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Generalized arterial calcification of infancy (GACI) is a rare genetic disease characterized by arterial calcifications or stenoses and hypertension. GACI is caused by mutations in the ENPP1 or ABCC6 genes, and it often causes intrauterine or early infancy death. Here, we report a case of rare GACI caused by a homozygous variation in ENPP1, in a Chinese infant initially presenting with hypertension. The proband was an 8-month-old boy with in utero tricuspid valve calcification, presenting with hypertension at birth. Enhanced computed tomography revealed extensive arterial calcification. Genetic testing identified a homozygous variation in ENPP1 (c.783C > G p.Y261X), which led to the diagnosis of GACI. This mutation has been reported in only three Chinese patients, which all initially presented with hypophosphatemic rickets rather than GACI. This case enriches the clinical and genetic spectrum of ENPP1 mutations and reminds us that GACI should be considered in an infant presenting with hypertension and extensive arterial calcification, and that genetic testing should be performed.

[Display omitted] • Vascular calcification is prevalent in chronic kidney disease patients. • ABCC6 is a candidate gene for vascular calcification seen in kidney disease. • ABCC6 variants cause a pseudoxanthoma elasticum phenotype with calcification. • Pathogenic ABCC6 variants are more common in calcification patients than controls. • ABCC6 and ENPP1 in the ectopic calcification pathway may be digenic. Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10–20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality. [ABSTRACT FROM AUTHOR]

While the clinical consequences of severe ENPP1 deficiency leading to the rare disorders generalized arterial calcification of infancy (GACI) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2) are well defined and understood, much less is known about how this evolves into adulthood and how moderate ENPP1 deficiency can first manifest in adulthood. Moreover, growing evidence substantiates an association of genetic variants in the ENPP1 gene with a wide range of further clinical manifestations including early-onset osteoporosis, osteoarthritis, and different forms of spinal ligament calcifications, i.e., diffuse idiopathic skeletal hyperostosis (DISH) and ossification of the posterior/anterior longitudinal ligament (OPLL/OALL). Furthermore, conditions with primarily extraskeletal signs and symptoms such as Cole disease, coagulopathies, and metabolic syndrome can seemingly result from ENPP1 variants. The causality and the pathophysiology behind these different clinical presentations appear complex and require further research, especially since the coincidence of these different phenotypes is rarely described and available evidence suggests that part of the aforementioned manifestations may result from ENPP1 effects beyond the catalytic activity of processing ATP to AMP and inorganic pyrophosphate (PPi). Growing awareness of the additional ENPP1 -related manifestations across the lifespan will advance our understanding of this complex condition and help to standardize diagnostic approaches and develop individually tailored treatment concepts. [ABSTRACT FROM AUTHOR]

Generalized arterial calcification of infancy (GACI) is an ultra-rare autosomal recessive disorder associated with pathogenic variants in ENPP1, the major gene involved in this condition, and in ABCC6, which is involved in a small fraction of affected individuals. Loss-of-function pathogenic variants of ENPP1 and ABCC6 lead to perturbations in the PPi/Pi ratio, thereby promoting hydroxyapatite mineralization in peripheral tissues. GACI is initially characterized by an abnormal ectopic mineralization process in arteries and soft tissue. Nearly half of the patients die within the first 6 months of life from cardiovascular complications, hence the poor prognosis associated with an early diagnosis. In recent years, progress has been made in our understanding of the long-term natural history of GACI, the intricate symptoms due to vascular calcifications, the overmineralization of soft tissues, of hypophosphatemia designated as ARHR2, and of the consequences such as undermineralization of the skeleton, but also of the features possibly seen in pseudoxanthoma elasticum (PXE). Indeed, GACI, PXE, and ARHR2 share common pathophysiological pathways and clinical features beyond the vascular calcifications. Treatment options for severe forms of GACI are mostly based on symptomatic management, including the option of starting bisphosphonates early after birth, such as etidronate and pamidronate, analogues of PPi. Follow-up within an expert and coordinated multidisciplinary team includes treatment of arterial hypertension, calcitriol and phosphorus adjustments, hearing aids, and early detection of possible angioid streaks. It is hoped that ongoing basic and clinical research will lead to the development of effective therapies that specifically target the abnormal PPi regulation and the other mechanisms involved in this disorder. [ABSTRACT FROM AUTHOR]

