Pyridoxine-dependent epilepsy is a condition that involves seizures beginning in infancy or, in some cases, before birth. Those affected typically experience prolonged seizures lasting several minutes (status epilepticus). These seizures involve muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures). Additional features of pyridoxine-dependent epilepsy include low body temperature (hypothermia), poor muscle tone (dystonia) soon after birth, and irritability before a seizure episode. In rare instances, children with this condition do not have seizures until they are 1 to 3 years old.

Anticonvulsant drugs, which are usually given to control seizures, are ineffective in people with pyridoxine-dependent epilepsy. Instead, people with this type of seizure are medically treated with large daily doses of pyridoxine (a type of vitamin B6 found in food). If left untreated, people with this condition can develop severe brain dysfunction (encephalopathy). Even though seizures can be controlled with pyridoxine, neurological problems such as developmental delay and learning disorders may still occur.

Mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy. The ALDH7A1 gene provides instructions for making an enzyme called α-aminoadipic semialdehyde (α-AASA) dehydrogenase, also known as antiquitin. This enzyme is involved in the breakdown of the protein building block (amino acid) lysine in the brain.

When antiquitin is deficient, a molecule that interferes with vitamin B6 function builds up in various tissues. Pyridoxine plays a role in many processes in the body, such as the breakdown of amino acids and the productions of chemicals that transmit signals in the brain (neurotransmitters). It is unclear how a lack of pyridoxine causes the seizures that are characteristic of this condition.

Some individuals with pyridoxine-dependent epilepsy do not have identified mutations in the ALDH7A1 gene. In these cases, the cause of the condition is unknown.

Normal Function

The ALDH7A1 gene is a member of the aldehyde dehydrogenase (ALDH) gene family. These genes provide instructions for producing enzymes that alter molecules called aldehydes. The ALDH7A1 gene provides instructions for making an enzyme called α-aminoadipic semialdehyde (α-AASA) dehydrogenase, also known as antiquitin. Within the cell, antiquitin is found in the internal fluid of the cell (cytosol) and in the nucleus. This enzyme is involved in the breakdown of the protein building block (amino acid) lysine in the brain. In one step in the breakdown of lysine to other molecules, antiquitin facilitates the conversion of α-aminoadipic semialdehyde to α-aminoadipate. The breakdown of lysine in the brain is necessary for energy production and to produce other needed molecules.

Health Conditions Related to Genetic Changes

Pyridoxine-dependent epilepsy

A variety of mutations in the ALDH7A1 gene have been found to cause pyridoxine-dependent epilepsy. Most of these mutations are specific to single families. One mutation occurs in multiple people with this condition; it replaces the amino acid glutamine with the amino acid glycine at position 399 in the antiquitin protein (written as Glu399Gln or E399Q). All mutations that cause pyridoxine-dependent epilepsy produce a nonfunctional antiquitin protein. A shortage (deficiency) of antiquitin leads to the buildup of α-aminoadipic semialdehyde, resulting in a disruption in the activity of pyridoxine, a form of vitamin B6 derived from food. Pyridoxine plays a role many processes in the body, such as the breakdown of amino acids and chemicals in the brain called neurotransmitters. It is unclear how a lack of pyridoxine causes the seizures characteristic of this condition.

Other Names for This Gene

• AL7A1_HUMAN
• aldehyde dehydrogenase 7 family, member A1
• aldehyde dehydrogenase 7A1
• antiquitin
• antiquitin 1
• ATQ1
• EPD
• PDE

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Pyridoxine-dependent epilepsy occurs in 1 in 100,000 to 700,000 individuals. At least 100 cases have been reported worldwide.