This article was published in March of 2023 and reviews the most up-to-date progress in pyridoxine-dependent epilepsy (PDE-ALDH7A1). I’ve included the original article here. CurePDE has broken up the article into smaller sections and adapted it for non-medical readers looking for a concise introduction to the topic using plain scientific language. We are aware that we have different types of readers, and thus, we will present information in a more direct scientific language and in a simplified version as well.
If you would like to read the introduction, please go here.
Three forms of PDE, a scientific perspective
Since the initial description of PDE, additional clinical reports of patients with PDE have appeared. In a review of the Medline database, between 1954 and 2022, 333 papers concerning PDE have been published. It is now established that there are at least three forms of PDE which need to be studied in order to develop specific treatments for PDE.
The first form is associated with variants of the PNPO gene, which encodes an enzyme pyridox(am)ine 5′‐phosphate oxidase. This condition is designated as PDE‐PNPO, or PNPO deficiency, and an important feature of this disorder is that approximately 60% of affected patients require treatment with pyridoxal‐5′‐phosphate (PLP), the biologically active form of pyridoxine, rather than pyridoxine.
The second form of PDE discovered in 2016 is due to variants in PLPBP gene, which encodes PLP homeostasis protein (PLPHP) involved in the control of PLP levels. PLP binds to PLPHP, but little is known about the function of this protein. The most thoroughly studied form of PDE is due to biallelic pathogenic variants in ALDH7A1, the gene that encodes the enzyme α‐aminoadipic acid semialdehyde (α‐AASA) dehydrogenase.
PDE‐ALDH7A1 is a metabolic encephalopathy due to an inborn error of lysine catabolism resulting in absence or dysfunction of α‐AASA dehydrogenase (also known as antiquitin), the enzyme that converts α‐AASA to α‐aminoadipic acid. The underlying pathophysiology is due to an accumulation of several intermediate metabolites in the lysine biochemical pathways resulting in deactivation of PLP, the compound that is required for the function of more than 160 enzymatic activities in human cells. Dysfunction of one or several PLP‐dependent enzymes likely contributes to the epileptic encephalopathy experienced by these patients.
Natural history of patients is variable, both with respect to control of seizures and intellectual development. While the sine qua non of PDE is that the affected patient’s seizures only come under (often dramatic) control once pyridoxine is added, there are patients who, over time, may require one or more anti‐ seizure medications. Approximately 75% of patients have some degree of neurodevelopmental disability, ranging from mild to severe intellectual disability, autistic features, and other behavioral problems. Verbal skills, particularly expressive language, tend to be more impaired. Patients with later‐onset of seizures and those with a prompt early diagnosis and treatment tend to have a better prognosis, but this is not always the case.
Three forms of PDE, a simplified perspective
Since we first learned about Pyridoxine-Dependent Epilepsy (PDE), more cases have been reported. Between 1954 and 2022, 333 papers about PDE have been published. Now, we know there are at least three forms of PDE, and we need to study them to find specific treatments.
The first form is linked to changes in the PNPO gene, which makes an enzyme called pyridox(am)ine 5′‐phosphate oxidase. This type is called PDE‐PNPO, and about 60% of these patients need treatment with pyridoxal‐5′‐phosphate (PLP), the active form of pyridoxine, instead of pyridoxine itself.
The second form, discovered in 2016, comes from changes in the PLPBP gene, which makes a protein (PLPHP) involved in controlling PLP levels. PLP and PLPHP work together, but we don’t know much about PLPHP’s job.
The third form is the most studied form of PDE and occurs because of issues in the ALDH7A1 gene, which makes the enzyme α‐aminoadipic acid semialdehyde (α‐AASA) dehydrogenase. PDE‐ALDH7A1 is a metabolic problem causing a breakdown in lysine, leading to a lack or dysfunction of α‐AASA dehydrogenase. This enzyme normally changes α‐AASA into α‐aminoadipic acid. The problem comes from a buildup of substances in the lysine pathways, which deactivates PLP. PLP is needed for over 160 activities in human cells. Issues with PLP-dependent enzymes likely contribute to the epilepsy in these patients.
Patients’ experiences can vary, both in controlling seizures and intellectual development. A key feature of PDE is that seizures only get better when pyridoxine is added, but some patients may need other seizure medications over time. About 75% of patients have some level of neurodevelopmental issues, ranging from mild to severe intellectual problems, autism features, and other behavior difficulties. Verbal skills, especially expressive language, are often more affected. Patients with later-onset seizures and those diagnosed and treated early usually have a better outlook, but not always.
