Clinical manifestations

Presentation and course

Aicardi-Goutieres syndrome is a genetically heterogeneous disease typically characterized by encephalopathy or intellectual disability, microcephaly during the first year, psychomotor delay, dystonia, spasticity, sterile pyrexias, hepatosplenomegaly, and chilblain lesions. Some affected children display features at birth, but most infants with Aicardi-Goutieres syndrome seem to have disease manifestations in the first 12 months after birth. Clinical observations suggest the presence of an early period of active regression occurring for several months, followed by a stable disease course with stable encephalopathy (13).

Various clinical phenotypes with different mutations have been reported. Crow and colleagues published a paper that summarized the disease, with Aicardi-Goutieres syndrome–related genes and clinical phenotypes. This article uses the same classification as it is a clinically applicable and basic classification (23).

Clinical phenotypes

Prenatal and infantile–onset Aicardi-Goutieres syndrome. Affected infants present with microcephaly, feeding problems, jitteriness, abnormal movements, and epileptic disorders. Hematologic disturbances, such as anemia, thrombocytopenia, and elevated liver function tests with hepatomegaly, can be seen and remarkably mimic a transplacentally acquired infection (“pseudo-TORCH”). The onset of disease is considered to be in utero or infantile. Affected infants demonstrate clinical features at birth or abrupt-onset crying, irritability, excessive startle, and eye movement abnormalities. Progressive loss of acquired skills may be noted a few months after birth. Encephalopathy lasts for a few months and is associated with developmental delay, neurologic regression, and microcephaly. Although TREX1 mutations are most commonly associated with in utero onset, and RNASEH2B gene mutations are frequently associated with infantile onset, many Aicardi-Goutieres syndrome–related mutations (AGS1-7) can result in this clinical phenotype. This phenotype is associated with an increased mortality rate in infancy. Neuroimaging findings with intracranial calcifications, frontotemporal white matter abnormalities, leukodystrophy, and cerebral atrophy are valuable for the diagnosis (23).

Later-onset Aicardi-Goutieres syndrome. Later-onset Aicardi-Goutieres syndrome begins after the first year of life with subacute encephalopathy and neurologic regression and demonstrates similar clinical findings and neuroimaging markers. Orcesi and colleagues described a case who was healthy until the age of 16 months, when she developed hypersomnia, irritability, and high-grade fever (25). Infectious work-up was unremarkable, including TORCH panel. Neurologic exam revealed axial hypotonia with pyramidal signs and loss of all milestones within 3 weeks. MRI brain showed bilateral lentiform nucleus calcifications. CSF demonstrated raised levels of interferon alfa, and genetic analysis revealed an AGS2/RNASEH2B gene mutation. At 32 months of age, neurologic exam showed truncal and neck hypotonia as well as pyramidal and extrapyramidal signs. There was no recovery of previously acquired milestones. Similar cases of RNASEH2B and ADAR1 gene mutations have been reported in the literature.

Bilateral striatal necrosis. Dystonia is the key element of this clinical picture. Patients may also present with developmental delay, neurologic regression, eye movement abnormalities, spastic paraparesis, and autoimmune features similar to the classic Aicardi-Goutieres syndrome phenotype. Neuroimaging demonstrates bilateral striatal necrosis. ADAR1 gene mutations represent an important cause of bilateral striatal necrosis. Onset of the disease can be early or later in life. The clinical course can be severe, with progressive dystonia and early death. ADAR1-related disease should be considered in any child with bilateral striatal necrosis or unexplained subacute onset dystonia (23).

Hereditary spastic paraparesis. Patients with slowly progressive (“nonsyndromic”) spastic paraparesis due to mutations in ADAR1, RNASEH2B, and IFIH1 have been reported in recent years. According to the literature, cranial and spinal cord imaging can be completely normal, or only nonspecific findings may be seen. Spastic paraparesis can be slowly progressive over the years (23). A dominant variant in the ADAR gene (c.3019G> A) was specifically associated with neurologic manifestations that mimic spastic paraplegia and dystonic cerebral palsy (11).

