Abstract
Aicardi-Goutières syndrome (AGS) is a rare and likely
underdiagnosed genetic leukoencephalopathy, typically presenting in infancy
with encephalopathy and characteristic neuroimaging features, with residual
static neurological deficits. We describe a patient who, following an initial
presentation at the age of 12 months in keeping with AGS, exhibited a highly
atypical relapsing course of neurological symptoms in adulthood with
essentially normal neuroimaging. Whole-exome sequencing confirmed a pathogenic
RNASEH2B gene variant consistent with AGS. This case highlights the expanding
phenotypes associated with AGS and the potential role of whole-exome sequencing
in facilitating an increase in the rate of diagnosis.
Courtesy of a colleague
Gilani A, Adang LA, Vanderver A, Collins A,
Kleinschmidt-DeMasters BK. Neuropathological Findings in a Case of
IFIH1-Related Aicardi-Goutières Syndrome. Pediatr Dev Pathol.
2019;22(6):566–570. doi:10.1177/1093526619837797
Abstract
Aicardi-Goutières syndrome (AGS) is a rare syndrome
characterized by calcification, diffuse demyelination, and variable degree of
brain atrophy. The syndrome is genetically heterogeneous with mutations in 7
genes, including TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1
(interferon-induced helicase c domain-containing protein 1) associated with the
syndrome, so far. These mutations lead to the overproduction of α-interferon
within the central nervous system. Mutations in IFIH1 have been recently
described in a subset of AGS, with only 1 previous report of neuropathological
findings. We report neuropathological findings in a second case of AGS with a
known mutation in IFIH1 gene. The patient is a 16-year-old adolescent boy with
early-onset symptoms that progressed to profound loss of cognitive and motor
functions. The patient experienced sudden cardiopulmonary arrest at the age of
16 years. At autopsy, the cause of death was determined to be pulmonary
thromboembolism. Neuropathological examination revealed microcephaly (brain
weight: 916 g) with relatively mild brain atrophy on gross examination. Microscopic
examination revealed multifocal calcifications limited to small to medium
central nervous system arteries (no evidence of calcification in other organs),
involving bilateral cerebral cortex, basal ganglia, thalamus, and cerebellum.
Ultrastructural examination showed Calcospherules limited to the vessel walls
and the perivasulcar area without evidence of neuronal ferrugination or
tubuloreticular bodies. The extent of calcifications was variable across
different brain regions, resembling findings in previously reported cases and
correlated with the extent of IFIH1 protein expression (data derived from Allen
Brain Institute). AGS is a rare cause of brain calcifications that can closely
mimic congenital and neonatal infections such as Rubella and similar
infections.
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