Clinical Diagnosis

In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical handicap. The diagnosis can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial CT and MRI, and identifiable mutations in one of the five known related genes.

The following features are seen in the majority of affected individuals [Goutières et al 1998, Lanzi et al 2002, Rice et al 2007b]:

• Calcification of the basal ganglia, particularly the putamen, globus pallidus, and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution. See Figure 1.
• White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See Figure 2.
• Cerebral atrophy
• Chronic cerebrospinal fluid (CSF) leukocytosis
• Increased concentration of interferon-alpha (IFN-α) in the CSF
• Increased concentration of neopterin in the CSF [Rice et al 2007b]

Figure

Figure 1. Examples of intracranial calcification on CT scan in individuals with AGS. Calcification is seen in the basal ganglia (panel A), in the dentate nuclei of the cerebellum (panel B), and in a periventricular distribution (panel C).
Rice (more...)

Figure

Figure 2. The spectrum of brain changes seen on MRI in AGS. Hypointensity on T₁-weighted imaging (panel A) and hyperintensity on T₂-weighted imaging (panel B) of the white matter, extensive bitemporal cystic lesions (panel C), and significant thinning (more...)

The following additional features can be regarded as supportive of the diagnosis:

• Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Figure 3.
• Appearance of microcephaly during the first year of life
• Dystonia
• Sterile pyrexias

Figure

Figure 3. Examples of chilblains seen in AGS
Rice et al [2007b]. Reprinted with permission of The American Journal of Human Genetics, University of Chicago Press.

Exclusion criteria include the following:

• Evidence of prenatal/perinatal infection including CMV, toxoplasmosis, rubella, herpes simplex, and HIV
• Evidence of a known metabolic disorder or neurodegenerative disorder

Testing

The most important clinical laboratory tests contributing to the diagnosis of AGS involve an assessment of the CSF for numbers of white cells and concentrations of interferon alpha (IFN-α) and neopterin. These tests are most likely to be informative early on in the disease process and are frequently normal after the first few years of life [Rice et al 2007b].

Interferon-alpha (IFN-α). CSF IFN-α concentration is greater than 2 IU/mL (normal: <2 IU/mL) [Goutières et al 1998, Lebon et al 2002].

• Levels are highest in the early stages of the disease. The IFN-α CSF concentration tends to normalize over the first three to four years of life [Rice et al 2007b].
• The concentration of IFN-α is usually higher in CSF than in blood, where it may be normal.
• High levels of IFN-α have been identified in fetal blood at 26 weeks' gestation [Desanges et al 2006].

CSF lymphocytosis. Lymphocytosis is defined as more than five lymphocytes/mm³ CSF. Typical values range from five to 100 lymphocytes/mm³ [Goutières et al 1998, Rice et al 2007b].

• A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years.
• A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [Crow et al 2003, Rice et al 2007b].

CSF neopterin. CSF concentrations of neopterin (and less so biopterin) are frequently raised in molecularly proven AGS [Rice et al 2007b], so it appears that this is a good marker of the disease:

• Levels are highest in the early stages of the disease and tend to normalize over time.
• Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal.

Note: Levels of CSF protein can also be raised without oligoclonal bands [Lanzi et al 2002].

Molecular Genetic Testing

Genes. Mutations in the following genes are associated with AGS (Figure 4):

Figure

Figure 4. Percentages of 127 families with AGS with biallelic mutations in RNASEH2A, RNASEH2B, RNASEH2C, TREX1, and SAMHD1 as well as those with no identifiable mutation(s)

• TREX1 (AGS1 locus) [Crow et al 2006a]
• RNASEH2B (AGS2 locus), the gene encoding subunit B of ribonuclease H2 [Crow et al 2006b]
• RNASEH2C (AGS3 locus), the gene encoding subunit C of ribonuclease H2 [Crow et al 2006b]
• RNASEH2A (AGS4 locus), the gene encoding subunit A of ribonuclease H2 [Crow et al 2006b]
• SAMHD1, the gene encoding the SAM domain and HD domain-containing protein 1 [Rice et al 2009]

Evidence for locus heterogeneity. Genetic data indicate that at least one further gene may be associated with the AGS phenotype [Rice et al 2009].