SAMHD1-related cerebrovascular disease. A particular feature of this phenotype is intracerebral large-vessel disease, including aneurysms, moyamoya disease, intracranial stenosis with infarcts, and intracerebral hemorrhage, which is frequently associated with biallelic pathogenic variants in the SAMHD1 gene. Mutations in this gene can be associated with clinically heterogeneous phenotypes, including classic Aicardi-Goutieres syndrome or cerebrovasculopathy, with normal intellectual function (27). Some case studies suggest that non-neurologic features, such as glaucoma and skin disease, are generally present with this genotype (23). Although intracerebral large artery involvement has been a particular feature of SAMHD1-associated disease, similar pathology has also been described with the homozygous TREX1 variant (38).

Epileptic seizures occur in approximately one quarter of patients with Aicardi-Goutieres syndrome, and the electroclinical basis still requires further studies. Electroencephalography may show a diffuse background slowing and disruption of electrical organization (16).

Non-neurologic features. It is important to recognize non-neurologic features of the disease as a clue in diagnosis. Chilblains, glaucoma, sterile pyrexias, deforming arthropathy, and some autoimmune features, including lupus-like disease and thyroiditis, can be seen.

Aicardi-Goutieres syndrome was initially considered a progressive neurodegenerative disease. However, with the identification of more cases and genes, it is now thought that the disease does not progress beyond the encephalopathic period in most cases. The disease generally has a “plateau” period after the neurologic regression episode with encephalopathy in the classic presentation.

Table 1. Summary of Clinical Manifestations in Aicardi-Goutieres Syndrome

Prognosis and complications

The classic clinical course of the disease is a period of encephalopathy, loss of acquired milestones, and neurologic regression with progressive radiological changes. Clear progression has been noted in some types of ADAR1 mutations. The disease generally has a “plateau phase” after the initial regression; however, profound disabilities do not improve. Early death occurs in childhood in some patients (approximately 20%); however, most patients (approximately 70% to 75%) survive after the initial regression episode without further deterioration (10).

Mortality is considered to be correlated with genotype. RNASEH2B mutations were associated with later age at presentation and lower mortality when compared to individuals with RNASEH2A, RNASEH2C, and TREX1 mutations (29). LSM11 was reported in two siblings who presented with neonatal irritability, seizures, and developmental delay who died at 2 years of age. The RNU71 gene was described in 16 patients who presented with increased tone in the neonatal period, spastic dystonia, and diplegia or quadriplegia. Early deaths were noted in five patients due to different reasons (kidney failure, liver failure, seizure). Clinical prognosis and presentation vary between patients (36).

Increasing knowledge of the molecular basis of the disease mechanism has led to novel targeted therapies. Multicenter studies are needed on the efficacy of novel treatments and the potential outcome of the disease (17).

Biological basis

The identification of the genetic basis of Aicardi-Goutieres syndrome has marked an era of understanding of the clinical phenotypes and disease pathogenesis. The first gene mutation to be revealed was TREX1, which was described in 2006 in 10 families (09). Mutation screening in patients from 127 pedigrees with a clinical diagnosis revealed RNASEH2A, RNASEH2B, and RNASEH2C mutations, in addition to TREX1 mutations (29). Subsequent analysis revealed SAMHD1, ADAR2, and IFIH1 mutations, which broadened the clinical phenotypes. LSM11 and RNU71 gene mutations were described in 2020 in patients with a classic presentation of Aicardi-Goutieres syndrome (36).

