Generalized arterial calcification of infancy


GACI - Pronounced "GACK-EE"
Generalized arterial calcification of infancy is an extremely rare, genetic disorder. It is caused by mutations in the ENPP1 gene in 75% of the subjects or in mutations in the ABCC6  genes in 10% of patients. However, sometimes individuals affected with GACI do not have mutations in the ENPP1 or ABCC6 gene and in those cases the cause of the disorder is unknown.
The condition usually affects infants during the first 6 months of life. This condition is inherited as an autosomal recessive pattern. It is characterized by generalized calcification of the arterial internal elastic lamina, leading to rupture of the lamina and occlusive changes in the tunica intima with stenosis and decreased elasticity of the vessel wall. Unfortunately, many infants die of vaso-occlusive disease, especially of the coronary arteries.
There are 2 forms of GACI that can be indicated on a genetic test:
GACI Type 1 is caused by mutations in the ENPP1 gene. It is called ENPP1 Deficiency. Patients with the ENPP1 Deficiency are at risk of developing Autosomal Recessive Hypophosphatemic Rickets Type 2.  ARHR2 can cause weakening in the bones, pain in bones and joints bone deformities, dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened and side effects minimized.
GACI Type 2 is caused by mutations in the ABCC6 gene. It is called ABCC6 Deficiency. As children affected by GACI due to ABCC6 Deficiency get older, they can develop characteristics similar to pseudoxanthoma elasticum. This condition affects the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.

Signs and symptoms

Clinical presentation is variable. First symptoms usually occur at birth but can take place in the first 6 months of life or in utero.
Clinical Signs for GACI can include:
The condition results from an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase-1 '' or the ATP-binding C member 6, leading to decreased inorganic pyrophosphate. This is a potent inhibitor of calcium deposition in the vessel wall. These mutations allow for unregulated calcium deposition within muscular arteries. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries.
Recently, homozygous or compound heterozygous mutations for ENPP1 gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate, a major inhibitor of extracellular matrix calcification.
The critical period for babies affected by GACI is during the first 6 months after birth. This is due to calcium continuing to build up in the artery walls. If blood flow becomes restricted it can become life threatening.
GACI affects males and females equally and occurs in populations all across the world. It is estimated to occur in approximately 1 out of every 391,000 births with the carrier rate being 1:312. Survival statistics vary greatly.

Diagnosis

Generalized arterial calcification of infancy should always be considered in infants and children presenting with hypertension, cardiac failure, or sudden death. Plain radiography, sonography and MRI can aid in the diagnosis. Postnatal gray-scale and color Doppler echocardiographic and sonographic examinations allowed noninvasive diagnosis, assessment of severity, and monitoring of progression. Contrast-enhanced MR angiography with breath-hold and cardiac gating techniques can allow evaluation of the extent of the disease.
In 2015, Demetrios Braddock, MD, PhD, a pathologist and professor from Yale University along with his team published an article in Nature Communications. Their research revealed when mice with GACI were given a replacement version of the enzyme, it helped to reduce the calcifications and prevented the animals from dying. This discovery has led to the development of Inozyme Pharma a biotechnology company developing new medicines to treat rare disorders of calcification including GACI.