Aicardi-Goutières Syndrome

AGS mainly impacts the developing brain and immune system of infants and toddlers, typically leading to profound developmental delays, lifelong physical disabilities, and persistent neurological changes. Most newborns with AGS show no signs or symptoms at birth, but develop severe brain dysfunction within the first two years of life, often after months of normal development and good health.

​

In AGS, the body’s immune system turns destructively against itself, attacking the myelin or white matter in the brain and significantly affecting the nervous system. Additionally, the immune dysfunction associated with AGS can affect many other organs in the body, sometimes in life-threatening ways. These may include the lungs, liver, heart, skin, blood cells, and kidneys.

​

Because the signs and symptoms of the disorder resemble those of a congenital viral infection, AGS is extremely difficult to diagnose. To manage severe progression and improve the quality of life of affected individuals and their families, both early identification and timely access to emerging treatments are essential.

​

 

SYMPTOMS

​

Most people with Aicardi-Goutières syndrome have a severe disability. They also experience significant neuromuscular problems, including muscle stiffness (spasticity); involuntary muscle contractions (dystonia), especially in the arms; and weak muscle tone (hypotonia) in the torso. About 40 percent of individuals with AGS develop painful, itchy skin lesions, typically on the fingers, toes, and ears. These swollen, red lesions—called chilblains—are caused by inflammation of small blood vessels and may be triggered or worsened by exposure to cold. Vision problems, such as cortical visual impairment (CVI), joint stiffness, and mouth ulcers may also occur. Due to the severe neurological complications associated with AGS, some individuals do not survive childhood. However, those with later onset and milder neurological symptoms may live into adulthood.

 

CURRENT MUTATIONS

​

Currently, nine genes have been identified in which mutations lead to AGS. These are labeled AGS 1–9.

Mutations for AGS 1–5 are inherited, while mutations for AGS 6–7 may occur spontaneously. In terms of prenatal testing, some parents who test positive as carriers of AGS 1–5 mutations undergo advanced preimplantation genetic diagnosis (PGD) through IVF to determine whether embryos are affected.

​

AGS1 TREX1

AGS2 RNASEH2B

AGS3 RNASEH2C

AGS4 RNASEH2A

AGS5 SAMHD1

AGS6 ADAR

AGS7 IFIH1

AGS8 LSM11

AGS9 RNU7-1

 

THE FIRST YEAR

​

Within the first year of life, most individuals with AGS experience an episode of severe brain dysfunction (encephalopathy), typically lasting several months. During this phase, affected infants are often extremely irritable and feed poorly. They may develop intermittent fevers without infection (sterile pyrexia) and may experience seizures. They stop developing new skills and begin to lose previously acquired abilities (developmental regression). Brain and skull growth slows, resulting in an abnormally small head size (microcephaly). During this stage, white blood cells and inflammatory molecules can be detected in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. These findings are consistent with inflammation and tissue damage in the central nervous system.

 

THE ENCEPHALOPATHIC PHASE

​

The encephalopathic phase of AGS causes permanent neurological damage, which is usually severe. Medical imaging reveals deterioration of the brain’s white matter (leukodystrophy). White matter consists of nerve fibers covered with myelin, a substance that insulates and protects nerves.

Affected individuals also show abnormal calcium deposits (calcifications) in the brain.

 

FREQUENCY

​

Aicardi-Goutières syndrome is a rare condition, estimated to occur in fewer than 1 in 100,000 children. The exact prevalence is unknown.

 

CAUSES

​

Mutations in several genes can cause Aicardi-Goutières syndrome. Some of these genes, including TREX1, RNASEH2A, RNASEH2B, and RNASEH2C, provide instructions for making nucleases—enzymes that help break down DNA and RNA molecules when they are no longer needed. These DNA and RNA fragments may be generated during processes such as transcription (the first step of protein production), DNA replication, DNA repair, apoptosis (cell death), and other cellular functions. Mutations in these genes may result in absent or impaired enzyme function, leading to the accumulation of unwanted DNA and RNA within cells. These molecules may be mistaken by the body as viral genetic material, triggering immune responses across multiple systems. This leads to encephalopathy, skin lesions, and other symptoms of AGS. Mutations in other genes, including SAMHD1, IFIH1, and ADAR, also contribute to AGS. These genes are involved in regulating the immune system. Mutations cause inappropriate activation of immune responses, leading to inflammatory damage in the brain, skin, and other organs.

 

INHERITANCE

​

Aicardi-Goutières syndrome can be inherited in different ways. In most cases—caused by mutations in ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1—the condition is inherited in an autosomal recessive pattern. This means both copies of the gene in each cell carry mutations. The parents typically carry one mutated gene each but do not show symptoms. When caused by mutations in the IFIH1 gene, or certain severe mutations in TREX1 or ADAR, AGS is inherited in an autosomal dominant pattern. This means one mutated copy of the gene is sufficient to cause the disorder. These dominant cases often result from new (de novo) mutations and may occur in individuals with no family history of the condition.