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Aicardi-Goutières Syndrome

, MBBS, BMedSci, MRCP, PhD
Laboratory of Neurogenetics and Neuroinflammation
Institut Imagine
Paris, France
Manchester Centre for Genomic Medicine
University of Manchester
Manchester, United Kingdom

Initial Posting: ; Last Update: November 22, 2016.

Summary

Clinical characteristics.

Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

Diagnosis/testing.

The diagnosis of AGS is established in a proband:

  • With typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes);
    and/or
  • By the identification of one of the following:
    • Biallelic pathogenic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or TREX1
    • Specific heterozygous autosomal dominant pathogenic variants in TREX1 and ADAR
    • A variety of heterozygous autosomal dominant pathogenic variants in IFIH1

Management.

Treatment of manifestations: Chest physiotherapy and treatment of respiratory complications; attention to diet and feeding methods to assure adequate caloric intake and avoid aspiration; management of seizures using standard protocols.

Surveillance: Monitoring for signs of diabetes insipidus in the neonatal period; repeat ophthalmologic examinations at least for the first few years of life to evaluate for evidence of glaucoma; monitoring for evidence of scoliosis, insulin-dependent diabetes mellitus (IDDM), and hypothyroidism.

Genetic counseling.

AGS is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific de novo or inherited autosomal dominant pathogenic variants in ADAR or TREX1, and a variety of heterozygous autosomal dominant pathogenic variants in IFIH1. At conception, each sib of an affected individual with autosomal recessive AGS 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. Individuals with AGS do not typically reproduce. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for AGS, and preimplantation genetic diagnosis are possible options.

Diagnosis

In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability.

Suggestive Findings

Aicardi-Goutières syndrome (AGS) should be suspected in individuals with the following clinical, neuroimaging, and supportive laboratory findings [Goutières et al 1998, Lanzi et al 2002, Rice et al 2007b, Livingston et al 2013].

Clinical features

  • Encephalopathy and/or significant intellectual disability
  • Acquired microcephaly during the first year of life
  • Dystonia and spasticity
  • Sterile pyrexias
  • Hepatosplenomegaly
  • Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Figure 1.
Figure 1. . Examples of chilblains seen in AGS Rice et al [2007b]; reprinted with permission of The American Journal of Human Genetics, University of Chicago Press.

Figure 1.

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, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika and HIV
  • Evidence of a known other metabolic disorder or neurodegenerative disorder

Neuroimaging

  • Calcification (best visualized on CT scan) 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 [Lanzi et al 2002, Uggetti et al 2009, Livingston et al 2013]. See Figure 2.
    Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units.
  • White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See Figure 3.
    • On MRI, appears on T2-weighted images as a hyperintense signal most commonly located around the horns of the ventricles (Figure 3B)
  • Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci
  • Bilateral striatal necrosis
  • Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms
Figure 2. . Examples of intracranial calcification on CT scan in individuals with AGS.

Figure 2.

Examples of intracranial calcification on CT scan in individuals with AGS. Calcification is seen: A. In the basal ganglia; B. In the dentate nuclei of the cerebellum; C. In a periventricular distribution. Rice et al [2007b]; reprinted with permission (more...)

Figure 3. . The spectrum of brain changes seen on MRI in AGS A.

Figure 3.

The spectrum of brain changes seen on MRI in AGS A. Hypointensity on T1-weighted imaging of the white matter B. Hyperintensity on T2-weighted imaging of the white matter C. Extensive bitemporal cystic lesions D. Significant thinning of the brain stem (more...)

Supportive Laboratory Findings

Peripheral blood

Cerebrospinal fluid (CSF)

  • Chronic CSF leukocytosis, defined as more than five lymphocytes/mm3 CSF.
  • Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL)
    • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [Rice et al 2007b, Rice et al 2013a].
    • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal.
    • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [Desanges et al 2006].
  • Increased concentration of neopterin in the CSF [Rice et al 2007b]
    • Levels are highest in the early stages of the disease and can normalize over time.
    • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal.

