What is Aicardi-Goutières syndrome?

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder that affects the brain, spinal cord and immune system. It is a type of leukodystrophy, a group of conditions that affect the white matter of the brain. These diseases damage the myelin sheath, which surrounds and protects the nerve cells in the brain and spinal cord and speeds transmission of messages between cells.

In AGS, the body’s immune system turns on itself in a destructive way, targeting this white matter (myelin). It is the loss of myelin that is responsible for the symptoms of AGS. Most children with AGS end up with mild to severe intellectual or physical impairments.

Causes of Aicardi-Goutières syndrome

AGS is caused by genetic variants in one or more of a small group of specific genes. Changes in these genes are thought to trigger an immune response that leads to the symptoms of AGS.

Signs and symptoms of AGS

There are two forms of AGS: an early-onset form and a later-onset form. Symptoms for both begin in infancy, but at different times.

Symptoms of early-onset AGS

Infants with early-onset AGS have jittery behavior and poor feeding ability from birth. They also have neurological and liver abnormalities at birth, which can be detected through imaging tests. Early-onset AGS is the more serious form of the syndrome. The symptoms can become more severe over time, and can include smaller head size (microcephaly), liver inflammation, seizures and skin rashes.

Loss of myelin in early-onset AGS often leads to permanent damage to brain function, and to severe lifelong intellectual and physical disabilities.

Symptoms of later-onset AGS

Babies with later-onset AGS develop and behave normally for their first few weeks or months. When symptoms appear, they may include:

• Intermittent, unexplained fever
• Irritability or inconsolable crying
• Skin problems, including chilblains (rash, lesions, or swelling on fingers, toes and ears that get worse in cold weather)
• Weak or stiffened muscles
• Feeding difficulties
• A decline in growth of the head
• Developmental delays
• Seizures

In later-onset AGS, these symptoms may last for several months. They then generally lessen and stabilize, but may leave persistent neurologic difficulties. Additionally, the immune dysfunction associated with AGS can affect many other organs of the body, sometimes in a life-threatening manner. This can include the lungs, the liver, the heart, the skin, blood cells and the kidneys.

Testing and diagnosis

Diagnosis of Aicardi-Goutières syndrome is made based on the physical symptoms, imaging of the brain, cerebrospinal fluid testing and the results of genetic tests.

• Magnetic resonance imaging (MRI) of the brain is a key diagnostic tool of AGS, as it can detect patterns in brain tissue that are characteristic of the disease. When testing for AGS, your child’s doctor will look for areas of calcium buildup (calcifications) as well as shrinking or unusually small (atrophy) areas of the brain.
• Genetic testing can identify changes in one of the genes known to be associated with AGS. This analysis is done from a blood, saliva, or cheek swab sample.
• Biochemical testing of blood or cerebrospinal fluid is important in diagnosing AGS. Testing looks for an increased level of immune system activity.

Treatment for Aicardi-Goutières syndrome

There is no currently approved treatment for AGS, but it is expected that decreasing the immune response will help with disease management. A new class of medications, Janus Kinase inhibitors, are thought to be helpful in managing AGS symptoms. While not FDA-approved for use in children with AGS, these drugs have been shown to be both safe and effective in clinical trials with AGS subjects. Speak with your doctor about whether this medication is appropriate for your child.

Some children with AGS need treatment for respiratory problems. Some need support with feeding, including therapy and special diets. Seizures may need to be managed with medication.

Children with AGS should also be monitored for:

• Signs of glaucoma (with a yearly test)
• Diabetes insipidus and underactive thyroid
• Specific problems with the heart and lungs, including pulmonary hypertension and inflammatory cardiomyopathy
• Problems with blood cells, in particular with platelets, which can cause an increased risk of bleeding
• Problems with the blood vessels of the brain
• Gradual problems with the bones such as scoliosis and dislocated joints, which may be associated with the motor problems in AGS

If detected, these conditions can all be treated by pediatric subspecialists.

Many children with AGS benefit from physical and speech therapy to combat weaknesses caused by neurological damage.