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. Refer to earlier sections in our Blog.
Pyridoxine in Seizure Control, a Scientific Perspective
Prior to the discovery of the genetic etiologies of the now three established forms of PDE, the disorder could only be clinically proven by withdrawing the vitamin from a patient in order to demonstrate that clinical seizures would reemerge and then be controlled once again by reintroducing the vitamin. Now, as clinicians have become more familiar with PDE, many patients are treated proactively with pyridoxine, and the diagnosis of the disorder is demonstrated either through the detection of biomarkers and/or by genetic testing. In addition, with the availability of targeted genetic screening for epileptic abnormalities, some patients with PDE are diagnosed prior to institution of pyridoxine treatment.
Initial recommendations for the diagnosis, treatment, and follow‐up of patients with PDE‐ALDH7A1 were published in 2011, and treatment recommendations were updated after the first study using a lysine‐restricted diet. In 2021 the first consensus guidelines for the diagnosis and management of PDE‐ALDH7A1 were published by the International PDE Consortium (www.pdeonline.org). However, many recommendations were based on the relatively low level of available evidence as well as expert consensus.
Pyridoxine supplementation in PDE is historically defined based on the resolution of seizures following treatment with pharmacologic doses of pyridoxine, and treatment with pyridoxine remains central to the treatment of the epilepsy that has defined this disorder. Patients with PDE‐ALDH7A1 have a secondary deficiency of PLP most likely due to a reaction between the accumulating Δ1‐P6C and PLP. There is an association between PLP supplementation and cirrhosis. Commercial pyridoxine preparations are relatively easy to obtain and stable, whereas PLP degrades quickly.
Consensus guideline for pyridoxine supplementation are substantially higher than the recommended dietary allowance (physiologic doses). While there is a risk of peripheral neuropathy when the dose of pyridoxine exceeds 500 mg/day, the vast majority of patients with PDE‐ALDH7A1 do not require such large doses for seizure control. Some patients may require one or more anti‐seizure medications, in addition to the maximum recommended dose of pyridoxine. Maternal pyridoxine supplementation during gestation has been proposed for these at‐risk pregnancies to help control of intrauterine seizures and improve developmental outcome.
Lysine‐Reduction Therapies, a Scientific Perspective
From the early description of the disorder, patients with PDE were described as having intellectual or developmental disability (IDD). The discovery that PDE‐ALDH7A1 led to the current hypothesis that accumulating α‐AASA (or related) metabolites are neurotoxic and contribute to the IDD phenotype. Current adjunct (to pyridoxine) therapies attempt to reduce the nutritional intake of lysine or reduce the transport of lysine and are collectively referred to as lysine‐reduction therapies (LRTs).
Several subjects with PDE‐ALDH7A1 treated with pyridoxine and a lysine‐free medical formula demonstrated a decrease in pipecolic acid, α‐AASA, and Δ1‐P6C. In other studies the patients were treated with pyridoxine and arginine. The rationale for this was that lysine and arginine as dibasic amino acids are transported by the same cationic transporter in the intestine, the kidney, and the blood‐brain barrier. It was expected that the supplemented arginine will compete with lysine and reduce its levels. In agreement with this it was found that upon daily arginine supplementation the patients had a decrease in urine and cerebrospinal fluid (CSF) α‐AASA and improved neuropsychiatric testing.
Patients who were initially treated with pyridoxine and lysine‐restricted diet had arginine supplementation added to their treatment regimen (also referred to as triple therapy). These patients demonstrated a significant decrease in plasma α‐AASA and Δ1‐P6C. Although not the primary outcome measure in these studies, all of the reports noted improved development in those patients treated with a form of LRTs.
A recent cohort study evaluated the association between treatment with LRTs and cognitive outcomes. Cohort assignment was based on treatment at the time of developmental testing, and treatment with pyridoxine and LRT was associated with a nonsignificant increase on developmental testing compared to treatment with pyridoxine alone. Notably, treatment with pyridoxine and LRTs in the first six months of life was associated with a significant increase on developmental testing scores, which emphasizes both the efficacy of LRTs and the importance of early, if not newborn, diagnosis and treatment.
Treatment Guidelines, Simplified
In 2011, the first recommendations for diagnosing and treating PDE-ALDH7A1, a rare form of epilepsy, were published. Updates followed in 2021 by the International PDE Consortium, considering factors like age and phenotype severity. Here’s a breakdown:
Pyridoxine Supplementation:
- PDE has long been treated with pyridoxine, a form of vitamin B6.
- Patients with PDE-ALDH7A1 have a secondary deficiency of PLP, a crucial compound.
- Pyridoxine is recommended over PLP due to safety and stability reasons.
- The International PDE Consortium provides dosage guidelines by age.
| Age of Patient | Pyridoxine Dose Range | Maximum Daily Dose (mg) |
|---|---|---|
| Newborns | 100 mg/day | 100 |
| Infants | 30 mg/kg/day | 300 |
| Children and Adolescents | 20 mg/kg/day (Range: 5–30 mg/kg/day) | 500 |
| Adults | 200–500 mg/day | 500 |
Maternal Supplementation:
- In cases of a 25% recurrence risk for PDE-ALDH7A1 in newborns, maternal pyridoxine supplementation during pregnancy is proposed.
- Delivery plans should ensure care for newborns at risk.
Lysine-Reduction Therapies (LRTs):
- PDE patients often experience intellectual or developmental disability (IDD).
- LRTs aim to reduce lysine intake or transport, addressing the neurotoxic effects of accumulating metabolites.
- Studies show improvements in patients treated with LRTs, including better development outcomes.
- Early diagnosis and treatment with LRTs in the first six months of life show significant positive effects on developmental testing scores.
Understanding PDE-ALDH7A1 and its treatment options can provide hope and better outcomes for affected individuals and their families. Always consult with healthcare professionals for personalized guidance.
Please note that we are not providing medical guidance. This is simply a summary of a scientific publication.
