Aicardi-Goutieres Syndrome (AGS) is a disorder of the immune system that most strikingly affects the brain.
Cooper at 3 years old with AGS7. Meet Cooper.
AGS primarily affects the developing brain and immune system of infants and toddlers, most often resulting in profound developmental delays, lifelong physical impairments, and persistent neurological changes. Most newborns with AGS do not display any signs or symptoms at birth but go on to develop severe brain dysfunction within the first two years of life, often after months of typical development and good health. In AGS, the body’s immune system turns on itself in a destructive way, targeting myelin, or white matter in the brain, and significantly impacting the nervous system. Additionally, 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. Because the signs and symptoms of the disorder are similar to those of a congenital viral infection, AGS is extremely difficult to diagnose. In order to manage severe progression and improve quality of life for affected individuals and their families, both early identification and timely access to emerging treatments are essential interventions.
SYMPTOMS
Most people with Aicardi-Goutieres syndrome have profound disability. They also have significant neuromuscular problems including muscle stiffness (spasticity); involuntary tensing of various muscles (dystonia), especially those in the arms; and weak muscle tone (hypotonia) in the trunk.
About 40 percent of people with Aicardi-Goutieres syndrome have painful, itchy skin lesions, usually on the fingers, toes, and ears. These puffy, red lesions, which are called chilblains, are caused by inflammation of small blood vessels. They may be brought on or made worse by exposure to cold. Vision problems, like cortical visual impairment (CVI), joint stiffness, and mouth ulcers may also occur in this disorder.
As a result of the severe neurological problems usually associated with Aicardi-Goutieres syndrome, some 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.
16 year-old Jackson had AGS 7. Meet Jackson
Current Mutations
There are currently nine genes identified in which mutations give rise to AGS. They are labeled as such: AGS 1-9.
The mutations for AGS 1-5 are inherited while the mutations for AGS 6-7 can be spontaneous events. Regarding prenatal testing, there are parents who, once they've tested positive as a carrier for a genetic mutation of AGS 1-5, have undergone extensive preimplantation genetic diagnostic testing through IVF to determine whether there are affected embryos.
Specific genetic information about each AGS associated gene can be found on OMIM.
AGS1 TREX1
AGS2 RNASEH2B
AGS3 RNASEH2C
AGS4 RNASEH2A
AGS5 SAMHD1
AGS6 ADAR
AGS7 IFIH1
AGS8 LSM11
AGS9 RNU7-1
The First Year
Within the first year of life most individuals with Aicardi-Goutieres syndrome experience an episode of severe brain dysfunction (encephalopathy), typically lasting for several months. During this phase of the disorder, affected babies are usually extremely irritable and do not feed well. They may develop intermittent fevers in the absence of infection (sterile pyrexias) and may have seizures. They stop developing new skills and begin losing skills they had already acquired (developmental regression). Growth of the brain and skull slows down, resulting in 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, which 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.
The encephalopathic phase
The encephalopathic phase of Aicardi-Goutieres syndrome leaves behind permanent neurological damage that is usually severe. Medical imaging reveals deterioration of white matter in the brain (leukodystrophy). White matter consists of nerve fibers covered by myelin, which is a substance that insulates and protects nerves. Affected individuals also have abnormal deposits of calcium (calcification) in the brain.