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The Aicardi-Goutieres syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis).

ABSTRACT: Aicardi-Goutières syndrome (Mendelian inheritance in man Catalog No *225750) is an autosomal recessive encephalopathy which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs together with chronic CSF lymphocytosis. The syndrome has superficial resemblance to the neurological sequelae of congenital infection, thus a rigorous search for microbiological and serological evidence of embryopathic infections should be carried out in each case.

SUBMITTER: Tolmie JL

PROVIDER: S-EPMC1051740 | biostudies-literature | 1995 Nov

REPOSITORIES: biostudies-literature

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The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis).

Tolmie J L JL Shillito P P Hughes-Benzie R R Stephenson J B JB

Journal of medical genetics 19951101 11

Aicardi-Goutières syndrome (Mendelian inheritance in man Catalog No *225750) is an autosomal recessive encephalopathy which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs t ...[more]

PMID: 8592332

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Project description:Aicardi-Goutières syndrome (AGS) is a rare interferon (IFN)-related encephalopathy with onset during the first year of life. AGS, is clinically characterized by progressive microcephaly, bilateral basal ganglia calcification, cerebral atrophy, cerebrospinal fluid (CSF), lymphocytosis, delayed development of psychomotor abilities with pyramidal-extrapyramidal syndrome and mimics congenital viral infections. Microarray analysis examining the expression of 18 880 human genes has been applied to the CSF lymphocytes of 20 AGS cases (age 4.5 +/- 4.4 years, mean +/- standard deviation) characterized by high IFN-alpha levels in CSF and 20 matched controls (age 4.4 +/- 4.3 years, mean +/- standard deviation). Gene-expression data reveal significant differences between AGS cases and controls for all controls and 18 AGS cases. The two AGS cases unclassified as compared with controls were both older than 7 years. AGS cases presented upregulation of genes involved in IFN-dependent pathways and lymphocyte functions, paralleled by the downregulation of genes encoding for angiopoietic activities. The cystatin F and DNAJ genes, having a negative feedback on IFN pathways, underwent a progressive age-related increase in their expression. These gene-expression signature parallels a progressive attenuation of clinical symptoms with age. Obtained results provide evidence that exposure to IFN-alpha is harmful for developing brain.

| S-EPMC8094786 | biostudies-literature

Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.

Project description:TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.

| S-EPMC1852703 | biostudies-literature

Developmental Outcomes of Aicardi Goutieres Syndrome.

Project description:Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or TREX1-related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

| S-EPMC7402202 | biostudies-literature

Late diagnosis and atypical brain imaging of Aicardi-Goutieres syndrome: are we failing to diagnose Aicardi-Goutieres syndrome-2?

Project description:Aicardi-Goutières syndrome (AGS) is a rare disorder with in utero or postnatal onset of encephalopathy and progressive neurological deterioration. The seven genetic subtypes of AGS are associated with abnormal type I interferon-mediated innate immune response. Most patients with AGS present with progressive microcephaly, spasticity, and cognitive impairment. Some, especially those with type 2 (AGS2), manifest milder phenotypes, reduced childhood mortality, and relative preservation of physical and cognitive abilities. In this report, we describe two siblings (sister and brother) diagnosed with AGS2 in their second decade, who exhibited static encephalopathy since 1 year of age with spastic quadriplegia and anarthria but preserved intellect. Both were homozygous for the common pathogenic RNASEH2B allele (c.529G>A, p.Ala177Thr). Rather than manifesting calcifications and leukoencephalopathy, both had increased iron signal in the basal ganglia. Our report broadens the clinical and imaging spectrum of AGS2 and emphasizes the importance of including AGS2 in the differential diagnosis of idiopathic spastic cerebral palsy. WHAT THIS PAPER ADDS:We identified two siblings (sister and brother) with atypical Aicardi-Goutières syndrome type 2 due to RNASEH2B mutation. Manifestations included spastic quadriplegia and anarthria but preserved intellect and increased iron signal in the basal ganglia. RNASEH2B-related Aicardi-Goutières syndrome type 2 can have present with a variable phenotype, including idiopathic spastic cerebral palsy.

| S-EPMC5685901 | biostudies-literature

Aicardi-Goutieres syndrome is caused by IFIH1 mutations.

Project description:Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy. To date, mutations in six genes have been identified as etiologic for AGS. Our Japanese nationwide AGS survey identified six AGS-affected individuals without a molecular diagnosis; we performed whole-exome sequencing on three of these individuals. After removal of the common polymorphisms found in SNP databases, we were able to identify IFIH1 heterozygous missense mutations in all three. In vitro functional analysis revealed that IFIH1 mutations increased type I interferon production, and the transcription of interferon-stimulated genes were elevated. IFIH1 encodes MDA5, and mutant MDA5 lacked ligand-specific responsiveness, similarly to the dominant Ifih1 mutation responsible for the SLE mouse model that results in type I interferon overproduction. This study suggests that the IFIH1 mutations are responsible for the AGS phenotype due to an excessive production of type I interferon.

| S-EPMC4085581 | biostudies-literature

Aicardi-Goutieres syndrome: neuroradiologic findings and follow-up.

