Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Schizencephaly (Schizencephaly) - Genes SIX3, SHH, EMX2 and COL4A1.

The Schizencephaly (SCHZC) is a malformaciĆ³n cerebral extremely rare, characterized by abnormal grooves or indentations in the cerebral hemispheres . Brain hemispherical recesses can be unilateral or bilateral. Often, individuals with clefts in both hemispheres have developmental delays and capabilities of habla and corticospinal dysfunction. Individuals with more unilateral clefts, may have weakness on one side of the body and have a normal or near normal intelligence. Other signs and symptoms of the disease may include microcephaly , retraso mental , hemiparesis or cuadriparesia , hypotonia , convulsiones and hydrocephalus .

They described two types of Schizencephaly, depending on the size of the area involved and separation cleft lips. The type I Schizencephaly not associated with hydrocephalus and condition area is small, while in type II Schizencephaly there is a greater impact area and associated with hydrocephalus. Clinical manifestations depend on the severity of the injury. Often, individuals with type I may have seizures and spasticity. Usually, the type II, affected individuals have a more severe phenotype that includes mental retardation, seizures, hypotonia, spasticity, inability to walk or talk and blindness.

This process is due to mutations in the SIX3, SHH, EMX2 and COL4A1 genes.

The SIX3 gene, located on the short arm of chromosome 2 (2p21), encodes a protein transcription factor which plays an important role in the development of eyes and forebrain. The SIX3 protein regulates genes involved in several signaling pathways that are important for embryonic development. Some of these genes are activated by SIX3 protein and others are inactive. A gene activated by SIX3 SHH protein is the gene encoding a protein called "Sonic Hedgehog". Among its many functions, the protein "Sonic Hedgehog" helps establish the hemispheres of the forebrain. The SIX3 protein also regulates genes involved in the formation of the ocular lens and retina. SIX3 gene mutations disrupt the ability of the protein to bind to DNA. As a result, the genes involved in eye development and forebrain are not properly activated or repressed. Without proper activity of these genes, the eyes are not formed normally and the brain is not separated into two hemispheres.

The SHH gene, located on the long arm of chromosome 7 (7q36), encoding a protein "Sonic Hedgehog". This protein functions as a chemical signal that is essential for embryonic development. Protein "Sonic Hedgehog" plays a role in cell growth, cell specialization, and the normal conformation of the organism. This protein is important for the development of the central nervous system, eyes, limbs and many other parts of the body. Protein "Sonic Hedgehog" is necessary for the development of the forebrain. This signaling protein helps establish the middle line between the right and left sides of the forebrain. Specifically, this protein provides the ventral surface of the forebrain. Furthermore, this protein and other signaling proteins are necessary for the formation of the brain hemispheres. Protein also plays an important role in the formation of the eyes. In early development, cells that develop in the eyes form a single structure called the eye field. This structure is located in the center of the face in development. Signaling protein "Sonic Hedgehog" makes the eye field is separated into two distinct eyes. Mutations in the gene SHH reduce or eliminate the activity of this protein. Without proper activity of this protein, the eyes are not formed normally and the brain is not separated into two hemispheres. The development of other parts of the face is affected if the eyes do not move from its correct position.

The EMX2 gene, located on the long arm of chromosome 10 (10q26.1), encodes a transcription factor containing homeobox gene is homologous to the 'empty spiracles' Drosophila. This gene is expressed in three tissues: dorsal telencephalon, olfactory neuroepithelium, and urogenital system. It is expressed in the dorsal telencephalon during development by establishing the defined functional areas. It is also expressed in embryonic and adult olfactory neuroepithelium where complex is formed with the initiation factor 4E (eIF4E) and possibly regulates mRNA transport or translation. In the urogenital system under development, it is expressed in epithelial tissues and are downregulated by HOXA10. It can operate in combination with Otx1 / 2 to specify cell fates in the developing central nervous system. Mutations in the gene EMX2 are a rare cause of Schizencephaly and result type II Schizencephaly. These mutations can be inherited or sporadic. An identified mutation alters the splicing of the first intron of EMX2 gene, leading to loss of its function. Alteration affects the Neuroblastic migration and the structural pattern of the forebrain.

The COL4A1 gene, located on the long arm of chromosome 13 (13q34), encodes a component of type IV collagen, important in the structure many tissues throughout the body. Specifically, this gene encodes alpha1 chain of collagen type IV. Types IV collagen molecules are joined together to form complex networks of proteins. These networks proteins are the major component of basement membranes. Mutations in the COL4A1 gene that properly develop prevent formation of protein networks and basement membranes. Mutations identified in the COL4A1 gene occur in highly conserved glycine residues in the Gly-XY repeat collagen triple helical domain.

In most cases, the disease is sporadic and not inherited. It is likely that certain factors such as infection, stroke, hemorrhage or exposure to toxins during embryonic development leading to the disease. In cases where the disease is hereditary, you can have an autosomal dominant pattern of inheritance or autosomal recessive. Autosomal dominant inheritance means that a copy of the altered gene in each cell is sufficient to express the disease. Meanwhile, in the autosomal recessive inheritance both gene copies in each 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 Schizencephaly (SCHZC), by complete PCR amplification of the exons of SIX3, SHH, EMX2 and COL4A1 genes, respectively, and subsequent sequencing.

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).