RARE DISEASE
Generalized arterial calcification of infancy
Generalized arterial calcification of infancy
Generalized arterial calcification of infancy
Synonyms: Idiopathic infantile arterial calcification, Idiopathic obliterative arteriopathy, Infantile arteriosclerosis, Occlusive infantile arteriopathy
Synonyms: Idiopathic infantile arterial calcification, Idiopathic obliterative arteriopathy, Infantile arteriosclerosis, Occlusive infantile arteriopathy
Synonyms: Idiopathic infantile arterial calcification, Idiopathic obliterative arteriopathy, Infantile arteriosclerosis, Occlusive infantile arteriopathy
Drug discovery
2
drugs
With orphan designations
Overview
Generalized Arterial Calcification of Infancy (GACI) is a rare, autosomal recessive disorder caused by mutations in ENPP1 (75% of cases) or ABCC6 genes, leading to deficient pyrophosphate levels and widespread calcification of large/medium arteries. Presenting prenatally or in infancy with heart failure, hypertension, and respiratory distress, it carries ~50% mortality within the first year. Survivors may develop hypophosphatemic rickets, pseudoxanthoma elasticum-like symptoms, or hearing loss. Current management includes bisphosphonates, antihypertensives, and emerging enzyme replacement therapies [1][6][16].
Burden
Mortality: Up to 55% in infancy, primarily from myocardial infarction or heart failure [6][13].
Morbidity: Chronic hypertension, rickets, hearing loss, and multisystem complications requiring lifelong multidisciplinary care [5][13][16].
Healthcare impact: High costs due to intensive neonatal care, imaging, and specialty management [3][13].
Therapies
Bisphosphonates (e.g., etidronate) to reduce calcification, ideally initiated early [1][7][18].
Sodium thiosulfate (calcium chelation) and antihypertensive therapy [2][14].
Emerging therapies: ENPP1 enzyme replacement, antibody-targeted nanoparticle chelation, and prenatal etidronate trials [3][14][18].
Categories: rare circulatory system diseases, rare genetic diseases
Research Papers
145 drug discovery papers about Generalized arterial calcification of infancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
145 drug discovery papers about Generalized arterial calcification of infancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | When Arteries Harden Early: A Case of Generalized Arterial Calcification of Infancy
Generalized arterial calcification of infancy (GACI) is a rare, often fatal, autosomal recessive genetic disorder, primarily caused by mutations in the ENPP1 or ABCC6 genes. While most GACI cases are associated with ENPP1 mutations (GACI type 1), a minority are linked to ABCC6 variants (GACI type 2). We report a 30-month-old female with severe, treatment-resistant hypertension. Ultrasonography and computed tomography angiography revealed calcifications in medium- to large-caliber arteries, raising the suspicion of GACI. Next-generation sequencing identified a heterozygous nonsense mutation in exon 23 of the ABCC6 gene, confirming the diagnosis. The patient was initiated on a combination of antihypertensive medications and was later started on bisphosphonate therapy. At last follow-up, the child was clinically stable. This case highlights the importance of early radiological recognition and genetic testing in GACI.
2026-05-18 | Long-term survival and phenotypic expansion in siblings with generalized arterial calcification of infancy.
Generalized arterial calcification of infancy (GACI) is a rare, autosomal recessive disorder caused by pathogenic variants in ENPP1 or ABCC6. While typically fatal in infancy, survival into childhood is increasingly recognized. We report a family with 3 affected siblings homozygous for an ENPP1 variant (c.1367G > A, p.Arg456Gln). The oldest died in infancy, the surviving 2 received early bisphosphonate therapy. Both survivors demonstrate persistent vascular calcifications, early-onset pseudoxanthoma elasticum (PXE)-like skin lesions, and chronic hypophosphatemia without radiographic rickets. Uniquely, this report contrasts the clinical course of a late preterm sibling against a sibling born extremely premature. Additional findings include auricular cartilage, renal and retinal calcifications, highlighting the systemic nature of ENPP1 deficiency. Our report expands the phenotypic spectrum of ENPP1-related GACI.
2026-03-04 | Diffuse Vascular Calcification Presenting as Refractory Pulmonary Hypertension in a Neonate: A Diagnostic Unravelling
Background: Persistent pulmonary hypertension of the newborn (PPHN) is a recognized cause of neonatal hypoxemic respiratory failure, most commonly associated with parenchymal lung disease or maladaptation of pulmonary circulation. Rarely, severe and refractory pulmonary hypertension may signal an underlying systemic vasculopathy. Generalized arterial calcification of infancy (GACI) is a rare genetic disorder characterized by diffuse arterial wall calcification and intimal proliferation, frequently resulting from ENPP1 mutations. Early manifestations may mimic common neonatal cardiopulmonary conditions, leading to diagnostic delay. Case Presentation: We report a late preterm neonate (34+5 weeks) presenting at birth with severe respiratory failure and persistent hypoxemia requiring mechanical ventilation. Initial evaluation suggested respiratory distress syndrome with severe pulmonary hypertension. Despite optimized ventilatory support, surfactant therapy, pulmonary vasodilators, and inotropic support, pulmonary hypertension remained refractory. The emergence of systemic hypertension, depressed biventricular function, and differential oxygen saturations prompted further evaluation. Serial imaging revealed progressive arterial wall echogenicity on echocardiography and abdominal ultrasonography. Plain chest radiography demonstrated linear, tubular radio-opaque densities tracking along major vascular pathways, mimicking intravascular lines. Contrast-enhanced CT angiography confirmed extensive circumferential calcification involving the thoracic and abdominal aorta, pulmonary arteries, and major systemic branches with preserved luminal patency. Genetic testing identified a pathogenic ENPP1 mutation, establishing the diagnosis of generalized arterial calcification of infancy. The patient was managed with intensive cardiopulmonary support, antihypertensive therapy, and bisphosphonate treatment. Conclusion: This case highlights generalized arterial calcification of infancy as an important differential diagnosis in neonates with refractory pulmonary hypertension, particularly when accompanied by early systemic hypertension and atypical vascular imaging findings. Careful review of plain radiographs and progressive arterial wall echogenicity on ultrasound may provide early diagnostic clues. Prompt recognition and genetic confirmation are essential for targeted management, prognostication, and family counseling in this rare but potentially fatal neonatal vasculopathy.
