Lissencephaly Health Article

Definition

Lissencephaly, literally meaning smooth brain, is a rare birth abnormality of the brain that results in profound mental retardation and severe seizures.

Lissencephaly is caused by an arrest in development of the fetal brain during early pregnancy. The cerebral cortex, the top layer of the brain controlling higher thought processes, does not develop the normal sulci, the indentations or valleys in the cortex, and gyri, the ridges or convolutions seen on the surface of the cortex. Instead, the cortex in a person with lissencephaly is thickened and smooth with disorganized neurons that have not migrated to their proper places. The typical cortex has six layers of neurons, but brains with lissencephaly usually have only four.

Description

The condition was first reported in 1914 by pathologists Culp and Erhardt, who described a human brain with a smooth surface, lacking the normal gyri. They called it lissencephaly.

Lissencephaly is one of a number of conditions called "neural migration disorders" that occur because the developing neurons do not proceed correctly to their normal place in the brain's cortex during fetal development. In fact, the brain of a person with lissencephaly, with its smooth and immature cortex, resembles a typical human fetal brain at about 10 to 14 weeks of development.

Children with lissencephaly are almost always severely to profoundly mentally retarded, and the vast majority develop seizures that are difficult to treat. Life expectancy is reduced, and survivors need constant care.

Lissencephaly can occur as an isolated birth abnormality or can be one of many birth abnormalities occurring together in a specific inherited syndrome. There are at least 10 inherited syndromes that include lissencephaly and many more that include variants of this brain malformation. Lissencephaly can also occur by itself without other characteristics.

Some cases of lissencephaly are caused by new changes in the genetic material of that particular baby—these cases are caused by sporadic, or random, gene mutations (also called de novo). This means that the genetic change is not present in the parents or anyone else in the family. Some cases of lissencephaly are caused by rearrangements of chromosome material that can be inherited from a healthy parent. Other types of lissencephaly are inherited in an autosomal recessive pattern. This means that a couple who has a child with an autosomal recessive lissencephaly syndrome has a 25% chance in any future pregnancy to have another affected child. There are also types of lissencephaly caused by changes in a gene or genes on the X chromosome. X-linked lissencephaly affects mainly males, who have only one X chromosome. Females who carry an X-linked gene change on one of their two X chromosomes often have mild brain changes.

Other known causes of lissencephaly include viral infections of the fetus or insufficient blood supply to the brain during the first trimester of pregnancy.

Genetic profile

There are a number of subtypes of lissencephaly that are distinguished by differences in the physical structure of the brain. "Classical," or type 1, lissencephaly and cobblestone dysplasia, or type 2, lissencephaly are the most common subtypes.

Classical, or type 1, lissencephaly consists of a brain surface that is completely smooth except for a few shallow valleys (sulci). The cortex is thicker than normal and there are clumps of neurons found in areas outside the cortex (heterotopia). The corpus callosum, the band of tissue between the hemispheres of the brain, is often small and is sometimes absent. The posterior ventricles, the fluid-filled spaces in the center of the brain, are often larger than normal.

Type 1 lissencephaly can be seen in a number of genetic syndromes and can also occur by itself in a condition called Isolated Lissencephaly Sequence (ILS). The vast majority of cases of ILS is a result of mutations or deletions (missing sections) in one of two different genes involved in brain development.

The gene causing the majority of cases of ILS is called the LIS1 and is located on the short arm of chromosome 17. Between 40% and 64% of persons with ILS have a deletion of a portion of the LIS1 gene, and about 24% have a mutation that disrupts the normal function of the gene. Most deletions and mutations in the LIS1 gene are sporadic and are not present in other family members.

Another 12% of persons with ILS have a mutation in a gene called XLIS (or DCX), located on the long arm of the X chromosome. Mutations in XLIS cause X-linked lissencephaly in males and may or may not cause symptoms in the mothers who carry the mutation.

There are also a few cases of ILS that appear to be inherited in an autosomal recessive pattern. As of 2001, the mutated genes for this and other types of ILS have not been discovered.

An example of a genetic syndrome involving type 1 lissencephaly is Miller-Dieker syndrome (MDS). This disorder is caused by a deletion of part of the short arm of chromosome 17 (17p13) that includes the LIS1 gene. In addition to lissencephaly, children with MDS have distinctive facial features including a high forehead, short upturned nose, and thin lips. They also have narrowing at the temples and a small jaw, although these traits can also be seen in ILS and other lissencephaly syndromes. Children with MDS occasionally have other birth abnormalities of the heart, kidneys, or palate. Calcium deposits in the midline of the brain are common in MDS, but not in ILS or other syndromes.

Type 2 lissencephaly is also called cobblestone dysplasia because of the pebbled appearance to the surface of the cerebral cortex. Brains with cobblestone dysplasia often show abnormalities of the white matter, enlarged ventricles, underdeveloped brainstem and cerebellum, and absence of the corpus callosum. There are four known syndromes that include cobblestone dysplasia: cobblestone lissencephaly without other birth defects (CLO); Fukuyama congenital muscular dystrophy (FCMD); muscle-eye-brain disease (MEB); and Walker-Warburg syndrome (WWS). These disorders are quite rare and all are inherited in an autosomal recessive pattern. Diagnosis depends on MRI studies and clinical evaluations. As of 2001, there are no specific genetic tests available for clinical use for these conditions.

There are other rare syndromes involving lissencephaly and variants of lissencephaly, some of which are autosomal recessive and some X-linked. None of the genes responsible for these other conditions have been identified as of Spring 2001.