Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts

Abstract

Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.

Generalized Arterial Calcification of Infancy

“…Although rarely diagnosed prenatally, GACI can be diagnosed by obstetrical ultrasound and fetal echocardiogram and there is some evidence in a mouse model that supplemental magnesium provided to the mother and the pups can reduce ectopic mineralization in the offspring [8]. GACI follows an autosomal recessive pattern of inheritance and molecular analysis of the ENPP1 and ATP-binding cassette subfamily C number 6 (ABCC6) genes can provide a prenatal diagnosis or confirm the diagnosis postnatally [1,9,10 ]. Compound heterozygous or homozygous mutations in the ENPP1 gene have been found in approximately 75% of cases of GACI.…”

“…The ENPP1 gene is important for production of ecto-nucleotide pyrophosphatase/phosphodiesterase 1, an enzyme that produces inorganic pyrophosphate. Inorganic pyrophosphate prevents hydroxyapatite deposition [1]. The exact function of ABCC6 is unknown.…”

“…Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a rare inherited autosomal recessive disorder usually diagnosed postnatally or at autopsy. Survival into adulthood has been reported, but most infants succumb to the cardiovascular effects of the disease within the first 6 months of life [1][2][3][4][5]. We highlight the importance of considering GACI in an infant with unexplained heart failure or myocardial infarction and provide molecular confirmation of the diagnosis.…”

The role of the gasotransmitter hydrogen sulfide in pathological calcification

“…Vascular calcification (VC) is associated with both hereditary conditions (Nitschke & Rutsch, 2017) and acquired diseases such as atherosclerosis (Doherty et al, 2003), diabetes (Chen & Moe, 2003), and chronic kidney disease (CKD; Palit & Kendrick, 2014). There are two main types of VC, which are based on the layer of the vessel wall in which BCP crystals accumulate, medial or intimal.…”

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

“…In 2000, Ho et al showed that medium of Ank ank/ank fibroblasts contained reduced concentrations of the physiological mineralization inhibitor inorganic pyrophosphate (PPi), leading to the now prevailing view that ANKH/ANK was the transport of PPi into the extracellular environment 1,8 . An important source of extracellular PPi is ATP, which is extracellularly converted into AMP and PPi by membrane-bound ecto-nucleotidase pyrophosphatase/phosphodiesterase 1 (ENPP1) 9 . We have previously shown that ATP release mediated by the hepatic membrane protein ATP-Binding Cassette subfamily C member 6 (ABCC6) is responsible for 60-70% of all PPi present in plasma 10,11 .…”