4.4 Review

Generalized Arterial Calcification of Infancy (GACI): Optimizing Care with a Multidisciplinary Approach

Journal

JOURNAL OF MULTIDISCIPLINARY HEALTHCARE
Volume 15, Issue -, Pages 1261-1276

Publisher

DOVE MEDICAL PRESS LTD
DOI: 10.2147/JMDH.S251861

Keywords

generalized arterial calcification of infancy; ectonucleotide pyrophosphatase/phosphodiesterase 1; ATP binding cassette subfamily C member 6; vascular calcification

Funding

  1. Leducq Foundation Grant
  2. 4C Medical
  3. 4Tech
  4. Abbott Vascular
  5. Ablative Solutions
  6. Absorption Systems
  7. Advanced NanoTherapies
  8. Aerwave Medical
  9. Alivas
  10. Amgen
  11. Asahi Medical
  12. Aurios Medical
  13. Avantec Vascular
  14. BD
  15. Biosensors
  16. Biotronik
  17. Biotyx Medical
  18. Bolt Medical
  19. Boston Scientific
  20. Canon USA
  21. Cardiac Implants
  22. Cardiawave
  23. CardioMech
  24. Cardionomic
  25. Cerus EndoVascular
  26. Chansu Vascular Technologies
  27. Children's National Medical Center
  28. Concept Medical
  29. Cook Medical
  30. Cooper Health
  31. Coramaze Technologies GmbH
  32. CRL/AccelLab
  33. Croivalve
  34. CSI
  35. Dexcom
  36. Edwards Lifesciences
  37. Elucid Bioimaging
  38. eLum Technologies
  39. Emboline
  40. Endotronix
  41. Envision
  42. Filterlex
  43. Imperative Care
  44. Innovalve
  45. Innovative Cardiovascular Solutions
  46. Intact Vascular
  47. Interface Biologics
  48. Intershunt Technologies
  49. Invatin Technologies
  50. Lahav CRO
  51. Limflow
  52. LJ Biosciences
  53. Lutonix
  54. Lyra Therapeutics
  55. Mayo Clinic
  56. Maywell
  57. MD Start
  58. MedAlliance
  59. Medanex
  60. Medtronic
  61. Mercator
  62. Microport
  63. Microvention
  64. Neovasc
  65. Nephronyx
  66. Nova Vascular
  67. Nyra Medical
  68. Occultech
  69. Olympus
  70. Ohio Health
  71. OrbusNeich
  72. Ossio
  73. Phenox
  74. Pi-Cardia
  75. Polares Medical
  76. Polyvascular
  77. Profusa
  78. ProKidney LLC
  79. Protembis
  80. Pulse Biosciences
  81. Qool Therapeutics
  82. Recombinetics
  83. Recor Medical
  84. Regencor
  85. Renata Medical
  86. Restore Medical
  87. Ripple Therapeutics
  88. Rush University
  89. Sanofi
  90. Shockwave
  91. Sahajanand Medical Technologies
  92. SoundPipe
  93. Spartan Micro
  94. Spectrawave
  95. Surmodics
  96. Terumo Corporation
  97. Jacobs Institute
  98. Transmural Systems
  99. Transverse Medical
  100. TruLeaf Medical
  101. UCSF
  102. UPMC
  103. Vascudyne
  104. Vesper
  105. Vetex Medical
  106. Whiteswell
  107. WL Gore
  108. Xeltis
  109. Celonova
  110. [NIH-HL141425]

Ask authors/readers for more resources

It is rare to see evidence of arterial calcification in infants and children, and when detected, genetic disorders of calcium metabolism should be suspected. Generalized arterial calcification of infancy (GACI) is a hereditary disease characterized by severe arterial calcification, mostly involving the media with marked intimal proliferation and ectopic mineralization. ENPP1 and ABCC6 gene variants are associated with the disease, with higher mortality in subjects carrying ENPP1 variants. Overall mortality in individuals with GACI is high, and there is currently no ideal therapy, but gene-targeted treatments are being developed.
It is very unusual to see evidence of arterial calcification in infants and children, and when detected, genetic disorders of calcium metabolism should be suspected. Generalized arterial calcification of infancy (GACI) is a hereditary disease, which is characterized by severe arterial calcification of medium sized arteries, mostly involving the media with marked intimal proliferation and ectopic mineralization of the extravascular tissues. It is caused by inactivating variants in genes encoding either ENPP1, in a majority of cases (70-75%), or ABCC6, in a minority (9-10%). Despite similar histologic appearances between ENPP1 and ABCC6 deficiencies, including arterial calcification, organ calcification, and cardiovascular calcification, mortality is higher in subjects carrying the ENPP1 versus ABCC6 variants (40% vs 10%, respectively). Overall mortality in individuals with GACI is high (55%) before the age of 6 months, with 24.4% dying in utero or being stillborn. Rare cases show spontaneous regression with age, while others who survive into adulthood often manifest musculoskeletal complications (osteoarthritis and interosseous membrane ossification), enthesis mineralization, and cervical spine fusion. Despite recent advances in the understanding of the genetic mechanisms underlying this disease, there is still no ideal therapy for the resolution of vascular calcification in GACI. Although bisphosphonates with anti-calcification properties have been commonly used for the treatment of CAGE their benefit is controversial, with favorable results reported at one year and questionable benefit with delayed initiation of treatment. Enzyme replacement therapy with administration of recombinant form of ENPP1 prevents calcification and mortality, improves hypertension and cardiac function, and prevents intimal proliferation and osteomalacia in mouse models of ENPP1 deficiency. Therefore, newer treatments targeting genes are on the horizon. In this article, we review up to date knowledge of the understanding of GACI, its clinical, pathologic, and etiologic understanding and treatment in support of more comprehensive care of GACI patients.

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