Natural History of GACI With or Without ARHR2 or PXE

Study Overview
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Brief Summary
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Generalized arterial calcification of infancy (GACI) is an ultra-rare disorder with an estimated birth prevalence of around 1 in 400,000.1 GACI is generally fatal before birth or within the first six months after birth. The cause of death is frequently myocardial infarction or stroke. GACI is strongly associated with inactivating mutations in ectonucleotide pyrophosphate/ phosphodiesterase 1 (ENPP1). Many patients with GACI, including some without an ENPP1 mutation also present with mutations in adenosine triphosphate binding cassette transporter protein subfamily C member 6 (ABCC6). Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and pseudoxanthoma elasticum (PXE) are believed to be closely related to GACI. ARHR2 is caused by mutations in the ENPP1 gene and PXE is caused by mutations in the ABCC6 gene, with both being observed among patients with GACI. The natural history of GACI and in particular its long term morbidity and mortality are poorly understood. The primary objective of this study is to characterize overall survival among patients with GACI, over time from birth.

Detailed Description
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Background: Generalized arterial calcification of infancy (GACI) is an ultra-rare disorder with an estimated birth prevalence of around 1 in 400,000.1 GACI is characterized by extensive arterial calcifications, arterial stenosis, myointimal proliferation and periarticular calcifications. Individuals with GACI also experience calcification in other body areas, such as joints and organs. GACI is generally fatal before birth or within the first six months after birth. The cause of death is frequently myocardial infarction or stroke. GACI is strongly associated with inactivating mutations in ectonucleotide pyrophosphate/ phosphodiesterase 1 (ENPP1); around three quarters of GACI cases investigated had one or several ENPP1 mutations. Many patients with GACI, including some without an ENPP1 mutation also present with mutations in adenosine triphosphate binding cassette transporter protein subfamily C member 6 (ABCC6). Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and pseudoxanthoma elasticum (PXE) are believed to be closely related to GACI. ARHR2 is caused by mutations in the ENPP1 gene5 and PXE is caused by mutations in the ABCC6 gene,3 with both being observed among patients with GACI. The natural history of GACI and in particular its long term morbidity and mortality are poorly understood, but a strong understanding of the condition will be crucial for further therapy development and drug testing. This study aims to address this knowledge gap. Objectives: The primary objective of this study is to characterize overall survival among patients with GACI, over time from birth. Secondary objectives are to: Characterize the patient and disease characteristics; Describe symptomology at diagnosis and the change in symptomology over time; Describe treatment patterns specific to GACI or rickets Characterize mental/physical impairment, education, and employment situation; Characterize the sequelae of the disease; Prevalence of rickets; and Growth velocities. Eligibility: GACI genotype (mutation in ENPP1 and/or ABCC6) confirmed through mutational analysis of the patient and a GACI phenotype confirmed by imaging or biopsy; or GACI phenotype confirmed with imaging, biopsy, or mutational analysis of the parents indicating a GACI genotype (mutation in ENPP1 and/or ABCC6) coinciding with symptoms of the patient. Data will be collected for both living and deceased patients Design: Retrospective multicenter chart review

Official Title
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The Natural History of Generalized Arterial Calcification of Infancy (GACI) With or Without Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) or Pseudoxanthoma Elasticum (PXE)

Conditions
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Generalized Arterial Calcification in Infancy, Autosomal Recessive Hypophosphatemic Rickets, Pseudoxanthoma Elasticum

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: GACI genotype (mutation in ENPP1 and/or ABCC6) confirmed through mutational analysis of the patient and a GACI phenotype confirmed by imaging or biopsy; or GACI phenotype confirmed with imaging, biopsy, or mutational analysis of the parents indicating a GACI genotype (mutation in ENPP1 and/or ABCC6) coinciding with symptoms of the patient. Data will be collected for both living and deceased patients Exclusion Criteria: Caregivers are not able to give written consent.
Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: No intervention|This is a retrospective chart review study.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | This study will record the survival rate in patients with GACI | Recruitment for this study will end in March 2019 |