Study of ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) and related diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

In FY25, in collaboration with Dr. Dan Kastner, we have continued to characterize a disease termed ROSAH for the association with Retinal dystrophy, Optic nerve elevation, Splenomegaly, Anhidrosis and Headache. To date, we have enrolled 57 individuals with ROSAH onto our natural history protocol to better characterize the clinical manifestations of disease and elucidate the natural history of the disease course. Comprehensive phenotyping includes multimodal retinal imaging, neurological evaluation, and immune system profiling. Using patient-derived data and cellular models, we have identified innate immune activation driven by mutations in the ALPK1 gene, which responds to bacterial metabolites such as ADP-heptose. Building on these insights, we demonstrated mechanistic crosstalk between ALPK1 signaling and the Stimulator of Interferon Genes (STING) pathway, providing a link between bacterial sensing and cytosolic DNA sensing (Shi and Kozycki et al. bioRxiv. 2025). These findings expand our understanding of tissue-specific immune activation and likely have important implications for both ROSAH as well as more common diseases characterized by chronic inflammation and degeneration, including age-related macular degeneration and osteoarthritis.