2026-03-02 | Optimizing diagnosis and management of patients with ENPP1 deficiency: an expert opinion.
PURPOSE: Ectonucleotide pyrophosphate/phosphodiesterase family member 1 (ENPP1) deficiency is a rare genetic disorder caused by loss-of-function ENPP1 gene mutations. Characterized by abnormally low circulating inorganic pyrophosphate concentrations, bone hypomineralization, soft tissue calcification, and arterial stenosis, ENPP1 deficiency is associated with a phenotypic spectrum that includes generalized arterial calcification of infancy type 1 (GACI1) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2). Despite phenotypic differences, patients with GACI1 and ARHR2 have a marked, lifelong physical and emotional burden, with a negative impact on quality of life. METHODS: A scientific board, comprising seven specialist physicians (endocrinologists, nephrologists, and pediatricians) practicing in Italy, held two virtual meetings to exchange knowledge regarding real-world clinical experience of GACI1 and ARHR2 using case examples, and to discuss strategies on how to increase disease awareness and optimize the diagnosis and management of these patients. RESULTS: Five real-world clinical cases are described. The specialist physicians also provide guidance for optimizing the management pathway for patients with ENPP1 deficiency. Early identification of the clinical signs of disease, in combination with comprehensive diagnostic and follow-up testing, is essential for effective patient management. CONCLUSION: Early and accurate identification of ENPP1 deficiency by healthcare providers and comprehensive diagnostic testing is essential for the effective management of patients with GACI1 and ARHR2. Consistent follow-up is key to preventing complications and adverse outcomes. Although treatment options are limited, novel therapies are currently under clinical development.
2025-06-07 | Prenatal Diagnosis and 10-Year Follow-up of Type-II Generalized Arterial Calcification of the Infancy.
Generalized arterial calcification of infancy (GACI) is an ultra-rare, potentially life-threatening disorder of the mineralization of which obstetricians and neonatologists shall be aware.This study aimed to describe twins with ATP binding cassette subfamily C member-6 (ABCC6) mutations leading to type II-GACI phenotype in one of them, their multidisciplinary management, and very long-term (10 years) follow-up.One of the twins had typical calcifications in the ascending aorta and the aortic arc, leading to severe neonatal arterial hypertension needing anti-hypertensive treatment. A therapy with bisphosphonates was also provided for 3 weeks with the disappearance of calcifications and resolution of hypertension. Ten-year follow-up was completely normal. Patients were found to carry a heterozygous mutation of ABCC6.Type II-GACI can be managed with a multi-disciplinary approach and good long-term outcomes despite the occurrence of severe neonatal arterial hypertension. · GACI is an ultra-rare, potentially life-threatening disorder of the mineralization processes of which obstetricians and neonatologists shall be aware.. · Type II-GACI can be managed with a multi-disciplinary approach and good long-term outcome despite the occurrence of severe neonatal arterial hypertension.. · Type-II GACI phenotype can be similar to that of pseudoxanthoma elasticum due to heterozygous mutations of the ABCC6 gene.. · Further research is needed to understand the pathobiology of this disorder..
gene therapies
2025-06-23 | A Multi-State Structural Genomics Approach Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases
Purpose Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). Despite both diseases being rare, there are already 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to interpret and classify these VUS mechanistically. Methods We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants and identify 3D mutational hotspots. With this and additional functional information, we categorized variants in a mechanistic ontology based on which critical functions of ABCC6 they impact. We then compared PXE and GACI -associated variants. Results We identified two three-dimensional hotspots of pathogenic variants and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function, 30 of which could be reclassified as Likely Pathogenic from our non-clinical data. Finally, we found slight differences between PXE and GACI-associated variants. Conclusion The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. Further, our VUS reclassification will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation.
2019-01-11 | Adenovirus-Mediated ABCC6 Gene Therapy for Heritable Ectopic Mineralization Disorders
Loss-of-function mutations in the ABCC6 gene cause pseudoxanthoma elasticum and type 2 generalized arterial calcification of infancy, heritable ectopic mineralization disorders without effective treatment. ABCC6 encodes the putative efflux transporter ABCC6, which is predominantly expressed in the liver. Although the substrate of ABCC6 remains unknown, recent studies showed that pseudoxanthoma elasticum is a metabolic disorder caused by reduced circulating levels of pyrophosphate, a potent mineralization inhibitor. We hypothesized that reconstitution of ABCC6 might counteract ectopic mineralization in an Abcc6–/– mouse model of pseudoxanthoma elasticum. Intravenous administration of a recombinant adenovirus expressing wild-type human ABCC6 in Abcc6–/– mice showed sustained high-level expression of human ABCC6 in the liver for up to 4 weeks, increasing pyrophosphate levels in plasma. In addition, adenovirus injection every 4 weeks restored plasma pyrophosphate levels and, consequently, significantly reduced ectopic mineralization in the skin of young mice. By contrast, the same treatment in old mice with already established mineral deposits failed to reduce mineralization. These results suggest that adenovirus-mediated ABCC6 gene delivery, when initiated early, is a promising prevention therapy for pseudoxanthoma elasticum and generalized arterial calcification of infancy, diseases that currently lack preventive or therapeutic options.
2013-10-27 | The Level of Hepatic ABCC6 Expression Determines the Severity of Calcification after Cardiac Injury
Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6−/− mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/− mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.
antibodies
2024-08-11 | Inherited phosphate and pyrophosphate disorders: New insights and novel therapies changing the oral health landscape.
Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes the following 4 mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, although manifestations are distinct from those in the skeleton. The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may affect oral health and dental treatments of affected patients. Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia and hyperphosphatemic familial tumoral calcinosis and disruptions in pyrophosphate levels in hypophosphatasia and generalized arterial calcification of infancy contribute to dental mineralization defects. Traditionally, there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected patients. Research over the past 2 decades has exponentially expanded the understanding of mineral metabolism, and has led to novel treatments for mineralization disorders. Newly implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral health care that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams.
2023-11-21 | Future treatments for the arteriopathy of ectopic calcification disorders
Ectopic calcification disorders, including Generalized Arterial Calcification of Infancy (GACI) and Pseudoxanthoma Elasticum are rare but impactful on individuals, healthcare and society, with significant associated morbidity, mortality and healthcare costs. Available therapies are not curative and focus on reducing extracellular calcification to limit progression of the arteriopathy that is responsible for much of the morbidity and, in the case of GACI, significant early mortality (approximately 50% in infancy). In this article, current and emerging medical approaches are reviewed and critiqued, including dietary manipulation, phosphate binders, bisphosphonates, tissue nonspecific alkaline phosphatase inhibitors, ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) enzyme replacement, allele-specific therapies, gene therapies, and antibody targeted treatment. Available therapies may limit further arterial calcification, but in GACI in particular, significant calcification can be present at birth, contributing to high infant mortality. This highlights the need for new approaches that aim to reverse established calcification, rather than merely slow its progression. Recently, a promising new class of antibody-targeted nanoparticle therapeutics has emerged that can reverse established arterial calcification in animals, restoring arterial elasticity. In one realization, nanoparticles carry established chelators, such as ethylenediaminetetraacetic disodium acid, to sites of arterial damage, concentrating the impact of the chelator where it is needed and limiting off-target effects. Such drugs would complement existing and emerging therapies, such as ENPP1 enzyme replacement, that slow or prevent progression of calcification, by offering an opportunity to “reset” arterial health in ectopic calcification disorders. At present, ectopic calcification disorders are challenging to treat effectively and carry a high burden of morbidity and mortality, particularly in GACI. Recent drug developments offer good reason to be hopeful for a new era of effective therapeutics that may reverse established arterial disease as well as halt its progression.
2021-07-20 | Creation of the first monoclonal antibody recognizing an extracellular epitope of hABCC6.
Mutations in the ABCC6 gene result in calcification diseases such as pseudoxanthoma elasticum or Generalized Arterial Calcification of Infancy. Generation of antibodies recognizing an extracellular (EC) epitope of ABCC6 has been hampered by the short EC segments of the protein. To overcome this limitation, we immunized bovine FcRn transgenic mice exhibiting an augmented humoral immune response with Human Embryonic Kidney 293 cells cells expressing human ABCC6 (hABCC6). We obtained a monoclonal antibody recognizing an EC epitope of hABCC6 that we named mEChC6. Limited proteolysis revealed that the epitope is within a loop in the N-terminal half of ABCC6 and probably spans amino acids 338-347. mEChC6 recognizes hABCC6 in the liver of hABCC6 transgenic mice, verifying both specificity and EC binding to intact hepatocytes.
2021-01-12 | 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 (PPi) were investigated in recent years, but reversion of calcification could not be achieved. With this study, we pursued the idea of a combination of controlled drug delivery through nanoparticles and active targeting via antibody conjugation to develop a treatment for GACI and PXE. To establish a suitable drug delivery system, the chelating drug diethylenetriamine pentaacetic acid (DTPA) was conjugated to nanoparticles composed of human serum albumin (HSA) as biodegradable and non-toxic particle matrix. To accomplish an active targeting of the elastic fibers exposed through calcification of the affected areas, the nanoparticle surface was functionalized with an anti-elastin antibody. Cytotoxicity and cell interaction studies revealed favorable preconditions for the intended i.v. application. The chelating ability was evaluated in vitro and ex vivo on aortic ring culture isolated from two mouse models of GACI and PXE. The positive results led to the conclusion that the produced nanoparticles might be a promising therapy in the treatment of GACI and PXE.
2016-12-23 | VASCULAR CALCIFICATION, ATHEROSCLEROSIS AND BONE LOSS (OSTEOPOROSIS): NEW PATHOPHYSIOLOGICAL MECHANISMS AND FUTURE PERSPECTIVES FOR PHARMACOLOGICAL THERAPY
Vascular calcification or ectopic mineralization in blood vessels is an active, cell-regulated process, increasingly recognized as a general cardiovascular risk factor. Ectopic artery mineralization is frequently accompanied by decreased bone mineral density or disturbed bone turnover and development of the osteoporosis. The latest data support the correlation of osteoporosis and atherosclerosis, indicating the parallel progression of two tissue destruction processes with increased fatal and nonfatal coronary events, as well as a higher fracture risk. Patients with osteoporosis, have a higher risk of cardiovascular diseases than subjects with normal bone. Many proteins responsible for bone formation and resorption have been identified in the arterial wall. Vascular calcification includes mostly osteogenic and, to a lesser extent chondrogenic differentiation of osteoblasts and osteoclast-like cells. It has been shown that many of the regulators of bone formation and resorption some bone structural proteins, such as osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) are also expressed in the atherosclerotic plaque. When RANKL binds to RANK, osteoclasts are activated and bone resorption occurs and processes of vascular calcification become also activated. OPG, protein homologue to receptor activator of nuclear factor-κB (RANK), can bind to RANKL, blocking the binding of RANKL to RANK, that results in inhibition of differentiation of preosteoclasts to mature osteoclasts, lower osteoclast capacity for resorption of bone mineral matrix, and development vascular calcification. The latest data supports that cathepsin K, a cysteine protease, can efficiently degrade type I and II collagen, both of which are major matrix components of the bone and atherosclerotic plaque. These findings further underscore the potential of cathepsin K as a target for novel molecules to treat osteoporosis and atherosclerosis. Thus, the discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in the process of bone remodeling, vascular calcification and atherosclerosis has made progress in understanding the mechanisms of disease development and possibly to develop new dual therapies. New therapies for osteoporosis and atherosclerosis that may potentially improve or augment existing treatments include the recently approved anti-receptor activator of NF-κB-ligand monoclonal antibody fms (denosumab) and the cathepsin K inhibitor odanacatib, presently in the late stage of clinical development.
proteins
2026-05-26 | Generalized Arterial Calcification of Infancy (GACI): State of the Art and Clinical Perspectives.
