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Diving deeper into orphan diseases - Generalized arterial calcification of infancy

The next orphan disease we want to focus on is the Generalized arterial calcification of infancy (GACI).

Disclaimer: Since we just touch on some facts in this article, more in-depth information and contacts for affected patients can be found here:


GACI (also known as idiopathic infantile arterial calcification) is a rare, inherited diseases causing systemic mineralization disorder of early pediatric onset primarily affects the cardiovascular system. The genetic disease is inherited in an autosomal recessive manner.

GACI was first described 1899 in medical literature and only approximately 300 cases have been reported worldwide (2019) suggesting an incidence of approximately 1:500,000. All cases of GACI are of early pediatric onset, diagnosed either in utero or at a median age of 3 month. Infants suffering of GACI have a poor prognosis with survival rates varying greatly but are estimated around 50%.

But what is GACI?

Mutations in the ENPP1 and ABCC6 genes have been identified as causing abnormal tissue mineralization. Pathologically, GACI is characterized by abnormal deposition of calcium within the walls of arteries, more specifically in the internal elastic membrane accompanied by fibrous thickening of the intima. Luminal narrowing of large and medium-sized vessels results in coronary artery blockage, reduced blood flow to the heart (myocardial ischemia) or narrowing of other arteries causing damage of end-organs leading to serious, life-threatening symptoms.

What are symptoms of GACI?

GACI has a unique clinical presentation with two distinct models. About half of the cases are present in utero or at birth with symptoms such as heart failure or respiratory distress. The other half of cases are present later in infancy with cardiovascular symptoms. Nevertheless, symptoms are more commonly diagnosed after birth. Affected infant develop major cardiovascular features including arterial calcification, arterial stenosis, arterial hypertension, myocardial ischemia, and death within the first 6 months of life.

How is GACI inherited?

This condition is inherited in an autosomal recessive pattern. GACI usually occurs during fetal development due to a genetic mutation in either the ENPP1 or ABCC6 genes. These genes encode the proteins ectonucleotide pyrophosphatase/phosphodiesterase 1 and multidrug resistance-associated protein 6, respectively. The latter is a transmembrane protein that belongs to the ATP-binding cassette (ABC) transport protein family. There are two types of GACI: Type 1, caused by a deficiency in the ENPP1 gene, and Type 2, caused by a deficiency in the ABCC6 gene.

ENPP1 converts extracellular nucleotides as ATP to AMP and thereby generates extracellular pyrophosphate (PPi), which serves as a physiological inhibitor of hydroxyapatite crystal deposition and growth. A deficiency of ENPP1 activity results in a deficiency of and PPi causing ectopic calcification and AMP causing intimal proliferation. And contributing to a constant narrowing of the ateries.

ABCC6 encodes a plasma membrane transporter mainly found in the liver. Thus, the substrate of which is still mainly unknown, ABBC6 was shown to contributes to cellular ATP export from hepatocytes. Consequently, the of ABCC6 resulted in a decrease in extracellular ATP of ENPP1. Even among individuals with the same genetic cause of GACI, the disease can manifest itself differently with very different in medical characteristics within patients.

How is GACI diagnosed?

The diagnosis of GACI is made using a combination of clinical, imaging, histopathological, and genetic findings and is made upon cardiovascular symptoms during infancy showing widespread arterial calcification on imaging , after other potential causes have been ruled out. Whole-body computed tomography combined with CT angiography is the preferred imaging method for evaluating the extent of calcification. This diagnosis can be confirmed through molecular genetic testing for pathogenic variants in ENPP1 or ABCC6, or through histologic findings on arterial biopsy if genetic testing is not diagnostic.

Treatments and Outlook

GACI is a serious and potentially life-threatening condition that requires prompt medical attention. Although prognosis is poor and most infants die from myocardial infarction within the first year of life, it was shown that infants treated and surviving the first critical period of 6 month may life till adulthood. Treatment includes medications and procedures to remove calcium deposits like biphosphates, which showed to highly increase the survival rate as well as a supportive care to manage symptoms and prevent further complications.

That is where our technology platform DESTiNED comes into place and will hopefully help those, suffering from orphan indications such as GACI.

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Rutsch F, Buers I, Nitschke Y. Hereditary Disorders of Cardiovascular Calcification. Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):35-47 doi: 10.1161/ATVBAHA.120.315577.


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