This article was published in March of 2023 and reviews the most up-to-date progress in pyridoxine-dependent epilepsy (PDE-ALDH7A1). Please find the original article here: https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20016. CurePDE has broken up the article into smaller sections and adapted 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.
Scientific Abstract
Pyridoxine‐dependent epilepsy (PDE) was historically defined by a dramatic clinical response to a trial of pyridoxine and the re‐emergence of seizures after withdrawal of pyridoxine. Research conducted over the last seven decades has revealed that the phenotype of PDE results from multiple genetic disorders, and the most common disorder, PDE‐ALDH7A1, is caused by a deficiency of an enzyme involved in lysine metabolism. PDE‐ALDH7A1 is characterized by more than epilepsy, as many patients have abnormalities of brain development, and most patients have intellectual and developmental disability. Treatment aimed at the underlying metabolic defect, in addition to pyridoxine supplementation, has improved clinical outcomes. Recently discovered biomarkers and genetic testing allow for the diagnosis of PDE‐ALDH7A1 without the need of a pyridoxine trial and hold the promise for newborn screening. Despite these many advances, PDE‐ALDH7A1 remains a clinical and biochemical conundrum. The increasing use of model systems and an international collaboration of clinician‐scientists are among the reasons to be optimistic that these questions will be answered in the near future and that the clinical outcomes and quality of life will continue to improve for patients with PDE‐ALDH7A1.
Simplified Abstract
Pyridoxine-dependent epilepsy (PDE) is a condition where people show a significant improvement when they take pyridoxine, but their seizures return when they stop. Research over the last 70 years has taught us that PDE is caused by different genetic disorders. The most common one, PDE-ALDH7A1, happens because of a shortage of an enzyme related to lysine metabolism. People with PDE-ALDH7A1 not only experience epilepsy but also often have issues with how their brains develop. Many also face intellectual and developmental challenges. Treating the underlying metabolic problem, along with taking pyridoxine, has led to better outcomes.
Now, we can diagnose PDE-ALDH7A1 using biomarkers and genetic testing, without needing a pyridoxine trial. This brings hope for newborn screening. Despite these improvements, PDE-ALDH7A1 is still a complex issue. Researchers around the world working together and using model systems make us hopeful that we’ll find more answers soon. This gives us optimism that the lives of people with PDE-ALDH7A1 will keep getting better.
Historical Aspects, a Scientific Version
PDE was discovered in 1954 when Hunt and colleagues first described it as the prototypical metabolic epileptic encephalopathy that is unresponsive to anti-seizure drugs, but generally successfully controlled with a vitamin B6 (pyridoxin). The patients commonly present with medication‐resistant neonatal seizures that may lead to status epilepticus and that come under control only with the addition of pharmacologic doses of pyridoxine. Hence, these individuals are dependent on the vitamin; they are not deficient. Indeed, clinical pyridoxine deficiency is rare, with an incidence of 0.23 cases/100 000 person‐year in US military personal; significant deficiency is associated with irritability, abdominal pain, insomnia, weakness, and difficulty with ambulation. In childhood, the most often cited example was iatrogenic pyridoxine deficiency secondary to an error in the manufacturing of infant formula, which led to an epileptic encephalopathy quite similar to the neonatal presentation of PDE. Importantly, a pyridoxine deficiency may be induced by treatment with isoniazid, and pyridoxine is the antidote for isoniazid overdose. 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.
Historical Aspects, a Simplified Version
Pyridoxine-Dependent Epilepsy (PDE) is a type of epilepsy that was first reported in 1954. It’s often seen as a unique form of epilepsy that doesn’t respond well to regular seizure medications but can be successfully treated with high doses of vitamin B6 (pyridoxine). People with PDE usually experience seizures that are difficult to control with regular drugs, especially during the neonatal period. The addition of large amounts of pyridoxine to their treatment plan helps bring these seizures under control. Long-term management involves daily high doses of pyridoxine.
It’s important to note that individuals with PDE are not deficient in vitamin B6; instead, they are dependent on it for seizure control. Actual vitamin B6 deficiency is rare and can lead to symptoms like irritability, abdominal pain, insomnia, weakness, and difficulty walking. In the past, some cases of PDE were mistakenly induced by errors in infant formula manufacturing, causing symptoms similar to neonatal PDE.
Before the discovery of the genetic causes of PDE, the only way to confirm the diagnosis was to withdraw pyridoxine from a successfully treated patient, leading to the reappearance of seizures. Nowadays, with increased awareness of PDE, many patients are proactively treated with pyridoxine, and diagnosis can be confirmed through biomarkers or genetic testing. Some patients respond well to pyridoxine and don’t experience seizures even after the vitamin is withdrawn, suggesting that pyridoxine may have inherent antiseizure effects. Studies have reported the effectiveness of pyridoxine in treating seizures in certain genetic conditions like mutations in KCNQ2 and in some cases of infantile spasms.
The follow up Blog will be Titled: The Three Established Forms of PDE
