Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 230312006; ICD10CM: E79.81; ORPHA: 51; DO: 0050629;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Aicardi-Goutieres syndrome 1, dominant and recessive | 225750 | Autosomal dominant; Autosomal recessive | 3 | TREX1 | 606609 |
A number sign (#) is used with this entry because of evidence that Aicardi-Goutieres syndrome-1 (AGS1) is caused by homozygous, compound heterozygous, or heterozygous mutation in the TREX1 gene (606609) on chromosome 3p21.
Aicardi-Goutieres syndrome (AGS) is a genetically heterogeneous encephalopathy characterized in its most severe form by cerebral atrophy, leukodystrophy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon (IFNA1; 147660), and negative serologic investigations for common prenatal infections (Ali et al., 2006). AGS is phenotypically similar to in utero viral infection. Severe neurologic dysfunction becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process (Crow et al., 2006).
In a review of AGS, Stephenson (2008) noted that an expanded phenotypic spectrum has been recognized and that most of the original criteria for diagnosis no longer apply: affected individuals may show later onset and may not have severe or progressive neurologic dysfunction, calcification of the basal ganglia, or CSF lymphocytosis. The appearance of chilblains is an important clinical sign for correct diagnosis. The most severe neonatal form of AGS is typically due to mutation in the TREX1 gene.
Cree encephalitis was originally considered a separate disorder, but genetic evidence has shown that it is the same as AGS1. See also pseudo-TORCH syndrome (251290), which shows phenotypic overlap and may in some cases represent AGS (Crow et al., 2000; Crow et al., 2003). AGS is distinct from the similarly named Aicardi syndrome (304050), which is characterized by agenesis of the corpus callosum, spinal skeletal abnormalities, and chorioretinal abnormalities.
Genetic Heterogeneity of Aicardi-Goutieres Syndrome
See also AGS2 (610181), caused by mutation in the gene encoding subunit B of ribonuclease H2 (RNASEH2B; 610326) on chromosome 13q14; AGS3 (610329), caused by mutation in the RNASEH2C gene (610330) on chromosome 11q13; AGS4 (610333), caused by mutation in the RNASEH2A gene (606034) on chromosome 19p13; AGS5 (612952), caused by mutation in the SAMHD1 gene (606754) on chromosome 20q11; AGS6 (615010), caused by mutation in the ADAR1 gene (146920) on chromosome 1q21; AGS7 (615846), caused by mutation in the IFIH1 gene (606951) on chromosome 2q24; AGS8 (619486), caused by mutation in the LSM11 gene (617910) on chromosome 5q33; and AGS9 (619487), caused by mutation in the RNU7-1 gene (617876) on chromosome 12p13.
Aicardi and Goutieres (1984) reported 8 cases of progressive familial encephalopathy in infancy, with calcification of the basal ganglia and chronic CSF lymphocytosis, occurring in 5 families and leading rapidly to a vegetative state and early death. The authors considered this to be a distinct type of leukodystrophy transmitted as an autosomal recessive.
Giroud et al. (1986) reported an affected son of consanguineous Algerian parents. After a period of apparent normality, evidence of encephalopathy began at age 3 months. The CT scan at that time was normal, but the CSF showed lymphocytosis (75 cells per cubic mm; 85% lymphocytes). Serologic studies for the TORCH group showed no evidence of infection. CT scan at 9 months showed frontal atrophy, hypodensity in the white matter, and calcification of the lenticular nuclei. Death occurred before age 4 years.
Mehta et al. (1986) described 2 related infants, a boy and a girl, with microcephaly, spastic quadriplegia, profound retardation, extensive bilateral symmetrical calcification of the basal ganglia, and cerebrospinal fluid pleocytosis. The parents of the boy were known to be consanguineous; they were Muslims living in England. Mehta et al. (1986) suggested that 3 sibs reported by Babbitt et al. (1969) as familial cerebrovascular ferrocalcinosis, or Fahr disease (213600), had, in fact, suffered from this disorder.