Establishing the Diagnosis

The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes) and/or by the identification of biallelic pathogenic variants in ADAR, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or TREX1; specific heterozygous autosomal dominant pathogenic variants in TREX1 and ADAR; or a variety of heterozygous autosomal dominant pathogenic variants in IFIH1.

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing can be pursued based on the individual’s ethnicity and/or in the order in which pathogenic variants most commonly occur (see Table 1).

A multi-gene panel that includes ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, TREX1, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multi-gene panels vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

More comprehensive genomic testing (when available) including whole-exome sequencing (WES), whole mitochondrial sequencing (WMitoSeq), and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1) fails to confirm a diagnosis in an individual with features of AGS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Aicardi-Goutières Syndrome

Gene 1Proportion of AGS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by Test Method
Sequence analysis 3, 4Gene-targeted deletion/duplication analysis 5
ADAR7%32/32 alleles 6Unknown 7
IFIH13%17/17 alleles 8Unknown 7
RNASEH2A5%34/34 alleles 9Unknown 7
RNASEH2B36%~99% 10Unknown 11
RNASEH2C12%~99% 12, 13Unknown 7
SAMHD113%up to 95% 14up to 30% 14, 15
TREX123%~99% 16Unknown 7
Unknown1%NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Sequence analysis of the coding regions and splice sites of ADAR, IFIH1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and TREX1 has identified pathogenic variants in approximately 90%-95% of individuals with clinical and MRI presentation of AGS [Rice et al 2007b, Rice et al 2009, Crow et al 2015].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

32/32 alleles were detectable by sequence analysis [Crow et al 2015]. A dominant p.Gly1007Arg variant in ADAR has been reported [Rice et al 2012, Livingston et al 2014a]. A recurrent ADAR variant, p.Pro193Ala, is seen in affected persons of European origin.

7.

No deletions or duplications involving ADAR, IFIH1, RNASEH2A, RNASEH2C, or TREX1 have been reported to cause Aicardi-Goutières syndrome.

8.
9.
10.

90% of individuals with biallelic pathogenic variants in RNASEH2B are either homozygous or compound heterozygous for the missense change (p.Ala177Thr).

11.

A deletion of RNASEH2B exons two through five has been reported [Crow et al 2015].

12.
13.

The RNASEH2C variant p.Arg69Trp is seen particularly frequently in Asian (most commonly Pakistani) families and represents an ancient founder variant [Rice et al 2007b].

14.

25/26 alleles [Rice et al 2009] and 47/67 alleles [Crow et al 2015] were detected by sequence analysis. Note: Rice et al [2009] did not perform deletion/duplication analysis and in some families in the study no pathogenic variants were detected.

15.

A recurrent deletion including exon 1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder variant [Ramesh et al 2010]. 20/67 alleles in Crow et al [2015] were detectable by deletion/duplication analysis; however, this study included persons of Ashkenazi Jewish decent. Note: A homozygous deletion of ≥1 exons can be suspected by the failure of exons to amplify by PCR. A recurrent splice acceptor site pathogenic variant (c.1411-2A>G) in intron 12 is seen in persons of Amish ancestry and represents an ancient founder variant [Xin et al 2011].

16.

In approximately 100 individuals with TREX1-related AGS, all pathogenic variants were detectable by sequence analysis [Rice et al 2007b, Crow et al 2015]. A recurrent p.Arg164Ter founder variant in TREX1 is seen in individuals of Cree ancestry. The most prevalent TREX1 variant in AGS is a missense change (p.Arg114His) that is particularly common in people from northern Europe.

Clinical Characteristics

Clinical Description

In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability.

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 biallelic pathogenic variants in TREX1, 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 weeks 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; occasionally, however, affected individuals do appear to show progression and/or episodes of regression. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression. Several affected individuals older than age 30 years show no obvious signs of disease progression.

Neurologic features. Typically, affected individuals have peripheral spasticity, dystonic posturing (particularly of the upper limbs), truncal hypotonia, and poor head control. Seizures are reported in up to half of affected children, but are usually relatively easily controlled [Goutières et al 1998, 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 sibs. Most affected children exhibit a severe acquired microcephaly; in children with preserved intellect head circumference can be normal.

