Aicardi-Goutières syndrome

Aicardi-Goutières syndrome is a disorder with variable signs and symptoms, but it primarily affects the brain, the immune system, and the skin.

Aicardi-Goutières syndrome is often divided into two types, which are distinguished by the severity of features and the age at which they begin: the early-onset form (sometimes called the classic form) and the later-onset form. 

Individuals with the early-onset form of Aicardi-Goutières syndrome can experience severe brain dysfunction (encephalopathy) within the first months of life. This encephalopathic phase of the disorder can last for weeks or months. Affected infants stop developing new skills and begin losing skills they had already acquired (developmental regression). Infants with this form can have seizures. Medical imaging reveals loss of white matter in the brain (leukodystrophy). White matter consists of nerve cells covered by myelin, which is a substance that protects nerves and allows them to rapidly transmit nerve impulses. Growth of the brain and skull slows down, resulting in an abnormally small head size (microcephaly). Affected individuals may have abnormal deposits of calcium (calcification) in the brain. As a result of this neurological damage, most people with Aicardi-Goutières syndrome have profound intellectual disabilities.

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). They can have vision problems including vision loss and increased pressure in the eye (glaucoma).

Some newborns have a combination of features that include an enlarged liver and spleen (hepatosplenomegaly), elevated blood levels of liver enzymes, and a shortage of blood cells called platelets that are needed for normal blood clotting (thrombocytopenia). They may develop intermittent fevers in the absence of infection (sterile pyrexias). While this combination of signs and symptoms is typically associated with the immune system's response to a viral infection that is present at birth (congenital), no actual infection is found in these infants. For this reason, Aicardi-Goutières syndrome is sometimes referred to as a "mimic of congenital infection."

In some affected newborns, white blood cells, interferon proteins, and other immune system molecules can be detected in the cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord (central nervous system). These findings are consistent with inflammation and tissue damage in the central nervous system.

About 40 percent of people with the early-onset form of Aicardi-Goutières syndrome 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. 

In about 20 percent of cases, the early-onset form of Aicardi-Goutières syndrome begins prenatally. Slow growth (intrauterine growth retardation) and brain abnormalities, especially brain calcification, may be seen on ultrasound imaging. These individuals have the most severe neurological problems and the highest risk for early death.

People with the later-onset form of Aicardi-Goutières syndrome typically have normal development in infancy. In these individuals, encephalopathy typically occurs after 1 year of age. Similar to those with the early-onset form, babies with the later-onset form experience irritability, poor feeding, and sterile pyrexias. Over time, affected individuals show developmental delays and regression. They may also have spasticity and hypotonia, and the growth of the brain and head may slow leading to microcephaly. The health and developmental problems in people with the later-onset form are typically not as severe as those in individuals with the early-onset form, though the severity can vary among affected individuals.

As a result of the severe neurological problems that are usually associated with Aicardi-Goutières syndrome, most people with this disorder do not survive past childhood. However, some affected individuals with the later-onset form of the condition and milder neurological problems can live into adolescence or adulthood.