about AGS

What do we know about Aicardi-Goutières syndrome?

As it is rare, most people will never have heard of Aicardi–Goutières Syndrome. It can be very difficult to quickly understand all that there is to know about AGS and you’ll probably have lots of questions. Please join our network through one of the media channels for support from other parent carers.

On this page, we will start with the very basics about AGS and build up to more technical information and reference medical documents.

What is AGS?

Aicardi–Goutières Syndrome or AGS is a rare genetic disease. It affects the brain and immune system causing the body to produce chemicals that would normally fight viral infections but instead attack healthy cells (this is called an autoimmune response). One of the healthy cells that are attacked makes up some of the white matter in the brain called Myelin. Myelin surrounds and protects nerves in the brain and spinal cord and speeds the transmission of messages throughout the body.

The severity of the autoimmune response has a direct impact on the severity of the disability and the timing. The range of disability can be different not only between the different gene types but within the same gene type too. There can be one sibling with significant intellectual and physical problems and another sibling from the same parents that has a mild skin condition but both have the same gene causing AGS.

How is AGS caused?

As a genetic disease, AGS is caused by a gene mutation or a spelling mistake in a specific gene’s DNA code. In most cases AGS is inherited and that inheritance occurs only when both parents carry the genetic mutation, generally with no symptoms themselves (This is called an autosomal recessive pattern of inheritance). We carry pairs of each of our genes and inherit one from each parent. If only one copy of a gene’s pair has the mutation, that person will not present with symptoms of AGS but will be a carrier.

When two carriers have children together, the odds are one in four that they will have a child will have AGS. Less often, AGS can be caused by a single mutation inherited from an unaffected parent. In rare cases, the gene mutation associated with AGS is not inherited from a parent, it is simply a random mutation and is new in the person who develops the syndrome.
The genes that are currently known to cause AGS are;

Type	Gene
AGS1	TREX1
AGS2	RNASEH2B
AGS3	RNASEH2C
AGS4	RNASEH2A
AGS5	SAMHD1
AGS6	ADAR
AGS7	IFIH1

What are the signs and symptoms of AGS?

In approximately ten percent of cases, AGS presents at or soon after birth (i.e. in the neonatal period) and we refer to this as early-onset. This presentation of the disease is characterized by microcephaly, neonatal seizures, poor feeding, jitteriness, cerebral calcifications (accumulation of calcium deposits in the brain), white matter abnormalities, and cerebral atrophy; thus indicating that the disease process became active before birth i.e. in utero. These infants can have hepatosplenomegaly and thrombocytopenia (an enlarged liver or spleen), very much like cases of transplacental viral infection. Loss of myelin in early-onset often leads to permanent damage to brain function, and to severe lifelong intellectual and physical disabilities.

Otherwise, the majority of AGS cases present in early infancy, sometimes after an apparently normal period of development and we refer to this as late-onset. During the first few months after birth, these children develop features of encephalopathy with irritability, persistent inconsolable crying, feeding difficulties, an intermittent fever (without obvious infection), and abnormal neurology with disturbed tone, dystonia, an exaggerated startle response, development delays and sometimes seizures.
In later-onset, these symptoms may last for several months. They then generally lessen and stabilize, but may leave persistent neurologic difficulties. Additionally, the 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.

Glaucoma can be present at birth or develop later. Many children retain apparently normal vision, although a significant number are cortically blind. Hearing is almost invariably normal. Over time, up to 40% of patients develop so-called chilblain lesions, most typically on the toes and fingers and occasionally also involving the ears that are usually worse in the winter.

What tests can be done to diagnose AGS?

Diagnosis of Aicardi-Goutières syndrome is made based on a combination of physical symptoms, blood tests, imaging of the brain, cerebrospinal fluid testing and the results of genetic tests.

An increase in the number of white cells (particularly lymphocytes) in the cerebrospinal fluid and high levels of interferon-alpha activity and neopterin are important clues – however, these features are not always present. More recently, a persistent elevation of mRNA levels of interferon-stimulated gene transcripts have been recorded in the peripheral blood of almost all cases of AGS with mutations in TREX1, RNASEH2A, RNASEH2C, SAMHD1, ADAR1, IFIH1 and in 75% of patients with mutations in RNASEH2B. These results are irrespective of age. Thus, this interferon signature appears to be a very good marker of disease.

The spectrum of neuroradiological features associated with AGS is broad, but is most typically characterised by the following:

-Calcifications on a CT scan (computed tomography) are seen as areas of abnormal signal, typically bilateral and located in the basal ganglia, but sometimes also extending into the white matter. Calcifications are usually better detected using CT scans and can be missed completely on MRI (magnetic resonance imaging) without gradient-echo sequences.

-White matter abnormalities are found in 75-100% of cases and are best visualised on MRI. Signal changes can be particularly prominent in frontal and temporal regions. White matter abnormalities sometimes include cystic degeneration.

-Cerebral atrophy is seen frequently.

-Pathogenic mutations in any of the seven genes known to be involved in AGS.

The condition is not routinely picked up in the womb or in infant screening so when a child is born with any combination of symptoms such as increased infection markers, elevated liver enzymes, a decrease in blood platelets, an abnormal neurological response or an enlarged liver and spleen; this can be misinterpreted as a viral infection affecting a child in the womb. Some characteristics of AGS overlap with the autoimmune disease, Systemic Lupus Erythematosus (SLE) and the condition can also be known as Encephalopathy with basal ganglia calcification, Cree Encephalitis, Pseudo-TORCH syndrome or Microcephaly-Intracranial Calcification Syndrome (MICS).

Aicardi–Goutières Syndrome should also not be confused with the similarly named Aicardi Syndrome which is completely distinct but shares the same name as the professor who first described both conditions.

What treatments are available?

Although there is currently no cure for AGS, clinical trials are in the pipeline and symptomatic treatment is very beneficial.

Depending upon the severity of symptoms, children may require a variety of therapies that can be accessed through the NHS by referral from your GP or Community Consultant. These may include but are not limited to; Speech & Language (SALT), Physio Therapy, Occupational Therapy (OT) and Hydro Therapy. You may also wish to involve your local Wheelchair Service or Sensory Support Service.

A medication that found positive results in children with AGS from clinical trials is called Baricitinib. You will find the NHS documentation here

NHS England – Baricitinib

History of AGS

In 1984, Jean Aicardi and Francoise Goutières described eight children from five families presenting with severe early-onset encephalopathy, which was characterized by calcification of the basal ganglia, abnormalities of the cerebral white matter and diffuse brain atrophy. An excess of white cells, chiefly lymphocytes, was found in the cerebrospinal fluid (CSF), thus indicating an inflammatory condition. During the first year of life, these children developed microcephaly, spasticity and dystonia. Some of the parents of the children were genetically related to each other, and the children were both male and female, which suggested that the disease was inherited as an autosomal recessive genetic trait.

In 1988, Pierre Lebon and his colleagues identified the additional feature of raised levels of interferon-alpha in patient CSF in the absence of infection. This observation supported the suggestion that AGS was an inflammatory disease, as did the later finding of increased levels of the inflammatory marker neopterin in CSF, and the demonstration that more than 90% of individuals with a genetic diagnosis of AGS, tested at any age, demonstrate an upregulation of interferon-induced gene transcripts – a so-called interferon signature.

All cases of Cree encephalitis (an early-onset progressive encephalopathy in a Cree First Nations community in Canada) and many cases previously described as pseudo-TORCH syndrome, (Toxoplasmosis, Rubella, Cytomegalovirus, and Herpes simplex virus), initially considered to be separate disorders, were later found to be the same as AGS (although other causes of genetically distinct ‘pseudo-TORCH’ phenotypes exist).