Subcortical band heterotopia – DCX and PAFAH1B1 genes
Subcortical band heterotopia or double cortex syndrome (DCS) is a condition in which neurons don’t migrate to their proper locations in the brain of the fetus early in development. In people affected by this process some neurons that should be part of the cerebral cortex do not reach it. These neurons stop their migration process in areas of the brain where they are not supposed to be and form clusters similar to bands beneath the cerebral cortex. In most cases the bands are symmetrical, that is, they are in the same places on the right and left sides of the brain.
The signs and symptoms related to this process can range from severe intellectual disability and generalized seizures, to normal intelligence with focal seizures. Other signs may include hypotonia, loss of motor skills and behavior problems.
In most cases, subcortical band heterotopia is due to mutations in the DCX (doublecortin) gene. Less frequently, this disease is due to mutations in the PAFAH1B1 gene (platelet activating factor acetylhydrolase 1b regulatory subunit 1). Both genes encode proteins that are involved in neuronal migration.
The DCX (doublecortin) gene, located on the long arm of the X chromosome (Xq23), encodes the doublecortin protein. This protein is involved in neuronal migration, and binds to microtubules to promote their stability. The microtubules help to boost neurons, by forming structures inside the cell that elongate in a specific direction, altering the cytoskeleton and thus moving the neuron. At least 100 mutations in the DCX gene have been identified in individuals with subcortical band heterotopia, most of which change individual amino acids in the doublecortin protein. The mutations described can affect the function of the protein, or alter its structure or stability. As a consequence, the doublecortin protein has a reduced ability to bind to microtubules, which in turn affects its ability to move neurons during neuronal migration. Without proper neuronal migration, neurons in the developing brain may be out of place, leading to neurological problems.
The PAFAH1B1 gene (platelet activating factor acetylhydrolase 1b regulatory subunit 1), also known as LIS1, located on the short arm of chromosome 17 (17p13.3), encodes a protein that is a subunit of the complex platelet activating factor acetylhydrolase 1B (PAFAH1B). In the brain, this complex regulates the level of platelet activation factor (PAF), which is believed to be involved in directing neuronal migration. Adequate neuronal migration is essential for normal brain function and development. Regardless of its role in the PAFAH1B complex, it is likely that this protein also participates in the organization of the cytoskeleton. In addition, this protein interacts with microtubules and regulates a variety of proteins that are involved in their function.
At least seven mutations in the PAFAH1B1 gene have been described in individuals with subcortical band heterotopia, most of which change individual amino acids in the PAFAH1B1 protein subunit. The abnormal PAFAH1B1 protein is less able to interact with microtubules and bind to other subunits to form the PAFAH1B complex, which are necessary for neuronal migration. As previously mentioned, without proper neuronal migration, neurons in the developing brain may be misplaced, leading to neurological problems.
The inheritance pattern of subcortical band heterotopia depends on its genetic cause. When due to mutations in the DCX gene, it is inherited with an X-linked pattern. In women, who have two copies of the X chromosome, an altered copy of the gene in each cell can cause the condition, sometimes with less severe symptoms than the affected men. In men, who have only one X chromosome, a mutation in the single copy of the gene in each cell usually results in the development of a more serious condition known as isolated lissencephaly sequence (ILS). Most men with subcortical band heterotopia have a mutation of the DCX gene that is not inherited and is present in only some of the body's cells, a situation known as mosaicism. A characteristic of the X-linked inheritance is that parents cannot transmit X-linked traits to their children. On the other hand, when this disease is due to a mutation of the PAFAH1B1 gene, it is generally not inherited, but arises from a somatic mutation that takes place in the body's cells after conception. Mutations of the PAFAH1B1 gene that occur in all body cells generally cause ILS.
Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with subcortical band heterotopia, by means of the complete PCR amplification of the exons of the DCX or PAFAH1B1 genes, and their subsequent sequencing.
Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).