Interferonopathies

Interferonopathies are a group of rare genetic disorders characterized by excessive activity of the type I interferon (IFN) system, leading to chronic inflammation and tissue injury. They arise from mutations that cause abnormal synthesis, sensing, or signaling of nucleic acids, resulting in a persistent IFN response even in the absence of infection.

The central feature is a sustained type I IFN signature, with elevated IFN-α or related mediators and upregulation of interferon-stimulated genes in blood or tissue. This ongoing signaling drives inflammatory pathways and can affect multiple organ systems.

Genetic causes include mutations in TREX1, RNASEH2A/B/C, SAMHD1, ADAR1, IFIH1, TMEM173, DNASE1L3, among others. These genes disrupt nucleic acid metabolism or sensing, triggering pathways such as MDA5 or the cGAS-STING axis that promote interferon production.

Clinical features vary by syndrome. Some disorders present with neurodevelopmental impairment, microcephaly, brain calcifications, and leukodystrophy (for example Aicardi-Goutières syndrome). Others show autoinflammatory manifestations and cutaneous lesions (chilblains) or early-onset interstitial lung disease (as in SAVI).

Diagnosis relies on recognizing a characteristic interferon signature together with genetic confirmation. Evaluation often includes measurement of IFN-related biomarkers in blood or CSF, neuroimaging findings such as intracranial calcifications or white matter changes, and targeted sequencing panels or exome/genome sequencing to identify causal mutations.

Management is largely supportive and aimed at limiting IFN signaling. Treatments include JAK inhibitors in select patients, along with other immunosuppressants and supportive care for organ involvement. Research continues into targeted therapies and a deeper understanding of genotype-phenotype correlations.