Natural History of GACI With or Without ARHR2 or PXE

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

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.

Study Overview

• Status: Unknown
• Conditions: Pseudoxanthoma Elasticum; Generalized Arterial Calcification in Infancy; Autosomal Recessive Hypophosphatemic Rickets
• Intervention / Treatment: Other: No intervention

Detailed Description

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

• Study Type: Observational
• Enrollment (Anticipated): 80

Contacts and Locations

• Study Contact: Name: Frank Rutsch, MD; Phone Number: +49251-8347700; Email: frank.rutsch@ukmuenster.de
• Study Contact Backup: Name: Kerstin Mueller, PhD; Phone Number: +16042352172; Email: kerstin.mueller@iconplc.com

Study Locations

• Germany
  • Münster, Germany, 48149
    • Recruiting
    • WWU Münster
    • Contact: Frank Rutsch, MD; Phone Number: +492518347700; Email: frank.rutsch@ukmuenster.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Probands with proven history of generalized arterial calcification of infancy.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Westfälische Wilhelms-Universität Münster
• Collaborators: ICON plc
• Investigators: Principal Investigator: Frank Rutsch, MD, WWU Münster

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: November 28, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (Actual): November 29, 2018

Study Record Updates

• Last Update Posted (Actual): November 29, 2018
• Last Update Submitted That Met QC Criteria: November 28, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Skin Diseases; Arterial Occlusive Diseases; Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Hematologic Diseases; Nutrition Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Hemostatic Disorders; Skin Diseases, Genetic; Avitaminosis; Deficiency Diseases; Malnutrition; Bone Diseases; Metabolism, Inborn Errors; Bone Diseases, Metabolic; Skin Abnormalities; Renal Tubular Transport, Inborn Errors; Calcium Metabolism Disorders; Metal Metabolism, Inborn Errors; Phosphorus Metabolism Disorders; Vitamin D Deficiency; Hypophosphatemia, Familial; Hypophosphatemia; Arteriosclerosis; Rickets; Pseudoxanthoma Elasticum; Familial Hypophosphatemic Rickets; Rickets, Hypophosphatemic; Calcinosis
• Other Study ID Numbers: GACI Natural History

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No