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Aicardi-Goutières Syndrome

Includes: ADAR-Related Aicardi-Goutières Syndrome, RNASEH2A-Related Aicardi-Goutières Syndrome, RNASEH2B-Related Aicardi-Goutières Syndrome, RNASEH2C-Related Aicardi-Goutières Syndrome, SAMHD1-Related Aicardi-Goutières Syndrome, TREX1-Related Aicardi-Goutières Syndrome
, MBBS, BMedSci, MRCP, PhD
Genetic Medicine, University of Manchester
Manchester Academic Health Science Centre
Central Manchester Foundation Trust University Hospitals
Manchester, United Kingdom

Initial Posting: ; Last Update: March 13, 2014.

Summary

Disease characteristics. Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical handicap. 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 mutation of the AGS-related genes is not yet known. For example, mutation of ADAR has recently been associated with a clinical presentation of acute bilateral striatal necrosis.

Diagnosis/testing. The diagnosis of AGS can be made with confidence in individuals with typical clinical findings, characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), with identifiable mutations in one of the six known related genes. Disease-causing allelic variants in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, or ADAR are identified in approximately 90% of individuals with consistent clinical and radiologic findings of AGS. At least one other gene in which mutation is disease causing is postulated but remains unknown.

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 de novo autosomal dominant mutation of TREX1 or ADAR. 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic allelic variant(s) in the family have been identified.

Diagnosis

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 six known related genes.

The following features are seen in a majority of affected individuals [Goutières et al 1998, Lanzi et al 2002, Rice et al 2007b, Livingston et al 2013]:

  • 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
  • Interferon signature identified using quantitative PCR analysis of RNA / cDNA in peripheral blood [Rice et al 2013a]
  • 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 1

Figure

Figure 1. 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 (more...)

Figure 2

Figure

Figure 2. 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. (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 3

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 other metabolic disorder or neurodegenerative disorder

Neuroimaging

Calcification. Intracranial calcifications are best visualized on CT scan. The following are noted:

  • Calcifications frequently involve the globus pallidus, putamen, caudate nucleus, thalamus, and dentate nucleus [Lanzi et al 2002, Uggetti et al 2009, Livingston et al 2013] (Figure 1A, 1B).
  • They frequently extend into the white matter, in particular the para- (rather than true peri-) ventricular area (Figure 1C).
  • They are often punctate but may be dense and rock-like.
  • Those identified at diagnosis tend to remain stable, although progression can be observed [Lanzi et al 2002, Lanzi et al 2005].
  • Extent of calcification is not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may / may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [Aicardi & Goutières 1984].

Leukodystrophy. Hypodensity of the white matter is present in a significant number of affected individuals [Lanzi et al 2002]. On MRI, hypodensity appears on T2-weighted images as a hyperintense signal most commonly located around the horns of the ventricles (Figure 1). White matter changes in severe early-onset cases can be particularly prominent frontally [Crow et al 2004a].

Of note, intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units.

Cerebral atrophy

Bilateral striatal necrosis is observed in a subgroup of individuals with AGS who have pathogenic variants in ADAR (see Genotype-Phenotype Correlations).

Intracerebral vasculopathy, including intracranial stenosis and aneurysms, have been reported in individuals who have pathogenic variants in SAMHD1 (see Genotype-Phenotype Correlations).

Testing

Previously, the most important clinical laboratory tests contributing to the diagnosis of AGS involved 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 can be normal after the first few years of life [Rice et al 2007b, Rice et al 2013a].

More recently, it has been shown that most individuals with AGS demonstrate markedly increased expression of interferon-stimulated genes (ISGs) in peripheral blood – called an ‘interferon signature’. This feature is sustained over time, can be used to reliably differentiate individuals with AGS from controls, and is more sensitive than tests of interferon activity and levels of neopterin in CSF [Rice et al 2013a].

Interferon signature can be assessed by quantitative PCR analysis of RNA / cDNA in peripheral blood.

  • In a series of 82 individuals with AGS, seventy-four (90%) had a positive interferon score.
  • Of the eight affected individuals with a negative interferon score, seven had mutations in RNASEH2B.
  • 55 of 56 individuals (98%) with mutations in the other known AGS-related genes (TREX1, RNASEH2A/B/C and SAMHD1) demonstrated a positive score.
  • Of the eight affected individuals tested who were over the age of 20 years all demonstrated a positive interferon score.

Repeat sampling in 16 affected individuals tested was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. These, data confirm that testing for an interferon signature is highly reliable for the recognition of AGS as an aid to molecular screening.

Interferon-alpha (IFN-α). CSF IFN-α concentration may be elevated (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 can 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 elevated in molecularly proven AGS [Rice et al 2007b], so this appears to be a good marker of the disease:

  • 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.