Generalized Arterial Calcification of Infancy (GACI) is a rare autosomal recessive disorder characterized by pathological calcium deposition in large and medium-sized arteries, leading to severe cardiovascular complications such as hypertension, heart failure, and stroke. The mortality rate is approximately 50% within the first six months of life if untreated. The disease is primarily caused by mutations in the ENPP1 or ABCC6 genes, resulting in a deficiency of inorganic pyrophosphate (PPi), a key inhibitor of arterial calcification. This review provides a comprehensive overview of the pathophysiology, genetic basis, and clinical features of GACI. In addition, we summarize current and emerging therapeutic strategies, including enzyme replacement therapy with recombinant ENPP1 (INZ-701), critically discussing available preclinical and early clinical evidence, as well as current limitations.
2025-12-25 | Six cases of ENPP1 pathogenic variants causing autosomal recessive hypophosphatemic rickets type 2 and generalized arterial calcification of infancy.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.
2025-06-11 | Improvements in hearing loss with bone-targeted enzyme replacement therapy are associated with corrected hypomineralization and osteocyte properties of auditory ossicles in Enpp1-deficient mice.
Hearing loss is common in conditions caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency, such as generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. Mechanistically, it is hypothesized that poor mineralization of the auditory ossicles leads to impaired sound transmission in the middle ear. Here we investigated whether enzyme replacement therapy (ERT) improves hearing loss in an Enpp1-deficient mouse model and whether this is associated with corrected bone properties in the ossicles. For this purpose, male Enpp1asj/asj mice were subjected to either a soluble or bone-targeted ERT of ENPP1-Fc. Hearing function and bone properties of the malleus, the first bone of the ossicular chain, were evaluated and compared to untreated Enpp1asj/asj and WT mice at the age of 17 wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32 kHz, suggesting a generalized impairment of hearing. The hearing deficits observed in Enpp1asj/asj mice were partially or fully corrected by both soluble and bone-targeted ERT, as evidenced by the restoration of auditory brainstem response thresholds, with dose dependence and generally stronger effect of bone-targeted ERT. This was not only associated with corrected blood plasma markers of mineral metabolism but also improved matrix mineralization and restored osteocyte properties in the malleus. In addition, for the first time in mice, we were able to demonstrate the occurrence of mineralized osteocyte lacunae in Enpp1asj/asj mice, a phenomenon that was corrected by bone-targeted but not soluble ERT, underscoring the need for targeted delivery for effective treatment. In contrast to osteocyte lacunar mineralization in humans (ie, micropetrosis), the intra-lacunar mineral was overall less mineralized than the adjacent bone. In conclusion, our results point toward the potential benefit of correcting ossicular mineralization to prevent hearing loss in ENPP1 deficiency.
2025-01-01 | Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis
Abstract Background ABCC6 deficiency is caused by variants in the ABCC6 gene, leading to dysfunction of the ABCC6 protein. This can result in the development of the infantile phenotype, generalized arterial calcification of infancy type 2 (GACI2), or the adolescent-adult phenotype, pseudoxanthoma elasticum (PXE). To date, the impact of ABCC6 deficiency in a pediatric population has not been comprehensively studied. This analysis aimed to collectively characterize the genotypic and phenotypic presentation of ABCC6 deficiency in the pediatric population. Results A literature review and analysis identified 95 individuals with ABCC6 variant(s) and documented clinical manifestations occurring from ages 0 to < 18 years. Of the 133 ABCC6 variants found, 57.1% were pathogenic, 26.3% were likely pathogenic, and 10.5% were of uncertain significance. A high prevalence of ectopic calcification with cardiovascular, dermatologic, neurologic, and ocular complications was observed across this pediatric ABCC6 deficiency cohort. While 56% were diagnosed with GACI and 44% with PXE, many individuals exhibited overlapping features of both conditions. There was a relatively high frequency of clinical manifestations through 6 years of age with lower frequency from ages 7 to 18 years. There was significant phenotypic variability observed across patients harboring the same ABCC6 variant(s). Conclusions These findings demonstrate the wide spectrum and early emergence of cardiovascular, neurologic, and ocular complications in pediatric patients with ABCC6 deficiency. Given the variability of clinical presentations and absence of systematic phenotype characterization, pediatric ABCC6 deficiency is likely underdiagnosed. Establishing guidelines for assessment, genetic diagnosis, monitoring, and prognostic counseling would assist in the timely diagnosis and multidisciplinary management of pediatric patients with ABCC6 deficiency.
2024-12-26 | Prenatal Diagnosis of Idiopathic Infantile Arterial Calcinosis – A Case Report on A Rare Fatal Condition
Idiopathic infantile arterial calcinosis also known as Generalised arterial calcinosis of infancy (GACI) is a rare genetic disorder causing extensive premature calcification of major vessels. About 200 cases have been reported till date as per literature.
other
2005-10-21 | Idiopathic infantile arterial calcification: Two case reports, a review of the literature and a role for cardiac transplantation
Abstract: Idiopathic infantile arterial calcification (IIAC) is a rare, but important, cause of rapidly progressive ischemic heart disease in children. In this paper, we report two recent cases of IIAC seen at tertiary referral hospitals. Both cases presented in infancy with signs of heart failure and, ultimately, died with the diagnosis of IIAC confirmed at postmortem examination. A thorough review of the literature reveals approximately 160 reported cases of IIAC. The clinical outcomes, radiographic findings and pathologic details are summarized. Proposed etiologic mechanisms are reviewed, including promising research into the role of inorganic pyrophosphate as a regulatory factor in the development of IIAC. Because of the typically fatal outcome of IIAC and the lack of proven therapies, the potential role for cardiac transplantation is discussed.
