ARX

The ARX gene provides instructions for producing a protein that regulates the activity of other genes. On the basis of this action, the ARX protein is called a transcription factor. The ARX gene is part of a larger family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the ARX protein is believed to be involved in the development of the pancreas, gastrointestinal tract, testes, and brain. The ARX protein is thought to play a role in the migration of specialized nerve cells, called interneurons, to their proper location in the developing brain. Interneurons relay signals between other nerve cells (neurons).

X-linked infantile spasm syndrome - caused by mutations in the ARX gene

Mutations in the ARX gene can cause X-linked infantile spasm syndrome, a disorder characterized by recurrent seizures called infantile spasms that begin in the first year of life. Children with this condition also have intellectual disability. The normal ARX protein contains four regions where a protein building block (amino acid) called alanine is repeated multiple times. These stretches of alanines are known as polyalanine tracts. The most common ARX gene mutations that cause X-linked infantile spasm syndrome add extra alanines to the first or second polyalanine tract in the ARX protein. This type of mutation is called a polyalanine repeat expansion. How these expansions lead to X-linked infantile spasms is unknown. Other ARX gene mutations that cause this condition are believed to reduce the function of the ARX protein. However, it is unclear how a decrease in ARX protein function leads to seizures and intellectual disability.

X-linked lissencephaly - caused by mutations in the ARX gene

There are more than 20 mutations in the ARX gene that cause X-linked lissencephaly with abnormal (ambiguous) genitalia. These mutations usually lead to the production of a nonfunctional ARX protein or no ARX protein at all. As a result, the ARX protein cannot perform its role in regulating the activity of certain genes. In addition to impairing normal brain development, a shortage of functional ARX protein can also disrupt normal function in the pancreas and the testes, leading to the signs and symptoms of X-linked lissencephaly with ambiguous genitalia.

other disorders - caused by mutations in the ARX gene

Different mutations in the ARX gene can cause a variety of conditions that impair brain function. Some ARX gene mutations result in intellectual disability without other neurological problems. Because the ARX gene is on the X chromosome, this condition is known as X-linked intellectual disability (XLID) or sometimes nonsyndromic X-linked intellectual disability. XLID can also occur in combination with other neurological problems as part of distinct conditions called X-linked intellectual disability syndromes. ARX gene mutations cause several X-linked intellectual disability syndromes, including X-linked lissencephaly with ambiguous genitalia and X-linked infantile spasm syndrome (described above). Others include X-linked myoclonic epilepsy with intellectual disability and spasticity, which causes intellectual disability and recurrent seizures (epilepsy), and Partington syndrome, which is characterized by mild to moderate intellectual disability and abnormal muscle stiffness (spasticity) with involuntary tensing of the muscles (dystonia). Unlike X-linked lissencephaly, none of these other ARX-related conditions have associated structural brain abnormalities. For unknown reasons, the same mutation can result in the development of different conditions in different people, even among individuals within the same family. It is not clear why mutations in the ARX gene cause this array of conditions.