Ectopia lentis isolated (Isolated ectopia lentis) - Genes FBN1 or ADAMTSL4.

Ectopia lentis isolated is an alteration affecting the eyes, namely positioning of the lens. Generally, this disease becomes evident in childhood. In people with ectopia lentis isolated, the lens in one or both eyes is displaced. Over time, the lens may deviate further from the center. Vision problems are common in individuals affected and often have myopia and an irregular curvature of the lens or cornea, which causes astigmatism. Other signs and symptoms of the disease may include cataracts, glaucoma and retinal detachment, which can lead to other problems of vision and possible blindness. In individuals with isolated lens ectopia, each eye may be affected differently. In addition, eye problems vary among affected individuals, even those within the same family.

This disease is classified as isolated when presented alone, without signs and symptoms affecting other body systems. However, when the disease is part of a syndrome that affects multiple body parts it can be classified as syndromic. Ectopia lentis is a common feature of genetic syndromes such as Marfan syndrome and Weill-Marchesani syndrome.

This process is due to mutations in genes FBN1 and ADAMTSL4. These genes encode proteins which are necessary for the formation of microfibrils. Microfibrils provide support for many tissues, including the lens of the eye.

FBN1 gene, located on the long arm of chromosome 15 (15q21.1), encodes fibrillin-1 protein. This protein is transported to the outside of cells in the extracellular matrix. In this matrix molecules fibrillin-1 adhere to each other and with other proteins to form microfibrils. The microfibrils are elastic fibers, allowing the skin, ligaments and blood vessels stretch. Microfibrils also provide more rigid support to tissues such as bone and tissues supporting the nerves, muscles and the lens of the eye. Microfibrils store a protein called transforming growth factor beta (TGF-?), a critical growth factor. TGF-? affects the development, helping to control the growth and proliferation, differentiation, motility and apoptosis. Have identified more than 30 mutations in the FBN1 gene in people with ectopia lentis isolated. Most mutations change individual amino acids in the fibrillin-1 protein. As a result, the protein coding fibrillin-1 normal leading to a decrease in the formation of microfibrils or disability in the formation of microfibrils is reduced. Without sufficient functional microfibrils to anchor the lens in its central position in the front of the eye, the lens is displaced, resulting in ectopia lentis isolated and vision related problems.

Ectopia lentis is classified as isolated when it occurs alone, without signs and symptoms affecting other organ systems. However, some people initially diagnosed with ectopia lentis isolated due to mutations in the FBN1 later develop additional typical features of an alteration called Marfan syndrome, such as abnormalities of the aorta. In these cases, the diagnosis often changes ectopia lentis isolated to Marfan syndrome.

The ADAMTSL4 gene, located on the long arm of chromosome 1 (1q21.3), encoding a protein found throughout the body. The ADAMTSL4 protein is released from cells to the extracellular matrix. In this matrix, the protein aggregates bind ADAMTSL4 fibrillin-1 protein encoded by the FBN1 gene. The fibrillin-1 proteins bind to each other and other proteins to form microfibrils. It is likely that binding ADAMTSL4 to fibrillin-1 promotes the assembly of microfibrils. Have been described at least 15 mutations in the gene responsible ADAMTSL4 ectopia lentis isolated. A genetic mutation ADAMTSL4 found frequently in affected individuals of European ancestry removes 20 nucleotides of the gene (767_787del20). This mutation leads to encoding a protein that is abnormally short, nonfunctional. Lack of functional proteins ADAMTSL4 probably decreases the ability of fibrillin-1 to form microfibrils. As a result, the formation of microfibrils decreases. Without sufficient functional microfibrils to anchor the lens in its central position in the front of the eye, the lens is displaced, resulting in ectopia lentis isolated and vision related problems. While the ADAMTSL4 protein found throughout the body, it is believed that other proteins may compensate for their function in different tissues of the eye, which probably explains why only the eyes are affected in this disease.

When isolated ectopia lentis is due to mutations in the FBN1 gene, it is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In some cases, an affected person inherits the mutation from an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family. Meanwhile, when ectopia lentis isolated is due to mutations in the ADAMTSL4 gene is inherited in an autosomal recessive pattern, which means that 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 ectopia lentis isolated by PCR amplification the complete exons of FBN1 and ADAMTSL4, 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).