Generalized arterial calcification of infancy

(often shortened to GACI)

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What is GACI?

Generalized arterial calcification of infancy (GACI) is a disorder affecting the circulatory system that becomes apparent before birth or within the first few months of life. It is characterized by abnormal accumulation of the mineral calcium (calcification) in the walls of the blood vessels that carry blood from the heart to the rest of the body (the arteries). This calcification often occurs along with thickening of the lining of the arterial walls (the intima). These changes lead to narrowing (stenosis) and stiffness of the arteries, which forces the heart to work harder to pump blood. As a result, heart failure may develop in affected individuals, with signs and symptoms including difficulty breathing, accumulation of fluid (edema) in the extremities, a bluish appearance of the skin or lips (cyanosis), severe high blood pressure (hypertension), and an enlarged heart (cardiomegaly).

People with GACI may also have calcification in other organs and tissues, particularly around the joints. In addition, they may have hearing loss or softening and weakening of the bones (rickets).

Some individuals with GACI also develop features similar to those of another disorder called pseudoxanthoma elasticum (PXE). PXE is characterized by the accumulation of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue. Connective tissue provides strength and flexibility to structures throughout the body. Features characteristic of PXE that also occur in GACI include yellowish bumps called papules on the underarms and other areas of skin that touch when a joint bends (flexor areas); and abnormalities called angioid streaks affecting tissue at the back of the eye, which can be detected during an eye examination.

As a result of the cardiovascular problems associated with GACI, individuals with this condition often do not survive past infancy, with death typically caused by a heart attack or stroke. However, affected individuals who survive their first six months, known as the critical period, can live into adolescence or early adulthood.

Read more about pseudoxanthoma elasticum.

How common is GACI?

The prevalence of GACI has been estimated to be about 1 in 391,000. At least 200 affected individuals have been described in the medical literature.

What genes are related to GACI?

In about two-thirds of cases, GACI is caused by mutations in the ENPP1 gene. This gene provides instructions for making a protein that helps break down a molecule called adenosine triphosphate (ATP), specifically when it is found outside the cell (extracellular). Extracellular ATP is quickly broken down into other molecules called adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate is important in controlling calcification and other mineralization in the body. Mutations in the ENPP1 gene are thought to result in reduced availability of pyrophosphate, leading to excessive calcification in the body and causing the signs and symptoms of GACI.

GACI can also be caused by mutations in the ABCC6 gene. This gene provides instructions for making a protein called MRP6, also known as the ABCC6 protein. This protein is found primarily in the liver and kidneys, with small amounts in other tissues such as the skin, stomach, blood vessels, and eyes.

MRP6 is thought to transport certain substances across the cell membrane; however, the substances have not been identified. Some studies suggest that the MRP6 protein stimulates the release of ATP from cells through an unknown mechanism, allowing it to be broken down into AMP and pyrophosphate and helping to control deposition of calcium and other minerals in the body as described above. Other studies suggest that a substance transported by MRP6 is involved in the breakdown of ATP. This unidentified substance is thought to help prevent mineralization of tissues.

Mutations in the ABCC6 gene lead to an absent or nonfunctional MRP6 protein. It is unclear how a lack of properly functioning MRP6 protein leads to GACI. This shortage may impair the release of ATP from cells. As a result, little pyrophosphate is produced, and calcium accumulates in the blood vessels and other tissues affected by GACI. Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium characteristic of GACI.

Some people with GACI do not have mutations in the ENPP1 or ABCC6 gene. In these affected individuals, the cause of the disorder is unknown.

Read more about the ABCC6 and ENPP1 genes.

How do people inherit GACI?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of GACI?

These resources address the diagnosis or management of GACI and may include treatment providers.

You might also find information on the diagnosis or management of GACI in Educational resourcesand Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about GACI?

You may find the following resources about GACI helpful. These materials are written for the general public.

MedlinePlus - Health information (3 links)
Educational resources - Information pages (3 links)
Patient support - For patients and families (3 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary
Genetic Testing Registry - Repository of genetic test information (1 link)
PubMed - Recent literature
OMIM - Genetic disorder catalog (2 links)

What other names do people use for GACI?

arteriopathia calcificans infantum
diffuse arterial calcifying elastopathy of infancy
idiopathic infantile arterial calcification
idiopathic obliterative arteriopathy
IIAC
infantile calcifying arteriopathy
medial coronary sclerosis of infancy
occlusive infantile arteriopathy

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about GACI?

Ask the Genetic and Rare Diseases Information Center

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding GACI?

adenosine triphosphate ; angioid streaks ; arteries ; arteriopathy ; ATP ; autosomal ;autosomal recessive ; breakdown ; calcification ; calcium ; cardiovascular ; cell ; cell membrane ;connective tissue ; coronary ; cyanosis ; edema ; elastic ; extracellular ; gene ; heart attack ;heart failure ; hypertension ; idiopathic ; inherited ; joint ; mineral ; molecule ; prevalence ; protein ;recessive ; rickets ; sclerosis ; stenosis ; stomach ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References (8 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook