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Aicardi-Goutières syndrome

Also known as: Cree Encephalitis, Pseudo-TORCH syndrome, Microcephaly-intracranial Calcification syndrome (MICS)

Background

Aicardi-Goutières syndrome (AGS) is a genetic brain disease which can be mistaken for the consequences of viral infections affecting a child in the womb. Most children with AGS show signs of the condition in the first few months of life. Features allowing a doctor to make a diagnosis of AGS include:

  • calcification in the brain
  • changes in the white nerve tissue of the brain
  • raised levels of interferon-related proteins (chemicals produced by the body to fight viral infection - but in the case of AGS found in the absence of such infection) in the blood and the cerebrospinal fluid (CSF)
  • distinctive 'chilblain-like' lesions on the hands and feet, which are usually worse in the cold.

Credits

Last updated July 2016 by Professor Yanick Crow, Genetic Medicine, University of Manchester, Manchester, UK. 

Although great care has been taken in the compilation and preparation of all entries to ensure accuracy, we cannot accept responsibility for any errors or omissions. Any medical information is provided is for education/information purposes and is not designed to replace medical advice by a qualified medical professional.

What are the symptoms?

In general terms there are two types of presentation in AGS. Some babies, especially those with AGS1 mutations (see 'What are the causes?'), experience problems at or very soon after birth. Features include feeding difficulties, abnormal neurological signs, low platelets (blood cells involved in clotting), and liver abnormalities. In contrast, other children, most frequently those with AGS2 mutations, develop normally for the first few weeks or months of life. They then experience the sudden onset of a period of intense irritability, cry a lot for hours at a time, sleep poorly, and can develop fevers without infection. During this period there is a loss of skills.

After a few months the disease process seems to 'stop'. Many individuals with AGS are still stable in their late teens and early twenties. Typical neurological features of AGS include learning problems, stiffness of the limbs with poor body and head control, dystonia (impairment in muscle tone) of the limbs, and seizures (see entry Epilepsy). Although the neurological problems seen in AGS are often severe, a small number of children, usually those with AGS2 or AGS5-7 mutations, display good communication skills, and a few children can have completely normal intellectual development.

What are the causes?

Seven different genes (see table) have been identified that, when damaged by a mutation, can cause Aicardi-Goutières syndrome (AGS). Only one gene is involved in any one family.

Gene

Chromosome

Gene name

% of families with mutations

AGS1

3

TREX1

22

AGS2

13

RNASEH2B

36

AGS3

11

RNASEH2C

12

AGS4

19

RNASEH2A

<5

AGS5

20

SAMHD1

13

AGS6

1

ADAR1

7

AGS7

2

IFIH1

3

How is it treated?

The following treatments may be used for the management of AGS:

  • management of seizures (which are quite common in more severely affected children) using standard protocols
  • in some cases, treatments may be considered for chilblains
  • some children need tube or gastrostomy feeding because of difficulties with feeding secondary to the associated neurological problems
  • chest physiotherapy and antibiotic treatment may be needed for respiratory complications, which can occur secondary to the associated neurological problems.

Surveillance includes the following:

  • assessment for glaucoma (seen in a small percentage of cases)
  • monitoring of the spine for the development of scoliosis (which can sometimes occur because of muscle imbalance)
  • monitoring for signs of insulin-dependent diabetes mellitus (IDDM) and hypothyroidism (these are rare, but treatable, associations seen in a small percentage of patients)
  • in the case of SAMHD1-related disease, there may be need for monitoring of the blood vessels in the brain with special scans.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
AGS is most frequently inherited as an autosomal recessive genetic disorder. This means that for a couple with one affected child there is a 1 in 4 risk of having a further affected child in any future pregnancy. However, there are rare autosomal dominant cases with specific genetic changes in AGS1 and AGS6, and the same dominant situation applies to all cases due to genetic changes in AGS7. Where the disease occurs due to a single 'new mutation' in the affected child, known as a sporadic mutation, the risk of recurrence is very low. Very rarely with dominantly inherited disease, a 'carrier' parent is at risk of having a more severely affected child.

Prenatal diagnosis
The availability of genetic testing allows for confirmation of the diagnosis of AGS in most, but not all, families. For couples where mutations have been identified in their child it may be possible to offer testing during a subsequent pregnancy.

Is there support?

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