small molecules
2026-08-13 | When Arteries Harden Early: A Case of Generalized Arterial Calcification of Infancy
Generalized arterial calcification of infancy (GACI) is a rare, often fatal, autosomal recessive genetic disorder, primarily caused by mutations in the ENPP1 or ABCC6 genes. While most GACI cases are associated with ENPP1 mutations (GACI type 1), a minority are linked to ABCC6 variants (GACI type 2). We report a 30-month-old female with severe, treatment-resistant hypertension. Ultrasonography and computed tomography angiography revealed calcifications in medium- to large-caliber arteries, raising the suspicion of GACI. Next-generation sequencing identified a heterozygous nonsense mutation in exon 23 of the ABCC6 gene, confirming the diagnosis. The patient was initiated on a combination of antihypertensive medications and was later started on bisphosphonate therapy. At last follow-up, the child was clinically stable. This case highlights the importance of early radiological recognition and genetic testing in GACI.
2026-05-18 | Long-term survival and phenotypic expansion in siblings with generalized arterial calcification of infancy.
Generalized arterial calcification of infancy (GACI) is a rare, autosomal recessive disorder caused by pathogenic variants in ENPP1 or ABCC6. While typically fatal in infancy, survival into childhood is increasingly recognized. We report a family with 3 affected siblings homozygous for an ENPP1 variant (c.1367G > A, p.Arg456Gln). The oldest died in infancy, the surviving 2 received early bisphosphonate therapy. Both survivors demonstrate persistent vascular calcifications, early-onset pseudoxanthoma elasticum (PXE)-like skin lesions, and chronic hypophosphatemia without radiographic rickets. Uniquely, this report contrasts the clinical course of a late preterm sibling against a sibling born extremely premature. Additional findings include auricular cartilage, renal and retinal calcifications, highlighting the systemic nature of ENPP1 deficiency. Our report expands the phenotypic spectrum of ENPP1-related GACI.
2026-03-04 | Diffuse Vascular Calcification Presenting as Refractory Pulmonary Hypertension in a Neonate: A Diagnostic Unravelling
Background: Persistent pulmonary hypertension of the newborn (PPHN) is a recognized cause of neonatal hypoxemic respiratory failure, most commonly associated with parenchymal lung disease or maladaptation of pulmonary circulation. Rarely, severe and refractory pulmonary hypertension may signal an underlying systemic vasculopathy. Generalized arterial calcification of infancy (GACI) is a rare genetic disorder characterized by diffuse arterial wall calcification and intimal proliferation, frequently resulting from ENPP1 mutations. Early manifestations may mimic common neonatal cardiopulmonary conditions, leading to diagnostic delay. Case Presentation: We report a late preterm neonate (34+5 weeks) presenting at birth with severe respiratory failure and persistent hypoxemia requiring mechanical ventilation. Initial evaluation suggested respiratory distress syndrome with severe pulmonary hypertension. Despite optimized ventilatory support, surfactant therapy, pulmonary vasodilators, and inotropic support, pulmonary hypertension remained refractory. The emergence of systemic hypertension, depressed biventricular function, and differential oxygen saturations prompted further evaluation. Serial imaging revealed progressive arterial wall echogenicity on echocardiography and abdominal ultrasonography. Plain chest radiography demonstrated linear, tubular radio-opaque densities tracking along major vascular pathways, mimicking intravascular lines. Contrast-enhanced CT angiography confirmed extensive circumferential calcification involving the thoracic and abdominal aorta, pulmonary arteries, and major systemic branches with preserved luminal patency. Genetic testing identified a pathogenic ENPP1 mutation, establishing the diagnosis of generalized arterial calcification of infancy. The patient was managed with intensive cardiopulmonary support, antihypertensive therapy, and bisphosphonate treatment. Conclusion: This case highlights generalized arterial calcification of infancy as an important differential diagnosis in neonates with refractory pulmonary hypertension, particularly when accompanied by early systemic hypertension and atypical vascular imaging findings. Careful review of plain radiographs and progressive arterial wall echogenicity on ultrasound may provide early diagnostic clues. Prompt recognition and genetic confirmation are essential for targeted management, prognostication, and family counseling in this rare but potentially fatal neonatal vasculopathy.
2026-03-02 | Optimizing diagnosis and management of patients with ENPP1 deficiency: an expert opinion.
PURPOSE: Ectonucleotide pyrophosphate/phosphodiesterase family member 1 (ENPP1) deficiency is a rare genetic disorder caused by loss-of-function ENPP1 gene mutations. Characterized by abnormally low circulating inorganic pyrophosphate concentrations, bone hypomineralization, soft tissue calcification, and arterial stenosis, ENPP1 deficiency is associated with a phenotypic spectrum that includes generalized arterial calcification of infancy type 1 (GACI1) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2). Despite phenotypic differences, patients with GACI1 and ARHR2 have a marked, lifelong physical and emotional burden, with a negative impact on quality of life. METHODS: A scientific board, comprising seven specialist physicians (endocrinologists, nephrologists, and pediatricians) practicing in Italy, held two virtual meetings to exchange knowledge regarding real-world clinical experience of GACI1 and ARHR2 using case examples, and to discuss strategies on how to increase disease awareness and optimize the diagnosis and management of these patients. RESULTS: Five real-world clinical cases are described. The specialist physicians also provide guidance for optimizing the management pathway for patients with ENPP1 deficiency. Early identification of the clinical signs of disease, in combination with comprehensive diagnostic and follow-up testing, is essential for effective patient management. CONCLUSION: Early and accurate identification of ENPP1 deficiency by healthcare providers and comprehensive diagnostic testing is essential for the effective management of patients with GACI1 and ARHR2. Consistent follow-up is key to preventing complications and adverse outcomes. Although treatment options are limited, novel therapies are currently under clinical development.
