Proposal of a New Diagnostic Score for Aicardi–Goutières Syndrome

Objectives: Aicardi–Goutières syndrome (AGS) is a rare inherited neurological condition related to an abnormal up-regulation of type I interferon signalling. To date, mutations in seven genes have been associated with AGS. Clinical diagnostic criteria have been established when the syndrome has been described. With the discovering of the genetic causes of the disease and due to recent use of next generation sequencing (NGS) techniques, we assisted to the progressive widening of the clinical spectrum of AGS-related phenotypes including atypical cases and “non-AGS presentation”. In fact, some already knew conditions, such as retinal vasculopathy with cerebral leukodystrophy (RVCL) and Singleton–Merten syndrome, has been found to be caused by AGS genes, as also previously unknown phenotypes like bilateral striatal degeneration, spastic paraparesis, and other still unclassified clinical pictures. Even if current AGS diagnostic criteria appear helpful to recognize classic AGS, they are not able to discriminate atypical and non-AGS phenotypes.

Methods: We revised AGS diagnostic criteria according to recent advances in the field, in order to produce an expert based and up–to-date diagnostic score. We retrospectively selected a group of patients with a clinical diagnosis of AGS and/or harbouring pathogenic mutations in one of the seven AGS genes. Each patient was classified as affected by classic AGS, atypical AGS, and “non-AGS” on the basis of clinician experience on the disease. On the same series of patient, we applied our proposed diagnostic score.

Results: A total of 20 patients have been selected. 12 patients received a score consistent with classic AGS, five with atypical AGS, and three with “non-AGS”. The score results coincided with the “gestaltic” diagnosis on 100% of cases.

Conclusion: Based on our experience on the disease and based on literature available data, we propose an update of the diagnostic criteria for AGS. Our score represents a standardized tool able to distinguish classic and atypical AGS and this will be useful for new studies on the disease. The three groups should be compared in order to find out if there are any genetic and nongenetic factors that have influenced the final phenotype. Moreover, this classification will be helpful in designing forthcoming clinical trials. Larger series of patients will be needed in order to validate our scoring system.