Generalized Arterial Calcification of Infancy (GACI): State of the Art and Clinical Perspectives

Generalized Arterial Calcification of Infancy (GACI) is a rare autosomal recessive disorder characterized by pathological calcium deposition in large and medium-sized arteries, leading to severe cardiovascular complications such as hypertension, heart failure, and stroke. The mortality rate is approximately 50% within the first six months of life if untreated. The disease is primarily caused by mutations in the ENPP1 or ABCC6 genes, resulting in a deficiency of inorganic pyrophosphate (PPi), a key inhibitor of arterial calcification. This review provides a comprehensive overview of the pathophysiology, genetic basis, and clinical features of GACI. In addition, we summarize current and emerging therapeutic strategies, including enzyme replacement therapy with recombinant ENPP1 (INZ-701), critically discussing available preclinical and early clinical evidence, as well as current limitations.