ENPP1 Deficiency
ENPP1 Deficiency is a lifelong and progressive disease which is caused by mutations in the ENPP1 gene. This results in low levels of pyrophosphate (PPi) and adenosine in the blood. Low levels of PPi lead to abnormal mineralization and calcification, while low levels of adenosine lead to intimal proliferation (overgrowth of smooth muscle cells inside blood vessels). These issues can drive systemic and progressive conditions known as GACI and ARHR2.
Individuals who present in utero, or in infancy, are typically diagnosed with GACI Type 1 (Generalized Arterial Calcification of Infancy), which is characterized by extensive vascular calcification and intimal proliferation. This can result in myocardial infarction, stroke, cardiac or multi-organ failure. Children with ENPP1 Deficiency typically develop a form of rickets called ARHR2 (Autosomal Hypophosphatemic Rickets Type). Adults with ENPP1 Deficiency experience progression of the disease and osteomalacia (softened bones). Patients of all ages can experience a range of signs and symptoms that include arterial calcification, hearing loss, cardiac and/or neurological involvement, pain, fatigue, hearing, eye, and skin issues.
The spectrum of manifestations for ENPP1 Deficiency includes an infantile phase, a pediatric phase, and an adult phase.
Generalized Arterial Calcification of Infancy
The acute infantile phase, GACI, is characterized by calcification of large and medium-sized arteries and neointimal proliferation. This causes narrowing of the vessels and reduced blood flow, which can result in dysfunction and potential failure of major organs. Read more about GACI here.
Approximately 50% of babies born with GACI do not survive past 6 months of age.
Autosomal Recessive Hypophosphatemic Rickets Type 2
ARHR2 is characterized by skeletal deformities, short stature, severe bone pain, fractures, fatigue, and hearing loss. Read more about ARHR2 here.
Approximately 70% of patients who survive GACI Type 1 will go on to develop ARHR2.
Marked softening of the bones
Adults can experience painful progression of the disease due to increasing bone and joint issues. Calcific enthesopathies can develop which cause significant pain and decreased mobility. Patients can experience softening of the bones, severe bone pain, fractures, fatigue, and muscle weakness.
Around 85% of patients experience issues related to bone or joint pain, fatigue, mobility issues, and calcification of arteries, organs, or joints.
Complications of ENPP1 Deficiency
Cardiovascular
Cardiac symptoms can include: calcification of arteries and heart valves, narrowing of blood vessels, high blood pressure, heart attack, and stroke.
Joint
Calcification in the joints can cause significant pain and reduced mobility. This can occur in both infants and adults. Approximately 64% of infants present with joint calcification.
Skeletal
Skeletal complications can include bone deformities, knock knees / bowed legs, cervical spine fusion, severe pain and increased risk of fractures.
Hearing
The lifetime risk for developing hearing loss is around 75% for patients with ENPP1 Deficiency. Hearing loss can be present from birth or develop at any age and can be progressive.
Skin
Some patients may develop loose, wrinkled skin that resembles pseudoxanthoma elasticum (PXE). This typically appears in body folds like the neck, armpits, groin, and behind the knees.
Eye
Some patients may be at risk of developing angioid streaks. These are cracks in Bruch’s membrane which separate the outer layer of the retina from the blood vessels beneath. This can lead to retinal bleeding.
Dental
Dental issues in patients are common and include: infraocclusion, over-retained primary teeth, ankylosis, slow orthodontic movement, and excess build-up of cementum on the roots of the teeth.
GI
Gastrointestinal complications can include bloody stool and irritability due to ischemia of the bowel, discomfort, pain, nausea and upset stomach due to medication.
Growth
Growth can be affected in all age groups. Infants can present with failure to thrive; babies, children, and adolescents may experience slow growth; and patients of all ages may present with short stature.
