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.

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.

Normal Function

The ABCC6 gene provides instructions for making a protein called multidrug resistance-associated protein 6 (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. The MRP6 protein belongs to a group of proteins that transport molecules across cell membranes; however, little is known about the substances transported by MRP6.

Some studies suggest that MRP6 stimulates the release of a molecule called adenosine triphosphate (ATP) from cells through an unknown mechanism. This ATP is quickly broken down into other molecules called adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate helps control deposition of calcium (calcification) and other minerals (mineralization) in the body.

Other studies suggest that MRP6 transports a substance that is involved in the breakdown of ATP. This unidentified substance is thought to help prevent mineralization of tissues.

Health Conditions Related to Genetic Changes

Generalized arterial calcification of infancy

At least 13 mutations in the ABCC6 gene have been identified in individuals with generalized arterial calcification of infancy (GACI), a life-threatening disorder characterized by abnormal calcification in the blood vessels that carry blood from the heart to the rest of the body (the arteries). Most of these mutations have also been identified in people with pseudoxanthoma elasticum (PXE), described below. These mutations 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. It is not known why the same mutations can cause GACI in some individuals and PXE in others.

Pseudoxanthoma elasticum

More than 200 ABCC6 gene mutations that cause pseudoxanthoma elasticum (PXE) have been identified. PXE is a condition characterized by abnormal accumulation of calcium and other minerals in elastic fibers, a component of connective tissues that provide strength and flexibility to structures throughout the body. The ABCC6 gene mutations involved in this condition lead to an absence of MRP6 protein or an altered protein that does not function properly. The most common mutation in the United States, found in about 28 percent of people with PXE, deletes part of the ABCC6 gene. (This mutation is written as Ex23_29del.)

It is unclear how loss of MRP6 function leads to PXE. As in GACI (described above), this loss may impair the release of ATP or the transport of a substance that normally prevents mineralization. Without MRP6 function, calcium and other minerals accumulate in elastic fibers of the skin, eyes, blood vessels and other tissues affected by PXE.

Other Names for This Gene

• ABC34
• anthracycline resistance-associated protein
• ARA
• ATP-binding cassette, sub-family C (CFTR/MRP), member 6
• EST349056
• MLP1
• MOAT-E
• MRP6
• MRP6_HUMAN
• multidrug resistance-associated protein 6
• multispecific organic anion transporter-E

Genomic Location

Normal Function

The ENPP1 gene provides instructions for making a protein called ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). The ENPP1 protein 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 preventing the accumulation of abnormal deposits of calcium (calcification) and other minerals (mineralization) in the body.

The ENPP1 protein also plays a role in controlling cell signaling in response to the hormone insulin, through interaction between a part of the ENPP1 protein called the SMB2 domain and the insulin receptor. The insulin receptor is a protein that attaches (binds) to insulin and initiates cell signaling.

Insulin plays many roles in the body, including regulating blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. Cell signaling in response to insulin is also important for the maintenance of the outer layer of skin (the epidermis). It helps control the transport of the pigment melanin from the cells in which it is produced (melanocytes) to epidermal cells called keratinocytes, and it is also involved in the development of keratinocytes.

Health Conditions Related to Genetic Changes

Cole disease

At least three ENPP1 gene mutations have been identified in people with Cole disease. People with this disorder have areas of unusually light-colored skin (hypopigmentation), typically on the arms and legs, and spots of thickened skin on the palms of the hands and the soles of the feet (punctate palmoplantar keratoderma).

The ENPP1 gene mutations that cause Cole disease change the structure of the SMB2 domain, which alters its interaction with the insulin receptor and affects cell signaling. The resulting impairment of ENPP1's role in melanin transport and keratinocyte development leads to hypopigmentation and keratoderma. The mutations may also impair the protein's ability to control calcification, which likely accounts for the abnormal calcium deposits that occur in some people with this disorder. For reasons that are unclear, the changes in insulin signaling resulting from these ENPP1 gene mutations do not seem to affect blood glucose control.

Generalized arterial calcification of infancy

More than 40 mutations in the ENPP1 gene have been identified in individuals with generalized arterial calcification of infancy (GACI), a life-threatening disorder characterized by calcification in the blood vessels that carry blood from the heart to the rest of the body (the arteries). The mutations that cause GACI are thought to impair the ENPP1 protein's role in extracellular ATP breakdown and the production of pyrophosphate. Reduced availability of pyrophosphate likely interferes with the control of calcification in the body and leads to the signs and symptoms of GACI.

Hereditary hypophosphatemic rickets

MedlinePlus Genetics provides information about Hereditary hypophosphatemic rickets

Other disorders

A normal variation (polymorphism) in the ENPP1 gene has been associated with an increased risk of type 2 diabetes (the most common form of diabetes). Type 2 diabetes is caused by resistance to the hormone insulin, which results in impaired control of blood glucose. The polymorphism associated with type 2 diabetes leads to the production of a protein with the protein building block (amino acid) glutamine in protein position 121, written as Q121, rather than the amino acid lysine in this position (K121). The Q121 variant of the ENPP1 protein inhibits the function of the insulin receptor more strongly than the K121 version, increasing insulin resistance and the risk of type 2 diabetes.

Other Names for This Gene

• alkaline phosphodiesterase 1
• E-NPP 1
• ectonucleotide pyrophosphatase/phosphodiesterase family member 1
• Ly-41 antigen
• M6S1
• membrane component chromosome 6 surface marker 1
• membrane component, chromosome 6, surface marker 1
• NPP1
• NPPS
• PC-1
• PCA1
• PDNP1
• phosphodiesterase I/nucleotide pyrophosphatase 1
• plasma-cell membrane glycoprotein 1
• plasma-cell membrane glycoprotein PC-1

Genomic Location

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.

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.