Hearing is almost always normal.

Ophthalmology. Visual function varies from normal to cortical blindness. Ocular structures are almost invariably normal on examination. However, there is a risk of congenital glaucoma or later-onset glaucoma [Crow et al 2004a, Crow et al 2015].

Skin lesions. As many as 40% of affected individuals [Rice et al 2007b] have skin lesions with chilblains on the fingers and toes and sometimes the ears and other pressure points (e.g., elbows) [Tolmie et al 1995, Stephenson 2002] (see Figure 1). The cutaneous lesions may be complicated by periungual infection and necrosis.

Other

  • Intracranial large-vessel disease. An additional previously undescribed feature of AGS, which so far appears to be almost exclusively related to biallelic pathogenic variants in SAMHD1, is intracranial large-vessel disease causing both intracranial stenoses (in some cases reminiscent of moyamoya syndrome) and aneurysms (see Phenotype Correlations by Gene) [Ramesh et al 2010, Thiele et al 2010, du Moulin et al 2011, Xin et al 2011].
  • Refractory four-limb dystonia. Several individuals with ADAR pathogenic variants have been reported to demonstrate an acute or subacute onset of refractory four-limb dystonia starting between age eight months and five years [Livingston et al 2014a, Crow et al 2015] (see Phenotype Correlations by Gene).
    • Individuals can be developmentally normal at initial presentation.
    • This phenotype can occur due to either biallelic pathogenic variants in ADAR or the autosomal dominant pathogenic variant p.Gly1007Arg in ADAR.
    • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in ADAR or the recurrent dominant pathogenic p.Gly1007Arg variant in ADAR1 are typically associated with an upregulation of ISGs.

Additional infrequently observed features of AGS are summarized in Table 2.

Table 2.

Infrequent Features Seen in a Cohort of 123 Individuals with Molecularly Confirmed AGS

FeatureNumber of Affected Individuals by Gene
RNASEH2ARNASEH2BRNASEH2CTREX1
Scoliosis0900
Cardiomegaly1014
Abnormal antibody profile0312
Preserved language0600
Demyelinating peripheral neuropathy0211
Congenital glaucoma0012
Micropenis0011
Hypothyroidism0101
Insulin-dependent diabetes mellitus0101
Transitory deficiency of antidiuretic hormone0001

Rice et al [2007b]. Note: This paper was published before it was determined that pathogenic variants in ADAR, IFIH1, and SAMHD1 can cause AGS.

Neuroimaging/neuropathologic findings

  • Calcifications on neuroimaging:
    • Are often punctate but may be dense and rock-like;
    • When identified at diagnosis tend to remain stable, although progression can be observed [Lanzi et al 2002, Lanzi et al 2005];
    • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [Aicardi & Goutières 1984].
  • The main neuropathologic findings identified in severely affected individuals include [Kumar et al 1998, Barth 2002]:
    • Diffuse but non-homogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown;
    • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy;
    • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei;
    • Calcification in the media, adventitia, and perivascular spaces of small vessels;
    • Inflammation in the leptomeninges and areas of necrosis.

Phenotype Correlations by Gene

In general, the early-onset neonatal form of AGS is most frequently seen in association with biallelic pathogenic variants in RNASEH2A, RNASEH2C, or TREX1. 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 biallelic pathogenic variants in RNASEH2B, SAMHD1, or ADAR but may also be seen in individuals who have an autosomal dominant heterozygous pathogenic variant in ADAR or IFIH1 [Crow et al 2015].

Mortality is correlated with genotype: 34% of individuals with RNASEH2A, RNASEH2C, and TREX1 pathogenic variants were known to have died compared to 8% with RNASEH2B pathogenic variants (p=0.001) [Rice et al 2007b]. The mortality associated with other genotypes is less clear.

ADAR. Pathogenic variants in ADAR have been associated with a clinical presentation of acute bilateral striatal necrosis.

