Endocrine Abstracts

JOINT1718

ENPP1 Deficiency is a rare genetic disorder caused by inactivating mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene (biallelic prevalence 1:64000). ENPP1 Deficiency is associated with low levels of plasma pyrophosphate (PPi) and AMP leading to ectopic (especially vascular) calcification (Generalized Arterial Calcification of Infancy [GACI] Type 1), pathologic skeletal mineralization (Autosomal Recessive Hypophosphatemic Rickets Type 2 [ARHR2]) and occlusive neo-intimal proliferation. Infants with ENPP1 Deficiency have 50% mortality in the first 6 months of life. Survivors typically develop hypophosphatemic rickets and experience bone deformities, hearing loss, impaired growth, pain and immobility leading to poor quality of life and function. Similarly, ABCC6 Deficiency, caused by biallelic mutations in the ABCC6 (ATP-binding cassette transporter protein subfamily C member 6) gene, is a disorder of pathological mineralization and intimal proliferation manifesting in a spectrum of phenotypes, likely resulting from low PPi and adenosine due to reduced ATP, the substrate for ENPP1. The infantile-onset form (GACI Type 2) resembles ENPP1 Deficiency - infants present with widespread arterial calcification and severe cardiovascular complications. In both cases early genetic testing is key for apt treatment decision-making. Much of the current knowledge of ENPP1 and ABCC6 Deficiency is based on case reports or small retrospective studies. No targeted therapy exists for these diseases. This global, multicenter, prospective observational registry co-sponsored with GACI Global (PROPEL, NCT06302439) is designed to systematically collect clinical information to inform a comprehensive understanding of the burden of illness and progressive nature of these diseases. The key objectives are to determine the onset, variability and progression of pathological calcification and clinical complications and to assess the burden of disease on patients, including patient-reported outcomes (PROs). Except for optional PRO questionnaires, all data collected and recorded to the registry will be part of routine clinical exams. Patients will have an opportunity for optional blood draw to assess PPi levels. The registry is planned to open in 50 sites globally with the goal of recruiting up to 1,000 participants over the next 10 years, adding significant value to the existing body of evidence. Study updates and preliminary patient data will be presented.