Aicardi-Goutières syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in several genes can cause Aicardi-Goutières syndrome. The TREX1, RNASEH2A, RNASEH2B, and RNASEH2C genes, provide instructions for making nucleases, which are enzymes that help break down molecules of DNA and its chemical cousin RNA when they are no longer needed. These DNA and RNA molecules or fragments may be generated during the first stage of protein production (transcription), the replication of cells' genetic material that occurs when the cell is preparing for cell division, DNA repair, cell death (apoptosis), and other processes. The nuclease enzymes produced by genes with variants may not function properly, and some variants may prevent the enzyme from being produced at all. Researchers suggest that this may result in the accumulation of unneeded DNA and RNA in cells. The unneeded DNA and RNA may be mistaken by cells for the genetic material of viral invaders. This triggers an immune system reaction that includes the abnormal activation of interferon proteins, which play a critical role in the immune system including regulating inflammation. The abnormal immune response results in encephalopathy, skin lesions, and other signs and symptoms of Aicardi-Goutières syndrome.

Variants in other genes, including the SAMHD1, IFIH1, and ADAR genes, can also cause Aicardi-Goutières syndrome. These genes provide instructions for making proteins that are involved in the immune system. Variants in these genes cause inappropriate activation of interferon proteins and the body's immune system, resulting in inflammatory damage to the brain, skin, and other body systems that leads to the characteristic features of Aicardi-Goutières syndrome.

Variants in other genes, including the RNU7-1 and LSM11 genes, can also cause Aicardi-Goutières syndrome. These genes provide instructions for making proteins that play a critical role in the cell cycle, DNA replication, and protein production. Variants in these genes disrupt these processes, causing DNA to build up in cells. This excessive amount of DNA may be mistaken for viral invaders, triggering activation of interferon proteins and other immune system reactions that lead to the other signs and symptoms of Aicardi-Goutières syndrome.

Variants in the TREX1, RNASEH2A, and RNASEH2C genes tend to cause the early-onset form of Aicardi-Goutières syndrome, while variants in the RNASEH2B, SAMHD1, IFIH1, and ADAR genes tend to cause the later-onset form. However, not every case of Aicardi-Goutières syndrome follows this pattern.

Because the signs and symptoms of Aicardi-Goutières syndrome are caused in part by abnormal activation of interferon proteins, it one of a group of disorders known as interferonopathies.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Aicardi-Goutières syndrome can have different inheritance patterns. In most cases, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. Autosomal recessive inheritance occurs when Aicardi-Goutières syndrome is caused by variants in the ADAR, LSM11, RNASEH2A, RNASEH2B, RNASEH2C, RNU7-1, SAMHD1, and TREX1 genes. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

When Aicardi-Goutières syndrome is caused by variants in the IFIH1 gene or by certain variants in the TREX1 or ADAR gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Aicardi-Goutières syndrome is a rare disorder. More than 500 people with Aicardi-Goutières syndrome have been described in the scientific literature, though the exact prevalence of the condition is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Arrhinencephaly · Very frequent (99-80%)

A defect of development of the brain characterized by congenital absence of the part of the brain that includes the olfactory bulbs, tracts, and other structures associated with the sense of smell.

Global developmental delay · Very frequent (99-80%)

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

Hypertonia · Very frequent (99-80%)

A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.

Intellectual disability, profound · Very frequent (99-80%)

Profound intellectual disability (ID) is defined as a type of ID characterized by profoundly sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) below 20.

Porencephaly · Very frequent (99-80%)

A cavity within the cerebral hemisphere, filled with cerebrospinal fluid, that communicates directly with the ventricular system.

Spasticity · Very frequent (99-80%)

A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.

Multifocal cerebral white matter abnormalities · Very frequent (99-80%)

Abnormality of extrapyramidal motor function · Frequent (79-30%)

A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).

Other findings in the same source

From: Orphanet

Additional reported features include Autoimmunity (Frequent (79-30%)); Axial hypotonia (Frequent (79-30%)); Brain atrophy (Frequent (79-30%)); Cerebral calcification (Frequent (79-30%)); Chilblains (Frequent (79-30%)); Chronic CSF lymphocytosis (Frequent (79-30%)); Convex nasal ridge (Frequent (79-30%)); Developmental regression (Frequent (79-30%)); Dry skin (Frequent (79-30%)); Dystonia (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Aicardi-Goutières syndrome is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Aicardi-Goutières syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.