SNP Shot: Genomic Insights

Aicardi-Goutières syndrome (AGS) is a disease that primarily impacts the brain, immune system, and skin.

Many babies born with AGS initially show no signs of the condition. However, approximately 20% present at birth with a combination of symptoms, including an enlarged liver and spleen (hepatosplenomegaly), elevated liver enzyme levels in the blood, a low platelet count (thrombocytopenia) affecting blood clotting, and neurological issues. This combination often suggests a viral infection present from birth (congenital infection). Yet, no actual infection is found in these infants. This is why AGS is sometimes called a "mimic of congenital infection."

Within their first year, most children with AGS experience a period of serious brain dysfunction (encephalopathy), usually lasting several months. During this phase, babies are often very irritable, have feeding difficulties, and may experience unexplained fevers (sterile pyrexias) and seizures. They stop acquiring new skills and lose previously learned abilities (developmental regression). The growth of the brain and skull slows, leading to an abnormally small head size (microcephaly). During this phase, white blood cells and inflammatory molecules are found in the cerebrospinal fluid, the fluid surrounding the brain and spinal cord (central nervous system), indicating inflammation and damage within the central nervous system.

The encephalopathic phase of AGS causes permanent and typically severe neurological damage. Brain scans show a loss of white matter (leukodystrophy). White matter is composed of nerve fibers coated with myelin, a substance protecting nerves and ensuring quick nerve impulse transmission. Affected individuals also develop abnormal calcium deposits (calcification) in the brain. Due to this neurological damage, most people with AGS have significant intellectual disability. They also experience muscle stiffness (spasticity), involuntary muscle contractions (dystonia), particularly in the arms, and reduced muscle tone (hypotonia) in the trunk.

Some individuals with AGS exhibit characteristics of autoimmune disorders, where the immune system mistakenly attacks the body's own tissues and organs. Some of these features overlap with those of systemic lupus erythematosus (SLE). One SLE symptom also present in about 40% of AGS patients is a skin condition called chilblains. Chilblains are painful, itchy, puffy, and red skin lesions usually found on fingers, toes, and ears. They are caused by inflammation of small blood vessels and can be triggered or worsened by cold exposure. Other overlapping features include vision problems, joint stiffness, and mouth ulcers.

Due to the severe neurological problems typically associated with AGS, most individuals with the disorder do not survive past childhood. However, some individuals who develop the condition later in life or have milder neurological symptoms may live into adulthood.

Inheritance:

AGS has various inheritance patterns. Most cases, caused by mutations in the ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 genes, follow an autosomal recessive inheritance. This means both copies of the gene in each cell must have mutations for the condition to develop. Parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but usually do not show any symptoms. When AGS is caused by mutations in the IFIH1 gene or by certain severe mutations in the TREX1 or ADAR gene, it follows an autosomal dominant pattern. This means only one copy of the altered gene in each cell is enough to cause the disorder. These cases often arise from new gene mutations and occur in individuals with no family history of AGS.