A subgroup of individuals with ADAR pathogenic variants can present with symmetric signal changes in the caudate and putamen, often associated with swelling and later shrinkage in the context of an acute or subacute onset of refractory four-limb dystonia. Cases have been identified with onset as late as age four years on a background of completely normal development [Livingston et al 2014a, La Piana et al 2014].

ADAR-related disease should be considered in the differential diagnosis of apparently nonsyndromic bilateral striatal necrosis (BSN) with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR pathogenic variants in this context.

RNASEH2B. Some individuals with biallelic pathogenic variants in RNASEH2B have relatively preserved intellectual function, with a few having a completely normal IQ and head circumference [McEntagart et al 1998]. RNASEH2B-related

RNASEH2C. A family with a recurrent Asian founder variant in RNASEH2C and striking intrafamilial variability has been described [Crow et al 2015].

SAMHD1

  • Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in SAMHD1.
  • Dale et al [2010] reported two sibs who had biallelic null variants 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 sibs 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] (see also Crow et al [2015]).
  • Biallelic pathogenic variants in SAMHD1 are most frequently associated with chilblains and glaucoma [Crow et al 2015].

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 persons with AGS in whom pathogenic variants in one of the associated genes have been identified [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]. Additional individuals with AGS who have signs and symptoms similar to systemic lupus erythematosus have also been described.

Prevalence

The actual frequency of AGS is unknown.

Pathogenic variants have been found in affected individuals of all ethnic origins [Crow et al 2006a, Crow et al 2006b, Rice et al 2007b, Rice et al 2013b] (see Table 1).

Differential Diagnosis

Calcification of the basal ganglia is a nonspecific finding seen in many diseases. However, in the context of an early-onset encephalopathy, conditions to consider include the following:

  • TORCH congenital infections are the most common conditions in the differential and the most important to rule out because misdiagnosis would result in erroneous counseling as to risk of recurrence.
    Note: Other congenital infections, such as those associated with Zika and HIV, should also be considered in the differential diagnosis.
  • The microcephaly-intracranial calcification syndrome (MICS). Given the phenotype of early-onset Aicardi-Goutières syndrome (AGS) cases (see Clinical Characteristics) [Reardon et al 1994], it is likely that most cases of MICS are in fact AGS (see Nomenclature). However, a number of other phenotypes are associated with neonatal intracranial calcification [Knoblauch et al 2003, Gardner et al 2005]; thus, this phenotype undoubtedly represents a heterogeneous group of diseases (see Nomenclature).
  • Band-like calcification polymicrogyria (BLC-PMG; pseudo-TORCH syndrome) (OMIM) [Abdel-Salam et al 2008, Briggs et al 2008] shows radiologic and clinical overlap with AGS, demonstrating intracranial calcification and significant psychomotor retardation with microcephaly and epilepsy. The condition can be differentiated by the observation of polymicrogyria (which has never been reported in AGS) and the identification of biallelic pathogenic variants in OCLN [O’Driscoll et al 2010].
  • Superficially, at least, the MRI scan findings in AGS with frontotemporal white matter changes and cysts can be confused with Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts, and childhood ataxia with central nervous system hypomyelination/vanishing white matter disease. The degree of white matter hypomyelination at an early age has also prompted consideration of Pelizeaus-Merzbacher disease in some individuals. In general terms, AGS should be considered in the differential diagnosis of an unexplained leukoencephalopathy. This clinical point is of particular importance because intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most medical facilities.
  • Classic Cockayne syndrome (CS type 1), a leukodystrophy with striocerebellar calcifications, is variably characterized by its distinctive facial features, dwarfism, nerve deafness, cataracts, retinal dystrophy, and skin photosensitivity. Inheritance is autosomal recessive.
  • Neonatal lupus erythematosus. Prendiville et al [2003] described basal ganglia calcifications and patchy white matter attenuation in infants with neonatal lupus erythematosus reminiscent of the imaging findings seen in AGS. These children demonstrated extensive erythematous skin lesions distinct from the chilblain lesions seen in AGS. The authors reported normal neurologic outcome in these cases.
  • Hoyeraal Hreidarsson syndrome, a severe form of dyskeratosis congenita, is caused by mutation in DKC1 (X-linked) or TINF2 (autosomal dominant). Hoyeraal Hreidarsson syndrome presents in the first months of life with microcephaly, cerebellar hypoplasia, and intracerebral calcifications. Affected males develop a pancytopenia that persists (in contrast to the thrombocytopenia seen in some individuals with AGS, which usually resolves in the first few weeks of life).
  • Mitochondrial cytopathies, including Leigh syndrome and the familial mitochondrial encephalopathy with intracerebral calcifications described by Samson et al [1994]. See also Mitochondrial Disorders Overview.
  • 3-hydroxyisobutyric aciduria (OMIM). Chitayat et al [1992] described monozygotic male twins, born to non-consanguineous parents, who had dysmorphic facial features, microcephaly, migrational brain disorder, and congenital intracerebral calcification.
  • Blau et al [2003] described three individuals with microcephaly, severe intellectual disability and motor retardation, dyskinesia, spasticity, and occasional seizures with extremely high CSF concentrations of neopterin and biopterin and low CSF concentration of 5-methyltetrahydrofolate. Although reported as having AGS, they did not demonstrate a CSF lymphocytosis or elevation of IFN-α concentration. Thus, these individuals may have an undefined syndrome within the group of infants with encephalopathy and intracranial calcifications. However, it is now known that a similar pterin profile can be observed in individuals with molecularly confirmed AGS [Rice et al 2007b].
  • Cerebroretinal microangiopathy with calcifications and cysts (CRMCC; Coats plus) (OMIM) is caused by biallelic pathogenic variants in CTC1 [Crow et al 2004b, Linnankivi et al 2006, Anderson et al 2012, Livingston et al 2014b].
  • Leukoencephalopathy, brain calcifications, and cysts (Labrune syndrome) (OMIM)

