Generalized arterial calcification of infancy (Generalized arterial calcification of infancy -GACI-) - Genes ENPP1 or ABCC6.
Systemic arterial calcification of infancy (GACI) is an alteration affecting the circulatory system, characterized by calcification in the walls of arteries. This disease becomes evident before birth or in the first months of life. Often this calcification occurs along with thickening of the intimal lining. These changes lead to stenosis and stiffness of the arteries, forcing the heart to work harder to pump blood. As a result, affected individuals can manifest heart failure signs and symptoms include shortness of breath, edema in the extremities, cyanosis, hypertension and cardiomegaly. Furthermore, people with GACI may also have calcification in other organs and tissues, especially around the joints, as well as hearing loss and rickets.
Some individuals develop GACI also similar to other known alteration pseudoxanthoma elastic (PXE), characterized by the accumulation of calcium and mineralization of elastic fibers in characteristics. Some characteristic features of PXE also occur in GACI include papules underarm and other flexor surface and angioid streaks that affect tissue at the back of the eye. As a result of cardiovascular problems associated with GACI, those affected often do not survive beyond infancy due, usually a heart attack or stroke. However, affected individuals who survive the first six months, known as the critical period may live into adolescence or even early adulthood.
This may be due to mutations in ABCC6 ENPP1 or genes. Some affected individuals have mutations in these genes. These individuals affected, the cause of the disease is unknown.
The ABCC6 gene, located on the short arm of chromosome 16 (16p13.1), encoding the protein associated with multidrug resistance 6 (MRP6). This protein is found primarily in the liver and kidneys, with small amounts in other tissues such as skin, stomach, blood vessels and eyes. The MRP6 protein belongs to a group of proteins that transport molecules across cell membranes. Although little is known about the substances carried by MRP6, it is believed to stimulate the release of adenosine triphosphate (ATP) from the cells by an unknown mechanism. This ATP rapidly decomposes to adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate helps calcification and mineralization in the body. Furthermore, it is likely MRP6 transport a substance involved in the degradation of ATP. This unidentified substance is believed to help inhibit tissue mineralization. At least 13 mutations in the gene ABCC6 have been identified in individuals with generalized arterial calcification of infancy (GACI). Most of these mutations have also been identified in people with pseudoxanthoma elasticum (PXE). These mutations lead to an absent or non - functional protein MRP6. Although it is unclear how the lack of a proper functioning of proteins leads to GACI MRP6, it is likely that this deficiency could affect the release of ATP from cells. Consequently, soon it occurs pyrophosphate and calcium accumulates in blood vessels and other tissues affected by GACI. Alternatively, MRP6 function deficiency may impair the transport of a substance normally inhibits mineralization, leading to abnormal accumulation of calcium GACI feature. It is not known why the same mutations can lead to GACI in some individuals and PXE others.
The ENPP1 gene, located on the long arm of chromosome 6 (6q22-q23), encodes a protein that prevents minerals, including calcium, deposited in the tissues of the body where not correspond. Also it plays a role in the control of cell signaling in response to the hormone insulin, through the interaction between a part of the protein ENPP1 SMB2 called the domain and the insulin receptor. Cell signaling in response to insulin, is also important for the maintenance of the epidermis, as it helps to control the transport of melanin from melanocytes to keratinocytes, and is also involved in the development of keratinocytes. They have identified more than 40 mutations in the gene ENPP1 in individuals with generalized arterial calcification of infancy (GACI). These mutations jeopardize the function of the ENPP1 protein decomposition of extracellular ATP and pyrophosphate production. Reduced availability of pyrophosphate probably interferes with controlling calcification in the body and leads to the signs and symptoms of GACI.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with generalized arterial calcification of infancy (GACI), by complete PCR amplification of the exons of the ABCC6 ENPP1 or, respectively, and subsequent sequencing genes.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).