{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:46:27Z","timestamp":1777481187809,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/jcdd13050184","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T13:26:41Z","timestamp":1777382801000},"page":"184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generalized Arterial Calcification of Infancy (GACI): State of the Art and Clinical Perspectives"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8140-6798","authenticated-orcid":false,"given":"Biagio","family":"Castaldi","sequence":"first","affiliation":[{"name":"Paediatric Cardiology Unit, Department of Woman\u2019s and Child\u2019s Health, University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9242-4897","authenticated-orcid":false,"given":"Giuseppe","family":"Imperatore","sequence":"additional","affiliation":[{"name":"Health Science Interdisciplinary Centre, Sant\u2019Anna School of Medicine, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1104-9398","authenticated-orcid":false,"given":"Elettra","family":"Pomiato","sequence":"additional","affiliation":[{"name":"Paediatric Cardiology Unit, Department of Woman\u2019s and Child\u2019s Health, University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-0113","authenticated-orcid":false,"given":"Giovanni","family":"Di Salvo","sequence":"additional","affiliation":[{"name":"Paediatric Cardiology Unit, Department of Woman\u2019s and Child\u2019s Health, University of Padua, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41436-020-00983-0","article-title":"Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)","volume":"23","author":"Ferreira","year":"2021","journal-title":"Genet. 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