Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by seizures that are specifically responsive to the administration of pyridoxine, which is a form of vitamin B6. This condition is also known as antiquitin deficiency. The prevalence of pyridoxine-dependent epilepsy is estimated to be between 1 in 20.000 and 1 in 783.000 live births.
Pyridoxine-dependent epilepsy genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of pyridoxine-dependent epilepsy include:
- Seizures: Individuals with pyridoxine-dependent epilepsy typically experience seizures that may begin in the neonatal period or early infancy. The seizures are often resistant to standard antiepileptic medications but show a rapid and sustained response to pyridoxine supplementation.
- Pyridoxine Responsiveness: One of the defining features of pyridoxine-dependent epilepsy is the remarkable response to pyridoxine (vitamin B6) supplementation. When given a sufficient dose of pyridoxine, the seizures in affected individuals can be effectively controlled or eliminated.
- Genetic Basis: Pyridoxine-dependent epilepsy is caused by mutations in the ALDH7A1 gene, which encodes the enzyme alpha-aminoadipic semialdehyde dehydrogenase (antiquitin). Mutations in this gene result in a deficiency of antiquitin, accumulating alpha-aminoadipic semialdehyde, which is toxic to the central nervous system.
- Neurological and Developmental Features: In addition to seizures, individuals with PDE may exhibit developmental delay, intellectual disability, and other neurological abnormalities. The severity of these features can vary among affected individuals.
- Diagnostic Testing: The diagnosis of pyridoxine-dependent epilepsy is confirmed through genetic testing to identify mutations in the ALDH7A1 gene. Additionally, the characteristic response to pyridoxine administration during a seizure episode can support the diagnosis.
- Treatment: The primary and essential treatment for pyridoxine-dependent epilepsy is the continuous administration of pyridoxine. In most cases, individuals with PDE require lifelong supplementation with pyridoxine to prevent seizures and support normal neurological development. In some instances, other medications may be used in conjunction with pyridoxine.
- Genetic Counseling: Due to its autosomal recessive inheritance pattern, individuals with pyridoxine-dependent epilepsy inherit mutations in the ALDH7A1 gene from both parents. Genetic counseling is essential for affected families to understand the risk of recurrence in future pregnancies.
Early diagnosis and prompt initiation of pyridoxine supplementation are critical for managing pyridoxine-dependent epilepsy and preventing long-term neurological damage. Genetic testing is essential for confirming the diagnosis and guiding treatment decisions.
More Information
Pyridoxine-dependent epilepsy is caused by the presence of homozygous and compound heterozygous pathogenic variants in the ALDH7A1 gene encoding for antiquitin. This molecule is an enzyme involved in aldehyde detoxification.
More than 80 pathogenic variants have been described in ALDH7A1, among which the variant c.1279G>C or p.Glu427Gln is the most frequent. It is present in approximately 30% of the alleles detected in patients with European ancestry. This variant substitutes a highly conserved amino acid, rendering the enzyme non-functional.
Pyridoxine-dependent epilepsy genetic testing analyzes the 9 most frequent pathogenic mutations of the ALDH7A1 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
