Aicardi-Goutieres Syndrome

What Causes Aicardi-Goutieres Syndrome?

Mutations in a child’s genes cause AGS. The mutated genes involved in AGS often regulate the production of specific enzymes in the body’s cells. These enzymes help break down waste molecules when they’re no longer needed by the cells. Scientists think the lack of enzymes caused by the gene mutations results in the accumulation of waste molecules in the cells. The accumulated waste may then be mistaken by the body’s immune system for an infectious invader, causing the immune system to attack otherwise healthy cells in the brain and skin.

Sometimes AGS seems to be caused by mutations in genes that regulate proteins vital to the immune system. These mutations may cause the immune system to activate and inappropriately attack healthy cells.

Is Aicardi-Goutieres Syndrome Hereditary?

In many cases, the genetic mutations that cause AGS are inherited. How the mutations cause the disorder varies depending on which type of mutation is involved.

In most cases, mutations are passed from parent to child in an autosomal recessive pattern. That means that each of the child’s parents carries one copy of the gene. Because the parents only have one copy of the gene, they do not develop the syndrome. However, if both parents pass on the mutated gene, the child will have two copies of the mutation and develop AGS.

With certain specific mutations, the syndrome occurs in an autosomal dominant pattern. In these cases, one copy of the mutated gene causes the disorder. These cases seem to come from uninherited mutations, and the child’s family has no history of AGS.

How Is Aicardi-Goutieres Syndrome Detected?

Babies born with AGS do not usually show signs of the disorder at birth. Early signs of the condition, which may start weeks or months after birth, are typically behavioral. The baby is usually very irritable and has trouble feeding. Symptoms such as fever and seizures mimic those of a viral infection. As the disorder affects the brain, developmental symptoms emerge. Babies do not meet developmental milestones when they should, and they may lose developmental skills that they’ve already achieved.

How Is Aicardi-Goutieres Syndrome Diagnosed?

Diagnosis of AGS is challenging because the early signs of the disorder mimic the symptoms of a viral or other infection. Doctors may suspect AGS if they determine that no infection is present despite the symptoms. Diagnostic steps used to confirm AGS include:

• Magnetic resonance imaging (MRI). MRI scans can show brain abnormalities characteristic of AGS.
• Lumbar puncture (spinal tap). This test examines a sample of the baby’s cerebrospinal fluid (CSF). If the CSF contains an elevated level of infection-fighting immune system cells, but there is no infection present, AGS could be the cause.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Aicardi-Goutieres Syndrome Treated?

AGS has no cure. No treatment will reverse or stop the symptoms caused by the disorder’s neurological damage. Treatment is supportive, meaning that it is focused on controlling symptoms and preventing complications. Aicardi Goutieres syndrome treatments may include:

• Feeding assistance
• Respiratory therapy
• Anti-seizure medications
• Monitoring for secondary conditions such as glaucoma, diabetes, scoliosis, or thyroid dysfunction

How Does Aicardi-Goutieres Syndrome Progress?

The effects of AGS vary depending on the severity of the disorder. The early on-set form of AGS, which affects about 20% of all children with AGS, is most likely to be fatal in childhood.

Abnormal brain development usually occurs in the first year and lasts several months. Damage done during this time causes life-long neurological impairments. Intellectual impairments are generally severe. Muscle stiffness, spasms, vision impairment, skin lesions, and weak muscle tone in the torso are also often continuing problems.

How Is Aicardi-Goutieres Syndrome Prevented?

There is no known way to prevent AGS. People with a family history of the disorder who may be carriers of the syndrome-causing gene mutations may want to seek genetic counseling before having children. A genetic counselor can help parents assess their risk of passing the mutations on to their children.

Aicardi-Goutieres Syndrome Caregiver Tips

You can do some things to help your child and your family live with AGS.

• Learn about AGS. New research is being conducted, and that means that scientists are learning more about AGS every day. The more you know about the disorder, the more likely you are to be able to cope. You’ll be able to do your best to improve your child’s quality of life if you understand as much as possible about the challenges they face.
• Find support. AGS is a rare disease, and it can be very helpful to find others who understand what you and your child are going through. Online support groups can help you find information, answers to your questions and concerns, and a feeling of community.

Aicardi-Goutieres Syndrome Brain Science

Some researchers are exploring the possibility that existing antiretroviral medications may be effective at treating AGS. They believe that AGS occurs when the body’s immune system mistakes normal cell materials for foreign viruses. The body then produces an immune response to kill the perceived viruses and, as a result, kills or damages normal, healthy cells. Antiretroviral drugs such as those used to treat HIV may control the inappropriate immune response and thereby decrease or prevent the neurological damage caused by AGS. Upcoming research will test the effectiveness of the drugs Tenofovir (TDF) and Emtricitabine (FTC) in AGS cases.

Aicardi-Goutieres Syndrome Research

Title: Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome (RTI in AGS)

Stage: Not Yet Recruiting

Principal Investigator: Adeline Vanderver, MD 

Children’s Hospital of Philadelphia

Philadelphia, PA

The investigators propose that a trial to assess the proof of principle that antiretroviral therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease endogenous retroelement accumulation and alter interferon signaling in Aicardi Goutières Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro and animal data. Additionally, this trial will further the investigators’ understanding of this disorder, measuring for the first time retroelements in human participants, exploring the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response, as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with more clinically relevant outcomes.

Title: Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome (AGS-RTI)

Stage: Recruiting

Principal Investigator: Yanick Crow 

University of Edinburgh

Edinburgh, UK

Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Typically humans only produce interferon when they are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code in these individuals, it is believed that the cells in the body are fooled into thinking that the person’s own DNA is viral – that is to say, there is a confusion in telling ‘self’ from ‘non-self.’

A large amount of our own DNA is composed of ancient virus (called ‘endogenous retrovirus’ and sometimes also referred to as ‘junk DNA’) that have been absorbed into our genetic material over millions of years. These endogenous retroviruses can still act like a virus coming from outside of the body so that they need to be controlled. The Investigators have wondered if the genetic changes causing AGS mean that these normal control mechanisms don’t work. If that is true, the endogenous retroviruses could start to make copies of themselves which might be recognized by our immune system as ‘non-self’ (‘foreign,’ i.e., viral), leading to the continuous production of interferon, which then damages the cells in our body.

Since humans cannot repair the genetic code in every cell, the investigators wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, it is not treating HIV-1, but the investigators wonder if the same drugs might control endogenous retroviruses that are driving interferon production. Indeed, in a recently completed study, the investigators gathered early information to suggest that treatment of patients with AGS with RTIs for one year did lead to a reduction in interferon, with levels increasing again when we stopped the drugs.

The current study will involve three treatment arms and an assessment of interferon status and other markers that may yield information about AGS and about how RTIs may work in the treatment of AGS.

This study is of potential importance for patients with AGS and their families since there are no licensed drugs for this disorder at present. Scientifically, the project will be of considerable interest if the results support the possibility that ‘junk DNA’ can be associated with human disease. RTIs are very safe drugs that have been used in millions of people with HIV-1 around the world. If the results turn out to be convincing, the investigators believe that it might be worth thinking about using RTIs to treat other diseases that have also been linked to increased levels of type I interferon, for example, the relatively common immune condition called systemic lupus erythematosus.