This group brings together atypical leukodystrophies that could not be classified in the different existing categories such as:


In 1984, Jean Aicardi and Françoise Goutières, two French paediatric neurologists, described a childhood onset genetic brain disorder mimicking the features of viral infections affecting children in the womb. Clinical indicators of this disease now known as Aicardi-Goutieres syndrome (AGS) include:

• The accumulation of calcium (calcification) in the brain, best seen on CT scan

• Changes in the white nerve tissue of the brain and spinal cord brain best seen on MRI scan

• Raised levels of white cells, interferon-alpha and pterins (proteins produced by the body to fight viral infection) in the cerebrospinal fluid (tested by lumbar puncture)

• Distinctive ‘chilblain-like’ lesions on the hands and feet which are usually worse in the cold

Six different genes (see table) have so far been described that, when damaged by a genetic change/mutation, can cause AGS. As far as we know, only one gene is involved in any one family.

Gene        Chromosome Position        Other names             Percentage of families with mutations

AGS1                  3                                          TREX1                                                22%

AGS2                13                                     RNASEH2B                                           38%

AGS3                11                                     RNASEH2C                                           14%

AGS4                19                                     RNASEH2A                                            6%

AGS5                20                                   SAMHD1/DCIP                                     12,5%

AGS6                1                                            ADAR1                                               7,5%


Broadly speaking there are two types of presentation in AGS. Some babies, especially those with AGS1 mutations, 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, often 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 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 trunk and head control and impairment of muscle tone (dystonia) of the limbs. Although the neurological problems seen in AGS are often severe, a small number of children, usually those with AGS2 mutations, show good communication skills and other neurological function.



Aicardi-Goutières syndrome is usually 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. Three cases are known to us where AGS has been inherited as a ‘new dominant’. In these rare cases the risk of recurrence is very low.

The availability of genetic testing allows us to confirm the diagnosis of AGS in most, but not all, families. This is important in view of the associated 1 in 4 risk of recurrence. For some couples, if both mutations can be identified in their child it is now possible to offer testing during a subsequent pregnancy or even using a new technique called preimplantation genetic diagnosis (PGD which is becoming more readily available.




These genes make chemicals called nucleases which break down DNA and RNA. During the normal life-cycle of our cells, nucleases clean up naturally produced waste DNA and RNA. A failure of this process can induce the body to mount an immune reaction against its own DNA and RNA. A similar immune reaction is seen in response to viral DNA and RNA following an infection. This would explain why the clinical features of AGS and viral infection overlap and why we see high levels of the anti-viral agent interferon-alpha in children with AGS. Very importantly, interferon-alpha and the removal of self nucleic acids also seem to be crucial in preventing the body developing an immune-response against its own tissues in so-called autoimmune diseases such as systemic lupus erythematosus (SLE/lupus).



At the moment, once the child has incurred significant brain damage there is no treatment that has been shown to reverse this damage. However, if treatments could be instigated at an early stage of the disease, therapies might prove extremely useful. These might be medicines relevant to other leukodystrophies and inflamatory disorders, or compounds specific to the disease process involved in AGS.



We have been working on AGS for the last 10 years and our lab is currently dedicated to the development of treatments for the disease. Of great importance, understanding of the genetic basis and cellular pathology of AGS is providing remarkable new insights into key pathways of the innate immune response. Consequently, many laboratories interested in autoimmune diseases are taking note of what AGS can teach them about the diseases they study (such as lupus). The involvement of these groups in such ‘allied research’ means that major advances in our understanding of AGS can realistically be expected in the next few years. We are confident that such understanding will allow us to provide effective treatments for this devastating illness.


Pr. Yanick Crow, University of Manchester, United Kingdom.