NORD gratefully acknowledges GACI Global and it's medical advisors for the preparation of this report.
Generalized arterial calcification of infancy (GACI) is a rare genetic disorder that affects the circulatory system in addition to other body systems. It occurs in approximately 1:391,000 births. GACI affects males and females equally and occurs in populations all around the world. It has an autosomal recessive inheritance pattern and usually affects infants during the first 6 months of life. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899.
Symptoms of GACI include respiratory distress, arterial calcification, gastrointestinal issues, joint calcification, hearing loss, high blood pressure, stroke, reduced or absent pulses, and heart failure. GACI manifests itself differently even within families with the same genetic cause of the disease. No two persons with GACI will have identical medical characteristics.
GACI type 1 occurs in 75% of patients, is caused by mutations in the ENPP1 gene, and is also called ENPP1 deficiency. Patients with ENPP1 deficiency are at risk of developing autosomal recessive hypophosphatemic rickets type 2 (ARHR2). ARHR2 can cause bone pain, bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened and side effects minimized.
GACI type 2 occurs in 10% of patients, is caused by mutations in the ABCC6 gene, and is also called ABCC6 deficiency. As they get older, patients with ABCC6 deficiency are at risk of developing characteristics similar to pseudoxanthoma elasticum (PXE), involving the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.
Sometimes individuals affected with GACI do not have mutations in the ENPP1 or ABCC6 genes, and in those cases the cause of the disorder is unknown.
Currently, there is no curative treatment for GACI and survival rates vary greatly. Treatment with bisphosphonates might lead to increased survival rates. Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually.
Newborns with GACI may exhibit symptoms such as difficulty breathing, reduced or absent pulses, cardiomyopathy, cardiomegaly, or accumulation of fluid in the extremities (edema). They may struggle with heart failure or high blood pressure (hypertension). Newborns with GACI may also present with feeding difficulties, irritability, or failure to thrive. On ultrasound or echocardiograph, the condition is characterized by calcification of the arteries or the valves of the heart accompanied by thickening of the lining of the arteries (intima).
Calcification in blood vessels may cause arterial stiffness/hardening, therefore making pulses faint or absent altogether.
Infants with GACI may suffer from gastrointestinal complications such as inflammation of the wall of the small intestine or obstruction due to stenosis. Infants with gastrointestinal complications may present with irritability and/or bloody stool. The gastrointestinal complications tend to go away as the child grows, and thus the child’s blood vessels, grow in size.
In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. In other babies, GACI is recognized later, usually around 1-6 months of age after gradual or persisting symptoms. In some cases, prenatal diagnosis is possible. An ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart), or echogenicity (brightness) of the major arteries.
Joint calcifications are seen in roughly 30% of babies with GACI. These calcifications are frequently seen in the hip, ankle, wrist, shoulder, elbow, knee, foot, and sternoclavicular (SC) joint.
Many patients with GACI type 1 go on to develop a rare form of rickets known as autosomal recessive hypophosphatemic rickets type 2 (ARHR2). This can result in bone and joint pain, bone deformities, calcification of ligaments, and short stature.
Individuals with GACI are at risk for developing hearing loss. The hearing loss can be conductive, sensorineural, or mixed, and can present as early as infancy. The hearing loss might be caused by calcification of the arteries supplying the inner ear and/or immobility of the ear bone (stapedovestibular ankylosis).
Older patients with GACI may go on to develop symptoms 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 eye. Angioid streaks are small breaks in Bruch’s membrane, an elastic tissue between the retina and underlying blood vessels, that may become calcified and crack.
Patients with GACI frequently present with dental issues such as teeth that don’t fully erupt (infraocclusion), over-retained primary teeth, ankylosis, slow orthodontic movement and excessive build-up of normal cementum on the roots of the teeth.
