Developmental Outcomes of Aicardi Goutières Syndrome

Abstract

Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or TREX1-related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

Keywords: developmental disability; genetics; leukodystrophy; neurodevelopment; pediatric.

Figure 1.

Genetics and features at presentation of the US-Italian AGS cohort. A. Genotypic distribution of individuals with AGS across the US and Italian cohorts. B. The age at presentation in months is shown as sorted by genotype. The error bars represent min-max. Individuals with symptoms present at birth were noted as presenting at 0 months. C Features at presentation were classified into non-exclusive categories: neurologic symptoms [Neuro] (e.g. seizures, sudden change in tone, or developmental regression), altered mental status [AMS] (irritability or lethargy), systemic inflammation [Systemic] (e.g. feeding intolerance and fevers), rash [Rash], and Microcephaly. Clinical presentation is shown by age. PvalueswerecalculatedusingMann-Whitneytwo-tailedt-testsand designated as * = < 0.05, ** = < 0.01, and *** = < 0.005.

Figure 2.

Developmental milestone acquisition in microcephalic versus nonmicrocephalic individuals. Age at developmental skill acquisition was presented with Kaplan-Meier curves. P-values were calculated using the log-rank (Mantel-Cox) test comparing individuals with microcephaly (>2 standard deviations below the mean head circumference for age) to all other individuals and was <0.005 for all milestones.

Figure 3.

Gross motor milestone acquisition by genotype. Age at developmental skill acquisition was determined for the 5most prevalent genotypes, IFIH1, TREX1, RNASEH2B, SAMHD1, andADAR, as represented with Kaplan-Meier curves. P-values were calculated using the Log-rank(Mantel-Cox)test comparing genotype sand is designated as * for p<0.05, ** for p < 0.01, and *** for p < 0.005.

Figure 4.

Fine motor milestone acquisition by genotype. Age at developmental skill acquisition was determined for the 5 most prevalent genotypes, IFIH1, TREX1, RNASEH2B, SAMHD1, andADAR, as presented with Kaplan-Meiercurves. P-values were calculated using the Log-rank(Mantel-Cox)test comparing genotypes and is designated as * for p<0.05, ** for p < 0.01, and *** for p < 0.005.

Figure 5.

Social and language milestone acquisition by genotype. Age at developmental skillacquisitionwasdeterminedforthe5mostprevalentgenotypes, IFIH1,TREX1, RNASEH2B,SAMHD1, andADAR, as presented with Kaplan-Meiercurves. P-values were calculated using the Log-rank(Mantel-Cox)test comparing genotypes and is designated as * for p<0.05, ** for p < 0.01, and *** for p < 0.005.

Figure 6.

Developmental skill acquisition plots were created for the overall AGS population and for the 5 most common genotypes, TREX1, RNASEH2B, SAMHD1, ADAR, and IFIH1. The designation of ‘10’ represents less than 10% of the population has acquired a milestone by the age indicated on the x-axis, while the designation of ‘90’ represents that up to 90% of the population has acquired the skill by the given age. The color-coded heat map indicates the percentage of the population who has attained the milestone at a given age, as shown on the x-axis.

Figure 7.

A.Overall performance by retrospective functional assessment scales in the AGS population. The Gross Motor Function Classification System (GMFCS) describes motor impairment (‘I’ = independently ambulatory without limitations, ‘V’ = full assistance including with head control). The Manual Ability Classification Scale (MACS) helps to score fine motor skills (‘I’ = normal dexterity, ‘V’ = requirement for total assistance with manual tasks). The Communication Function Classification System (CFCS) is used to classify communication skills (‘I’ = effective communication as both sender and receiver, ‘V’ = severe impairment even between familiar partners).B-D. Performance by retrospective functional assessment scales in the AGS population by genotype.