Project description:BACKGROUND AND PURPOSE:To date, few studies have focused specifically on imaging findings in Aicardi-Goutières syndrome (AGS). We set out to evaluate retrospectively neuroradiologic data from a large sample of patients with AGS, focusing on the pattern of white matter abnormalities and the temporal evolution of the cerebral involvement to establish the radiologic natural history of the disease. MATERIALS AND METHODS:Thirty-six patients, 18 girls and 18 boys, were included. All had a clinical diagnosis of AGS, genetically confirmed in 31 of them. For every subject, we reviewed at least 1 CT and 1 MR imaging study; 19 (52.7%) had multiple examinations. In all, we reviewed 109 examinations. Clinical-neuroradiologic comparisons were analyzed by using the chi(2) test. RESULTS:Calcifications were found in all subjects, mainly in the basal ganglia, lobar white matter, and dentate nuclei. Abnormal white matter was present in all the subjects, showing 2 patterns of distribution: diffuse in 18 (50%) and an anteroposterior gradient in 18 (50%). Cystic areas were observed in the temporal and/or frontal lobes in 12/36 patients (33.3%). A correlation was found between early age at onset and severity of the leukoencephalopathy in the frontal (P = .024) and temporal (P = .034) regions. A significant degree of cerebral atrophy was found in 31/36 subjects (86.1%). The neuroradiologic presentation remained substantially stable with time. CONCLUSIONS:The different neuroradiologic presentations of AGS are here outlined for the first time in a large sample of patients. These findings may facilitate more precise and earlier diagnosis of this rare but probably underdiagnosed syndrome.

| S-EPMC7051307 | biostudies-literature

Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Project description:Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. 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. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological 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% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

| S-EPMC2227922 | biostudies-literature

Aicardi goutieres syndrome is associated with pulmonary hypertension.

Project description:While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

| S-EPMC6880931 | biostudies-literature

Cerebrospinal Fluid Hypovolemia and Posterior Reversible Encephalopathy Syndrome.

Project description:Posterior reversible encephalopathy syndrome (PRES) is a reversible neuroradiological syndrome characterized by reversible vasogenic edema. The pathophysiological mechanism is still unclear, but PRES may be triggered by various etiologies. To date, only a few PRES cases linked to cerebrospinal fluid (CSF) hypovolemia were reported. The association between PRES and CSF hypovolemia needs to be explored. We presented a case of PRES with CSF hypovolemia as a result of an inadvertent dural puncture and reviewed the literature to identify the clinical characterization and pathophysiological mechanism of PRES following CSF hypovolemia. A total of 31 cases of PRES-CSF hypovolemia was included for analysis. The median age was 33 years, with a notable female predominance (87.1%). Fifteen patients (48.4%) didn't have either a history of hypertension nor an episode of hypertension. The most common cause of CSF hypovolemia was epidural or lumbar puncture (n = 21), followed by CSF shunt (n = 6). The median interval between the procedure leading to CSF hypovolemia and PRES was 4 days. Seizure, altered mental state, and headache were the most frequent presenting symptom. The parietooccipital pattern was most frequent (71.0%). Conservative management remains the mainstay of treatment with excellent outcomes. Three patients had a second episode of PRES. CSF hypovolemia is a plausible cause of PRES via a unique pathophysiologic mechanism including arterial hyperperfusion and venous dysfunction. Patients with CSF hypovolemia is more susceptible to PRES, which is potentially life-threatening. Given that CSF hypovolemia is a common complication of anesthetic, neurological, and neurosurgical procedures, PRES should be early considered for prompt diagnosis and appropriate management.

| S-EPMC7324723 | biostudies-literature

Syndrome of Transient Headache and Neurologic Deficits with Cerebrospinal Fluid Lymphocytosis (HaNDL): HHV-7 Finding in Cerebrospinal Fluid Challenges Diagnostic Criteria.

Project description:The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare, self-limiting condition with severe headaches combined with neurological symptoms. However, evidence-based recommendations on diagnostics and treatments are unavailable due to the condition's rarity and unknown pathophysiology. A young man experiencing severe headache attacks fulfilled the HaNDL diagnostic criteria according to the third edition of the International Classification of Headache Disorders (ICHD-3). We present the dynamics of cerebrospinal fluid (CSF) biomarkers related to low human herpesvirus 7 (HHV-7) load and anti-inflammatory treatment outcomes. Low HHV-7 load may be an immunological trigger of HaNDL, such that elevated levels of CSF- chemokine (C-X-C motif) ligand 13 open a new way to interpret the role of B cells in HaNDL pathogenesis. We discuss the diagnostic challenge of HaNDL, according to the ICHD-3, in the case of pathogen presence at low load in CSF.

| S-EPMC10051435 | biostudies-literature

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