Aicardi-Goutières Syndrome

Aicardi-Goutières syndrome is a rare inherited disease that primarily attacks the brain’s white matter, triggering an immune system response that mistakenly turns against the body itself, leading to serious neurological problems that can appear at birth or develop within the first months of life.

Table of contents

• What is Aicardi-Goutières syndrome?
• Other names for this condition
• Two forms of the syndrome
• Signs and symptoms
• What causes AGS
• Who is more likely to get it
• How is it diagnosed
• Treatment options

What is Aicardi-Goutières syndrome?

Aicardi-Goutières syndrome (AGS) is a rare inherited disease that affects the brain, immune system, and the skin^[1]. The condition primarily impacts the brain and spinal cord, and is considered a type of leukodystrophy—a group of conditions that affect the white matter of the brain^[3]. White matter is made up of nerve fibers coated in myelin, which protects the nerves and allows them to rapidly send and receive information^[1].

In AGS, the body’s immune system mistakenly turns on itself and targets this white matter in the brain. Changes in specific genes cause an increase in the production of a chemical called interferon^[1]. This loss of white matter causes permanent brain damage that can lead to intellectual or physical disabilities^[1]. Most children with AGS end up with mild to severe intellectual or physical impairments^[3].

AGS is sometimes referred to as a “mimic of congenital infection” because affected newborns can show features that look like a viral infection present at birth, even though no actual infection is found^[2].

pseudotoxoplasmosis syndrome, encephalopathy with basal ganglia calcification, Cree encephalitis

Other names for this condition

AGS is also known by several other medical names, including pseudotoxoplasmosis syndrome, encephalopathy with basal ganglia calcification, and Cree encephalitis^[1]. It is important to note that AGS is completely different from Aicardi syndrome, which is a separate condition where the structure that connects the two sides of the brain (called the corpus callosum) is partly or completely missing^[1].

Two forms of the syndrome

There are two forms of AGS: an early-onset form and a later-onset form^[1]. The two types are distinguished by the severity of features and the age at which they begin^[2].

Early-onset AGS happens at birth and is the more serious form, often leading to permanent damage to brain function and severe lifelong disabilities^[1]. In about 20 percent of cases, the early-onset form of AGS begins before birth. Slow growth and brain abnormalities, especially brain calcification, may be seen on ultrasound imaging during pregnancy. These individuals have the most severe neurological problems and the highest risk for early death^[2]. About one third of such early presenting cases, most frequently in association with mutations in a specific gene, die in early childhood^[4].

Children with later-onset AGS develop and behave normally for the first few weeks or months of life^[1]. People with the later-onset form typically have normal development in infancy, with brain problems typically occurring after 1 year of age^[2]. Symptoms of later-onset AGS are not as severe as early-onset AGS. They may last for several months and then usually lessen and stabilize. But later-onset AGS may still leave neurological problems that never go away completely^[1].

Signs and symptoms

The symptoms of AGS vary depending on which form a child has and when it appears.

Early-onset AGS signs and symptoms

Infants with early-onset AGS have jittery behavior and poor feeding ability from birth^[3]. Early-onset AGS signs and symptoms include^[1]:

• Rapid, involuntary twitching of the arms, legs, and face
• Trouble eating or feeding
• Brain, liver, and spleen problems at birth
• Smaller head size (microcephaly)
• Buildup of calcium in the brain (calcification)
• Liver, brain, and spinal cord inflammation
• Seizures
• Skin rashes

Affected infants can experience severe brain dysfunction within the first months of life. This phase of the disorder can last for weeks or months. Affected infants stop developing new skills and begin losing skills they had already acquired^[2]. Affected babies are usually extremely irritable and do not feed well. They also have muscle stiffness (spasticity), involuntary tensing of various muscles (dystonia), and weak muscle tone (hypotonia)^[2].

Some newborns have a combination of features that include an enlarged liver and spleen, elevated blood levels of liver enzymes, and a shortage of blood cells called platelets that are needed for normal blood clotting^[2]. They may develop intermittent fevers in the absence of infection^[2]. They can have vision problems including vision loss and increased pressure in the eye (glaucoma)^[2].

Later-onset AGS signs and symptoms

Later-onset AGS signs and symptoms include^[1]:

• Weak or stiffened muscles (spasticity)
• Involuntary muscle contractions (dystonia)
• Irritability or inconsolable crying
• Intermittent, unexplained fever with no infection
• A decline in head growth
• Developmental delays
• Seizures
• Skin problems known as chilblains (rash, lesions, or swelling on fingers, toes, and ears that worsen in cold, wet weather)
• Vision problems
• Feeding problems
• Lack of blood cells (platelets) needed for normal blood clotting

About 40 percent of people with the early-onset form of AGS develop a skin problem called chilblains. Chilblains are painful, itchy skin lesions that are puffy and red, and they usually appear on the fingers, toes, nose, and ears. They are caused by inflammation of small blood vessels and may be brought on or made worse by exposure to cold temperatures^[2].

