocular symptoms, hepatosplenomegaly (enlargement of the liver and spleen), thrombocytopenia (a low platelet count), autoimmune features resembling systemic lupus erythematosus, and cerebrovascular disease similar to Moyamoya.

References

1. Vanderver, Adeline, et al. "Early-onset Aicardi-Goutieres syndrome: magnetic resonance imaging (MRI) pattern recognition." Journal of child neurology 30.10 (2015): 1343-1348.