Lissencephaly isolated (Isolated lissencephaly sequence) - Genes PAFAH1B1, DCX and TUBA1A.  

Isolated lissencephaly (ILS) is a disease that affects brain development before birth. In people with ILS, cells of the cortex are disrupted, and the brain surface is abnormally smooth with an absence (agiria) or reduction (pachygyria) of folds and grooves. In most cases, these abnormalities impair brain growth, resulting in microcephaly. This underdevelopment of the brain leads to severe mental retardation, developmental delay and epilepsy in affected individuals.

Over 90% of individuals develop epilepsy, often within the first year of life. Up to 80% of newborns with infantile spasms, which can cause severe epileptic encephalopathy. After the first few months of life, most children develop a variety of types of crises, including the persistence of infantile spasms with short periods of unconsciousness, sudden episodes of weak muscle tone, myoclonic seizures, episodes of stiffness muscle and tonic-clonic seizures. Additionally newborns may have hypotonia and feeding difficulty, which leads to poor growth. Hypotonia also cause respiratory problems such as aspiration pneumonia. With fecuencia, affected children develop spasticity in his arms and legs and scoliosis. Rarely, muscle stiffness progresses to spastic paraplegia. Affected individuals can not walk and rarely crawl. Most children with ILS do not develop communication skills.

Isolated lissencephaly is due to mutations in genes PAFAH1B1, located on the short arm of chromosome 17 (17p13.3), DCX, located on the long arm of the X chromosome (Xq22.3-q23), or TUBA1A, located in the long arm of chromosome 12 (12q13.12). These genes encode proteins which are involved in the migration of neurons to their proper places in the developing brain. Neuronal migration depends on the microtubules that form the cytoskeleton. The protein produced from TUBA1A gene is a component of microtubules. The proteins produced from the genes PAFAH1B1 DCX and promote neuronal migration through interaction with microtubules.

There are more than 70 mutations in the gene PAFAH1B1, more than 70 mutations in the DCX gene and approximately 40 mutations in the gene cause lissencephaly TUBA1A isolated. Mutations in any of these three genes disrupt microtubule function and normal migration of neurons during fetal development. As a result, the layers of the cerebral cortex are disorganized and no brain folds and grooves are formed. This alteration of brain development results in the development of a smooth brain and neurological problems characteristic of the disease. Some individuals with isolated lissencephaly, have a mutation identified in any of these three genes. In these individuals, the cause of the disease may be mutations in other genes that affect neuronal migration or other unknown factors.

The inheritance pattern of isolated lissencephaly varies depending on the gene involved. When the disease is caused by mutations in the PAFAH1B1 or TUBA1A gene is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to cause the alteration. Most cases are caused by new mutations in the gene and occur in people with no history of disease in your family. When the disease is caused by mutations in the DCX gene is inherited in a pattern linked to chromosome X. A disease is X - linked, if the mutated gene that causes it is on the X chromosome, one of the two chromosomes sex in each cell. In males, an altered copy of the DCX gene in each cell is sufficient to cause the alteration. In women, who have two copies of the X chromosome, one altered copy of the gene in each cell DCX may lead to a less serious condition called subcortical band heterotopia, or may cause no symptoms at all. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with lissencephaly isolated by PCR amplification the complete exons of PAFAH1B1, DCX and TUBA1A, 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).