propel - a prospective observational patient registry to evaluate enpp1 and abcc6 deficiency

Conditions: Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Deficiency; ATP-Binding Cassette Subfamily C Member 6 Deficiency

Summary: the purpose of this prospective registry is to characterize the natural history of ectonucleotide pyrophosphatase/phosphodiesterase1(enpp1) deficiency and the infantile-onset form of adenosine triphosphate (atp) binding cassette transporter protein subfamily c member 6 (abcc6) deficiency longitudinally. the registry will prospectively gather information about the genetic, biochemical, physiological, anatomic, radiographic, and functional manifestations (including patient reported outcomes \[pros\]) of each disease during routine, standard-of-care visits, with the aim of developing a comprehensive understanding of the burden of illness and progressive nature of the disease.

enpp1 deficiency is a rare, genetic disorder caused by inactivating mutations in the enpp1 gene that encodes the enpp1 enzyme. infantile-onset enpp1 deficiency has a high mortality (approximately 50%) in the first 0 to 6 months of life, a result of downstream cardiopulmonary complications. pediatric patients with enpp1 deficiency typically experience rickets, a condition also known as autosomal-recessive hypophosphatemic rickets type 2 (arhr2), while adults experience osteomalacia (softened bones), and they can exhibit a range of signs and symptoms that include hearing loss, arterial calcification, and cardiac and/or neurological involvement. like enpp1 deficiency, infantile-onset abcc6 deficiency is a rare, genetic disorder caused by mutations in the abcc6 gene. infantile-onset of abcc6 deficiency resembles the acute infantile form of enpp1 deficiency. pediatric patients with biallelic or monoallelic abcc6 mutations can present with cerebrovascular disease. this is an international, multicenter, prospective, non-interventional, observational registry of patients with biallelic variants in enpp1, symptomatic patients with monoallelic enpp1 variants and the infantile-onset form of abcc6 deficiency (\<18 years of age). the registry will include patients with enpp1 deficiency or infantile-onset of abcc6 deficiency independent of treatment regimen. note: patients participating in an inz-701 interventional clinical study are not eligible. registry participation will consist of a screening period and an observational period. during the screening period, both retrospective data (past medical history) and data available at the time of consent (baseline visit) will be collected. data collected will include standard of care assessments, which may consist of any or all of the following: laboratory testing, radiographical assessment of calcification and vascular stenosis, bone mineralization, with addition of performance outcomes, patient-, caregiver-, and physician-reported outcomes, and healthcare utilization. during the observational period, participants will be assessed during their routine visits for changes in their disease and pros and data will be added periodically to the database. there will be an opportunity for an optional blood draw to assess levels of inorganic pyrophosphate (ppi) at each routine visit.

Eligibility criteria:
inclusion criteria: individuals eligible to participate must meet all the following inclusion criteria: 1. must provide written or electronic consent after the nature of the registry has been explained, and prior to any research-related procedures, per international council for harmonisation (ich) good clinical practice (gcp) 2. agree to provide access to relevant medical records 3. one of the following genetic or clinical criteria 1. a confirmed prenatal or postnatal molecular genetic diagnosis of enpp1 deficiency with biallelic mutations (ie, homozygous or compound heterozygous) performed by a college of american pathologists/clinical laboratory improvement amendments (cap/clia) certified laboratory or regional equivalent or 2. monoallelic enpp1 mutation confirmed by a certified cap/clia laboratory or regional equivalent and any of the following clinical symptoms: i. ≥ 1 traumatic vertebral fracture ii. ≥ 2 fractures as an adult (eg, long-bones, digits, vertebrae) iii. low bone mineral density (dual-energy x-ray absorptiometry \[dxa\] z-score \<1.5) and \<55 years of age iv. bone or joint pain interfering with movement or daily activities v. history of myocardial infarction (mi), unstable angina, transient ischemic attack (tia) or low cardiac output before the age of 40 yrs. vi. history of rickets or bone deformity vii. diagnosis of ossification of the posterior longitudinal ligament (opll) viii. other clinical symptoms, with approval by inozyme or c. a confirmed prenatal or postnatal molecular genetic diagnosis of abcc6 deficiency with biallelic mutations confirmed by a certified cap/clia laboratory or regional equivalent, and \<18 years of age exclusion criteria: individuals who meet the following exclusion criteria will not be eligible to participate: 1. participant or their legally designated representative does not have the cognitive capacity to provide informed consent 2. patients who are currently participating in an inz-701 interventional clinical study, with the exception of expanded access programs and long-term safety follow-up studies 1. participants in interventional studies may be approached for inclusion in the registry once their involvement in the treatment period of the clinical study has been completed

Keywords: ectonucleotide pyrophosphatase enpp1 generalized arterial calcification of infancy gaci autosomal recessive hypophosphatemic rickets type 2 arhr2 observational registry atp-binding cassette subfamily c member 6 deficiency abcc6 propel phosphodiesterase 1