Black et al. (1988) described an early-onset progressive encephalopathy in an inbred Canadian Aboriginal community. They termed this disorder 'Cree encephalitis' and distinguished it from another neurologic condition, Cree leukoencephalopathy (603896), which is a form of leukoencephalopathy with vanishing white matter. Cree encephalitis is characterized by severe psychomotor retardation, progressive microcephaly, cerebral atrophy, white matter attenuation, intracerebral calcification, a CSF lymphocytosis, and systemic immune abnormalities. In 10 of 11 affected children described, premature death resulted in a median age of 20.6 months. Although these features were noted as reminiscent of Aicardi-Goutieres syndrome, the conditions were considered distinct because of the observation of immunologic abnormalities and an apparent susceptibility to infection in Cree encephalitis. Crow et al. (2003) demonstrated that patients with Cree encephalitis had elevated CSF interferon-alpha levels, as in AGS. They also noted that 1 affected child reported by Black et al. (1988) had acrocyanosis, resulting in autoamputation of the fingers, reminiscent of the chilblain-like lesions seen in AGS (Goutieres et al., 1998; Tolmie et al., 1995). Crow et al. (2003) proposed that AGS and Cree encephalitis are allelic disorders.
In a review, Tolmie et al. (1995) concluded that nearly 30 cases of AGS had been reported. A raised level of CSF interferon-alpha was noted.
Kumar et al. (1998) described 5 boys and 2 girls in 2 sibships related as first cousins in a consanguineous British Muslim family of Pakistani origin. All presented from infancy to early childhood with progressive moderate to severe developmental delay, postnatal microcephaly, spastic quadriplegia, refractory seizures, and visual handicap. CSF pleocytosis was present in 3 children. Neuroimaging of 3 boys and a girl showed generalized cortical atrophy, dilatation of the lateral, third, and fourth ventricles, widening of the surface CSF spaces, hypoplasia of the posterior fossa structures, and multiple and solitary calcifications in the cerebral cortex and punctate calcifications involving basal ganglia, cerebellum, and Sylvian fissure. Histopathologic examination of the brain from 3 boys and 1 girl confirmed generalized cortical and cerebellar atrophy with widespread calcifications within the cortical gray and white matter, the basal ganglia, the cerebellum, and in some areas along the capillaries. Although this autosomal recessive syndrome showed phenotypic overlap with Aicardi-Goutieres syndrome, Kumar et al. (1998) raised the question of whether it represented a distinct disorder. Similar microcephaly and intracranial calcification with developmental delay occurs following intrauterine infection but is distinguishable by purpuric rash and associated thrombocytopenia.
McEntagart et al. (1998) reported 2 brothers, born of consanguineous parents from Dublin, Ireland, who presented in the first year of life with features of AGS. The first boy was normocephalic with normal IQ, but had spastic diplegia. Brain imaging in the second year of life showed punctate calcification of the basal ganglia and subcortical white matter and CSF pleocytosis. At age 9 years, clinical and imaging features were unchanged and CSF studies, including IFN-alpha were normal. At 21 months, the second boy had dystonic cerebral palsy, slight fall-off in head growth, and cognitive delay. Imaging abnormalities were more severe than those in the brother, and CSF examination showed pleocytosis and marked increase in IFN-alpha. Although the clinical course was not progressive, McEntagart et al. (1998) suggested that the brothers had a mild form of AGS.
Crow et al. (2000) studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutieres syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, calcification of basal ganglia, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha.
Dale et al. (2000) described a congenital infection-like syndrome comprising intracranial calcification, hepatitis, thrombocytopenia, and immunologic abnormalities including hypocomplementemia, progressive autoantibody activation, and raised levels of IgG and IgM. So striking were the immunologic abnormalities that the disorder was described as 'familial systemic lupus erythematosus (SLE).' Commenting, Aicardi and Goutieres (2000) highlighted the similarity to Aicardi-Goutieres syndrome and suggested that immune system dysfunction may form part of the Aicardi-Goutieres syndrome phenotype. Crow et al. (2003) pointed out clinical and pathologic similarities of the skin lesions seen in Aicardi-Goutieres syndrome and Cree encephalitis to those observed in SLE. Additionally, intracranial calcification, with a predilection for the basal ganglia, is recognized in SLE, occurring in up to 30% of patients with cerebral lupus (Raymond et al., 1996).