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) codes for a type 2 transmembrane glycoprotein which hydrolyzes extracellular phosphoanhydrides into bio-active molecules that regulate, inter alia , ectopic mineralization, bone formation, vascular endothelial proliferation, and the innate immune response. The clinical phenotypes produced by ENPP1 deficiency are disparate, ranging from life-threatening arterial calcifications to cutaneous hypopigmentation. To investigate associations between disease phenotype and enzyme activity we quantified the enzyme velocities of 29 unique ENPP1 pathogenic variants in 41 patients enrolled in an NIH study along with 33 other variants reported in literature. We correlated the relative enzyme velocities with the presenting clinical diagnoses, performing the catalytic velocity measurements simultaneously in triplicate using a high-throughput assay to reduce experimental variation. We found that ENPP1 variants associated with autosomal dominant phenotypes reduced enzyme velocities by 50 % or more, whereas variants associated with insulin resistance had non-significant effects on enzyme velocity. In Cole disease the catalytic velocities of ENPP1 variants associated with AD forms trended to lower values than those associated with autosomal recessive forms – 8-32 % vs. 33 % of WT, respectively. Additionally, ENPP1 variants leading to life-threatening vascular calcifications in GACI patients had widely variable enzyme activities, ranging from no significant differences compared to WT to the complete abolishment of enzyme velocity. Finally, disease severity in GACI did not correlate with the mean enzyme velocity of the variants present in affected compound heterozygotes but did correlate with the more severely damaging variant. In summary, correlation of ENPP1 enzyme velocity with disease phenotypes demonstrate that enzyme velocities below 50 % of WT levels are likely to occur in the context of autosomal dominant disease (due to a monoallelic variant), and that disease severity in GACI infants correlates with the more severely damaging ENPP1 variant in compound heterozygotes, not the mean velocity of the pathogenic variants present. • ENPP1 pathogenic variants induce disease in AR and AD inheritance patterns. • ENPP1 enzyme velocities <50% induced disease phenotypes in an AD manner. • Compound GACI patients possessed pathogenic variants without reduced activity. • Disease severity in GACI correlated with the more severely damaging ENPP1 allele. • Variants associated with metabolic syndrome exhibit WT catalytic activities. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation between serum ectonucleotide pyrophosphatase/phosphodiesterase‐1 (ENPP1) level and severity of abdominal vascular calcification in end‐stage renal disease (ESRD) patients receiving dialysis. Methods: A total of 124 patients were consecutively enrolled into the study in our local institution. Based on the Kidney Disease Improving Global Outcomes (KDIGO) guidelines and recommendations, abdomen lateral X‐ray was used to determine abdominal aortic calcification score (AACS) for each patient at enrollment. Patients were divided into three groups based on AACS: no or mild calcification group, moderate calcification group, and severe calcification group. The relationships between ENPP1 levels and AACS were assessed by Spearman analysis and the value of ENPP1 in predicting severity of abdominal aortic calcification was evaluated by receiver operating characteristic (ROC). Results: The level of ENPP1 in dialysis patients was (7.68 ± 1.67) ng/ml. There was no significant difference in serum ENPP1 level between peritoneal dialysis patients and hemodialysis patients (p > 0.05). The AACS of dialysis patients was negatively correlated with ENPP1 value (r = −0.70). Compared to no/mild calcification patients, the levels of serum ENPP1 in patients with moderate/severe calcification were decreased significantly (p < 0.01). The severity of vascular calcification was correlated with serum ENPP1 value, the severer the vascular calcification, the lower the serum ENPP1 level, and the difference was statistically significant (all p < 0.05). The area under ROC curve of ENPP1 was 0.90, the corresponding sensitivity was 0.86, and the specificity was 0.87. Conclusion: Levels of serum ENPP1 in non‐diabetic ESRD patients are negatively related to the severity of abdominal aortic vascular calcification. [ABSTRACT FROM AUTHOR]

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. PPi was measured in proband plasma utilizing a validated adenosine triphosphate (ATP) sulfurylase method. Results: The analytical sensitivity of the ATP sulfurylase assay consisted of 0.15 to 10 µM PPi. Inter- and intra-assay coefficients of variability on identical samples were below 10%. The standard range of PPi in the blood plasma of children and adolescents aged 0 to 18 years was calculated as 2.36 to 4.44 µM, with a median of 3.17 µM, with no difference between male and female probands. PPi plasma levels did not differ significantly in different pediatric age groups. Main Conclusions: Our results yielded no noteworthy discrepancy to the reported standard range of plasma PPi in adults (2-5 µM). We propose the described ATP sulfurylase method as a diagnostic tool to measure PPi levels in plasma as a biomarker in the pediatric population. [ABSTRACT FROM AUTHOR]

