Generalized arterial calcification of infancy (GACI)

(OMIM phenotype number #208000)

Generalized arterial calcification of infancy (GACI) is caused, in most cases, by homozygous or compound heterozygous inactivating mutation in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate levels. It is an autosomal recessive disorder. GACI is characterized by early mineralization of blood vessels, but also on other soft connective tissues, often diagnosed by prenatal ultrasound. In most cases patients affected by GACI die during the first six months of life from cardiovascular complications. ENPP1 gene, encodes an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate (PPi), the latter being a powerful anti-mineralization factor. The loss-of-function mutations in the ENPP1 gene results in decreased synthesis of PPi, causing a low PPi/Pi ratio which then allows the ectopic mineralization processes to ensue. Loss-of-function ENPP1 mutations can also cause autosomal recessive hypophosphatemic rickets type 2 (see also ARHR2).

Treatment: There is no effective or specific treatment for GACI. Recently, a study on animal model has described that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in GACI caused by ENPP1 mutations.

Gene

ENPP1 gene, 6q23.2 (OMIM gene/locus number #173335).

Phenotype

Short stature, deafness, conductive (in some patients), angioid retinal streaks (in some patients), coronary and generalized artery calcification, cardiac dysfunction, periarticular calcification, hypophosphatemic rickets, and pseudoxanthoma.

Main biochemical alterations

Low Pi.

Images

a b

Fig. (a) Lateral radiograph of the neonate showing calcification of descending aorta and its bifurcation (arrows). (b) Ultrasonography of abdominal aorta showing calcification of descending aorta and its branches (arrows).

Reproduced from J Pediatr, Vol 162, Karthikeyan G, Generalized arterial calcification of infancy, Pages 1074.e1., Copyright 2013, with permission from Elsevier.


References

  1. Ferreira C, Ziegler S, Gahl W. Generalized Arterial Calcification of Infancy. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. 2014 Nov 13.
  2. Li Q, Guo H, Chou DW, et al. Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy. Dis Model Mech. 2013 Sep;6(5):1227-35.
  3. Li Q, Kingman J, Sundberg JP et al. Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy. J Invest Dermatol. 2015 Sep 29. doi: 10.1038/jid.2015.377. [Epub ahead of print]
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org