What is Aicardi-Goutières Syndrome?

Morgan - Aicardi-Goutières Syndrome (AGS)

Aicardi-Goutières Syndrome, a form of Leukodystrophy commonly known as AGS, is a genetic disorder that mainly affects the brain, immune system and skin. AGS is one of more than 50 known Leukodystrophies. Leukodystrophies are a group of rare, progressive, genetic diseases that affect the brain, spinal cord and often the peripheral nerves.

Photo: Morgan Malfara, 10/22/97, AGS

Each type of Leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter, or myelin, of the brain. The myelin sheath is the protective covering of the nerves. The nervous system cannot function normally without myelin. Each type of Leukodystrophy affects a different part of the myelin sheath, resulting in a range of neurological problems.

The mutations of seven different genes are associated with AGS. These seven genes include TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1.

Aicardi-Goutières Syndrome is listed as a rare disease by the Office of Rare Diseases of the National Institutes of Health (NIH). Aicardi-Goutières Syndrome affects less than 200,000 people in the US population. This neurological disease occurs in all populations worldwide, although it is almost certainly under-diagnosed. As of 2014, roughly 400 cases of AGS were known, and just over 120 cases had been reported in medical literature so far.

How does AGS affect the individual?

Usually within the first year of life, individuals affected by Aicardi-Goutières Syndrome (AGS) experience an episode of severe brain dysfunction (encephalopathy). This can typically last for several months. During this phase of the disorder, symptoms can include inconsolable crying, extreme irritability and feeding difficulties. Affected individuals may develop intermittent fevers in the absence of infection (sterile pyrexias) and may experience seizures. Over time, individuals with AGS slowly lose their ability to function due to the loss of previously attained milestones.

Many affected by AGS also show evidence of slowed growth of the brain and skull. As a result, many develop an abnormally small head size (microcephaly). In this phase of the disorder, white blood cells and molecules associated with inflammation can be detected in the cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord (central nervous system). These abnormal findings are consistent with inflammation and tissue damage in the central nervous system.

Symptoms of AGS

The encephalopathic phase of Aicardi-Goutières Syndrome leaves permanent neurological damage that is usually severe. Medical imaging reveals deterioration of white matter in the brain (leukodystrophy). Most people with AGS have profound intellectual disability. They also have significant neuromuscular problems including muscle stiffness (spasticity), involuntary tensing of various muscles (dystonia) especially in the arms, and weak muscle tone (hypotonia) in the trunk.

About 40 percent of people with AGS have painful, itchy skin lesions called chilblains. Chilblains usually develop on the fingers, toes, and ears. These puffy, red lesions are caused by inflammation of small blood vessels. They may be brought on or made worse by exposure to cold. Vision problems, joint stiffness, skin mottling and mouth ulcers may also occur with this disorder.

As a result of the severe neurological problems usually associated with AGS, most people with this disorder do not survive past childhood. However, some affected individuals who have later onset and milder neurological problems may live into adulthood.

Although there is currently no cure for AGS, the symptoms can be managed to ensure the best possible outcomes. With proactive, comprehensive medical care the symptoms of ALD can be managed and give the individual the best quality of life possible.

How do you get AGS?

AGS is a genetic, or inherited, disorder. It is also classified as an autosomal recessive disorder. This means that if both parents are carriers of the disease, each child they conceive will have a 1 in 4 chance of developing AGS.

When both parents are carriers of a specific mutated gene, such as those for AGS, their children have a 25% chance of being affected by the disease, a 25% chance of neither being a carrier nor affected, and a 50% chance of being an unaffected carrier, just like their parents. See illustration below.

AGS Carrier Model

Could other children in the family also have AGS?

If both parents are carriers of AGS, each child has a 1 in 4 chance of being affected. To determine if other children in the family are affected by or carriers of AGS, it is best to consult with your genetic counselor or your child’s physician.

How is AGS diagnosed?

AGS is difficult to diagnose since many of the symptoms are similar to those of other disorders. Diagnosis is made based on the clinical symptoms of the disease. Characteristic brain abnormalities that can be seen in an MRI brain scan can also help in diagnosis.

Cerebrospinal fluid (CSF), taken using a “spinal tap,” can also be tested for increased levels of a specific immune system cell (a lymphocyte), which indicates a condition known as chronic lymphocytosis. These cells are normally only elevated during infection, so that lymphocytosis without evidence of infection can be used as an indicator of AGS. CSF may also be tested for elevated levels of a substance known as interferon-gamma, which can also support a diagnosis of AGS.

What are the different forms of AGS?

There are two forms of the syndrome: an early-onset form that is severe, and a late-onset form that has less impact upon neurological function. Most newborns with Aicardi-Goutières Syndrome do not show any signs or symptoms of the disorder at birth.

No matter what form of AGS an individual is diagnosed with, optimal care is of timely importance. The Leukodystrophy Care Network (LCN) was established to provide individuals with the best quality of care at specialized centers across the country.

For more information and to find a Leukodystrophy Care Center nearest you, please visit the Leukodystrophy Care Network page.

Early-Onset Form

The early-onset form affects about 20 percent of babies affected by AGS. They are born with a combination of features that include an enlarged liver and spleen (hepatosplenomegaly), elevated blood levels of liver enzymes, a decrease in blood platelets (thrombocytopenia), and abnormal neurological responses. Their jittery behavior and poor feeding ability mimic a congenital viral infection.

Later-Onset Form

Babies with later-onset AGS begin having symptoms after the first weeks or months of normal development, which appear as a progressive decline in head growth, weak or stiffened muscles (spasticity), and cognitive and developmental delays that range from moderate to severe.

Is there a treatment for AGS?

Although there is currently no cure for AGS, symptomatic treatment is beneficial.

With proactive, comprehensive medical care, affected individuals can avoid unnecessary suffering and complications to have the best quality of life possible. For more information, visit the Leukodystrophy Care Network page.

Depending upon the severity of symptoms, children may require chest physiotherapy and treatment for respiratory complications. To ensure adequate nutrition and caloric intake, some infants may require special accommodations for diet and feeding.

Seizures may be managed with standard anticonvulsant medications. Children should be monitored for evidence of glaucoma in the first few months of life, and later for evidence of scoliosis, diabetes, and underactive thyroid.

There are some clinical trials going on for Aicardi-Goutières Syndrome aimed at finding new methods for treating and ultimately preventing or curing AGS. To learn more click here to see a list of clinical trials for AGS.

Additional Resources for Families

Leukodystrophy Care Network
Hunter’s Hope Foundation – Family Care
Hunter James Kelly Research Institute
Duke Children’s Hospital: Bone Marrow and Stem Cell Transplantation
Genetics Home Reference
United Leukodystrophy Foundation
AGS Facebook Group

Additional Resources for Medical Professionals

Genetic and Rare Diseases Information Center: AGS
Genetics Home Reference

A Special Thank You

Thank you to Kristen Malfara from The M.O.R.G.A.N. Project for the content provided on this page.