Aicardi-Goutieres syndrome is a genetically heterogeneous autosomal recessive 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 ... Aicardi-Goutieres syndrome is a genetically heterogeneous autosomal recessive 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 13q; AGS3 (610329), caused by mutation in the RNASEH2C gene (610330) on chromosome 11q13.2; AGS4 (610333), caused by mutation in the RNASEH2A gene (606034) on chromosome 19p13.13; AGS5 (612952), caused by mutation in the SAMHD1 gene (606754) on chromosome 20; and AGS6 (615010), caused by mutation in the ADAR1 gene (146920) on chromosome 1q21.
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 ... 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.
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 ... 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.
In affected members of 10 unrelated families with AGS1, Crow et al. (2006) identified 5 different mutations in the TREX1 gene (see, e.g., 606609.0001-606609.0004). Seven of the families were of European descent.
In a patient with ... In affected members of 10 unrelated families with AGS1, Crow et al. (2006) identified 5 different 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.