As more cases have been identified, it has become apparent that the disease is not always severe. Rare individuals with disease-causing mutations can be minimally affected (perhaps only with chilblains) and are in mainstream education, and even affected siblings within a family can show marked differences in severity^[4].

What causes AGS

AGS is caused by variants (also called mutations) in a small group of specific genes^[1]. Changes in these genes are thought to trigger an immune response that leads to the symptoms of AGS^[3]. These variants cause an increase in the production of a chemical called interferon^[1].

Nine different genes have been identified to date that can cause AGS when mutated: TREX1, RNASEH2A, RNASEH2B, RNASEH2C (which together encode an enzyme complex), SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1^[4][9]. These genes encode proteins involved in either processing or sensing nucleic acids (the building blocks of DNA and RNA), and mutations in these genes result in chronically enhanced activation of type I interferon signaling^[13].

Who is more likely to get it

AGS is autosomal, which means the gene variants that cause it are on non-sex chromosomes. It can pass down in families in different ways^[1].

In most cases, AGS is inherited in an autosomal recessive pattern. This means that both parents of a child with AGS must carry a single copy of the defective gene responsible for the disease^[5]. Parents do not have any symptoms of disease, but with every child they have together, there is a one in four chance that the baby will receive two copies of the defective gene and inherit AGS^[6].

However, autosomal dominant mutations in ADAR1, TREX1, and IFIH1 have also been described^[9]. This means that in some cases, only one parent needs to carry the mutation for a child to develop AGS.

AGS occurs in all populations worldwide, although it is almost certainly under-diagnosed^[4]. To date, at least 400 cases of AGS are known^[4].

How is it diagnosed

Aicardi-Goutières syndrome is difficult to diagnose, as many of the symptoms overlap with other disorders^[5]. Diagnosis is made based on the clinical symptoms of the disease, as well as characteristic brain abnormalities that can be seen in an MRI brain scan^[6].

Medical imaging reveals loss of white matter in the brain (leukodystrophy)^[2]. Growth of the brain and skull slows down, resulting in an abnormally small head size. Affected individuals may have abnormal deposits of calcium (calcification) in the brain^[2].

A sample of the cerebrospinal fluid (CSF)—the fluid that surrounds the brain and spinal cord—will be taken from a spinal tap. This fluid can then be tested for increased levels of a certain type of cell of the immune system (lymphocytes), a condition known as chronic lymphocytosis^[5]. These cells are normally only elevated during infection, so the combination of lymphocytosis combined with a lack of evidence of infection can be used as an indicator of AGS^[6]. In some affected newborns, white blood cells, interferon proteins, and other immune system molecules can be detected in the cerebrospinal fluid^[2].

Genetic testing can confirm the diagnosis by identifying mutations in one of the genes known to cause AGS^[6].

Treatment options

Currently, there is no cure for AGS, and treatment focuses on managing symptoms and supporting quality of life^[8]. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple complications^[9].

Symptom management

Depending upon the severity of symptoms, children may require chest physiotherapy and treatment for respiratory complications^[6]. Treatment may include medications to control seizures, manage spasticity, and address feeding difficulties. Some children may need specialized care for vision problems, including glaucoma^[2].

Emerging therapies

Several new treatment approaches are being explored based on understanding the disease mechanism. Since AGS is characterized by excessive interferon production, blocking this immune response is a logical therapeutic strategy.

Janus kinase inhibitors (JAKis), such as ruxolitinib, are drugs that block interferon signaling. These have been used in several patients with AGS, with some reports showing improvement in skin rash and developmental gains^[8]. However, experiences have been mixed, with some patients showing inflammation that was not fully controlled by these medications^[13].

Other treatments being explored include tocilizumab, a medication that blocks a different part of the immune system. In at least one case report, this medication helped reduce inflammation that was not fully controlled by ruxolitinib^[13].

An experimental approach using reverse transcriptase inhibitors (a combination of three drugs: abacavir, zidovudine, and lamivudine) was tested in patients with certain types of AGS mutations, but this treatment did not show obvious clinical benefit^[8].

Research from 2024 reported promising results from a new RNA-targeted therapy using antisense oligonucleotides that target the interferon receptor. In mouse studies, this therapy effectively halted the progression of AGS, reducing inflammation and neuronal damage while restoring the integrity of the blood-brain barrier^[11]. This research lays the groundwork for potential future human trials.

New drugs specifically targeting the interferon pathway may bring new hope to AGS patients^[9]. Clinical trials and research studies continue to explore potential treatments for AGS.