Aicardi-Goutieres syndrome 1; AGS1

What is Aicardi-Goutieres syndrome 1; AGS1?

Aicardi-Goutieres syndrome 1; AGS1 is a rare disease. It is also known as Ags Cree Encephalitis Encephalopathy, Familial Infantile, With Intracranial Calcification And Chronic Cerebrospinal Fluid Lymphocytosis Pseudotoxoplasmosis Syndrome.

This condition is progressive in nature and has an onset during the first year of life. There is rapid neurological deterioration resulting in bilateral spasticity and dystonia, accompanied by a head which fails to grow and abnormal eye movements. Convulsions are only occasionally present. Swelling and erythema of the toes with peeling of the skin (chilblains) may be a feature. Two useful signs are the presence of a CSF lymphocytosis (although this is not always present - Crow et al., 2003) and a CT scan which shows a combination of calcium in the lenticular nuclei (and occasionally in the dentate nucleus), areas of low attenuation resembling a leukodystrophy, and cerebral atrophy. In some cases the intracranial calcification is more widespread. In the report by Aicardi and Goutieres (1984) there were twelve cases in six families, and the parents of three were consanguineous. It should be noted that head circumference can be normal at birth, and the intracerebral calcification may not become apparent until after six months of age. Tolmie et al., (1995) provide a good review. In single cases an intrauterine infection is often diagnosed, incorrectly. Thrombocytopenia, haemolytic anaemia, abnormal liver function tests and hepatosplenomegaly have all been reported. Lebon et al., (1998) noted the association with raised CSF interferon-alpha. Glaucoma was a feature in three patients including sibs, reported by Crow et al., (2004). A follow-up study of 11 Italian patients was presented by Lanzi et al., (2005). The chillblain-like skin lesions developed late. A chronic arthropathy with contractures may develop (Dale et al., 2010). Neuromyelitis optica can occur (Hacohen et al., 2015).
Note the sibs reported by Taipa et al., (2010). Both have mutations, yet one had neonatal onset and the other (both are alive in their 20s) had late-onset dystonia and is fairly mild.
It should be noted that the three sibs described by Boltshauser et al., (1991) did not have a CSF pleocytosis and had severe dysmyelination. This may be a separate condition - infantile encephalopathy with cerebral calcification and leukodystrophy (qv). However a sib pair was reported by Ostergaard et al., (1999), in whom only one of the sibs had the pleocytosis and had a milder clinical course. Three cases were reported by Blau et al., (2003). There was no pleocytosis, but CSF analysis showed extremely high neopterin and biopterin combined with a low 5-methyltetrahydofolate.
Kumar et al., (1998) reported a large inbred pedigree where seven individuals had a condition with features of Aicardi-Goutieres syndrome. There was progressive postnatal microcephaly, spastic quadriplegia and visual handicap. There was diffuse cortical atrophy with enlarged ventricles and hypoplasia of the cerebellum. Multiple intracerebral calcifications involving the basal ganglia and Sylvian fissure, and the cerebellar hemispheres were noted. CSF pleocytosis was noted in two cases and a raised CSF interferon-alpha in another. The severity of the CSF abnormalities were thought to be more severe than that seen in classical Aicardi-Goutieres syndrome. Intracerebral large artery disease also occurs (Ramesh et al., 2010).
Two sibs with this condition were reported by Verrips et al., (1997). One (still alive at nine years) is now severely retarded whereas the other was normal until 12 months, before onset and now at four years he can still make social contact and play with other children. Both had basal ganglia calcification and cells in the CSF. More remarkable are the sibs reported by McEntagart et al., (1998) in that one at the age of nine years is of normal intelligence, despite his spastic diplegia, normocephay, intracranial calcification and pleocytosis. The other brother has a clinical picture of dyskinetic cerebral palsy. From these sib pairs, it is evident that not all cases have intracerebral calcification or white matter abnormalities, there is not always CSF lymphocytosis, and the condition is not always severe or progressive. Indeed, the sib of the case (with a RNASEH2C mutation) reported by Vogt et al., (2013) was of normal intelligence, but had chillblains and a mild hemiparesis. In an update of the condition (Goutieres et al., 1998), these authors found high levels of interferon-alpha in serum and CSF, in 14 out of 27 patients. Nineteen of their patients were still alive and six were older than 10 years. There is some evidence (at post-mortem) that the condition might be a microangiopathy (Barth et al., 1999). A microangiopathy occurred in the two sibs reported by Rasmussen et al., (2005). They had increased levels of interferon-alpha, and also antiphospholipid antibodies (in the living sister). Both of these findings occur in SLE and these authors suggest that the two conditions might be closely related. Ramantani et al., (2011) also reported a case who in early childhood developed SLE. Magnetic resonance spectroscopy studies have shown evidence of a brain lactic alkalosis (Robertson et al., 2004). In a follow-up study by Oostergaard and Christensen (2004) the white matter changes progressed and there was transient worsening of the calcification.
Faure et al., (1999) studied five families by homozygosity mapping but could not find linkage to one specific area. They concluded that there may be genetic heterogeneity. Crow et al., (2000) studied 23 children from 13 families and mapped the gene to chromosome 3p21, but with evidence of genetic heterogeneity, with an approximately 50% of families being linked. Cree encephalitis (Black et al., 1988) appears to be allelic (Crow et al., 2003). The condition is well reviewed by Goutieres (2005). He considers that MICS (see elsewhere) might also be allelic. The gene for AGS1 has been identified (Crow et al., 2006). It encodes the human ribonuclease H2 which has three subunits. TREX1 mutations have also been found to be causative (Crow et al., 2006). This is also at 3p21.
Rice et al., (2007) showed that AGS1 could also be caused by a heterozygous mutation of TREX1, and that a TREX1 mutation could also cause familial chilblain lupus. In a further study of 127 pedigrees with a clinical diagnosis, Rice et al., (2007) found 31 TREX1 mutations, three RNASEH2A mutations 47 RNASE2B and 18 RNASE2C mutations (A, B, and C are subunits of RNASEH2). Twenty-two families were without a mutation. The early-onset neonatal form looking like congenital infection was particularly seen with TREX1 mutations and a later presentation especially after several months of normal development was mostly due to mutations in RNASEH2B. Heterozygous mutations were also reported by Haaxma et al., (2010), as have homozygous deletions (Leshinsky-silver et al., 2011). Clinically, the features were those of an atypical Aicardi-Goutieres (white matter desruction and calcification) and multiple mtDNA deletions.
Mutations in ADAR1 - a putative suppressor of type I interferon signalling is also responsible for the phenotype (Rice et al., 2012). Note that heterozygous mutations cause dyschromatosis symmetrica hereditaria (DSH) - see elsewhere. Interestingly, the parents (heterozygous) did not show features of DSH.
Piekutowska-Abramczuk et al., (2016) described two siblings with compound heterozygous mutations in the ADAR gene. The symptoms started in the first year of life. Neurological features included dystonia, hypertonia and sensorimotor neuropathy of axonal type. Brain MRI revealed bilateral striatal sclerosis and symmetrical changes in putamen. Laboratory investigations showed high alanine in blood and in the CSF and high plasma lactate.
Tumiene et al., (2017) reported a patient with Aicardi-Goutieres syndrome due to a homozygous mutation in the TREX1 gene and an inflammatory myopathy.
Armangue et al., (2017) suggested to detect Aicardi Goutières syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.
Hebbar et al., (2017) described four male patients from three unrelated consanguineous Indian families with Aicardi–Goutieres syndrome due to a founder c.205C>T mutation in RNASEH2C gene. All patients presented with early onset encephalopathy, seizures, neurodevelopmental delay, spasticity, and brisk deep tendon reflexes. Brain abmormalities included delayed myelination, hypoplastic corpus callosum, white matter abnormalities, and intracranial calcifications. One patient had hypothyroidism, two had feeding difficulties and three had dystonia. The patients had mild coarse facial features.

