Introduction: ENPP1 Deficiency manifests as GACI type 1 in infants, a disorder characterized by extensive arterial calcifications and stenoses, often fatal in utero or in early infancy. Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. ABCC6 Deficiency also manifests as GACI type 2 in infants and is clinically indistinguishable from GACI type 1. Animal data suggest that enzyme replacement therapy with ENPP1-Fc may prevent the mortality of GACI and morbidity of ARHR2.
Objective: To collect data on 100 patients to characterize the natural history of the disease.
Methods: Two IRB-approved natural history studies at the National Institutes of Health (NCT03478839) and Münster University Childrens Hospital (NCT03758534).
Interim Results: Of 42 probands, 37 had GACI (median age at diagnosis 1.2mo), 17 had ARHR2 (median age at diagnosis 72mo). Thirteen probands had both GACI and ARHR2. Of 38 probands with genetic analyses, 29 had ENPP1 mutations and 8 had ABCC6 mutations. In GACI probands, initial symptoms included dyspnea (62%) and cyanosis (16%); 73% were ventilated. Arterial calcification was observed in 87%, presenting between 0.7 and 1.1mo, most commonly in the aorta (88%), coronary (72%), pulmonary (69%), renal (63%) and carotid (60%) arteries. Calcification resolved in 32% (aorta), 40% (renal) and 44% (coronaries) of cases, at median ages of 13.3, 11.9, and 14.7 months, respectively. Twenty-nine individuals had cardiac dysfunction, with cardiac failure in 16 and myocardial infarction in 6. Joint or organ calcification was present in 49% and 62%, respectively. In probands with ARHR2, 71% had pain, 53% had bowing, and 29% had short stature. Probands over 1-year old with ENPP1-deficiency developed rickets in 68% (13/19). 60% of GACI-patients were treated with bisphosphonates. Overall mortality for the GACI-cohort was 38% (14/37 patients, median age 1.2 months). Mortality rates in the bisphosphonate-treated vs. untreated sub-cohorts was 18% and 44%, respectively.
Conclusion: The natural history of GACI and ARHR2 shows significant mortality and morbidity indicating the need for better treatments. More understanding is needed prior to clinical trials; the current study aims to address this knowledge gap.
Disclosure: Grant support and consulting fees from Inozyme Pharma.