2025-06-07 | Prenatal Diagnosis and 10-Year Follow-up of Type-II Generalized Arterial Calcification of the Infancy.
Generalized arterial calcification of infancy (GACI) is an ultra-rare, potentially life-threatening disorder of the mineralization of which obstetricians and neonatologists shall be aware.This study aimed to describe twins with ATP binding cassette subfamily C member-6 (ABCC6) mutations leading to type II-GACI phenotype in one of them, their multidisciplinary management, and very long-term (10 years) follow-up.One of the twins had typical calcifications in the ascending aorta and the aortic arc, leading to severe neonatal arterial hypertension needing anti-hypertensive treatment. A therapy with bisphosphonates was also provided for 3 weeks with the disappearance of calcifications and resolution of hypertension. Ten-year follow-up was completely normal. Patients were found to carry a heterozygous mutation of ABCC6.Type II-GACI can be managed with a multi-disciplinary approach and good long-term outcomes despite the occurrence of severe neonatal arterial hypertension. · GACI is an ultra-rare, potentially life-threatening disorder of the mineralization processes of which obstetricians and neonatologists shall be aware.. · Type II-GACI can be managed with a multi-disciplinary approach and good long-term outcome despite the occurrence of severe neonatal arterial hypertension.. · Type-II GACI phenotype can be similar to that of pseudoxanthoma elasticum due to heterozygous mutations of the ABCC6 gene.. · Further research is needed to understand the pathobiology of this disorder..
gene therapies
2025-06-23 | A Multi-State Structural Genomics Approach Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases
Purpose Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). Despite both diseases being rare, there are already 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to interpret and classify these VUS mechanistically. Methods We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants and identify 3D mutational hotspots. With this and additional functional information, we categorized variants in a mechanistic ontology based on which critical functions of ABCC6 they impact. We then compared PXE and GACI -associated variants. Results We identified two three-dimensional hotspots of pathogenic variants and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function, 30 of which could be reclassified as Likely Pathogenic from our non-clinical data. Finally, we found slight differences between PXE and GACI-associated variants. Conclusion The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. Further, our VUS reclassification will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation.
2019-01-11 | Adenovirus-Mediated ABCC6 Gene Therapy for Heritable Ectopic Mineralization Disorders
Loss-of-function mutations in the ABCC6 gene cause pseudoxanthoma elasticum and type 2 generalized arterial calcification of infancy, heritable ectopic mineralization disorders without effective treatment. ABCC6 encodes the putative efflux transporter ABCC6, which is predominantly expressed in the liver. Although the substrate of ABCC6 remains unknown, recent studies showed that pseudoxanthoma elasticum is a metabolic disorder caused by reduced circulating levels of pyrophosphate, a potent mineralization inhibitor. We hypothesized that reconstitution of ABCC6 might counteract ectopic mineralization in an Abcc6–/– mouse model of pseudoxanthoma elasticum. Intravenous administration of a recombinant adenovirus expressing wild-type human ABCC6 in Abcc6–/– mice showed sustained high-level expression of human ABCC6 in the liver for up to 4 weeks, increasing pyrophosphate levels in plasma. In addition, adenovirus injection every 4 weeks restored plasma pyrophosphate levels and, consequently, significantly reduced ectopic mineralization in the skin of young mice. By contrast, the same treatment in old mice with already established mineral deposits failed to reduce mineralization. These results suggest that adenovirus-mediated ABCC6 gene delivery, when initiated early, is a promising prevention therapy for pseudoxanthoma elasticum and generalized arterial calcification of infancy, diseases that currently lack preventive or therapeutic options.
2013-10-27 | The Level of Hepatic ABCC6 Expression Determines the Severity of Calcification after Cardiac Injury
Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6−/− mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/− mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization.
antibodies
2024-08-11 | Inherited phosphate and pyrophosphate disorders: New insights and novel therapies changing the oral health landscape.
Mineral metabolism is critical for proper development of hard tissues of the skeleton and dentition. The dentoalveolar complex includes the following 4 mineralized tissues: enamel, dentin, cementum, and alveolar bone. Developmental processes of these tissues are affected by inherited disorders that disrupt phosphate and pyrophosphate homeostasis, although manifestations are distinct from those in the skeleton. The authors discuss original data from experiments and comparative analyses and review articles describing effects of inherited phosphate and pyrophosphate disorders on dental tissues. A particular emphasis is placed on how new therapeutic approaches for these conditions may affect oral health and dental treatments of affected patients. Disorders of phosphate and pyrophosphate metabolism can lead to reduced mineralization (hypomineralization) or inappropriate (ectopic) calcification of soft tissues. Disruptions in phosphate levels in X-linked hypophosphatemia and hyperphosphatemic familial tumoral calcinosis and disruptions in pyrophosphate levels in hypophosphatasia and generalized arterial calcification of infancy contribute to dental mineralization defects. Traditionally, there have been few options to ameliorate dental health problems arising from these conditions. New antibody and enzyme replacement therapies bring possibilities to improve oral health in affected patients. Research over the past 2 decades has exponentially expanded the understanding of mineral metabolism, and has led to novel treatments for mineralization disorders. Newly implemented and emerging therapeutic strategies affect the dentoalveolar complex and interact with aspects of oral health care that must be considered for dental treatment, clinical trial design, and coordination of multidisciplinary care teams.