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* This information is courtesy of the L M D.

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What gene changes cause Aicardi-Goutieres syndrome 1; AGS1?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.


In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 225750 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
TREX1 - 3p21.31
ADAR - 1q21.3
IFIH1 - 2q24.2
RNASEH2B - 13q14.3
USP18 - 22q11.21
SAMHD1 - 20q11.23

What are the main symptoms of Aicardi-Goutieres syndrome 1; AGS1?

The typical symptoms of the syndrome are:
Dystonia, Progressive encephalopathy, Elevated hepatic transaminase, Abnormality of extrapyramidal motor function, Fever, Feeding difficulties in infancy, Deep white matter hypodensities, Hepatosplenomegaly, Hepatomegaly, Global developmental delay, Increased CSF interferon alpha, Thrombocytopenia, Muscular hypotonia of the trunk, Multiple gastric polyps, Prolonged neonatal jaundice, Intellectual disability, profound, Progressive microcephaly, Leukoencephalopathy, Poor head control, Petechiae, Autosomal recessive inheritance, Seizure, Purpura, Nystagmus, Autosomal dominant inheritance, Strabismus, Splenomegaly, Spasticity, Morphological abnormality of the pyramidal tract, Chronic CSF lymphocytosis, Chilblains, Cerebral atrophy, Acrocyanosis, Basal ganglia calcification

How does someone get tested for Aicardi-Goutieres syndrome 1; AGS1?

The initial testing for Aicardi-Goutieres syndrome 1; AGS1 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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