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Consultation with a clinical geneticist and/or genetic counselor

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:

  • Monitoring for signs of diabetes insipidus in the neonatal period
  • Assessment for glaucoma at least for the first few years 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 into the role of immunosuppressive agents in the treatment of AGS is ongoing [Crow & Rehwinkel 2009, Crow et al 2014b].

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 biallelic pathogenic variants in SAMHD1 raises important questions about the management of such individuals. 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 play 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.

Given the lack of evidence, no definitive statement about these issues can be made at present. However, the potential for intervention exists, and 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 the affected individuals described by Ramesh et al [2010], and it may be that their presence predicts an increased risk for intracranial vasculopathy.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1-related Aicardi-Goutières syndrome (AGS) is inherited in an autosomal recessive manner.

TREX1 and ADAR-related AGS can be inherited in an autosomal recessive or autosomal dominant manner depending on the specific pathogenic variant.

IFIH1-related Aicardi-Goutières syndrome (AGS) is inherited in an autosomal dominant manner.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one AGS-related pathogenic variant).
  • Heterozygotes (carriers) are not at risk of developing AGS; 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), depending on the specific gene and pathogenic variant involved (see Genetically Related Disorders).

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.
  • Heterozygotes (carriers) are not at risk of developing AGS; however, heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL), depending on the specific gene and pathogenic variant involved (see Genetically Related Disorders).

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

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an AGS-related pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the AGS-related pathogenic variants in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • If the TREX1, ADAR, or IFIH1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant AGS has a 50% chance of inheriting the AGS-related pathogenic variant; however, most individuals with AGS do not reproduce.