Etiology and pathogenesis

Mutations in Aicardi-Goutieres syndrome–related genes account for most of the patients with classic Aicardi-Goutieres syndrome. It has been reported that these genes encode specific proteins involved in the metabolism of DNA or RNA. Mutations in these genes result in the accumulation of endogenous nucleic acids and are recognized as viral or nonself, which initiates the induction of type 1 interferon-related immune response (13). Interestingly, elevated CSF levels of interferon alfa are a diagnostic parameter for Aicardi-Goutieres syndrome. Furthermore, the presence of clinical overlaps between systemic lupus erythematosus and Aicardi-Goutieres syndrome has been well recognized. Therefore, the term “type 1 interferonopathy” is recommended to describe the wider spectrum of Aicardi-Goutieres syndrome, which is thought to be caused by the failure of self-versus-non-self recognition. It has been hypothesized that type 1 interferon is directly relevant to diagnosis. Mutations in these genes result in type 1 interferon response, which is similar to that after exposure to a virus and may explain the resemblance to a congenital infection. It was shown that type 1 interferon signaling dysregulation can happen in different mechanisms:

(1) Cytosolic accumulation of endogenous nucleic acids by loss-of-function mutations of genes that encode degradation

(2) Alterations in DNA-sensing and RNA-sensing pathways

(3) Activation of interferon signaling regulators

(4) Deactivation of negative interferon signaling regulators

(5) Proteasomal dysfunction causing increased interferon signaling (14)

In addition, many researchers have revealed the role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway in autoimmune disorders, including Aicardi-Goutieres syndrome (19). It has a key role in the recognition of invasive pathogens.

It is essential to highlight the complex molecular heterogeneity of the disorder for underlying mechanisms as the field of targeted therapies is emerging. For example, RNase H2 has been shown to play a role in the transcription of genes by maintaining a critical R-loop homeostasis (05). The RNase H2 mutation interferes with transcription, causing accumulation of R loops and a displaced DNA strand that causes short and intronless genes. The accumulation of R-loops leads to activation of the immune system caused by the damaged DNA.

ADAR converts adenosine to inosine in dsDNA and stabilizes the DNA helix (32). It protects dsRNA from dsRNA sensing molecules and inhibits the interferon-mediated response.

SAMHD1 functions as a ssRNA 3’exonuclease, and mutations cause RNA accumulation in cells and dissolution of RNA-protein condensates, which then triggers the activation of type 1 interferon (24).

Epidemiology

The actual frequency of Aicardi-Goutieres syndrome is unknown. Various pathological variants have been reported in different ethnic populations (09; 29; 30).

Prevention

Prenatal testing for pregnancies at increased risk and carrier testing are available. Prior identification of the pathogenic variant in the family is required (23).

Differential diagnosis

Confusing conditions

The literature has highlighted the exclusion of the presence of other prenatal or perinatal infections, including TORCH infections, Zika virus, and HIV, in the differential diagnosis of Aicardi-Goutieres syndrome. Considering the early-onset encephalopathy with white matter abnormalities, it is necessary to exclude metabolic and neurodegenerative disorders.

The differential diagnosis of Aicardi-Goutieres syndrome includes the following:

Diagnostic workup

Diagnostic workup should focus on raising early suspicion and on facilitating genetic testing and clinical and laboratory workup. Aicardi-Goutieres syndrome has characteristic clinical and radiological findings as well as supportive laboratory parameters. Aicardi-Goutieres syndrome should be considered in individuals with abrupt or subacute encephalopathy, acquired microcephaly, dystonia, sterile pyrexias, chilblain lesions, and characteristic neuroimaging findings. There has not been a standardized, validated tool that can measure symptom severity. However, the “Aicardi-Goutieres syndrome–specific neurologic scale,” which assesses gross motor, fine motor, speech, and cognitive skills as well as head circumference, seems to be a promising tool to longitudinally follow neurologic function in this population (01).

Neuroimaging demonstrates basal ganglia calcifications, which include the putamen, thalamus, and globus pallidus, in particular. White matter changes, particularly in frontotemporal regions, may include temporal lobe cyst formation. Progressive cerebral atrophy, cerebrovasculopathy, and intracranial stenosis are other findings.

