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Aicardi-Goutieres syndrome

Reviewed July 2010

What is Aicardi-Goutieres syndrome?

Aicardi-Goutieres syndrome is a disorder that mainly affects the brain, the immune system, and the skin.

Most newborns with Aicardi-Goutieres syndrome do not show any signs or symptoms of the disorder at birth. However, about 20 percent are born with a combination of features that include an enlarged liver and spleen (hepatosplenomegaly), elevated blood levels of liver enzymes, a decrease in blood platelets (thrombocytopenia), and abnormal neurological responses. While this combination of signs and symptoms is typically associated with the immune system's response to congenital viral infection, no actual infection is found in these infants. For this reason, Aicardi-Goutieres syndrome is sometimes referred to as a "mimic of congenital infection."

Within the first year of life most individuals with Aicardi-Goutieres syndrome experience an episode of severe brain dysfunction (encephalopathy), typically lasting for several months. During this phase of the disorder, affected babies are usually extremely irritable and do not feed well. They may develop intermittent fevers in the absence of infection (sterile pyrexias) and may have seizures. They stop developing new skills and begin losing skills they had already acquired (developmental regression). Growth of the brain and skull slows down, resulting in an abnormally small head size (microcephaly). In this phase of the disorder, white blood cells and molecules associated with inflammation can be detected in the cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord (central nervous system). These abnormal findings are consistent with inflammation and tissue damage in the central nervous system.

The encephalopathic phase of Aicardi-Goutieres syndrome leaves behind permanent neurological damage that is usually severe. Medical imaging reveals deterioration of white matter in the brain (leukodystrophy). White matter consists of nerve fibers covered by myelin, which is a substance that insulates and protects nerves. Affected individuals also have abnormal deposits of calcium (calcification) in the brain.

Most people with Aicardi-Goutieres syndrome have profound intellectual disability. They also have significant neuromuscular problems including muscle stiffness (spasticity); involuntary tensing of various muscles (dystonia), especially those in the arms; and weak muscle tone (hypotonia) in the trunk.

About 40 percent of people with Aicardi-Goutieres syndrome have painful, itchy skin lesions, usually on the fingers, toes, and ears. These puffy, red lesions, which are called chilblains, are caused by inflammation of small blood vessels. They may be brought on or made worse by exposure to cold. Vision problems, joint stiffness, and mouth ulcers may also occur in this disorder.

As a result of the severe neurological problems usually associated with Aicardi-Goutieres syndrome, most people with this disorder do not survive past childhood. However, some affected individuals who have later onset and milder neurological problems may live into adulthood.

How common is Aicardi-Goutieres syndrome?

Aicardi-Goutieres syndrome is a rare disorder. Its exact prevalence is unknown.

What genes are related to Aicardi-Goutieres syndrome?

Mutations in the TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 genes have been identified in people with Aicardi-Goutieres syndrome.

The TREX1, RNASEH2A, RNASEH2B, and RNASEH2C genes provide instructions for making nucleases, which are enzymes that help break up molecules of DNA and its chemical cousin RNA. Mutations in any of these genes are believed to result in an absent or dysfunctional nuclease enzyme. Researchers suggest that absent or impaired enzyme function may result in the accumulation of unneeded DNA and RNA in cells. These DNA and RNA molecules or fragments may be generated during the first stage of protein production (transcription), copying (replication) of cells' genetic material in preparation for cell division, DNA repair, cell death, and other processes. The unneeded DNA and RNA may be mistaken by cells for that of viral invaders, triggering immune system reactions that result in encephalopathy, skin lesions, and other signs and symptoms of Aicardi-Goutieres syndrome.

The SAMHD1 gene provides instructions for making a protein whose function is not well understood; however, it is believed to be involved in the immune system and the inflammatory process. Mutations in this gene likely result in a protein that does not function properly, resulting in immune system abnormalities, inflammatory damage to the brain and skin, and other characteristics of Aicardi-Goutieres syndrome.

Related Gene(s)

Changes in these genes are associated with Aicardi-Goutieres syndrome.

  • RNASEH2A
  • RNASEH2B
  • RNASEH2C
  • SAMHD1
  • TREX1

How do people inherit Aicardi-Goutieres syndrome?

Aicardi-Goutieres 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 have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Rarely, this condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. These cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Aicardi-Goutieres syndrome?

These resources address the diagnosis or management of Aicardi-Goutieres syndrome and may include treatment providers.

  • Gene Review: Aicardi-Goutieres Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1475)
  • Genetic Testing Registry: Aicardi Goutieres syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0393591)
  • Genetic Testing Registry: Aicardi Goutieres syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0796126)
  • Genetic Testing Registry: Aicardi Goutieres syndrome 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C3489724)
  • Genetic Testing Registry: Aicardi Goutieres syndrome 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1835916)
  • Genetic Testing Registry: Aicardi Goutieres syndrome 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1835912)
  • Genetic Testing Registry: Aicardi Goutieres syndrome 5 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2749659)

You might also find information on the diagnosis or management of Aicardi-Goutieres syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/aicardi-goutieres-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/aicardi-goutieres-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Aicardi-Goutieres syndrome?

You may find the following resources about Aicardi-Goutieres syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Aicardi-Goutieres syndrome?