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

Molecular Genetic Testing

Genes. Pathogenic variants in one of the following genes are known to cause AGS (Figure 4):

Figure 4

Figure

Figure 4. Percentages of families (n = 250) with AGS with either biallelic or recognized dominant mutations in RNASEH2A, RNASEH2B, RNASEH2C, TREX1, SAMHD1, or ADARI.

Evidence for locus heterogeneity. Genetic data indicate that at least one further gene may be associated with the AGS phenotype [Rice et al 2012].

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

Gene 1Proportion of AGS Attributed to Mutation of This GeneTest MethodMutations Detected 2
TREX1 22%Sequence analysis 3Sequence variants 4
Targeted mutation analysisc.490C>T (p.Arg164Ter) 5, 6
Deletion/duplication analysis 7Exonic deletions/duplications 8
RNASEH2B38%Sequence analysis 3Sequence variants 9
Deletion/duplication analysis 7Exonic deletions/duplications 8
RNASEH2C14%Sequence analysis 3Sequence variants, including an Asian founder mutation 10
Deletion/duplication analysis 7Exonic deletions/duplications
RNASEH2A6%Sequence analysis 3Sequence variants
Deletion/duplication analysis 7Exonic deletions/duplications 8
SAMHD112.5%Sequence analysis 3Sequence variants 11
Deletion/duplication analysis 7Exonic deletions/duplications 12
Targeted mutation analysisSee footnote 5
ADAR7.5%Sequence analysis 3Sequence variants 13

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis of the coding regions and splice sites of these six genes has identified mutations approximately 90%-95% of individuals with clinical and MRI presentation of AGS [Rice et al 2007b, Rice et al 2009].

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

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

5. Mutation panel may vary by laboratory.

6. A recurrent c.490C>T, p.Arg164Ter founder mutation in TREX1 is seen in individuals of Cree ancestry.

7. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. No deletions or duplications involving RNASEH2A, RNASEH2B, or TREX1 have been reported to cause Aicardi-Goutières syndrome.

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

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

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

12. 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. A recurrent splice acceptor site mutation (c.1411-2A>G) in intron 12 is seen in persons of Amish ancestry and represents an ancient founder mutation [Xin et al 2012].

13. A dominant c.3019G>A, p.Gly1007Arg mutation in ADAR has been reported [Rice et al 2012, Livingston et al 2014a].

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 the 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

  • Sequential sequence analysis can be pursued based on the individual’s ethnicity and/or in the order in which mutations most commonly occur. If only one mutant allele is identified, deletion/duplication analysis should be performed.
  • Multi-gene panel analysis. An alternative to the sequential molecular genetic testing described above is a panel in which some or all of the genes known to cause Aicardi-Goutières syndrome are evaluated simultaneously. 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 may be non-contributory; (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. However, testing for an interferon signature is now more helpful than CSF analysis for this purpose.

Clinical Description

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 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. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression. Several individuals are known to be alive beyond age 30 years with no obvious signs of disease progression.

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. Some individuals with RNASEH2B mutations have relatively preserved intellectual function, with a few having a completely normal IQ and head circumference [McEntagart et al 1998]. Moreover, a family with a recurrent Asian founder mutation in RNASEH2C and striking intrafamilial variability was recently described [Vogt et al 2013].

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 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 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. However, there is a risk of glaucoma congenital or later onset glaucoma [Crow et al 2004a]

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 3). The cutaneous lesions may be complicated by periungual infection and necrosis. Chilblains are associated with mutations in all six genes. Chilblains seem to be a common feature in individuals who have de novo dominant TREX1 mutations [Rice et al 2007, Haaxma et al 2010, Abe et al 2014].

Infrequently observed features of AGS are summarized in Table 2.

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].

Nine ADAR mutation-positive individuals from seven families were reported to demonstrate an acute (5 cases) or subacute (4 cases) onset of refractory four-limb dystonia starting between age eight months and five years. Eight affected individuals were developmentally normal at initial presentation. In seven cases the disease was inherited as an autosomal recessive trait, while two related affected individuals were found to have a heterozygous (dominant) ADAR mutation. All seven mutation-positive individuals assayed showed an upregulation of ISGs (median: 12.50, interquartile range (IQR): 6.43 – 36.36) compared to controls (median: 0.93, IQR: 0.57 – 1.30), present many years after disease onset. Thus, ADAR-related disease should be considered in the differential diagnosis of apparently non-syndromic 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 mutations in this context.

