Years published: 2023
NORD gratefully acknowledges Zachary LeMense, MD candidate, Creighton University School of Medicine and Adeline Vanderver, MD, Pediatric Neurologist, Children’s Hospital of Philadelphia, for the preparation of this report.
Aicardi-Goutières syndrome (AGS) is a progressive disease of the brain (encephalopathy) that presents within the first year of life. Some of the signs of this syndrome are a small head (microcephaly), brain calcifications (basal ganglia and other locations), abnormalities in the white matter tracts of the brain, excess lymphocytes (a type of white blood cell) in the cerebrospinal fluid (CSF) and increased chemical messengers (interferon-alpha) made by the immune system in the CSF and the blood. The immune system does not function normally and excess interferon is produced. These problems are thought to lead to disease in AGS.
Some children present as early as the first few weeks of life, but often children present in the first few years of life, after an initial period of normal development. As the disease progresses, infants may demonstrate skin sores or bumps (chilblains) on the toes, fingers and ears as well as with other rashes. Other organs, including the eyes (glaucoma), thyroid (hypothyroidism), lungs (pulmonary hypertension), heart (cardiomyopathy), liver (autoimmune hepatitis), muscle (myopathy) and joints (arthropathy) may become involved. Some infants presenting early in life may have an enlarged liver and spleen (hepatosplenomegaly), elevated liver enzymes and a low platelet count (thrombocytopenia) or other abnormalities of the blood cells, all of which may mimic a congenital infection.
Changes (pathogenic variants or mutations) in several different genes are known to cause AGS. AGS is most commonly inherited in an autosomal recessive fashion (mother and father are both carriers for the harmful gene variant), but the disease can also result from a de novo (new) gene variant in the child or from autosomal dominant inheritance from one parent.
AGS is a disease that affects the white matter of the brain (leukoencephalopathy) and may result in severe intellectual and physical disability. Some infants will present variably in the first few weeks of life with irritability, fever, abnormal muscle contractions (dystonia), microcephaly, basal ganglia calcifications, white matter tract abnormalities, CSF lymphocytosis and elevated CSF interferon-alpha. However, infants and young children may also present after a period of normal development, in some cases following a period of unexplained fever or rash due to inflammation. As the disease progresses, individuals with AGS may present with chilblain skin lesions, most commonly on the fingers, toes and ears, or with other atypical rashes. Some infants with AGS may present with symptoms resembling a congenital infection which should be ruled out prior to diagnosis. These signs include hepatosplenomegaly, elevated liver enzymes and thrombocytopenia (low platelets). Such infections include toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV or Zika virus infections. Multiple organ systems may become involved including the eyes (glaucoma and uveitis), endocrine (hypothyroidism, diabetes, diabetes insipidus, growth delay), cardiovascular (cardiomyopathy, pulmonary hypertension and other abnormalities), gastrointestinal (autoimmune hepatitis, inflammatory bowel disease), musculoskeletal (myopathy, neuropathy, arthropathy), renal (renal insufficiency) and hematologic (thrombocytopenia, anemia, leukopenia). Due to the significant neurologic involvement of AGS, affected individuals typically display muscular spasticity and dystonia, decreased muscular tone of their trunk (truncal hypotonia), poor head control, and seizures.
Two other clinical manifestations have been noted for specific subtypes of AGS. In patients who have a pathogenic variant of the SAMHD1 gene, intracranial large-vessel disease and aneurysms have been noted. This can lead to blood vessel narrowing (stenosis) in the brain, causing decreased blood flow to certain brain regions. It can also cause bulges (aneurysms) to form in vessels due to weakness in their walls, which can rupture and cause bleeding (hemorrhage) into the brain. In patients who have a pathogenic variant of the ADAR1 gene, refractory four-limb dystonia has been noted. This manifestation typically begins between the ages of eight months and five years and presents as abnormal postures or movements of all four limbs.
Milder forms of AGS have also been described in patients with atypical pathogenic gene variants.
Aicardi-Goutières syndrome is caused by changes (pathogenic variants or mutations) in several different genes including TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1, IFIH, LSM11 and RNU7-1. These variants disrupt cellular signaling and production of immune-related molecules (interferons). AGS is characterized as an “interferonopathy,” meaning that it is a disease related to dysregulated or dysfunctional interferons (interferon alpha in this case).
In certain forms of AGS, the inherited gene variants result in an inability to degrade old host RNA and DNA. The build-up of RNA and DNA leads to a response in the person’s body to attempt to clear the accumulation. Cellular proteins are activated by interferon alpha to engage cellular anti-viral defense mechanisms. The immune response that is activated then tries to clear a viral pathogen that does not exist in the person. The resulting inflammation leads to the characteristic signs and symptoms that were discussed earlier.
Patients with variants in LSM11 and RNU7-1 have shown that histones, key parts of DNA, are essential in preventing the immune system from attacking its own DNA. In these forms of AGS, the variants lead to abnormalities in the processing and structure of histones, which then prevents them from performing one of their functions of suppressing the immune system from attacking its own DNA.
Usually, AGS is inherited in an autosomal recessive fashion; however, certain subtypes have been found to be inherited in an autosomal dominant manner.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause the disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
The prevalence of AGS is unknown. Studies suggest that AGS is one of the most common genetic disorders affecting the white matter of the brain.
Aicardi-Goutières syndrome can be diagnosed when there is suspicion based on clinical features in addition to characteristic neuroimaging and laboratory findings. Neuroradiographic findings best visualized by CT scan or MRI include calcifications of the basal ganglia, particularly the putamen, globus pallidus and thalamus. Other neurologic findings include often diffuse white-matter changes and cerebral atrophy. Laboratory findings include characteristic features seen in the peripheral blood and cerebral spinal fluid (CSF). In the peripheral blood, abnormalities of the blood cells and elevated liver enzymes may be noted. In the CSF, leukocytosis (elevated white blood cell count), increased interferon-alpha and increased concentration of neopterin may all be found. Finally, the diagnosis can also be established through genetic and molecular testing. These tests include serial single-gene tests, a multigene panel and comprehensive genomic testing. These tests can search for pathogenic variants in genes known to cause AGS.
A multidisciplinary approach to the support and care of affected individuals is necessary.
There are no definitive or curative treatments for Aicardi-Goutières syndrome. However, recent medical advances have shown janus kinase inhibitors to be useful in suppressing interferon activation in individuals with AGS. In particular, baricitinib has been shown to help individuals with AGS achieve new milestones and develop new skills. Further management of AGS involves diagnosing the extent of symptoms and assessing the individual needs of the affected infant. This involves evaluating nutritional status, initiating chest physiotherapy if respiratory complications arise and monitoring the various organ systems that may become affected.
Genetic counseling is recommended for families with an affected child.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website. For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
International Aicardi-Goutières Syndrome Association (IAGSA)
United Leukodystrophy Foundation (ULF)
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