Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features

Abstract

Background: Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by early onset of severe neurological injury with intracranial calcifications, leukoencephalopathy, and systemic inflammation. Increasingly, a spectrum of neurological dysfunction and presentation beyond the infantile period is being recognized in AGS. The aim of this study was to characterize late-infantile and juvenile-onset AGS.

Methods: We conducted a multi-institution review of individuals with AGS who were older than one year at the time of presentation, including medical history, imaging characteristics, and suspected diagnoses at presentation.

Results: Thirty-four individuals were identified, all with pathogenic variants in RNASEH2B, SAMHD1, ADAR1, or IFIH1. Most individuals had a history of developmental delay and/or systemic symptoms, such as sterile pyrexias and chilblains, followed by a prodromal period associated with increasing symptoms. This was followed by an abrupt onset of neurological decline (fulminant phase), with a median onset at 1.33 years (range 1.00 to 17.68 years). Most individuals presented with a change in gross motor skills (97.0%), typically with increased tone (78.8%). Leukodystrophy was the most common magnetic resonance imaging finding (40.0%). Calcifications were less common (12.9%).

Conclusions: This is the first study to characterize the presentation of late-infantile and juvenile onset AGS and its phenotypic spectrum. Late-onset AGS can present insidiously and lacks classical clinical and neuroimaging findings. Signs of early systemic dysfunction before fulminant disease onset and loss of motor symptoms were common. We strongly recommend genetic testing when there is concern for sustained inflammation of unknown origins or changes in motor skills in children older than one year.

Keywords: ADAR1; Aicardi-Goutières syndrome; IFIH1; Leukodystrophy; RNASEH2B; SAMHD1; Type I interferonopathy.

Figure 1.

Progression of disease in atypical AGS cases is characterized by 3 phases: early phase, prodrome, and fulminant presentation. Each individual (n=33 with sufficient data) is represented by a row, with each phase of the disease color coded with age in years on the x-axis. Normal development with no systemic signs or symptoms of inflammation represented by grey boxes, early phase is represented by light blue; prodromal phase is represented by blue; the onset of fulminant symptoms is represented by a red box.

Figure 2.

Common features of the phases of atypical AGS by genotype. The most common clinical features during each phase were noted by genotype in non-exclusive categories. (A) In the early phase, developmental delay and systemic inflammation were most commonly noted; (B) in the prodrome phase, fatigue, irritability, sterile pyrexias (febrile illnesses), and chilblains were noted; while in the fulminant phase (C), abnormalities in tone, motor skills, communication, and systemic signs or symptoms were most common. (D) The age at fulminant presentation is presented by genotypic cohort. (E) The time to neurologic nadir (maximum symptoms) was categorized as acute (within a week), subacute (1 week to 1 month), or chronic (more than 1 month).

Figure 3.

Imaging features found in atypical AGS. Imaging findings include calcifications (*) as visualized by head CT (A) and GRE (B) as demonstrated in the same individual, mild ventriculomegaly on T2 imaging (*, C), diffuse white matter changes as demonstrated by T2 FLAIR hyperintensity (D), patchy white matter hyperintensities (T2 FLAIR, arrow, E), and basal ganglia and thalami involvement on T2 (*).