Mutations in the ABCC6 gene, also known as ABCC6 Deficiency, can cause an inability to regulate pyrophosphate levels in the blood. This disorder can manifest as either Generalized Arterial Calcification of Infancy (GACI) Type 2 or Pseudoxanthoma Elasticum (PXE). The following is a list of complications that can be caused by ABCC6 Deficiency. To read more about GACI, click here.
It is important to note that ABCC6 Deficiency and ENPP1 Deficiency are part of a closely related spectrum of diseases and there may be some crossover when it comes to the complications associated with each specific gene.
Generalized Arterial Calcification of Infancy causes an abnormal buildup of calcium within the walls of the arteries. This can cause critical blockages which can reduce blood flow to organs potentially resulting in high blood pressure, stroke, or heart attack. It can eventually lead to heart failure and death. Survivors of GACI may go on to develop something called intimal hyperplasia, which is the thickening of the innermost layer of the blood vessels.
Infants with GACI may suffer from gastrointestinal complications such as ulcerating inflammation of the wall of the small intestine or obstruction due to stenosis (narrowing of the blood vessels). These complications are thought to arise from insufficient blood flow to the gastrointestinal tract as a consequence of early vascular compromise. Infants with gastrointestinal complications may present with irritability and/or bloody stool. Fortunately, for patients with GACI who survive the critical period of infancy, the gastrointestinal complications dissipate as the child, and thus the child’s blood vessels, grow in size.
Approximately 30% of patients who develop GACI present with joint calcifications. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, and knee along with fingers, toes, and spine. Joint calcifications can cause pain and reduced mobility. There is no specific treatment for joint calcification in patients with ABCC6 Deficiency. In some patients, the calcifications spontaneously regress, while in other cases it has persisted. Currently, only one patient is known to have had the joint calcification surgically removed (prior to his diagnosis of ENPP1 Deficiency). If the calcification is causing functional impairment of the affected joint, such as reduced range of motion, it would be prudent to seek the assistance of a physical therapist who may be able to help with mobility and function.
Cervical spine fusion secondary to calcification has also been seen in patients with ABCC6 Deficiency. Prior to elective endotracheal intubation, patients should be evaluated via a lateral cervical spine x-ray. If cervical spine fusion is present, fiberoptic intubation is recommended.
Skin and Eye Complications (Pseudoxanthoma Elasticum)
Some patients with ABCC6 Deficiency go on to develop some features characteristic of Pseudoxanthoma Elasticum (PXE). PXE is a disorder that causes select elastic tissue in the body to become mineralized due to calcium and other minerals being deposited in the tissue. This can result in changes in the skin and eyes. The changes to the skin frequently present on the neck, underarms, inside of the elbows, the groin, and behind the knees. It may resemble a rash or have a cobblestone appearance. Another complication is the possible development of Angioid streaks in the eyes. Angioid streaks are small breaks in Bruch’s Membrane, an elastic tissue containing the membrane of the retina, that may become calcified and crack.
Although there have been no clinical studies, it seems prudent to avoid the use of warfarin if possible because matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in mice.