Inhibition of Vascular Smooth Muscle Cell Proliferation by ENPP1: The Role of CD73 and the Adenosine Signaling Axis.

The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. ENPP1 hydrolyzes extracellular ATP to pyrophosphate (PP) and AMP.

Improved Reversion of Calcifications in Porcine Aortic Heart Valves Using Elastin-Targeted Nanoparticles.

Calcified aortic valve disease in its final stage leads to aortic valve stenosis, limiting cardiac function. To date, surgical intervention is the only option for treating calcific aortic valve stenosis. This study combined controlled drug delivery by nanoparticles (NPs) and active targeting by antibody conjugation.

An Unusual Case of Transient Cardiac Calcification Identified on Antenatal Echocardiography: A Generalized Arterial Calcification of Infancy (GACI) Like Presentation.

Generalised arterial calcification of infancy (GACI) is an ultra-rare life-threatening genetic disorder. Arterial calcification is identified during foetal ultrasound scan (USS) as increased cardiac and/or vascular echogenicity. Inorganic pyrophosphate (PP) is the main inhibitor of arterial calcification.

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification.

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively.

A Reference Range for Plasma Levels of Inorganic Pyrophosphate in Children Using the ATP Sulfurylase Method.

Purpose: Generalized arterial calcification of infancy, pseudoxanthoma elasticum, autosomal recessive hypophosphatemic rickets type 2, and hypophosphatasia are rare inherited disorders associated with altered plasma levels of inorganic pyrophosphate (PPi). In this study, we aimed to establish a reference range for plasma PPi in the pediatric population, which would be essential to support its use as a biomarker in children with mineralization disorders.

Methods: Plasma samples were collected from 200 children aged 1 day to 18 years who underwent blood testing for medical conditions not affecting plasma PPi levels.

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.

Alkaline Phosphatases Account for Low Plasma Levels of Inorganic Pyrophosphate in Chronic Kidney Disease.

Introduction: Patients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PP) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD.

Hereditary Disorders of Cardiovascular Calcification.

Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification.

Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line.

Crisponi syndrome/cold-induced sweating syndrome type 2 (CS/CISS2) is a rare disease with severe dysfunctions of thermoregulatory processes. CS/CISS2 individuals suffer from recurrent episodes of hyperthermia in the neonatal period and paradoxical sweating at cold ambient temperatures in adolescence. Variants in CLCF1 (cardiotrophin-like-cytokine 1) cause CS/CISS2.

Generation of induced pluripotent stem cell lines from a Crisponi/Cold induced sweating syndrome type 1 individual.

Cytokine receptor like factor 1 (CRLF1) is the gene implicated, when mutated, in Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1). Here, we report the establishment of induced pluripotent stem cell lines (iPSCs) from fibroblasts of a Turkish CS/CISS1 individual with a homozygous variant in CRLF1 (c.708_709delinsT; p.

Reversion of arterial calcification by elastin-targeted DTPA-HSA nanoparticles.

Generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE) are characterized by pathologic calcifications in the media of large- and medium sized arteries. GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. Different treatment approaches including bisphosphonates and orally administered pyrophosphate (PP) were investigated in recent years, but reversion of calcification could not be achieved.

Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.

Crisponi/cold-induced sweating syndrome (CS/CISS) is an autosomal recessive disease characterized by hyperthermia, camptodactyly, feeding and respiratory difficulties often leading to sudden death in the neonatal period. The affected individuals who survived the first critical years of life, develop cold-induced sweating and scoliosis in early childhood. The disease is caused by variants in the CRLF1 or in the CLCF1 gene.

Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet.

The physicochemical deposition of calcium-phosphate in the arterial wall is prevented by calcification inhibitors. Studies in cohorts of patients with rare genetic diseases have shed light on the consequences of loss-of-function mutations for different calcification inhibitors, and genetic targeting of these pathways in mice have generated a clearer picture on the mechanisms involved. For example, generalized arterial calcification of infancy (GACI) is caused by mutations in the enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (eNPP1), preventing the hydrolysis of ATP into pyrophosphate (PP).

ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP.

Generalized arterial calcification of infancy (GACI) is associated with widespread arterial calcification and stenoses and is caused by mutations in ENPP1. ENPP1 encodes for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which cleaves ATP to generate inorganic pyrophosphate (PP) and adenosine monophosphate (AMP) extracellularly. The current study was designed to define the prevalence of arterial stenoses in GACI individuals and to identify the mechanism through which ENPP1 deficiency causes intimal proliferation.

Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts.

Purpose Of Review: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease.

Recent Findings: 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.

Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1.

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (E-NPP1), encoded by ENPP1, is a plasma membrane protein that generates inorganic pyrophosphate (PP ), a physiologic inhibitor of hydroxyapatite formation. In humans, variants in ENPP1 are associated with generalized arterial calcification of infancy, an autosomal-recessive condition causing premature onset of arterial calcification and intimal proliferation resulting in stenoses. ENPP1 variants also cause pseudoxanthoma elasticum characterized by ectopic calcification of soft connective tissues.

Lmbrd1 expression is essential for the initiation of gastrulation.

The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl-CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia.

Novel interferonopathies associated with mutations in RIG-I like receptors.

Type I interferonopathies are a relatively new class of inherited autoimmune disorders associated with an inborn elevated interferon response. Activation of cytosolic receptors which recognize viral double stranded RNA including the RIG-I (retinoic acid-inducible gene I) like receptors RIG-I and MDA5 (melanoma differentiation-associated gene 5) has been shown to induce the transcription of type I interferon genes. Within recent years, with the help of next generation sequencing techniques in syndromic families, mutations in the genes encoding for RIG-I and MDA5 have been identified to cause rare diseases including Aicardi-Goutières syndrome, Systemic Lupus Erythematosus in certain individuals as well as classic and atypical Singleton-Merten syndrome.

A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome.

Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.

Modulators of networks: molecular targets of arterial calcification identified in man and mice.

In recent years, mechanisms of arterial calcifications are beginning to be elucidated. Arterial calcification is now considered as an actively regulated process resembling osteogenesis within the arterial wall orchestrated by a number of systemic or constitutively expressed mediators. Genetic studies of rare monogenic human disorders and studies of naturally occurring or mutant mouse models have identified specific inductors and inhibitors of arterial calcification, which can be classified according to the networks they participate in.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum: two sides of the same coin.

Generalized arterial calcification of infancy (GACI) is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 (ATP-binding cassette subfamily C number 6) are known to cause pseudoxanthoma elasticum (PXE). However, ABCC6 mutations account for a significant subset of GACI cases, and ENPP1 mutations can also be associated with PXE lesions. Based on the considerable overlap of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification rather than two distinct disorders.

Genetics in arterial calcification: lessons learned from rare diseases.

Arterial calcification significantly contributes to morbidity and mortality. Insight into the pathophysiological mechanisms contributing to arterial calcification has come from genetic studies on four rare monogenic disorders. The disease-causing molecular defects in generalized arterial calcification of infancy (GACI), pseudoxanthoma elasticum (PXE), calcification of joints and arteries (CALJA), and familial idiopathic basal ganglia calcification (IBGC) have been identified within recent years.

Molecular diagnosis of generalized arterial calcification of infancy (GACI).

Generalized arterial calcification of infancy (GACI) is a life-threatening disorder in young infants. Cardiovascular symptoms are usually apparent within the first month of life. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries.