Late-onset Aicardi-Goutières syndrome caused by an ADAR variant presented with spastic quadriplegia

Abstract

  Aicardi-Goutières syndrome (AGS) is encephalopathy characterized by intracranial calcification and cerebrospinal fluid lymphocytosis. The pathogenesis of AGS is considered to be an overproduction of type I interferon (IFN). Recently, AGS has been classified as an autoinflammatory disease and named as interferonopathy. IFN signature, which represents the expression level of some IFN-stimulated genes, has attracted attention as a biomarker for diagnosis and disease status. To date, nine genes responsible for the metabolism and sensing of nucleic acids in AGS have been identified. The disease spectrum has been expanded to include late-onset and milder cases in contrast to early infantile-onset classic cases. Here, we report a case of a girl with late-onset AGS, who developed normally until 11 months of age, but onset symptoms triggered by the fever, and thereafter gradually developed spastic quadriplegia over several years. Whole-exome sequencing revealed a heterozygous variant with a dominant negative effect on ADAR (NM_001111.5:c.3019G>A:p.G1007R). Although brain CT was normal at the time of onset, calcification gradually became apparent in the globus pallidus and other areas. MRI showed only signal changes reflecting calcification. The cognitive functions did not regress in contrast to the motor functions. Moreover, she had mixed hypopigmented and hyperpigmented macules on the dorsal side of the fingers, which indicated the co-occurrence of dyschromatosis symmetrica hereditaria caused by a heterozygous variant of ADAR. AGS caused by ADAR is relatively more common in late-onset forms in many cases, including those showing bilateral striatal necrosis and those with spastic paraplegia with normal cognitive functions. The efficacy of Janus kinase inhibitors targeting the signaling pathway of type I IFN has also been reported. Thus, we must keep in mind that AGS shows a various phenotypes for its occurrence.