Miller-Dieker syndrome ... (Miller-Dieker syndrome) - Genes PAFAH1B1 and ywhae.  

The Miller-Dieker syndrome is a disorder characterized by abnormal brain development pattern known as lissencephaly. Normally the cerebral cortex has multiple layers with folds and furrows. However, people with lissencephaly have an abnormally smooth brain with less folds and grooves. These brain malformations cause severe mental retardation, developmental delay, seizures, spasticity, hypotonia and feeding difficulties. Generally, the smoother the more severe brain surface are associated symptoms. Other associated signs and symptoms may include distinctive facial features as a prominent forehead, midface hypoplasia, a small upward nose, low - set ears and abnormally, a small jaw and upper lip thickness. Some affected people also grow more slowly than other children. Rarely, these individuals have heart and kidney malformations and omphalocele. In addition, some individuals may have life - threatening breathing problems. Most people with this disease do not survive beyond infancy.

The signs and symptoms of the syndrome Miller-Dieker are due to a deletion of genetic material near the end of the short arm of chromosome 17. The chromosomal region is removed usually contains multiple genes, including genes PAFAH1B1 and ywhae.

The PAFAH1B1 gene, also known as LIS1, located on the short arm of chromosome 17 (17p13.3), encodes a protein which is a subunit activating factor acetylhydrolase platelet complex 1B (PAFAH1B). In the brain, this complex regulates the level of platelet activating factor (PAF). It is believed that PAF is involved in directing neuronal migration. Proper neuronal migration is essential for normal brain function and development. Independent of its role in the PAFAH1B complex, it is likely that this protein is also involved in the organization of the cytoskeleton. Furthermore, this protein interacts with microtubules and regulates a variety of proteins that are involved in its function. Following the deletion of genetic material, people with this disease have a single copy of the gene in every cell PAFAH1B1 instead of the normal two copies. A deletion of one copy of the gene in every cell PAFAH1B1 reduces the amount of protein PAFAH1B1 half. It is likely that this protein deficiency is responsible for many of the characteristics of Miller-Dieker syndrome, including mental retardation, developmental delay and epilepsy. A decrease in neuronal migration due to deficiency PAFAH1B1 protein is responsible for the characteristic lissencephaly the Miller-Dieker syndrome. Other eliminated in the same region of chromosome 17 genes are responsible for the other features of the syndrome Miller-Dieker as distinctive facial features, slow growth, respiratory difficulties.

The ywhae gene, located on the short arm of chromosome 17 (17p13.3), encoding the protein 14-3-3?, which is part of the great family of 14-3-3 proteins. The proteins of this family bind other proteins involved in cell signaling. 14-3-3 proteins activate or deactivate these other proteins. The 14-3-3? protein helps regulate a variety of processes, including cell division and insulin sensitivity. This protein is active in tissues throughout the body, although its exact function is unclear. In addition, it is believed that 14-3-3? protein is critical for proper neuronal migration and normal brain development. Following the deletion of genetic material, people with this disease have a single copy of the gene in every cell ywhae instead of the normal two copies. A deletion of one copy of the gene in every cell ywhae reduces the amount of protein 14-3-3? half. 14-3-3? protein deficiency increases the severity of lissencephaly in people with Miller-Dieker syndrome.

Most cases of Miller-Dieker syndrome are not inherited. The deletion occurs more frequently as a random event during the formation of reproductive cells or early fetal development. Affected individuals usually have no history of the disease in his family. When the disease is inherited, its pattern of inheritance is autosomal dominant considered because a deletion in one copy of chromosome 17 in each cell is sufficient to express the disease. About 12% of people with Miller-Dieker syndrome , a chromosomal abnormality inherited from an affected parent. In these cases, the parent has a balanced translocation. Balanced translocations usually do not cause any health problems; however, they may become unbalanced as they are transmitted to the next generation. Children who inherit an unbalanced translocation may have a chromosomal rearrangement extra or missing genetic material. People with Miller-Dieker syndrome inherit an unbalanced translocation present absence of genetic material on the short arm of chromosome 17, which leads to health problems characteristic of this disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Miller-Dieker syndrome of, by complete PCR amplification of the exons of PAFAH1B1 and ywhae, 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).