Table 1. Summary of Molecular Genetic Testing Used in Aicardi-Goutières Syndrome

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Gene Symbol	Proportion of AGS Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Test Availability
TREX1	25%	Sequence analysis	Sequence variants 2, 3	Clinical
		Targeted mutation analysis	c.490C>T (p.Arg164X)
		Deletion / duplication analysis 4	Exonic deletions / duplications 5
RNASEH2B	40%	Sequence analysis	Sequence variants 2, 6	Clinical
		Deletion / duplication analysis 4	Exonic deletions / duplications 5
RNASEH2C	15%	Sequence analysis	Sequence variants 2, including an Asian founder mutation 7	Clinical
RNASEH2A	5%	Sequence analysis	Sequence variants 2	Clinical
		Deletion / duplication analysis 4	Exonic deletions / duplications 5
SAMHD1	5%	Sequence analysis	Sequence variants 2, 8	Clinical
		Deletion / duplication analysis 4	Exonic deletions / duplications 9
Multi-gene Aicardi-Goutières panel 10				Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Sequence analysis of the coding regions and splice sites of these five genes has identified mutations approximately 90% of individuals with clinical and MRI presentation of AGS [Rice et al 2007b, Rice et al 2009].

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. A de novo heterozygous mutation has been reported [Rice et al 2007a, Haaxma et al 2010].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. No deletions or duplications involving RNASEH2A, RNASEH2B, or TREX1 have been reported to cause Aicardi-Goutières syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

6. A majority of individuals with RNASEH2B mutations have at least one mutation in exon 2, 6, or 7.

7. Observed in families of Asian, most particularly Pakistani, descent [Rice et al 2007b].

8. SAMHD1 mutations include missense and null mutations, and large deletions [Rice et al 2009].

9. A recurrent deletion including exon 1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder mutation [Ramesh et al 2010]. Note: A homozygous deletion of ≥1 exon(s) can be suspected by the failure of exons to amplify by PCR; however, when it occurs in the heterozygous form, it can be identified only by the use of primers designed to detect known deletions, the analysis of the mRNA of the individual, or use of a method to screen entire gene for copy number abnormalities (recently, an MLPA kit has become available for such an analysis of deletions in all of the AGS-associated genes).

10. The genes included and the methods used in multi-gene panels vary by laboratory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• AGS is usually considered following the identification of calcification on cranial CT in a child with clinical features described in Clinical Diagnosis. The finding on MRI of white matter changes with temporal cysts is highly suggestive of the diagnosis, as are chilblains.

To confirm the diagnosis in a proband using molecular genetic testing (see Table 1)

• Alternative 1. Sequential sequence analysis based on the individual’s ethnicity and/or in the order in which mutations most commonly occur (RNASEH2B, TREX1, RNASEH2C, RNASEH2A, SAMHD1). Targeted mutation analysis for the c.490C>T founder mutation in TREX1 should be performed first in individuals of Cree ancestry. If only one SAMHD1 mutant allele is identified, deletion / duplication analysis should be performed.
• Alternative 2. Multi-gene testing. Consider using a multi-gene Aicardi-Goutières panel or simultaneous sequence analysis of all AGS-related genes. Note: Multi-gene panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual with the Aicardi-Goutières phenotype also varies.

Note: With the advent of molecular testing, CSF analysis is not always undertaken: (1) After the first few years of life, assay of CSF white cells/IFN-α/pterins is likely to be non-contributory; however, (2) assay of CSF white cells/IFN-α/pterins is still of value in the younger child because it can provide further evidence in favor of the diagnosis before pursuing molecular genetic testing, an important consideration given that the molecular basis of AGS has not yet been clarified in all cases.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not considered at risk of developing AGS.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Natural History

Pregnancy, delivery, and the neonatal period are normal in approximately 80% of infants with Aicardi-Goutières syndrome (AGS) [Rice et al 2007b]. However, brain calcifications can be identified in utero [Le Garrec et al 2005] and 20% of cases, mainly those caused by TREX1 mutations, present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture reminiscent of congenital infection.

All other affected infants present at variable times after the first few days of life, frequently after a period of apparently normal development. The majority of these later-presenting infants exhibit subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. The encephalopathic phase usually lasts several months. The opinion of most pediatricians caring for such children is that the disease does not progress beyond the encephalopathic period. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression.

RNASEH2B mutations are associated with a significantly later age at presentation (in a number of cases after age 12 months) and a lower childhood mortality, with several individuals known to be alive beyond age 18 years with no signs of disease progression. Some individuals with RNASEH2B mutations have relatively preserved intellectual function, with one individual having a completely normal IQ and head circumference documented at age 19 years, his only feature of AGS being spastic cerebral palsy [McEntagart et al 1998].

Typically, affected individuals have peripheral spasticity, dystonic posturing particularly of the upper limbs, truncal hypotonia, and poor head control. Seizures have been reported in 53% of individuals with AGS [Rice et al 2007b]. A number of children demonstrate a marked startle reaction to sudden noise, and the differentiation from epilepsy can be difficult. Most affected individuals have severe intellectual and physical impairment. Variability in the severity of the neurologic outcome can be observed among siblings. Most affected children exhibit a severe acquired microcephaly; however, in those children with preserved intellect, head circumference is normal.

Hearing is almost always normal.

Visual function varies from normal to cortical blindness. Ocular structures are almost invariably normal on examination.

Between 20% and 50% of affected individuals [Goutières et al 1998, Rice et al 2007b] have seizures that are usually generalized tonic-clonic or focal tonic. Massive myoclonic jerks have been reported [Lanzi et al 2002].

As many as 40% of affected individuals [Rice et al 2007b] have skin lesions with chilblains on the fingers and toes and sometimes the ear and other pressure points (e.g., elbows) [Tolmie et al 1995, Stephenson 2002] (see Figure 3). The cutaneous lesions may be complicated by periungual infection and necrosis. Chilblains are associated with mutations in all five genes.

Infrequently observed features of AGS are summarized in Table 2.

Recently, milder phenotypes have been associated with mutations in SAMHD1. Dale et al [2010] reported two siblings compound heterozygous for null mutations in SAMHD1. The older girl showed mild intellectual disability with microcephaly. Her younger brother had significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains and recurrent mouth ulcers. One of the siblings had a chronic progressive deforming arthropathy of the small and large joints with secondary contractures. Similar joint involvement was described by Ramantani et al [2010].

An additional previously undescribed feature of AGS, which so far seems to be exclusively related to SAMHD1 mutations, is intracranial large-vessel disease causing both intracranial stenoses (in some cases reminiscent of moyamoya syndrome) and aneurysms [Ramesh et al 2010, Thiele et al 2010, du Moulin et al 2011, Xin et al 2011].

Genotype-Phenotype Correlations

The phenotypes associated with mutations in each of the five genes known to be associated with AGS overlap, but the early-onset neonatal form of AGS is most frequently seen in association with TREX1, RNASEH2A, and RNASEH2C mutations, while the later-onset presentation (sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurologic function) is most frequently seen in association with RNASEH2B [Rice et al 2007b] and SAMHD1 mutations [Abdel-Salam et al 2010, Dale et al 2010, Ramesh et al 2010].

A previously undescribed feature of AGS is the occurrence of intracranial large-vessel disease, causing both intracranial stenoses (in some cases reminiscent of moyamoya syndrome) and aneurysms. Ramesh et al [2010], Thiele et al [2010], du Moulin et al [2011], and Xin et al [2011] described five such cases, all of whom had SAMHD1 mutations. To date, this phenotype has not been described in association with mutations in TREX1, RNASEH2A, RNASEH2B, or RNASEH2C.

Mortality is correlated with genotype: 34% of individuals with TREX1, RNASEH2A, and RNASEH2C mutations were known to have died compared to 8% with RNASEH2B mutations (p=0.001) [Rice et al 2007b]. The mortality associated with SAMHD1-related disease is not yet known.

Nomenclature

The microcephaly-intracranial calcification syndrome (MICS; also known as pseudo-TORCH syndrome or Baraitser-Reardon syndrome) was previously differentiated from AGS on the basis of congenital microcephaly and the presence of non-neurologic abnormalities, including elevation of liver enzymes, hepatomegaly, and thrombocytopenia at birth [Reardon et al 1994]. However, recent studies have shown that these same features can be seen in mutation-positive persons with AGS [Rice et al 2007b]. Of note, in the majority of MICS cases reported no information is available on CSF cell count and IFN-α concentration; thus it is probable that most cases of MICS are in fact AGS.

“Familial systemic lupus erythematosus.” Dale et al [2000] described two children of consanguineous parents with early-onset encephalopathy, intracranial calcifications, chilblain skin lesions, and the progressive production of high levels of autoantibodies. CSF was not analyzed. These cases most likely represent AGS [Aicardi & Goutières 2000].

Prevalence

The actual frequency of AGS is unknown.