Other Family Members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for AGS are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Aicardi-Goutières Syndrome Association (IAGSA)
    Italy
    Email: associazione.iagsa@tiscali.it; iagsa@libero.it
  • National Library of Medicine Genetics Home Reference
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Aicardi-Goutieres Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Aicardi-Goutieres Syndrome (View All in OMIM)

146920ADENOSINE DEAMINASE, RNA-SPECIFIC; ADAR
225750AICARDI-GOUTIERES SYNDROME 1; AGS1
606034RIBONUCLEASE H2, SUBUNIT A; RNASEH2A
6066093-PRIME @REPAIR EXONUCLEASE 1; TREX1
606754SAM DOMAIN- AND HD DOMAIN-CONTAINING PROTEIN 1; SAMHD1
606951INTERFERON-INDUCED HELICASE C DOMAIN-CONTAINING PROTEIN 1; IFIH1
610181AICARDI-GOUTIERES SYNDROME 2; AGS2
610326RIBONUCLEASE H2, SUBUNIT B; RNASEH2B
610329AICARDI-GOUTIERES SYNDROME 3; AGS3
610330RIBONUCLEASE H2, SUBUNIT C; RNASEH2C
610333AICARDI-GOUTIERES SYNDROME 4; AGS4
612952AICARDI-GOUTIERES SYNDROME 5; AGS5
615010AICARDI-GOUTIERES SYNDROME 6; AGS6
615846AICARDI-GOUTIERES SYNDROME 7; AGS7

ADAR

Gene structure. ADAR is a single-copy 16-exon gene that encodes two main isoforms constitutively expressed in mammalian cells: a truncated protein (p110 NP_001020278.1) encoded by a transcript variant of 15 exons (NM_001025107.2) and an IFN inducible full-length protein (p150 NP_001102.2) induced isoform encoded by transcript variant NM_001111.4. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of pathogenic variants in ADAR result in autosomal recessive disease. Missense, nonsense, frameshift, and splice site pathogenic variants have been reported. One missense variant, p.Pro193Ala, is common in individuals of European origin. One dominant variant, p.Gly1007Arg, has been reported [Rice et al 2012, Livingston et al 2014a].

Table 4.

Selected ADAR Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.577C>Gp.Pro193AlaNM_001111​.4
NP_001102​.2
c.3019G>Ap.Gly1007Arg

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. DRADA, double-stranded RNA-specific adenosine deaminase, is a modular protein with a C-terminal deaminase catalytic domain, three centrally located dsRNA-binding domains (dsRBDs) and one or two N-terminal Z-DNA–binding domains; compared with p110, the p150 isoform of human DRADA possesses an additional 295 N-terminal amino acids containing a nuclear export signal and an extra Z-DNA/Z-RNA-binding domain.

Abnormal gene product. Pathogenic variants in ADAR are believed to cause AGS as a result of loss of protein activity; the precise mechanism leading to disease is unclear.

IFIH1

Gene structure. IFIH1 has 16 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All IFIH1 pathogenic variants associated with AGS to date have been missense variants that cause dominant disease.

Normal gene product. IFIH1 encodes the interferon-induced helicase C domain-containing protein 1, a cytosolic double-stranded RNA receptor.

Abnormal gene product. Pathogenic variants in IHIF1 associated with AGS encode missense variants that cause up-regulation of type I interferon signaling [Rice et al 2014].

RNASEH2A

Gene structure. RNASEH2A has eight exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of pathogenic variants in RNASEH2A are missense; splicing and frameshift pathogenic variants have also been reported [Crow et al 2006b, Rice et al 2007b] (see Table 5).

Table 5.

Selected RNASEH2A Pathogenic Variants

DNA Nucleotide Change 1Predicted Protein ChangeReference Sequences
c.69G>A 2p.Val23=NM_006397​.2
NP_006388​.2
c.75C>T 2p.Arg25=
c.109G>Ap.Gly37Ser
c.207_208insGp.Thr69AspfsTer50
c.322C>Tp.Arg108Trp
c.556C>Tp.Arg186Trp
c.690C>Ap.Phe231Leu
c.704G>Ap.Arg236Gln
c.716_717dupGCp.Thr239AlafsTer77
c.719C>Tp.Thr241Met
c.872G>Ap.Arg292His

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Frequency of each allele is less than 1%.

2.

Two synonymous variants (c.69G>A and c.75C>T) in RNASEH2A are pathogenic due to an alteration in RNA splicing [Rice et al 2013b].