  • AGS
  • Aicardi Goutieres syndrome
  • Cree encephalitis
  • encephalopathy with basal ganglia calcification
  • familial infantile encephalopathy with intracranial calcification and chronic cerebrospinal fluid lymphocytosis
  • pseudo-TORCH syndrome
  • pseudotoxoplasmosis syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Aicardi-Goutieres syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Aicardi-Goutieres syndrome?

autosomal ; autosomal dominant ; autosomal recessive ; blood platelets ; calcification ; calcium ; cell ; cell division ; central nervous system ; chronic ; congenital ; disability ; DNA ; DNA repair ; dystonia ; encephalopathy ; enzyme ; familial ; gene ; hepatosplenomegaly ; hypotonia ; imaging ; immune system ; infection ; inflammation ; inheritance ; inherited ; involuntary ; joint ; leukodystrophy ; microcephaly ; muscle tone ; nervous system ; neurological ; nuclease ; platelets ; prevalence ; protein ; recessive ; regression ; RNA ; spasticity ; stage ; syndrome ; thrombocytopenia ; tissue ; transcription ; white blood cells ; white matter

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Crow YJ, Livingston JH. Aicardi-Goutières syndrome: an important Mendelian mimic of congenital infection. Dev Med Child Neurol. 2008 Jun;50(6):410-6. doi: 10.1111/j.1469-8749.2008.02062.x. Epub 2008 Apr 14. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18422679?dopt=Abstract)
  • Crow YJ, Rehwinkel J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet. 2009 Oct 15;18(R2):R130-6. doi: 10.1093/hmg/ddp293. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19808788?dopt=Abstract)
  • Dale RC, Gornall H, Singh-Grewal D, Alcausin M, Rice GI, Crow YJ. Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A. 2010 Apr;152A(4):938-42. doi: 10.1002/ajmg.a.33359. (http://www.ncbi.nlm.nih.gov/pubmed/20358604?dopt=Abstract)
  • Gene Review: Aicardi-Goutieres Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1475)
  • Goutières F, Aicardi J, Barth PG, Lebon P. Aicardi-Goutières syndrome: an update and results of interferon-alpha studies. Ann Neurol. 1998 Dec;44(6):900-7. (http://www.ncbi.nlm.nih.gov/pubmed/9851434?dopt=Abstract)
  • Goutières F. Aicardi-Goutières syndrome. Brain Dev. 2005 Apr;27(3):201-6. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15737701?dopt=Abstract)
  • Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, Borozdin W, Mah JK, Ungerath K, Walkenhorst H, Richardt HH, Buckard J, Bevot A, Siegel C, von Stülpnagel C, Ikonomidou C, Thomas K, Proud V, Niemann F, Wieczorek D, Häusler M, Niggemann P, Baltaci V, Conrad K, Lebon P, Lee-Kirsch MA. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum. 2010 May;62(5):1469-77. doi: 10.1002/art.27367. (http://www.ncbi.nlm.nih.gov/pubmed/20131292?dopt=Abstract)
  • Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, Artuch R, Montalto SA, Bacino CA, Barroso B, Baxter P, Benko WS, Bergmann C, Bertini E, Biancheri R, Blair EM, Blau N, Bonthron DT, Briggs T, Brueton LA, Brunner HG, Burke CJ, Carr IM, Carvalho DR, Chandler KE, Christen HJ, Corry PC, Cowan FM, Cox H, D'Arrigo S, Dean J, De Laet C, De Praeter C, Dery C, Ferrie CD, Flintoff K, Frints SG, Garcia-Cazorla A, Gener B, Goizet C, Goutieres F, Green AJ, Guet A, Hamel BC, Hayward BE, Heiberg A, Hennekam RC, Husson M, Jackson AP, Jayatunga R, Jiang YH, Kant SG, Kao A, King MD, Kingston HM, Klepper J, van der Knaap MS, Kornberg AJ, Kotzot D, Kratzer W, Lacombe D, Lagae L, Landrieu PG, Lanzi G, Leitch A, Lim MJ, Livingston JH, Lourenco CM, Lyall EG, Lynch SA, Lyons MJ, Marom D, McClure JP, McWilliam R, Melancon SB, Mewasingh LD, Moutard ML, Nischal KK, Ostergaard JR, Prendiville J, Rasmussen M, Rogers RC, Roland D, Rosser EM, Rostasy K, Roubertie A, Sanchis A, Schiffmann R, Scholl-Burgi S, Seal S, Shalev SA, Corcoles CS, Sinha GP, Soler D, Spiegel R, Stephenson JB, Tacke U, Tan TY, Till M, Tolmie JL, Tomlin P, Vagnarelli F, Valente EM, Van Coster RN, Van der Aa N, Vanderver A, Vles JS, Voit T, Wassmer E, Weschke B, Whiteford ML, Willemsen MA, Zankl A, Zuberi SM, Orcesi S, Fazzi E, Lebon P, Crow YJ. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007 Oct;81(4):713-25. Epub 2007 Sep 4. (http://www.ncbi.nlm.nih.gov/pubmed/17846997?dopt=Abstract)
  • Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009 Jul;41(7):829-32. doi: 10.1038/ng.373. Epub 2009 Jun 14. (http://www.ncbi.nlm.nih.gov/pubmed/19525956?dopt=Abstract)
  • Rigby RE, Leitch A, Jackson AP. Nucleic acid-mediated inflammatory diseases. Bioessays. 2008 Sep;30(9):833-42. doi: 10.1002/bies.20808. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18693262?dopt=Abstract)
  • Stephenson JB. Aicardi-Goutières syndrome (AGS). Eur J Paediatr Neurol. 2008 Sep;12(5):355-8. doi: 10.1016/j.ejpn.2007.11.010. Epub 2008 Mar 14. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18343173?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2010
Published: November 17, 2014