Table 2. Infrequent Features Seen in a Cohort of 123 Individuals with Mutation-Positive AGS

FeatureNumber of Affected Individuals by Mutated Gene
TREX1RNASEH2BRNASEH2CRNASEH2A
Scoliosis0900
Cardiomegaly4011
Abnormal antibody profile2310
Preserved language0600
Demyelinating peripheral neuropathy1210
Congenital glaucoma2010
Micropenis1010
Hypothyroidism1100
Insulin-dependent diabetes mellitus1100
Transitory deficiency of antidiuretic hormone1000

Rice et al [2007b]. Note: This paper was published before the identification of SAMHD1 and ADAR mutation as a cause of AGS.

Pathology

Neuropathologic findings. The main neuropathologic findings identified in severely affected individuals include [Kumar et al 1998, Barth 2002]:

  • Marked microcephaly
  • 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

Skin biopsy. Tubuloreticular inclusions [Rich 1981] in endothelial cells have been observed in some individuals, particularly those with high circulating levels of IFN-α [Goutières et al 1998]. On direct immunofluorescence, fine granular staining for IgM may be seen in the basement membrane [Stephenson 2002]. Biopsy findings are frequently described as showing a lymphocytic vasculitis; however, other patients have been reported to demonstrate a leukocytoclastic vasculitis.

Genotype-Phenotype Correlations

The phenotypes associated with mutations in each of the six genes known to cause 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 recently described 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, Xin et al 2011]. To date, this phenotype has not been reported in association with mutation of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, or ADAR.

A subgroup of individuals with ADAR mutations 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].

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 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].

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, Rice et al 2013b]:

  • 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].
  • A recurrent splice-acceptor site mutation (c.1411-2A>G) in SAMHD1 intron 12 is seen in persons of Amish ancestry and represents an ancient founder mutation [Xin et al 2012].
  • A recurrent ADAR mutation, c.577C>G, is seen in affected persons of European origin.

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.
  • The microcephaly-intracranial calcification syndrome (MICS; also known as pseudo-TORCH syndrome or Baraitser-Reardon syndrome). Given the phenotype of early-onset Aicardi-Goutières syndrome (AGS) cases (see Clinical Description) [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.
  • Band-like calcification polymicrogyria (BLC-PMG) [Briggs et al 2008b, Abdel-Salam 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 mutations in OCLN [O’Driscoll et al 2010].
  • Superficially, at least, the MRI scan findings in AGS with frontotemporal white matter changes and cysts can cause confusion 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 loss 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.
  • Familial hemophagocytic lymphohistiocytosis (FHL) is also an inherited autoimmune disorder with sterile pyrexias, cerebrospinal fluid lymphocytosis, and occasional cerebral calcification; but serious confusion with AGS has not been reported. Inheritance is autosomal recessive.
  • Cockayne syndrome, a leukodystrophy with striocerebellar calcifications 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. This X-linked disorder caused by mutations in DKC1 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. 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 who are mutation positive for AGS [Rice et al 2007b].
  • Cerebroretinal microangiopathy with calcifications and cysts (CRMCC; also known as Coats plus, Labrune syndrome, and leukoencephalopathy with cysts/LCC) [Crow et al 2004b, Linnankivi et al 2006; Anderson et al 2012, Livingston et al 2014b]. A number of children with this condition have been misdiagnosed as having a later-onset form of AGS; however, Briggs et al [2008a] have also presented evidence of very early onset of this condition. CRMCC is not associated with raised CSF white cells, IFN-α, or pterins. CRMCC is now known to be caused by mutation of CTC1 [Anderson et al 2012].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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

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 (ec.europa.eu) [Crow & Rehwinkel 2009, Crow et al 2014].

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 mutation of 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.

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 patients described by Ramesh et al [2010], and it may be that their presence predicts an increased risk for intracranial vasculopathy.

Genetic Counseling

Mode of Inheritance

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

Less frequently, TREX1-related and ADAR-related AGS are 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 pathogenic variants have been identified in the family.

Risk to Family Members — De Novo Dominant Mutation

Parents of a proband

Sibs of a proband

  • Because heterozygous TREX1 mutation resulting in AGS occurs 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 mutation resulting in AGS occurs de novo, other family members of a proband are not at increased risk. Note: To date, the only exception is a report of one family segregating a heterozygous mutation in TREX1 (p.Asp18Asn) in which two of the affected family members had FCL and a third family member with the same pathogenic variant met diagnostic criteria for AGS [Abe et al 2013].

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

Molecular genetic testing. If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

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 an option for some families in which the pathogenic variant(s) have been identified.

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-Goutieres Syndrome Association (IAGSA)
    Via Vittadini, 1
    Pavia 27100
    Italy
    Phone: +39 0382 33342
    Fax: +39 0382 33342
    Email: iagsa@libero.it
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    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 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
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

TREX1 (AGS1)

Gene structure. TREX1 has one exon. GenBank accession numbers: AAK07616, AF319569. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

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 allelic variants. Stop mutations, deletions, and insertions are common in TREX1, but the most prevalent pathogenic variant is a missense mutation (c.341G>A) that affects the dimerization of the TREX1 protein (3' repair exonuclease 1) and is likely to be a functional null allele. The pathogenic variant c.341G>A is particularly common in people from northern Europe.