In 2003 it was discovered that the ENPP1 gene was the cause of approximately 75% of cases of GACI. The ENPP1 gene provides the instructions for making a protein that helps to break down a molecule called adenosine triphosphate (ATP), when it is found outside the cell (extracellular). Extracellular ATP is broken down into adenosine monophosphate (AMP) and pyrophosphate (PPi). Mutations in the ENPP1 gene result in low levels of pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Low pyrophosphate levels allow calcification to develop in the arteries. Low AMP levels lead to narrowing of the blood vessels, with restriction of blood flow.
In 2008, the ABCC6 gene was identified as a cause of GACI in approximately 10% of patients. The ABCC6 gene provides instructions for making a protein called MRP6 (ABCC6 protein). Mutations in the ABCC6 gene lead to non-functional or absent MRP6 protein. Although not proven, some researchers think that the lack of MRP6 protein impedes the release of ATP from cells and as a result pyrophosphate production is limited.
There are rare cases where patients with GACI do not have mutations in either the ENPP1 or ABCC6 gene. Therefore, it is thought than there may still be at least one other unknown gene that could be responsible for causing GACI in patients, or that mutations in one of the two known genes were missed by the sequencing technology.
GACI is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
GACI affects males and females equally and occurs in populations all across the world. There have been slightly over 200 cases documented since GACI was first described in medical literature in 1899. 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.
GACI usually affects infants during the first 6 months of life but mild cases may go undiagnosed until later in life, when other complications of the condition lead to a diagnosis.
GACI should always be considered in infants and children presenting with hypertension, cardiac failure, or sudden death. Ultrasonography can aid in the diagnosis. The preferred imaging modality to assess calcifications extension is whole-body computed tomography (CT) scan combined with CT angiography.
Antenatal diagnosis has been reported and an ultrasound may reveal polyhydramnios (excess amniotic fluid), pericardial effusion (fluid around the heart), or echogenicity (brightness) of the major arteries, abnormal cardiac contractility, hydrops, or hyperechoic kidneys.
To confirm a GACI diagnosis the baby (and parents) may be genetically tested for mutations in the ENPP1 or ABCC6 genes. Prenatal genetic testing for GACI can be confirmed through an amniocentesis or chorionic villus sampling (CVS) if the specific gene mutations in the parents have been determined.
Newborn babies with GACI are closely observed and are usually hospitalized in the neonatal intensive care unit (NICU).
Ongoing monitoring of GACI includes ultrasounds, echocardiograms, electrocardiogram (EKG/ECG’s), CT scans, X-rays, regular blood pressure measurements, checking pulses in all extremities, frequent lab and urine work, and hearing tests.
Currently, there is no curative treatment for GACI. Use of certain bisphosphonates appears to increase survival rates. Prenatal and postnatal treatment with bisphosphonates resulted in complete resolution of vascular calcifications in some patients; of note, complete resolution has also been noted in patients who never received treatment with bisphosphonates.
Sodium thiosulfate (STS) is a calcium-chelating agent typically used by patients who have excess calcium in their arteries due to kidney disease. In recent years, STS has also been used anecdotally to treat patients with GACI. STS is typically administered intravenously through a central line in the chest.
PGE1 infusion was successfully used in one baby with GACI complicated by severe hypertension refractory to conventional treatment.
Infants must reach a certain weight to allow for a transplant. There is some clinical evidence that heart transplants can be successful, without recurrence of calcifications. Heart transplant for individuals with GACI has occurred in at least three known cases.
Patients with GACI are usually followed by a team of specialists which may include cardiology, endocrinology, nephrology, orthopaedics, physical therapy, dental, audiology, and ophthalmology.
In 2015, Demetrios Braddock, MD, PhD, a pathologist and professor from Yale University along with his team published an article in Nature Communications demonstrating reduction of calcification and prevention of mortality in a mouse model of GACI given a replacement version of the enzyme ENPP1. This discovery has led to the establishment of a biotechnology company developing new medicines to treat rare disorders of calcification including GACI.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
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