2023-11-21 | Future treatments for the arteriopathy of ectopic calcification disorders
Ectopic calcification disorders, including Generalized Arterial Calcification of Infancy (GACI) and Pseudoxanthoma Elasticum are rare but impactful on individuals, healthcare and society, with significant associated morbidity, mortality and healthcare costs. Available therapies are not curative and focus on reducing extracellular calcification to limit progression of the arteriopathy that is responsible for much of the morbidity and, in the case of GACI, significant early mortality (approximately 50% in infancy). In this article, current and emerging medical approaches are reviewed and critiqued, including dietary manipulation, phosphate binders, bisphosphonates, tissue nonspecific alkaline phosphatase inhibitors, ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) enzyme replacement, allele-specific therapies, gene therapies, and antibody targeted treatment. Available therapies may limit further arterial calcification, but in GACI in particular, significant calcification can be present at birth, contributing to high infant mortality. This highlights the need for new approaches that aim to reverse established calcification, rather than merely slow its progression. Recently, a promising new class of antibody-targeted nanoparticle therapeutics has emerged that can reverse established arterial calcification in animals, restoring arterial elasticity. In one realization, nanoparticles carry established chelators, such as ethylenediaminetetraacetic disodium acid, to sites of arterial damage, concentrating the impact of the chelator where it is needed and limiting off-target effects. Such drugs would complement existing and emerging therapies, such as ENPP1 enzyme replacement, that slow or prevent progression of calcification, by offering an opportunity to “reset” arterial health in ectopic calcification disorders. At present, ectopic calcification disorders are challenging to treat effectively and carry a high burden of morbidity and mortality, particularly in GACI. Recent drug developments offer good reason to be hopeful for a new era of effective therapeutics that may reverse established arterial disease as well as halt its progression.
2021-07-20 | Creation of the first monoclonal antibody recognizing an extracellular epitope of hABCC6.
Mutations in the ABCC6 gene result in calcification diseases such as pseudoxanthoma elasticum or Generalized Arterial Calcification of Infancy. Generation of antibodies recognizing an extracellular (EC) epitope of ABCC6 has been hampered by the short EC segments of the protein. To overcome this limitation, we immunized bovine FcRn transgenic mice exhibiting an augmented humoral immune response with Human Embryonic Kidney 293 cells cells expressing human ABCC6 (hABCC6). We obtained a monoclonal antibody recognizing an EC epitope of hABCC6 that we named mEChC6. Limited proteolysis revealed that the epitope is within a loop in the N-terminal half of ABCC6 and probably spans amino acids 338-347. mEChC6 recognizes hABCC6 in the liver of hABCC6 transgenic mice, verifying both specificity and EC binding to intact hepatocytes.
2021-01-12 | 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 (PPi) were investigated in recent years, but reversion of calcification could not be achieved. With this study, we pursued the idea of a combination of controlled drug delivery through nanoparticles and active targeting via antibody conjugation to develop a treatment for GACI and PXE. To establish a suitable drug delivery system, the chelating drug diethylenetriamine pentaacetic acid (DTPA) was conjugated to nanoparticles composed of human serum albumin (HSA) as biodegradable and non-toxic particle matrix. To accomplish an active targeting of the elastic fibers exposed through calcification of the affected areas, the nanoparticle surface was functionalized with an anti-elastin antibody. Cytotoxicity and cell interaction studies revealed favorable preconditions for the intended i.v. application. The chelating ability was evaluated in vitro and ex vivo on aortic ring culture isolated from two mouse models of GACI and PXE. The positive results led to the conclusion that the produced nanoparticles might be a promising therapy in the treatment of GACI and PXE.
2016-12-23 | VASCULAR CALCIFICATION, ATHEROSCLEROSIS AND BONE LOSS (OSTEOPOROSIS): NEW PATHOPHYSIOLOGICAL MECHANISMS AND FUTURE PERSPECTIVES FOR PHARMACOLOGICAL THERAPY
Vascular calcification or ectopic mineralization in blood vessels is an active, cell-regulated process, increasingly recognized as a general cardiovascular risk factor. Ectopic artery mineralization is frequently accompanied by decreased bone mineral density or disturbed bone turnover and development of the osteoporosis. The latest data support the correlation of osteoporosis and atherosclerosis, indicating the parallel progression of two tissue destruction processes with increased fatal and nonfatal coronary events, as well as a higher fracture risk. Patients with osteoporosis, have a higher risk of cardiovascular diseases than subjects with normal bone. Many proteins responsible for bone formation and resorption have been identified in the arterial wall. Vascular calcification includes mostly osteogenic and, to a lesser extent chondrogenic differentiation of osteoblasts and osteoclast-like cells. It has been shown that many of the regulators of bone formation and resorption some bone structural proteins, such as osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) are also expressed in the atherosclerotic plaque. When RANKL binds to RANK, osteoclasts are activated and bone resorption occurs and processes of vascular calcification become also activated. OPG, protein homologue to receptor activator of nuclear factor-κB (RANK), can bind to RANKL, blocking the binding of RANKL to RANK, that results in inhibition of differentiation of preosteoclasts to mature osteoclasts, lower osteoclast capacity for resorption of bone mineral matrix, and development vascular calcification. The latest data supports that cathepsin K, a cysteine protease, can efficiently degrade type I and II collagen, both of which are major matrix components of the bone and atherosclerotic plaque. These findings further underscore the potential of cathepsin K as a target for novel molecules to treat osteoporosis and atherosclerosis. Thus, the discovery of the cytokine RANKL-RANK-OPG system and significant role of the cathepsin K in the process of bone remodeling, vascular calcification and atherosclerosis has made progress in understanding the mechanisms of disease development and possibly to develop new dual therapies. New therapies for osteoporosis and atherosclerosis that may potentially improve or augment existing treatments include the recently approved anti-receptor activator of NF-κB-ligand monoclonal antibody fms (denosumab) and the cathepsin K inhibitor odanacatib, presently in the late stage of clinical development.
proteins
2026-05-26 | Generalized Arterial Calcification of Infancy (GACI): State of the Art and Clinical Perspectives.
Generalized Arterial Calcification of Infancy (GACI) is a rare autosomal recessive disorder characterized by pathological calcium deposition in large and medium-sized arteries, leading to severe cardiovascular complications such as hypertension, heart failure, and stroke. The mortality rate is approximately 50% within the first six months of life if untreated. The disease is primarily caused by mutations in the ENPP1 or ABCC6 genes, resulting in a deficiency of inorganic pyrophosphate (PPi), a key inhibitor of arterial calcification. This review provides a comprehensive overview of the pathophysiology, genetic basis, and clinical features of GACI. In addition, we summarize current and emerging therapeutic strategies, including enzyme replacement therapy with recombinant ENPP1 (INZ-701), critically discussing available preclinical and early clinical evidence, as well as current limitations.