Crow et al. (2004) reported 3 children from 2 families with Aicardi-Goutieres syndrome. All 3 had congenital glaucoma. Additionally, neuroimaging demonstrated significant brainstem atrophy in the affected sib pair.
Lanzi et al. (2005) reported follow-up, after a mean of approximately 5 years, of 11 Italian patients with Aicardi-Goutieres syndrome. Mean age at symptom onset was 3.3 months, with irritability (45%), psychomotor delay (45%), fever, (35%), feeding difficulties (35%), and hyper- or hypotonia (35%). One patient (8%) had seizures and hepatosplenomegaly. The neurologic symptoms were progressive in the first year of life and stabilized by the end of the second year in 10 patients; 1 patient died of pneumonia at age 18 months. During the follow-up period, 3 patients developed seizures, 2 patients showed some improvement in psychomotor development and communication, and only 1 patient showed clear worsening. Five patients had skin lesions consistent with acrocyanosis, more commonly in the colder months. Serial brain imaging of 6 patients showed basal ganglia calcifications that were unchanged in 4 patients but increased in 2 patients. White matter abnormalities remained stable in all 6 patients. Diffuse cerebral atrophy remained stable in 4 patients but progressed in 2. Serial CSF studies in 3 patients showed reduction of alpha-interferon levels over time, although the level remained elevated in 1 patient.
Rice et al. (2007) described a child with classic Aicardi-Goutieres syndrome who was the child of nonconsanguineous Scottish parents. He presented at age 4 months with developmental delay. Cerebrospinal fluid examination at age 3 years demonstrated 4 white cells/cubic mm, and a raised titer of IFN-alpha (147660). MRI showed demyelination, and calcification of the basal ganglia was seen on CT scan. At age 7 years the patient was profoundly delayed, with no meaningful communication, and was fed by gastrostomy tube. He demonstrated severe spasticity with dystonic posturing and was microcephalic. He had never experienced seizures. He had several chilblain-like lesions on his toes and hands and a more generalized patchy mottling of the skin on all 4 limbs and over his trunk. These lesions first developed around the age of 12 months and, while present throughout the year, were significantly worse in the winter. Genetic analysis identified a de novo heterozygous missense mutation in the TREX1 gene (D200N; 606609.0006). A standard exonuclease assay indicated close-to-normal TREX1 enzymatic activity. Rice et al. (2007) hypothesized that the aspartic acid at position 200 of TREX1 represents 1 of 4 residues essential for coordinating 2 magnesium ions involved in DNA binding and catalysis, and that the D200N mutation represents a gain-of-function mutation conferring altered substrate specificity, DNA binding, or protein-protein interaction, which would not be detected in a standard TREX1 exonuclease assay.
Adang et al. (2018) reported a patient with AGS1 and compound heterozygous mutations in the TREX1 gene (see 606609.0010). He presented at 2 months of age with pulmonary hypertension that caused his death. Other symptoms of Aicardi-Goutieres syndrome included CNS perivascular calcifications and gastrointestinal symptoms, but no dermatologic manifestations.
By means of genomewide linkage analysis in families with AGS, Crow et al. (2000) mapped the disorder to chromosome 3p21 (maximum heterogeneity lod score of 5.28 at marker D3S3563, with alpha = 0.48, where alpha is the proportion of families showing linkage). The data suggested the existence of locus heterogeneity in this syndrome.
Crow et al. (2003) found that Cree encephalitis maps to the same region on chromosome 3p21 as does AGS1 and concluded that the 2 disorders are allelic.
Lee-Kirsch et al. (2006) pointed out that familial chilblain lupus (610448), an autosomal dominant monogenic form of cutaneous lupus erythematosus, maps to 3p21-p14, thus overlapping the map location of the autosomal recessive AGS1. Despite the clinical differences and the difference in mode of inheritance, Lee-Kirsch et al. (2006) raised the possibility that these 2 disorders may be allelic. Some patients with AGS1 have chilblain-like lesions that resemble those found in the large German family with chilblain lupus. Moreover, AGS1 has been suggested to be a form of systemic lupus erythematosus, because of the findings of hypocomplementemia and antinuclear autoantibodies in addition to lupus-like skin lesions in some patients.
