Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing¶

The finding¶

This case report describes a 31-year-old woman with compound heterozygous variants in the ADAR gene (p.Pro193Ala and p.Ser371Cysfs*3), diagnosed with Aicardi-Goutières syndrome (AGS) only in adulthood via whole-genome sequencing. Her presentation was non-classical: normal early milestones, progressive ataxia and hypotonia from age 3, later spasticity, dystonia, learning difficulties, and — notably — significant cardiac valvular calcification. She has been referred for baricitinib (JAK1/JAK2 inhibitor) treatment.

Where it fits¶

This case speaks most directly to Loop A (interferon/JAK-STAT) and the clinical outcome layer of the model. ADAR mutations are a canonical AGS cause, acting upstream of the same type I interferon amplification that SAMHD1 p.A565T drives through cGAS–STING sensing and IRF3-dependent IFN-I production. The referral for baricitinib — a JAK1 inhibitor — is the key translational point: it directly tests the JAK-inhibitor-responsive arm of Loop A, the same intervention predicted to dampen tonic IFN-I signaling in SAMHD1 A565T.

The extracerebral calcification is also relevant. In the SAMHD1 model, calcification is linked to the mitochondrial/NLRP3 arm (Loop B), where dNTP pool expansion drives POLG stress and NLRP3 licensing. That this ADAR-related AGS patient shows prominent valvular calcification suggests calcification may be a shared downstream consequence of chronic interferonopathy rather than a gene-specific effect — a useful cross-validation for the model's claim that Loop B is partly JAK-resistant and may require separate targeting.

Caveats¶

This is a single case with ADAR variants, not SAMHD1 p.A565T; the relevance is analogical, not direct.
Compound heterozygous (likely null) ADAR mutations differ mechanistically from a heterozygous partial loss-of-function SAMHD1 allele; the smoldering "non-acute chronic inflammation" phenotype may not translate.
The baricitinib referral is reported, not a treatment outcome; no response data are presented.

What to watch¶

Whether baricitinib treatment in this patient suppresses the ISG signature and whether calcification stabilizes or progresses — the latter would speak to whether JAK inhibition alone can touch Loop B, a central open question for the SAMHD1 model's two-rescue-point claim.

Source: Case of Aicardi-Goutières syndrome diagnosed in adulthood on whole-genome sequencing — 2026.