Aicardi-Goutières syndrome (ORPHA:51)
A rare inherited subacute encephalopathy characterized by the variable association of basal ganglia calcification, leukodystrophy, cerebrospinal fluid (CSF) lymphocytosis and evidence of enhanced type I interferon signaling in blood and CSF.
Epidemiology
More than 500 cases of Aicardi-Goutières syndrome (AGS) have been reported in the literature to date.
Clinical description
The majority of affected infants are born at full term with normal growth parameters. In its classic form, onset occurs within the first few days or months of life with severe, subacute encephalopathy (feeding problems, irritability and psychomotor regression or delay) associated with epilepsy, chilblain skin lesions on the extremities and episodes of aseptic febrile illness. These features can continue over several weeks/months (with the development of microcephaly and pyramidal signs) before the disease apparently stabilizes. Less severe forms have been described with onset after 1 year of age, and relative preservation of communication skills, cognitive function and head circumference. The phenotype can manifest with marked inter- and intrafamilial variation. Less frequently still, mutations in AGS-related genes can be associated with other distinct phenotypes, including bilateral striatal necrosis, non-syndromic spastic paraparesis of the lower limbs with normal intellect and neuroradiology, cerebrovascular disease similar to Moyamoya, and even complete clinical non-penetrance.
Etiology
Since 2006, causative mutations have been identified in nine genes encoding: (i) the 3'->5' exonuclease TREX1; (ii) the three components of the RNase H2 endonuclease complex (RNASEH2A, RNASEH2B and RNASEH2C), (iii) SAMHD1, which functions as a deoxynucleoside triphosphate triphosphohydrolase; (iv) ADAR1, which catalyzes the hydrolytic deamination of adenosine to inosine in RNA; (v) MDA5, (encoded by IFIH1) a cytosolic double stranded RNA sensor; and (vi) two components of the histone pre-mRNA processing complex (RNU7-1 and LSM11). Mutations in TREX1, RNASEH2C and RNASEH2A are more often associated with severe neurological problems, whereas mutations in RNASEH2B, SAMHD1, IFIH1 and ADAR1 can be associated with a relative preservation of skills. The phenotype associated with mutations in LSM11 and RNU7-1 have yet to be fully determined.
Diagnostic methods
Calcification (involving the basal ganglia and white matter), cystic leukodystrophy (predominantly frontotemporal in very early onset cases) and cortical-subcortical atrophy are cardinal features of typical AGS, sometimes associated with atrophy of the corpus callosum, the brain stem and cerebellum. Elevated IFN-alpha activity and lymphocytosis in the CSF are frequent but not constant findings in the initial stage of the disease, but tend to normalize or resolve within a few years. The expression of interferon stimulated genes (ISGs)—a so-called interferon signature—can be recorded in the blood of the majority of cases, except in patients carrying RNASEH2B variants (where ~ 20% of patients have normal ISG expression after age 4 years). The diagnosis is confirmed by detection of mutations in one of the nine disease-associated genes.
Differential diagnosis
The principle differential diagnoses are TORCH congenital infections (toxoplasma, rubella, cytomegalovirus, HSV1 and HSV2), and other diseases associated with white matter abnormalities and/or intracranial calcification.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Disease due to mutations in TREX1, RNASEH2A/B/C, SAMHD1, ADAR, LSM11 and RNU7-1 are almost always inherited as an autosomal recessive trait, although rare dominant mutations in TREX1 and ADAR —affecting highly specific residues— are well recognized. In contrast, mutations in IFIH1 are always inherited as an autosomal dominant trait.
Management and treatment
To date, treatment has been mostly symptomatic (management of feeding problems, tone, epilepsy etc.). However, JAK1 inhibition (JAKi) is a therapeutic option for the systemic features of AGS, such as recurrent fevers and chilblains. The efficacy of JAKi on the neurological features of the disease is less evident. Side effects of such targeted therapies should be considered.
Prognosis
Around 10% of patients die within the first 5 years of life, but prolonged survival into the third and fourth decades of life is well recognized.

                            Last update: 
                            May 2024


                            - Expert reviewer(s): 
                            Pr Yanick CROW | RITA* - Pr Marie-Louise FRÉMOND | RITA* - Pr Bénédicte NEVEN 


                                * European Reference Network