Vanderver et al. (2020) conducted an open-label study of a single-center, expanded-access program involving 35 patients with genetically confirmed AGS. The patients received baricitinib, an oral JAK1 and JAK2 inhibitor, at doses ranging from 0.1 to 0.6 mg per kg of body weight per day, administered in 2 to 4 dosing increments per day. Median age of onset of AGS was 6.0 months, and the median age at the initiation of baricitinib was 2.9 years (range 0.2 to 21.8 years). The patients participated in the study for a minimum of 12.0 months (range 11.8 to 43.8 months). Two patients died during the study: one had been receiving glucocorticoids for a decade, including a 7-year period before the study, and developed AGS-related multisystem organ failure with an opportunistic infection, and the other had AGS-related pulmonary hypertension with thrombotic microangiopathy. For all other patients, only thrombocytosis increased in severity during the study. Parents of the patients used diaries to record the children's AGS-related symptoms, including neurologic disability, crying, sleep disturbances, irritability, seizures, fever, and skin inflammation of the trunk, arms, and legs. Improvement was observed within 1 month of initiation of therapy and was sustained. Before treatment, 26 of the 35 patients had stable or declining neurologic function, and 9 of the 35 patients gained one or 2 skills after disease onset. During the study, 20 patients met new milestones, and 12 patients gained 2 to 7 new skills. This improvement was noted by 3 months and persisted. One patient lost skills during an acute illness while participating in the study. Children in a higher daily dose category of baricitinib met more milestones than those in a lower daily dose category according to weight-based calculations. The primary risks associated with baricitinib among patients with the AGS were thrombocytosis, leukopenia, and infection. Vanderver et al. (2020) suggested that patients that are receiving baricitinib should be monitored closely, especially those with underlying thrombotic risk factor or those who are receiving systemic glucocorticoids or immunosuppressive regimens.
The transmission pattern of AGS1 in the families reported by Crow et al. (2006) was consistent with autosomal recessive inheritance.
The heterozygous mutations identified in patients with AGS1 by Rice et al. (2007) and Haaxma et al. (2010) occurred de novo.
In affected members of 10 unrelated families with AGS1, Crow et al. (2006) identified 5 different biallelic mutations in the TREX1 gene (see, e.g., 606609.0001-606609.0004). Seven of the families were of European descent.
In a patient with Cree encephalitis, born of consanguineous parents, Crow et al. (2006) identified a homozygous nonsense mutation in the TREX1 gene (606609.0002).
To define the molecular spectrum of Aicardi-Goutieres syndrome, Rice et al. (2007) performed mutation screening in patients from 127 pedigrees with a clinical diagnosis of the disorder. Biallelic mutations in TREX1 (606609), RNASEH2A (606034), RNASEH2B (610326), and RNASEH2C (610330) were observed in 31, 3, 47, and 18 families, respectively. In 5 families, Rice et al. (2007) identified an RNASEH2A or RNASEH2B mutation on 1 allele only. In 1 child, the disease occurred because of a de novo heterozygous TREX1 mutation (606609.0006). In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe (arg114 to his; 606609.0001). Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. Rice et al. (2007) identified an RNASEH2C founder mutation in 13 Pakistani families (arg69 to trp; 610330.0001).
Haaxma et al. (2010) reported a second patient with Aicardi-Goutieres syndrome and a de novo heterozygous TREX1 mutation (D18N; 606609.0007). The 16-year-old girl had relatively mild AGS, and displayed additional features indicative of mitochondrial dysfunction and peripheral neuropathy. Analysis of 4 other AGS-related genes and the entire mitochondrial DNA did not reveal any other mutations. The D18N mutation in TREX1 had previously been identified in heterozygosity by Lee-Kirsch et al. (2007) in a family with chilblain lupus; Haaxma et al. (2010) had no explanation for how the same mutation might cause such distinct phenotypes.