Elevated liver enzymes, anemia, and thrombocytopenia are nonspecific but supportive laboratory findings for the diagnosis of Aicardi-Goutieres syndrome.

Increased expression of type 1 interferon-regulated genes (interferon signature) is a nonspecific finding in Aicardi-Goutieres syndrome and can be seen in any other autoimmune disease (29; 30; 12; 10). CSF analysis reveals chronic CSF pleocytosis, elevated interferon alfa activity, and raised neopterin levels.

Prompt and comprehensive genetic testing with next-generation sequencing is crucial to advancing potential targeted therapies. It is important to note that large deletions may be missed on exome sequencing.

The diagnosis is established in individuals with typical clinical findings, characteristic neuroimaging features, or the identification of pathogenic variants in Aicardi-Goutieres syndrome–related genes.

Management

Outcomes

There is no definitive cure for Aicardi-Goutieres syndrome. Current treatment options aim to prevent end organ damage by controlling inflammation and to improve quality of life. A multidisciplinary approach is recommended to optimize medical care in the setting of multisystemic involvement.

After the initial diagnosis and developmental assessment, the assessment of feeding and nutritional status is recommended to establish the extent of the disease. EEG can be performed to evaluate seizure-like activity, if clinically suspected. Given the hereditary nature of the disease, genetic counseling is essential. Anticipatory guidance and surveillance workup, including monitoring signs of diabetes insipidus in the neonatal period, glaucoma assessment in the first few years of life, assessment of the spine for the development of scoliosis, and monitoring signs of diabetes mellitus and hypothyroidism, are recommended.

There are currently therapies under investigation and ongoing research studies (13). Considering the inflammatory basis of the disease, immunosuppressive treatments have been investigated in a small number of individuals. In an open-label pilot study from France, eight patients with specific mutations were treated with reverse-transcriptase inhibitors over a period of 12 months (31). A reduction in interferon signaling and an increase in cerebral blood flow was reported in patients with Aicardi-Goutieres syndrome. A controlled trial with a larger group of patients is recommended.

Crow and colleagues reported definitive improvement in TREX1-related skin disease and IFIH1-related systemic inflammation. In 2020, another open-label study from a single center in the United States included 35 patients with genetically confirmed Aicardi-Goutieres syndrome (37). Patients received baricitinib, an oral JAK1 and JAK2 inhibitor, which resulted in some clinical improvement in some patients as well as changes in interferon signaling. Fremond and colleagues trialed JAK1/2 inhibition in 11 patients with Aicardi-Goutieres syndrome (18). A clear benefit of JAK1/2 inhibition was reported on certain systemic features of Aicardi-Goutieres syndrome over a follow-up period of 17 months. Only a limited benefit was reported on the neurologic symptoms of the disease, which the authors attribute to the late stage of the disease at treatment onset and poor CNS penetration of the drug. Glucocorticoids have been shown to decrease interferon levels in CSF, although empirical treatment with corticosteroids or immunoglobulin did not show any clear evidence of benefits (25).

Increasing knowledge of the biallelic SAMHD1 mutations related to intracranial large vessel disease raises questions about the management of arteriopathy. Given the lack of evidence, no definitive statement can currently be made, and each case should be evaluated individually.

Special considerations

Pregnancy

There are no reported cases of Aicardi-Goutieres syndrome in pregnancy.

Anesthesia

A careful preoperative evaluation must be obtained prior to the use of an anesthetic agent. The possibility for difficult airway management during ventilation and intubation must be considered, particularly in patients with microcephaly and temporomandibular joint sclerosis. Muscle relaxants should be avoided, if possible, in patients with Aicardi-Goutieres syndrome. Besides a difficult airway, thermal dysregulation, muscle weakness, and predisposition to seizures are other considerations that might impact the perioperative care of patients with Aicardi-Goutieres syndrome. Patients may have varied responses to nondepolarizing neuromuscular blockage (33).