Aicardi-Goutières Syndrome
Introduction
What is the Aicardi-Goutières Syndrome (AGS)?
Aicardi-Goutières syndrome (AGS) —is a rare hereditary disease involving the brain, immune system, and the skin. AGS 's involvement in the brain affects mostly the white matter. [1] This condition is also considered a genetic Type I interferonopathy [2] and some phenotypes are associated with severe morbidity and mortality. [3]
The disease is also referred to as pseudotoxoplasmosis syndrome, encephalopathy with basal ganglia calcification, familial infantile encephalopathy with intracranial calcification and chronic cerebrospinal fluid lymphocytosis, or Cree encephalitis. [1]
One may not confuse AGS with the similarly named Aicardi syndrome where absence of a brain structure (corpus callosum), and spinal, skeletal, and eye abnormalities are observed. [4]
What causes AGS?
The main cause is a mutation in one or more genes resulting in a buildup of calcium in the brain, which is thought to trigger the immune response that causes symptoms of AGS. [1]
The AGS-associated genes encode proteins responsible for the metabolism or sensing of nucleic acid (DNA; RNA). As a result, mutations in these genes lead to the induction of the type I interferon, which has been hypothesised to be closely linked to pathogenesis. [2] Interferon is typically produced by humans with a virus infection. In AGS, there is no viral infection, but instead, the cells of affected patients are confused into thinking that their own genetic material is coming from a virus, constantly producing interferon that is damaging the cells. [5]
Clinical presentation
The clinical presentation of AGS mimics the symptoms and signs of a viral infection acquired in utero. [3] However, one must note that clinical differences between patients are often observed, both within families and across genotypes. [2]
Based on Onset of Disease
Two forms of AGS depending on the age they begin were initially proposed: an early-onset neonatal form and a later-onset form.
Early-onset AGS
The early-onset form presents at birth and is the more serious form of the syndrome - with permanent damage of brain functions and severe lifelong impairments. This form is highly reminiscent of congenital infection and is usually common with TREX1 mutations. [3]
Early-onset AGS signs and symptoms may include:
- Jittery behavior
- Poor feeding ability from birth
- Neurological and liver abnormalities at birth
- Smaller head size (microcephaly)
- Liver inflammation
- Seizures
- Skin rashes
Later-onset AGS
The later-onset form is observed within the first few weeks or months of infancy and normal development. The infant may present with decreased symptoms and remarkably preserved neurological function, most frequently due to RNASEH2B mutations. [1] [3] Other symptoms may include:
- Irritability or inconsolable crying
- Intermittent, unexplained fever
- A decline in head growth
- Developmental delays
- Seizures
- Skin problems known as chilblains (rash, lesions, or swelling on fingers, toes, and ears that worsen in cold temperatures)
Other common presentation features
- Glaucoma in the first few months of life
- Scoliosis
- Diabetes
- Underactive thyroid
- Problems with the heart, lungs, and blood vessels and platelets
Based on Mutation-associated Phenotypes
Based on discovered phenotypes associated with mutations, Crow et al. [2] summarised the main clinical presentations to the paediatric neurologist:
| Cinical Presentation | Related gene mutation |
|---|---|
| Classic AGS presenting with prenatal or infantile onset, mimics trans-placentally acquired infection (‘pseudo-TORCH’) -irritability, feeding difficulties, microcephaly, abnormal movements, and epileptic seizures, haematological disturbances e.g. thrombocytopenia, anaemia, and liver dysfunction, associated with white matter disease and intracranial calcification on neuroimaging | |
| Spastic Dystonic Syndrome presenting after 1 year of age with either the subacute onset of profound neurological regression, or with a more slowly progressive, variable combination of spasticity and dystonia associated with normal neuroimaging or the presence of non-specific white matter changes and/or intracranial calcification | |
| Bilateral striatal necrosis (unexplained subacute onset dystonia) at a few months of age or in later childhood | Almost exclusively ADAR1 |