Abstract Background Generalized Arterial Calcification of Infancy (GACI) is a heritable ectopic mineralization disorder resulting in diffuse arterial calcifications and/or stenosis, mostly caused by mutations in the ENPP1 gene. Here we present a case report of GACI in a male infant with a new familial mutation of the ENPP1 gene and the clinical outcome after biphosphonates therapy. Case presentation The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. To investigate this atypical hypertension, a renal Doppler ultra-sonography was performed and diffuse echo-bright arteries were detected; then a low-dose whole-body computed tomography demonstrated extensive arterial calcifications, suggesting GACI. A novel homozygous mutation c.784A > G (p.Ser262Gly) was detected in the ENPP1 gene. The infant was administered four courses of bisphosphonates: arterial calcifications were found to decrease but severe refractory hypertension was persistent. Although GACI can be a rapidly fatal illness and frequently results in death in infancy, the patient was 24 months of age at the time of writing this report. Conclusions Three points of interest: the first one is to remind clinicians of this rare and atypical etiology in neonates with severe hypertension and in fetuses with cardiomyopathy and non-immune hydrops fetalis. The second point is the identification of a novel mutation in the ENPP1 gene associated with a clinical presentation of GACI. The third point is the fairly favourable outcome of our patient after bisphosphonates therapy, with calcifications regression but not hypertension.

Generalized Arterial Calcifications of Infancy (GACI) is an extremely rare autosomal recessive genetic condition, mostly due to pathogenic variations in the ENPP1 gene (GACI1, MIM #208000, ENPP1 , MIM #173335). To date 46 likely pathogenic or pathogenic distinct variations in ENPP1 have been described, including nonsense, frameshift, missense, splicing variations, and large deletions. Here we report a case of GACI in a male newborn with a homozygous stop-loss variant in ENPP1 treated in Nancy Regional University Maternity Hospital. Based on proband main clinical signs, clinical exome sequencing was performed and showed a deletion of one nucleotide leading to frameshift and stop-loss (NM_006208.3 (ENPP1):c.2746del,p.(Thr916Hisfs*23)). Clinical presentation is characterized by primary neonatal arterial hypertension resulting in hypertrophic cardiomyopathy decompensated by three cardiogenic shocks and a neonatal deep right sylvian stroke. The child died at 24 days of life. This is the first report of a pathogenic stop-loss variant in ENPP1. It is an opportunity to remind clinicians of GACI disease, a rare and severe etiology in neonates with severe hypertension, and possibility of bisphosphonates therapy. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

Newborn infants with generalized arterial calcification of infancy are at a substantial risk of sudden cardiac death. Treatment with bisphosphonates while helpful does not guarantee a favorable outcome. Herein we report a case of generalized arterial calcification of infancy from fetal diagnosis through childhood. The patient exhibited a previously unreported variant in the ENPP1 gene. Newborn echocardiogram and CT imaging showed extensive calcifications throughout the coronary arteries and aortic arch. Treatment started immediately after birth. Long-term follow-up has demonstrated disease regression. Early recognition and treatment were instrumental in reversing this infant's disease. Successful treatment included the previously reported use of pamidronate but with the novel inclusion of acetazolamide and Similac PM 60/40® (low calcium, low phosphate infant formula). • Generalized arterial calcification of infancy is a rare and frequently fatal disease in infants. • Treatment with bisphosphonates helps many but not all children with the disease. • Addition of specialized formula and acetazolamide to bisphosphonate therapy may improve outcomes. [ABSTRACT FROM AUTHOR]

Generalized arterial calcification of infancy (GACI) is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 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. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways.

Awareness for hypophosphatemic rickets has increased in the last years, based on the availability of specific medical treatments. Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hypophosphatemic rickets, which is known to develop in survivors of generalized arterial calcification of infancy (GACI). Both disorders are based on a deficiency of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and present with a high clinical variability and a lack of a phenotype-genotype association. ARHR2 is characterized by phosphate wasting due to elevated fibroblast growth factor 23 (FGF23) levels and might represent a response of the organism to minimize ectopic calcification in individuals with ENPP1-deficiency. This report reviews the recent clinical and preclinical data on this ultra-rare disease in childhood. • Deficiency of ENPP1 is associated GACI and ARHR2. • GACI and ARHR2 are recognized as two distinct clinical phenotypes which manifest at different ages. • ARHR2 is associated with elevated levels of FGF23, however FGF23-targeted treatments might increase the risk for ectopic calcification. [ABSTRACT FROM AUTHOR]

Abstract: Apart from clinical parallels, similarities in the pathogenesis of arterial and articular cartilage calcification have come to light in recent years. These include the roles of aging, of chronic low-grade inflammation and of genetic and acquired dysregulation of inorganic pyrophosphate (PPi) metabolism. This review focuses on recent developments in understanding the pathogenesis of artery calcification pertinent to interpretation of the mechanistic basis for articular cartilage calcification in aging and osteoarthritis. [Copyright &y& Elsevier]