Mutations have been found in affected individuals of all ethnic origins [Crow et al 2006a, Crow et al 2006b, Rice et al 2007b]:

• The most prevalent TREX1 mutation in AGS is a missense change (c.341G>A) that is particularly common in people from Northern Europe.
• The most prevalent RNASEH2B mutation is a missense change (c.529G>A) that was seen in 62% of RNASEH2B mutated alleles.
• The RNASEH2C mutation c.205C>T (p.Arg69Trp) is seen particularly frequently in Asian (most commonly Pakistani) families and represents an ancient founder mutation [Rice et al 2007b].
• A recurrent deletion including exon 1 of SAMHD1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder mutation [Ramesh et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Aicardi-Goutières syndrome (AGS), the following evaluations are recommended:

• Developmental assessment
• Assessment of feeding and nutritional status
• Ophthalmologic examination
• EEG to evaluate for seizures if suspected

Treatment of Manifestations

The following are appropriate:

• Chest physiotherapy and vigorous treatment of respiratory complications
• Attention to diet and method of feeding to assure adequate caloric intake
• Management of seizures using standard protocols

Surveillance

Surveillance includes the following:

• Assessment for glaucoma in the first few months of life
• Monitoring of the spine for the development of scoliosis
• Monitoring for signs of insulin-dependent diabetes mellitus (IDDM) and hypothyroidism

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Research is ongoing (ec.europa.eu) into the role of immunosuppressive agents in the treatment of AGS [Crow & Rehwinkel 2009].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Corticosteroids can lower the CSF concentration of interferon [PG Barth 2003, personal communication]; the clinical benefit of such treatment is unproven.

Note: The description of intracranial large-vessel disease in association with mutations in SAMHD1 raises important questions about the management of such patients. The occlusive and aneurysmal arteriopathies described could be amenable to treatment (revascularization for the former and coiling or clipping for the latter). Moreover, the likely inflammatory basis of the arteriopathy suggests that immunosuppression may have a role in management. A key question is whether inflammatory disease is active at the time of clinical presentation, or whether the arterial abnormalities observed represent the end result of a now-quiescent inflammatory process.

Due to a lack of evidence, no definitive statement about these matters can be made at this time. However, given the potential for intervention, it could be argued that some individuals (e.g., those with lesser psychomotor problems) warrant such intervention and should be actively screened for intracranial arteriopathy, if only by close inspection of the vasculature at the base of the brain seen on routine MRI. Chilblains were present in all those patients described by Ramesh et al [2010], and it may be that their presence predicts an increased risk of intracranial vasculopathy.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

RNASEH2A-related Aicardi-Goutières syndrome (AGS), RNASEH2B-related AGS, RNASEH2C-related AGS, SAMHD1-related AGS and most cases of TREX1-related AGS are inherited in an autosomal recessive manner.

Rarely, TREX1-related AGS is the result of a de novo dominant mutation.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic; however, the findings of Lee-Kirsch et al [2007b] and Richards et al [2007] suggest that heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Most individuals with AGS do not reproduce.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Risk to Family Members — De Novo Dominant Mutation

Parents of a proband

• To date, the two probands with AGS who had a heterozygous TREX1 mutation had the disorder as the result of a de novo mutation [Rice et al 2007b, Haaxma et al 2010].
• Parents of a proband are not affected.

Sibs of a proband

• Because heterozygous TREX1 mutations resulting in AGS occur de novo, the risk to the sibs of a proband is small.
• Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Most individuals with AGS do not reproduce.

Other family members of a proband. Because heterozygous TREX1 mutations resulting in AGS occur de novo, other family members of a proband are not at increased risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Percutaneous umbilical blood sampling (PUBS). Among families without a molecular diagnosis in which the clinical diagnosis has otherwise been established, sampling of fetal blood in the third trimester of at-risk pregnancies has in some cases been used to measure serum concentration of IFN-α [Le Garrec et al 2005, Desanges et al 2006]. The false positive and negative rates associated with such testing are unknown [P Lebon, personal communication] and this form of prenatal testing is not advised by the authors.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Suggested Reading

1. Akwa Y, Hassett DE, Eloranta ML, Sandberg K, Masliah E, Powell H, Whitton JL, Bloom FE, Campbell IL. Transgenic expression of IFN-alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration. J Immunol. 1998;161:5016–26. [PubMed: 9794439]
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Acknowledgments

We would like to thank Dr Gillian Rice for her help in compiling the gene mutation data.

Revision History

• 1 March 2012 (cd) Revision: targeted mutation analysis for the c.490C>T mutation in TREX1 available clinically
• 19 January 2012 (cd) Revision: deletion/duplication analysis available clinically for SAMHD1, TREX1, RNASEH2A, and RNASEH2B; multi-gene panels available
• 4 November 2010 (me) Comprehensive update posted live
• 17 April 2008 (me) Comprehensive update posted to live Web site
• 29 June 2005 (me) Review posted to live Web site
• 1 September 2004 (ja) Original submission