Pyridoxine-dependent epilepsy - ALDH7A1 gene.

Pyridoxine-dependent epilepsy is a condition characterized by seizures that occur in childhood or in some cases, before birth. Affected individuals often have status epilepticus. These attacks involve muscle rigidity, seizures and loss of consciousness. Additional features include hypothermia, dystonia shortly after birth and irritability. Rarely, affected children do not have seizures until the age of 1 to 3 years.

Anticonvulsant drugs, which are generally administered to control seizures, are not effective in individuals with pyridoxine-dependent epilepsy. Instead, people with this type of seizures are treated medically with large daily doses of pyridoxine. If left untreated, affected individuals may develop encephalopathy. Although seizures can be controlled with pyridoxine, neurological problems may occur such as developmental delay and learning disorders.

Pyridoxine-dependent epilepsy is due to mutations in the gene ALDH7A1, located on the long arm of chromosome 5 (5q31). This gene is a member of the family of genes aldehyde dehydrogenase (ALDH). These genes encode enzymes that alter molecules called aldehydes. The ALDH7A1 gene encodes an enzyme called aminoadipic semialdehyde dehydrogenase ? (?-AASA), also known as antiquitina. Inside the cell, the antiquitina is in the cytoplasm and nucleus. This enzyme is involved in the breakdown of the amino acid lysine in the brain. In the decomposition of lysine to other molecules, the antiquitina facilitates the conversion of ?-aminoadipic semialdehyde to ?-aminoadipate. The breakdown of lysine in the brain is necessary for energy production and for the synthesis of other molecules.

They have identified a variety of mutations in the gene ALDH7A1   in individuals with pyridoxine-dependent epilepsy. Most of these mutations are specific to individual families. A common mutation replaces the amino acid glutamine for the amino acid glycine at position 399 in the protein antiquitina (Glu399Gln or E399Q). All mutations result encoding a nonfunctional protein antiquitina. Antiquitina deficiency leads to the accumulation of ?-aminoadipic acid semialdehyde, which alters the activity of pyridoxine. Pyridoxine plays a role in many processes in the body, such as the breakdown of amino acids and neurotransmitters in the brain. It is unclear how the lack of pyridoxine leads to seizures characteristic of this disease.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with pyridoxine-dependent epilepsy, by complete PCR amplification of the exons of the gene ALDH7A1, 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).