Affected individuals are almost always homozygotes or compound heterozygotes for mutations within the same gene. However, children with clinically typical AGS had a de novo heterozygous mutation in TREX1 [Rice et al 2007a, Haaxma et al 2010, Abe et al 2014] (see Table 3).

Table 3. Selected TREX1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences 2
c.52G>Ap.Asp18AsnAAK07616​.1
AF319569​.1
c.58_59insG 1 p.Glu20GlyfsTer81
c.212_213dupTGp.Ala72Trpfster16
c.341G>A 1 p.Arg114His
c.365T>Cp.Val122Ala
c.366_368dupGGCp.Ala123dup
c.397delCp.Leu133CysfsTer26
c.393_408dupp.Glu137ProfsTer23
c.490C>Tp.Arg164Ter
c.500delGp.Ser166ThrfsTer12
c.598G>Tp.Asp200Asn
c.600_601insGATp.Asp200dup
c.602T>Ap.Val201Asp
c.609_662dupp.Leu204_Ala221dup
c.625_628dupCAGTp.Trp210SerfsTer31
c.868_885delp.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.

1. Frequency of alleles for this gene: c.341G>A (50%); c.58_59insG (1%); remaining alleles (<1%) [Rice et al 2007b]

2. www​.ncbi.nlm.nih.gov/Genbank

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 have 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 retroelements [Stetson et al 2008].

Abnormal gene product. The most prevalent mutation in TREX1 is a missense change (c.341G>A) that affects the dimerization of the TREX1 protein (3' repair exonuclease 1) and is likely to be a functional null allele.

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 Symbol.

Pathogenic allelic variants. Almost all mutations so far identified in RNASEH2B are missense [Crow et al 2006b, Rice et al 2007b] (see Table 4).

Table 4. Selected RNASEH2B Pathogenic Variants

DNA Nucleotide Change 1 Protein Amino Acid ChangeReference Sequences
c.64+1G>A--NM_024570​.1
NP_078846​.1
c.136+1delG 1 --
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>T 1 p.Thr163Ile
c.529G>A 1 p.Ala177Thr
c.547C>Ap.Val183Met
c.554T>G 1 p.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.

1. Frequency of alleles for this gene: c.529G>A (62%); c.488C>T (7%); c.554T>G (7%); c.136+1 delG (4%); remaining alleles (<2%) [Rice et al 2007b].

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

Abnormal gene product. Mutations 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 Symbol.

Pathogenic allelic variants. All mutations so far identified in RNASEH2C are missense [Crow et al 2006b, Rice et al 2007b] (see Table 5).

Table 5. Selected RNASEH2C Pathogenic Variants

DNA Nucleotide Change 1 Protein Amino Acid ChangeReference Sequences 2
c.38G>Ap.Arg13HisNM_032193​.3
NP_115569​.2
c.205C>T 1 p.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.

1. Frequency of alleles: c.205C>T (72%); all other alleles seen only in single families

2. www​.ncbi.nlm.nih.gov/Genbank

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.

RNASEH2A

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

Pathogenic allelic variants. Almost all mutations in RNASEH2A are missense [Crow et al 2006b, Rice et al 2007b] (see Table 6).

Table 6. Selected RNASEH2A Pathogenic Variants

DNA Nucleotide Change 1Protein Amino Acid ChangeReference Sequences 2
c.69G>A 3p.= 4
(Val23Val)
NM_006397​.2
NP_006388​.2
c.75C>T 3p.= 4
(Arg25Arg)
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. www​.ncbi.nlm.nih.gov/Genbank

3. 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].

4. p.= signifies that protein has been analyzed but no amino acid change is expected.

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.

SAMHD1

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

Pathogenic allelic variants. The majority of pathogenic variants are missense or stop mutations [Rice et al 2009]. Three large deletions plus a small deletion have also been identified.

Table 7. Selected SAMHD1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.359_370delp.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. Mutations in SAMHD1 are believed to cause AGS as a result of mislocalization of the protein or loss of protein.

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 Symbol.

Pathogenic allelic variants

Table 8. Selected ADAR Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.577C>Gp.Pro193AlaNM_001111​.4
NP_001102​.2
c.3019G>A p.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. Mutation of ADAR is believed to cause AGS as a result of loss of protein activity; the precise mechanism leading to disease is unclear.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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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Chapter Notes

Acknowledgments

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

  • 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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