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.

Ruxolitinib in Aicardi-Goutières syndrome

“…Aicardi-Goutières Syndrome (AGS) is a monogenic leukodystrophy with pediatric onset, clinically characterized by a variable degree of neurologic impairment (Adang et al 2020a). It is due to mutations in genes involved in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 or RNU7-1) that result in an abnormal overproduction of interferon alpha (IFN alpha), a mechanism shared by a group of condition now called type I interferonopathies (Livingston and Crow 2016;Uggenti et al 2020).…”

Case Report: Aicardi-Goutières Syndrome Caused by Novel TREX1 Variants

“…In a few cases, specific pathogenic mutations in ADAR or TREX1 were inherited in the autosomal dominant manner ( 9 ). It was currently reported that TREX1 and RNASEH2B were most common among the seven pathogenic genes, accounting for 17 and 35%, respectively ( 10 ).…”

Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy

“…We identified 17 skills from the Denver Developmental Screening Test II (DDST-II) to assess acquisition of developmental milestones in the TUBB4A-related leukoencephalopathy population (Supplemental Table S2), as previously applied in the leukodystrophy population. 18 The age at acquisition and loss of milestones was obtained from historical medical records. Information was extracted from medical records synchronous with the time of acquisition and loss of a specific milestone when feasible to minimize recall bias.…”

“…These heat maps display the ages at which a given percentiles of the cohort achieved a milestone (p10 for 10%, p25 for 25% etc.). 18 Additionally, the milestone status for each individual was divided into the categories of: not yet achieved, achieved, and lost. These milestone categories were assigned to each individual at 1-month intervals to tract the transition between each category.…”