Rice et al. (2007) analyzed clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infections seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurologic function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% of RNASEH2B mutation-positive patients were known to have died (P = 0.001). The data from the study of Rice et al. (2007) indicated that at least 1 further AGS-causing gene remained to be identified.
Peixoto de Barcelos et al. (2024) reviewed clinical features in 167 patients with AGS from the Myelin Disorders Biorepository Project natural history cohort. The natural history cohort included the following patients: 26 with TREX1 mutations, 50 with RNASEH2B mutations, 3 with RNASEH2C mutations, 7 with RNASEH2A mutations, 25 with SAMHD1 mutations, 34 with ADAR mutations, 19 with IFIH1 mutations, and 3 with RNU7-1 mutations. Median age at diagnosis was 1.83 years, but median age of systemic onset was 0.15 years. More severe neurologic burden of disease was associated with the presence of microcephaly, mutations in the TREX gene, systemic disease onset before 1 year of age, feeding tube placement, and seizures. Patients with ADAR mutations had better (less severe) AGS scores. Moyamoya syndrome was present in 6 patients, all of whom had mutations in SAMHD1, and 2 patients with mutations in RNASEH2B had strokes. The most common extra-neurologic features were gastrointestinal, including dysphagia or feeding intolerance in 124 patients, and dermatologic symptoms. Chilblains were reported in patients with mutations in RNASEH2B (12 patients), SAMHD1 (12 patients), TREX1 (11 patients) and IFIH1 (2 patients). Ocular or vision abnormalities were reported in 33% of patients and occurred later in patients with SAMHD1-related disease compared to TREX1-related disease. Overall, the time to feeding tube placement, the presence of chilblains, early motor delay, early cognitive delay, and motor regression were significantly associated with patient genotype.
At the level of its clinical presentation, AGS is a notable mendelian mimic of the sequelae of congenital viral infection. These resemblances are so strong as to suggest the likelihood of common mechanisms involved in the pathogenesis of the inherited and the infectious syndromes (Crow et al., 2003). Consistent with this notion, both AGS and a number of placentally acquired viral infections are characterized by the production of high levels of interferon-alpha. That this IFN-alpha may have a pathogenic role in the disease is indicated by the observation that astrocyte-specific chronic overproduction of IFN-alpha in transgenic mice recapitulates the neuropathologic findings seen in AGS (Akwa et al., 1998). Crow et al. (2006) suggested that the TREX1 gene and the apparently unrelated genes encoding the RNase H2 complex encode enzymes functioning in the same DNA processing pathway such that failure of these nuclease activities may result in the survival and accumulation of intracellular DNA repair and replication intermediates, which then trigger an inappropriate viral-like innate immune response. The findings of mutations in these genes in patients with AGS implicates a cellular process involving RNA-DNA hybrids as the pathogenic basis of the disorder.
Crow and Rehwinkel (2009) reviewed the pathogenesis of AGS with respect to the phenotypic overlap both with the sequelae of congenital infection and with systemic lupus erythematosus (SLE; 152700). Experimental evidence suggested that the nucleases defective in AGS are involved in removing endogenously produced nucleic acid species, and that a failure of this removal results in activation of the immune system. This hypothesis explains the phenotypic overlap of AGS with congenital infection and some aspects of SLE, where an equivalent type I interferon-mediated innate immune response is triggered by viral and self nucleic acids, respectively.
By differentiating neural stem cells into astrocytes and treating them with short hairpin RNA (shRNAs) to AGS genes, Cuadrado et al. (2015) observed increased apoptosis in cells treated with shRNA to TREX1. Similarly, TREX1 silencing led to reduced proliferation of endothelial cells, but not of cells involved in angiogenesis. Silencing of TREX1 or SAMHD1, but not RNASEH2A or ADAR1, resulted in enhanced expression of IFN-stimulated genes (ISGs), such as IFIT1 (147690). TREX1 shRNA treatment led to increased production of proinflammatory and chemotactic cytokines. Cuadrado et al. (2015) proposed that activation of antiviral status in astrocytes and endothelial cells may lead to cerebral pathology and ultimately severe disease in AGS.
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