Normal gene product. RNASEH2A encodes the ribonuclease H2 subunit A, which comprises 299 amino acids. Ribonuclease H (RNASEH) enzymes endonucleolytically cleave ribonucleotides from RNA:DNA duplexes. RNASEH2 has been proposed to function in the removal of lagging strand Okazaki fragment RNA primers during DNA replication, as well as in the excision of single ribonucleotides from DNA:DNA duplexes. However, the precise biologic function of the human RNASEH2 complex in the context of AGS is uncertain.

Abnormal gene product. See RNASEH2B, Abnormal gene product.

RNASEH2B

Gene structure. RNASEH2B has 11 exons and codes for a 308-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Almost all pathogenic variants so far identified in RNASEH2B are missense [Crow et al 2006b, Rice et al 2007b] (see Table 6).

The frequency of alleles identified in affected individuals is:

  • p.Ala177Thr (62%)
  • p.Thr163Ile (7%)
  • p.Val185Gly (7%)
  • c.136+1delG (4%)
  • Remaining alleles (<2%) [Rice et al 2007b]

Table 6.

Selected RNASEH2B Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.64+1G>A--NM_024570​.1
NP_078846​.1
c.136+1delG--
c.244+1G>T--
c.436+1G>T--
c.510+1G>A--
c.128C>Ap.Pro43His
c.132T>Ap.Cys44Ter
c.172C>Tp.Gln58Ter
c.179T>Gp.Leu60Arg
c.218G>Tp.Trp73Leu
c.247G>Ap.Gly83Ser
c.257A>Gp.His86Arg
c.412C>Tp.Leu138Phe
c.476G>Tp.Ser159Ile
c.485A>Cp.Lys162Thr
c.488C>Tp.Thr163Ile
c.529G>Ap.Ala177Thr
c.547C>Ap.Val183Met
c.554T>Gp.Val185Gly
c.655T>Cp.Tyr219His

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The precise function of the ribonuclease H2 subunit B protein within the human RNASEH2 complex is unknown.

Abnormal gene product. Pathogenic variants in genes encoding any of the three subunits of the ribonuclease H2 complex are thought to cause AGS resulting from a loss of enzymatic function.

RNASEH2C

Gene structure. RNASEH2C is a four-exon gene encoding a 164-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All pathogenic variants so far identified in RNASEH2C are missense [Crow et al 2006b, Rice et al 2007b] (see Table 7).

The frequency of alleles identified in affected individuals is:

  • p.Arg69Trp (72%)
  • Remaining alleles (seen only in single families)

Table 7.

Selected RNASEH2C Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.38G>Ap.Arg13HisNM_032193​.3
NP_115569​.2
c.205C>Tp.Arg69Trp
c.227C>Tp.Pro76Leu
c.412C>Tp.Pro138Leu
c.428A>Tp.Lys143Ile
c.451C>Tp.Pro151Ser

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The function of ribonuclease H2 subunit C (RNASEH2C) within the RNASEH2 complex is unknown.

Abnormal gene product. See RNASEH2B, Abnormal gene product.

SAMHD1

Gene structure. SAMHD1 has 16 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of pathogenic variants are missense, splice site, nonsense, or frameshift variants [Rice et al 2009].

Three large deletions plus a small deletion have also been identified. A large deletion of exon 1 is common among individuals of Ashkenazi Jewish descent [Crow et al 2015].

Table 8.

Selected SAMHD1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.359_370del12p.Asp120_His123delNM_015474​.3
NP_056289​.2
c.368A>Cp.His123Pro
c.427C>Tp.Arg143Cys
c.428G>Ap.Arg143His
c.433C>Tp.Arg145Ter
c.434G>Ap.Arg145Gln
c.445C>Tp.Gln149Ter
c.602T>Ap.Ile201Asn
c.625G>Ap.Gly209Ser
c.649_650insGp.Phe217CysTer2
c.760A>Gp.Met254Val
c.1106T>Cp.Leu369Ser
c.1153A>Gp.Met385Val
c.1324C>Tp.Arg442Ter
c.1411-2A>G(splice acceptor)
c.1503+1G>T(splice donor)
c.1642C>Tp.Gln548Ter
c.1609-1G>C(splice acceptor)
(exons 12-16del)--
(8984bp promoter+ex1del)--
(exons 1-13del)--

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. SAMHD1 is a 626-amino acid protein that consists of a SAM domain and an HD domain; the protein acts as a dNTP triphosphohydrolase [Goldstone et al 2011].

