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ENPP1 deficiency is a rare, inherited, genetic inborn error of metabolism caused by mutations in the ENPP1 gene, and it is estimated that there are between 11,000 and 12,000 individuals worldwide with ENPP1 deficiency. The condition is inherited as a recessive trait in which the genetic mutations result in decreased or absent activity of the ENPP1 enzyme. ENPP1 deficiency results in low plasma levels of pyrophosphate, or PPi, and AMP, a precursor to adenosine, and is a single, systemic and continuous disease with high mortality and morbidity. The spectrum of manifestations for ENPP1 deficiency includes an infantile phase, a pediatric phase and an adult phase.
In the acute infantile phase, which has been referred to as generalized arterial calcification of infancy (GACI) in the medical literature, ENPP1 deficiency is characterized by narrowing of large and medium arteries. This narrowing is caused by severe and pathological vascular calcification and neointimal proliferation, resulting in dysfunction and potential failure of major organs, such as the heart and kidneys. GACI can be diagnosed prenatally when an ultrasound shows characteristic calcifications in the fetus. Infants with ENPP1 deficiency have clinical signs of hypertension, heart disease, and kidney disease even at birth. ENPP1 deficiency is most deadly during the infantile phase; approximately 45 to 50 percent of infants with ENPP1 deficiency die within 12 months of birth. If they survive the crisis of infancy during those first 12 months of life, individuals with ENPP1 deficiency are likely to survive through adolescence and beyond, but with significant morbidity and a low quality of life.
The progressive pediatric phase of ENPP1 deficiency is characterized by continued vascular and organ calcification, as well as by the onset of rickets, which has been referred to in the medical literature as as autosomal-recessive hypophosphatemic rickets type 2, or ARHR2. The continuing calcification of skeletal arteries induces the bone to produce a hormone known as fibroblast growth factor-23 (FGF23), which in turn causes the kidneys to waste phosphate, giving rise to rickets. Rickets leads to severe skeletal deformities, short stature, severe bone pain, and an increased risk of bone fractures. In addition, children with ENPP1 deficiency may experience excess calcification in joints and dental problems caused by deformed adult teeth. Children with pediatric ENPP1 deficiency may also experience early onset of hearing loss, as well as impaired growth and development and generally decreased quality of life, including impaired activities of daily living.
In the adult phase, in addition to continuing vascular and organ calcification, ENPP1 deficiency manifests as osteomalacia, which leads to severe bone pain, fatigue, muscle weakness, and risk of recurring bone fractures. Adults with ENPP1 deficiency experience significant functional and cognitive impairment and generally decreased quality of life, including impaired activities of daily living.
Comprehensive Natural History Study in Patients with ENPP1 Deficiency
Together with the U.S. National Institutes of Health, or the NIH, and the University of Münster in Germany, Inozyme conducted what is widely viewed as the largest retrospective, cross-sectional, natural history study of infants, children and adults with a presumed diagnosis of ENPP1 deficiency, including subjects with the acute form of ABCC6 deficiency who may have been diagnosed as ENPP1 infants. The study included data on 127 subjects across 18 countries.
Preliminary results from the study suggest that ENPP1 deficiency, regardless of its phenotypic manifestation or original diagnosis as GACI or ARHR2, appears to be a systemic, progressive and continuous disease that occurs over the course of a patient’s lifetime.
Patient Survey Study in Patients with ENPP1 Deficiency and Acute ABCC6 Deficiency
In partnership with GACI Global, Inozyme conducted a patient survey study titled Understanding the Spectrum of ENPP1 Deficiency and Acute ABCC6 Deficiency Through the Eyes of Patients and Parents; Burden of Illness Perspectives from Patients and Parents Who Speak English, French or German.
The purpose of the study is to improve the understanding of the characterization and the burden of disease and the systemic progression of disease for both ENPP1 deficiency and ABCC6 deficiency from a patient and/or parent perspective. The results from this study will contribute to the overall understanding of these rare calcification diseases and will be instrumental in the clinical development process, including the clinical trial designs.