2025-12-25 | Six cases of ENPP1 pathogenic variants causing autosomal recessive hypophosphatemic rickets type 2 and generalized arterial calcification of infancy.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.
2025-06-11 | Improvements in hearing loss with bone-targeted enzyme replacement therapy are associated with corrected hypomineralization and osteocyte properties of auditory ossicles in Enpp1-deficient mice.
Hearing loss is common in conditions caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency, such as generalized arterial calcification of infancy and autosomal recessive hypophosphatemic rickets type 2. Mechanistically, it is hypothesized that poor mineralization of the auditory ossicles leads to impaired sound transmission in the middle ear. Here we investigated whether enzyme replacement therapy (ERT) improves hearing loss in an Enpp1-deficient mouse model and whether this is associated with corrected bone properties in the ossicles. For this purpose, male Enpp1asj/asj mice were subjected to either a soluble or bone-targeted ERT of ENPP1-Fc. Hearing function and bone properties of the malleus, the first bone of the ossicular chain, were evaluated and compared to untreated Enpp1asj/asj and WT mice at the age of 17 wk. In untreated Enpp1-deficient mice, we found elevated hearing thresholds at stimulus frequencies of 8, 16, and 32 kHz, suggesting a generalized impairment of hearing. The hearing deficits observed in Enpp1asj/asj mice were partially or fully corrected by both soluble and bone-targeted ERT, as evidenced by the restoration of auditory brainstem response thresholds, with dose dependence and generally stronger effect of bone-targeted ERT. This was not only associated with corrected blood plasma markers of mineral metabolism but also improved matrix mineralization and restored osteocyte properties in the malleus. In addition, for the first time in mice, we were able to demonstrate the occurrence of mineralized osteocyte lacunae in Enpp1asj/asj mice, a phenomenon that was corrected by bone-targeted but not soluble ERT, underscoring the need for targeted delivery for effective treatment. In contrast to osteocyte lacunar mineralization in humans (ie, micropetrosis), the intra-lacunar mineral was overall less mineralized than the adjacent bone. In conclusion, our results point toward the potential benefit of correcting ossicular mineralization to prevent hearing loss in ENPP1 deficiency.
2025-01-01 | Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis
Abstract Background ABCC6 deficiency is caused by variants in the ABCC6 gene, leading to dysfunction of the ABCC6 protein. This can result in the development of the infantile phenotype, generalized arterial calcification of infancy type 2 (GACI2), or the adolescent-adult phenotype, pseudoxanthoma elasticum (PXE). To date, the impact of ABCC6 deficiency in a pediatric population has not been comprehensively studied. This analysis aimed to collectively characterize the genotypic and phenotypic presentation of ABCC6 deficiency in the pediatric population. Results A literature review and analysis identified 95 individuals with ABCC6 variant(s) and documented clinical manifestations occurring from ages 0 to < 18 years. Of the 133 ABCC6 variants found, 57.1% were pathogenic, 26.3% were likely pathogenic, and 10.5% were of uncertain significance. A high prevalence of ectopic calcification with cardiovascular, dermatologic, neurologic, and ocular complications was observed across this pediatric ABCC6 deficiency cohort. While 56% were diagnosed with GACI and 44% with PXE, many individuals exhibited overlapping features of both conditions. There was a relatively high frequency of clinical manifestations through 6 years of age with lower frequency from ages 7 to 18 years. There was significant phenotypic variability observed across patients harboring the same ABCC6 variant(s). Conclusions These findings demonstrate the wide spectrum and early emergence of cardiovascular, neurologic, and ocular complications in pediatric patients with ABCC6 deficiency. Given the variability of clinical presentations and absence of systematic phenotype characterization, pediatric ABCC6 deficiency is likely underdiagnosed. Establishing guidelines for assessment, genetic diagnosis, monitoring, and prognostic counseling would assist in the timely diagnosis and multidisciplinary management of pediatric patients with ABCC6 deficiency.
2024-12-26 | Prenatal Diagnosis of Idiopathic Infantile Arterial Calcinosis – A Case Report on A Rare Fatal Condition
Idiopathic infantile arterial calcinosis also known as Generalised arterial calcinosis of infancy (GACI) is a rare genetic disorder causing extensive premature calcification of major vessels. About 200 cases have been reported till date as per literature.
other
2005-10-21 | Idiopathic infantile arterial calcification: Two case reports, a review of the literature and a role for cardiac transplantation
Abstract: Idiopathic infantile arterial calcification (IIAC) is a rare, but important, cause of rapidly progressive ischemic heart disease in children. In this paper, we report two recent cases of IIAC seen at tertiary referral hospitals. Both cases presented in infancy with signs of heart failure and, ultimately, died with the diagnosis of IIAC confirmed at postmortem examination. A thorough review of the literature reveals approximately 160 reported cases of IIAC. The clinical outcomes, radiographic findings and pathologic details are summarized. Proposed etiologic mechanisms are reviewed, including promising research into the role of inorganic pyrophosphate as a regulatory factor in the development of IIAC. Because of the typically fatal outcome of IIAC and the lack of proven therapies, the potential role for cardiac transplantation is discussed.
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Drug Discovery Landscape
2 orphan drug designations for Generalized arterial calcification of infancy.
2 orphan drug designations for Generalized arterial calcification of infancy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Recombinant human ectonucleotide pyrophosphatase/phosphodiesterase 1 fused to the Fc fragment of IgG1 | proteins | EMA | Inozyme Pharma Ireland Ltd | |
extracellular domain of Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 fused to the Fc region of human IgG1 | proteins | FDA | Inozyme Pharma Inc. |
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