| Slowly progressive (‘non-syndromic’) spastic paraparesis (some with completely normal spinal and cranial imaging) | ADAR1, IFIH1, and RNASEH2B |
| Cerebrovasculopathy including moyamoya and aneurysms with intracerebral haemorrhage and infarcts | SAMHD1 |
Diagnosis
Diagnosis is confirmed based on relevant clinical findings and genetic testing. [6] A mutation-screening strategy is followed for the majority of the phenotypic spectrum of AGS i.e. mutations in any of the following genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. [7] An AGS-causing gene remains to be identified. [3] Computed tomography is a diagnostic metod of coice over magnetic resonance imaging for identifying cerebral calcification. [2]
Management
To date, there is no established medical treatment for AGS. Progress in understanding the AGS disease pathogenesis has however encouraged some more targeted attempts. [2][8]
Data from in vitro and animal studies suggest that treatment may vary according to genotype: self-derived DNA relates to disease due to TREX1, RNase H2 complex, and SAMHD1 dysfunction; self-derived RNA is responsible for interferon signalling in the context of ADAR1 and IFIH1 mutations. [3] Some drugs called reverse transcriptase inhibitors (RTIs) have been investigated on a small pilot study for their the effect on interferon levels and other markers which might give further treatment clues. [5] The study suggested potential benefit of RTIs when used in combination with other drugs but a definite effect is still lacking. [5] Janus kinase (JAK) inhibitors are another group of medication suggested to be effective in blocking interferon activation in patients with the Aicardi–Goutières syndrome. [9] [10]
‘Broad spectrum’ immunosuppression has also been used in affected individuals, but the efficacy of these interventions is difficult to judge because of the small numbers involved, the different regimens employed, and the stage of the disease process at which treatment was started. [2]
In terms of physical treatments, the multisystemic and variable nature of the syndrome's presentation may require the collaborative work of an interdisciplinary team from an early age. Treatment mainly focuses on features of the clinical presentation, avoidance of complications and the patients' wellbeing. For example, children who have feeding difficulties may require dietary monitoring. Seizures may be managed with medications. [1] Most patients follow a regular physiotherapy programme to prevent musculoskeletal and respiratory complications. [1]
Resources
National Center for Advancing Translational Sciences
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 National Institute of Neurological Disorders and Stroke. Aicardi-Goutières Syndrome. Available from: https://www.ninds.nih.gov/health-information/disorders/aicardi-goutieres-syndrome [accessed 3/10/2024]
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutières syndrome. Dev Med Child Neurol. 2020 Jan;62(1):42-47.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Rice G, Patrick T, Parmar R, Taylor CF, Aeby A, Aicardi J, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007 Oct;81(4):713-25.
- ↑ Sutton VR, Van den Veyver IB. Aicardi Syndrome. 2006 Jun 30 [Updated 2020 Nov 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1381/ [accessed 3/10/2024]
- ↑ 5.0 5.1 5.2 Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, et al. Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome. N Engl J Med. 2018 Dec 6;379(23):2275-7.
- ↑ GTR. Aicardi Goutieres syndrome. Available from: https://www.ncbi.nlm.nih.gov/gtr/conditions/C0393591/?_ga=2.198734511.1659021179.1727948075-1531788097.1727948075 [accessed 3/10/2024]
- ↑ Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015 Feb;167A(2):296-312.
- ↑ Crow YJ, Vanderver A, Orcesi S, Kuijpers TW, Rice GI. Therapies in Aicardi-Goutières syndrome. Clin Exp Immunol. 2014 Jan;175(1):1-8.
- ↑ Briand C, Frémond ML, Bessis D, Carbasse A, Rice GI, Bondet V, et al. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency. Ann Rheum Dis. 2019 Mar;78(3):431-433.
- ↑ Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, et al. Janus Kinase Inhibition in the Aicardi-Goutières Syndrome. N Engl J Med. 2020 Sep 3;383(10):986-89.