ENPP1 deficiency is a rare genetic disorder that impacts the body’s ability to control where and when calcium deposits occur. It is caused by a defect in the ENPP1 gene, which disrupts the normal process of mineralization in bones and soft tissues. This deficiency results in a continuum of disease, ranging from life-threatening vascular calcification in infants to skeletal deformities later in life.
The Genetics and Function of ENPP1
The ENPP1 gene provides instructions for making the enzyme Ectonucleotide Pyrophosphatase/Phosphodiesterase 1. This enzyme regulates the body’s extracellular concentration of inorganic pyrophosphate (PPi). PPi is a natural inhibitor of mineralization, preventing calcium and phosphate crystals from forming in soft tissues and arteries.
When mutations occur in both copies of the ENPP1 gene, the enzyme’s function is impaired, resulting in low PPi levels. The loss of this inhibitor leads to excessive deposition of calcium phosphate (hydroxyapatite crystals) where it should not be present. This deficiency is inherited in an autosomal recessive pattern. The two main forms of disease are Generalized Arterial Calcification of Infancy (GACI) and Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2).
Recognizing the Clinical Signs
The clinical presentation of ENPP1 deficiency varies, evolving across the lifespan. The most severe form, GACI, often presents in utero or shortly after birth, characterized by widespread calcification of medium and large arteries. This arterial stiffening and narrowing can lead to cardiovascular complications, including heart failure, high blood pressure, and myocardial infarction. Infants with GACI frequently experience respiratory distress and face high mortality rates. Prenatal ultrasound examinations may show early indications, such as fetal hydrops (fluid accumulation) and polyhydramnios.
For individuals who survive the acute infantile phase, or whose condition manifests later, the signs transition to those characteristic of ARHR2. This form is dominated by skeletal abnormalities resulting from hypophosphatemia (low phosphate levels). Children and adults often exhibit rickets, leading to bowed legs and impaired growth. Other later-onset signs include osteomalacia, chronic bone pain, joint stiffness, hearing loss, and dental abnormalities.
Diagnostic Procedures
Confirming the diagnosis requires clinical observation, imaging studies, and laboratory tests. Suspicion arises when imaging reveals unusual calcification in soft tissues or arteries, or when a child presents with rickets. For infants, X-rays and computed tomography (CT) scans visualize the extent of arterial and soft tissue calcification. Echocardiograms assess cardiac involvement, including valve calcification and heart function. For older patients, imaging focuses on skeletal structure to identify rickets, fractures, and calcification around joints.
Biochemical analysis supports the diagnosis by measuring key markers in the blood. A common finding is hypophosphatemia (low phosphate levels), sometimes accompanied by elevated Fibroblast Growth Factor 23 (FGF23). Measuring inorganic pyrophosphate (PPi) in the plasma provides direct evidence, as levels are typically very low in affected individuals. Genetic testing remains the definitive method, involving sequencing the ENPP1 gene to identify the specific mutations.
Comprehensive Management Strategies
Management is complex, requiring a multidisciplinary team to address diverse manifestations. Treatment focuses on controlling abnormal calcification and managing cardiovascular and skeletal complications. For the acute infantile form (GACI), the immediate goal is halting vascular calcification progression. Bisphosphonates, such as etidronate, inhibit crystal formation and stabilize calcification in infants. For skeletal manifestations (ARHR2), conventional treatment involves oral phosphate and activated vitamin D (calcitriol) supplementation to address hypophosphatemia.
This conventional approach promotes bone mineralization and reduces rickets and osteomalacia. However, increasing phosphate levels risks worsening soft tissue calcification and can lead to kidney stones or nephrocalcinosis, requiring careful monitoring. Newer, more targeted treatments are being developed, including enzyme replacement therapies that aim to directly replace the missing ENPP1 enzyme. These therapies, such as INZ-701, are designed to restore PPi levels in the plasma, preventing ectopic calcification while supporting bone health. Continuous, specialized monitoring is an important part of the long-term care plan.