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


Child spasmodic X - linked syndrome ..., (X-linked infantile spasm syndrome) - Genes ARX and CDKL5.  

   Infantile spasm syndrome X - linked is a convulsive disorder characterized by a type of attack known as infantile spasms. Spasms usually appear before the age of 1 year. They described various types of spasms, but the most common involves bending at the waist and neck with the extension of the arms and legs (sometimes called a knife spasm). Each spasm lasts only a few seconds, but occur in groups of several minutes. Although people usually are not affected as they sleep, spasms commonly occur just after waking. Infantile spasms usually disappear around 5 years old, but many children develop other types of seizures that recur throughout their lives.

Most babies with this syndrome have characteristic results in an electroencephalogram (EEG), which shows hypsarrhythmia, this finding may help differentiate infantile spasms of other types of seizures. Because of frequent seizures, newborns fail to develop normally and experience developmental regression, such as sitting, rolling and babbling, so the later development of children affected is delayed. Most affected individuals also have intellectual disabilities throughout their lives.

Infantile spasm syndrome X - linked is caused by mutations in the gene or CDKL5 ARX gene. The ARX gene, located on the short arm of chromosome X (Xp21.3), encodes a protein that regulates the activity of other genes, so it is a transcription factor. This gene is part of a family of homeobox genes, which act during early embryonic development to control the formation of many structures in the body. Specifically, it is believed that the protein is involved in the development of the pancreas, testes, brain and skeletal muscles. In the pancreas, testes and skeletal muscles, the ARX protein helps regulate the process by which cells mature to perform specific functions. In the developing brain, the ARX protein is involved with movement and communication of neurons. In particular, this protein regulates genes that play a role in migration of interneurons to the correct location. Interneurons transmit signals between other neurons.

Frequent mutations causing ARX gene syndrome are repeated extensions polyalanine adding additional alanines to the first or second section of the ARX polyalanine protein. It is unknown how these extensions lead to spasms. It is believed that other mutations reduce the function of the protein. It is unclear how a decrease in protein function leading to seizures and mental retardation.

The CDKL5 gene located on the short arm of the X (Xp22) chromosome, encodes a protein that is essential for function and normal brain development. The protein acts as a kinase, which changes the activity of other proteins by adding a group of oxygen and phosphorus atoms in specific positions. One of the specific proteins is MeCP2, which is produced from the MECP2 gene. MeCP2 plays an important role in the function of neurons and other brain cells and in maintaining the synapse between neurons.

Mutations in the gene cause disease CDKL5 are deletions involving all or part of the gene. Other cases, result from mutations that alter the function of the protein or prevent the production of any functional protein. It is unclear how defects in this protein cause seizures and mental retardation.

This disease can have different inheritance patterns depending on the genetic cause. When the alteration is caused by mutations in the ARX gene is inherited in a recessive X - linked pattern in males, an altered copy of the gene in each cell is sufficient to cause disease. Usually, in women, the mutation would have to happen in both copies of the gene to cause the disorder. However, in some cases, an altered copy of the gene is sufficient because the X chromosome with the normal gene copy ARX longer expressed by a process called inactivation of X. In early embryonic development in women, one of the two chromosomes X is inactivated permanently in somatic cells. X inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. When caused by mutations in the CDKL5 gene, it is believed that this condition have a dominant inheritance pattern X - linked inheritance is dominant because a copy of the altered in every cell gene is sufficient to cause the condition in men and women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.  

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with syndrome X - linked infantile spasm, by complete PCR amplification of the exons of the ARX and CDKL5 respectively genes 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).