Abnormal gene product. Pathogenic variants in SAMHD1 are believed to cause AGS as a result of mislocalization of the protein or loss of protein function.

TREX1 (AGS1)

Gene structure. TREX1 has one exon. For a detailed summary of gene and protein information, see Table A, Gene.

Note: A great deal of confusion regarding TREX1 and the overlapping gene ATRIP exists in the databases. TREX1 and ATRIP are distinct genes that encode distinct proteins; they are not known to be relevant to one another [Yang et al 2007].

Pathogenic variants. Stop variants, deletions, and insertions are common in TREX1, but the most prevalent pathogenic variant is a missense variant (p.Arg114His) that affects the dimerization of the TREX1 protein (3' repair exonuclease 1) and is likely to be a functional null allele. The pathogenic variant p.Arg114His is particularly common in people from northern Europe.

Affected individuals are almost always homozygotes or compound heterozygotes for pathogenic variants within the same gene. However, children with clinically typical AGS had a de novo heterozygous pathogenic variant in TREX1 [Rice et al 2007a, Haaxma et al 2010, Abe et al 2014] (see Table 9).

The frequency of alleles identified in affected individuals is [Rice et al 2007b]:

  • p.Arg114His (50%)
  • c.58_59insG (1%)
  • Remaining alleles (<1%)

Table 9.

Selected TREX1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.52G>Ap.Asp18AsnAAK07616​.1
AF319569​.1
c.58_59insGp.Glu20GlyfsTer81
c.212_213dupTGp.Ala72Trpfster16
c.341G>Ap.Arg114His
c.365T>Cp.Val122Ala
c.366_368dupGGCp.Ala123dup
c.397delCp.Leu133CysfsTer26
c.393_408dup16p.Glu137ProfsTer23
c.490C>Tp.Arg164Ter
c.500delGp.Ser166ThrfsTer12
c.598G>Tp.Asp200Asn
c.600_601insGATp.Asp200dup
c.602T>Ap.Val201Asp
c.609_662dup54p.Leu204_Ala221dup
c.625_628dupCAGTp.Trp210SerfsTer31
c.868_885del18p.Pro289_Ala294del
c.907A>Cp.Thr303Pro

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TREX1 is a single-exon gene encoding a 314-amino acid residue protein.

TREX1 protein represents the major 3'→5' DNA exonuclease activity measured in mammalian cells. The protein has three conserved sequence motifs known as Exo I, II, and III. These motifs contain four conserved acidic residues that participate in coordination of divalent metal ions required for catalysis. In addition, the protein contains a C-terminal domain of about 75 amino acids, which is probably involved in subcellular localization of the protein, and a polyproline motif that may be involved in the interaction with other proteins. TREX1 appears to play a role in the disposal of single-stranded DNA possibly produced as a normal replication intermediate during S phase [Yang et al 2007], or derived from retro-elements [Stetson et al 2008].

Abnormal gene product. The most prevalent pathogenic variant in TREX1 is a missense change (p.Arg114His) that affects the dimerization of the TREX1 protein (3' repair exonuclease 1) and is likely to be a functional null allele, as are other reported frameshift variants.

References

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Suggested Reading

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Chapter Notes

Acknowledgments

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

Author History

Jean Aicardi, MD, FRCP; Hospital Robert-Debré, Paris (2005-2014)
Yanick J Crow, MBBS, BMedSci, MRCP, PhD (2005-present)
John BP Stephenson, DM, FRCP, HonFRCPCH; Royal Hospital for Sick Children, Glasgow (2008-2014)

Revision History

  • 22 November 2016 (MA) Comprehensive update posted live
  • 13 March 2014 (me) Comprehensive update posted live
  • 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
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