X-linked lissencephaly

X-linked lissencephaly is a condition of abnormal brain development that mainly affects males, though females may be mildly affected. Normally the exterior of the brain (cerebral cortex) is multi-layered with folds and grooves. People with lissencephaly have an abnormally smooth brain with fewer folds and grooves. This abnormality can cause severe intellectual disability and developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties. People without any folds in the brain (agyria) typically have more severe symptoms.

There are at least two forms of X-linked lissencephaly. The first is characterized by lissencephaly only, and usually involves no other parts of the body. The second is lissencephaly with abnormal (ambiguous) genitalia. This form of X-linked lissencephaly is typically more severe, with seizures often beginning within the first day of life, and sometimes even before birth. In addition, affected males can have an unusually small penis (micropenis), undescended testes (cryptorchidism), or external genitalia that do not look clearly male or clearly female (ambiguous genitalia). Males with this form of X-linked lissencephaly also can show a lack of development (agenesis) of the tissue connecting the left and right halves of the brain (corpus callosum), low body temperature (hypothermia), and chronic diarrhea.

The overall incidence of lissencephaly is estimated to be 1 in 85,000 individuals. The incidence of males with X-linked lissencephaly is unknown.

X-linked lissencephaly is caused by a mutation in either the DCX gene or the ARX gene. Mutations in the DCX gene cause isolated lissencephaly, which typically does not involve any other parts of the body. Mutations in the ARX gene can cause X-linked lissencephaly with ambiguous genitalia and other associated health issues. Both genes provide instructions for producing proteins that play a role in the development of the brain. The DCX protein, doublecortin, plays a role in the migration of nerve cells (neurons) to their proper location in the developing brain. The ARX protein is involved in the regulation of other genes that contribute to brain development. The ARX protein is also found in the pancreas and testes.

X-linked lissencephaly is seen primarily in males. Most females with a DCX mutation have a milder brain disorder called subcortical band heterotopia, or doublecortex. Females with an ARX mutation usually have some degree of intellectual disability, epilepsy, and agenesis of the corpus callosum.

Read more about the ARX and DCX genes.

This condition is inherited in an X-linked dominant pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.