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.
If you would like to read about the three forms of PDE go here.
If you would like to read about the clinical aspects, go here.
If you would like to read about biochemistry and genetics, go here.
The Scientific Version
The diagnosis of PDE‐ALDH7A1 is now facilitated through the detection of biomarkers in biological fluids and confirmation of pathogenic variants through testing of the ALDH7A1 gene. Assays for α‐AASA45 and pipecolic acid46 can be conducted on urine or blood, and if elevated in a patient with an epileptic encephalopathy would suggest a diagnosis of PDE‐ALDH7A1.3 It must be stressed that these metabolites are not specific and confirmation of PDE‐ALDH7A1 requires evaluation of the ALDH7A1 gene. There are multiple genetic causes of PDE that may present with a similar seizure phenotype, and each genetic cause has unique implications for treatment. The elevated pipecolic acid and α‐AASA/Δ1‐P6C as biomarkers have some limitations. Importantly, α‐AASA/Δ1‐P6C is relatively unstable at room temperature which makes the possibility of extending these biomarkers to newborn screening impractical. In 2019, a relatively stable metabolite 6‐oxo‐pipecolate (6‐oxo‐2‐piperidinecarboxylic acid) was identified in children and adolescents with PDE‐ALDH7A1. Shortly thereafter, a second novel biomarker 2S,6S‐/2S,6R‐oxopropyl-piperidine‐2‐carboxylic acid (2‐OPP) likely relevant to lysin degradation was identified.
The Simplified Perspective
Detecting and understanding PDE-ALDH7A1, a condition affecting brain metabolism, has become more advanced. Now, doctors can use biomarkers in bodily fluids and gene testing to diagnose it. Special tests on urine or blood, looking at substances like α-AASA and pipecolic acid, can suggest if someone has PDE-ALDH7A1, but these aren’t specific and may be seen in other conditions. To confirm, the ALDH7A1 gene is checked for specific changes.
Knowing about these biomarkers and having genetic tests was crucial in understanding PDE-ALDH7A1. It helps distinguish it from other conditions with similar symptoms, leading to better treatment decisions. Despite the usefulness of these biomarkers, there are some limitations. For instance, some need samples to be frozen before testing, making it challenging for widespread use, especially in newborn screening.
Recently, two new biomarkers, 6-oxo-pipecolate and 2-OPP, were discovered, offering more stability at room temperature. This is a big deal because it makes testing more practical. These new biomarkers are being explored for newborn screening, aiming to identify PDE-ALDH7A1 early. Early detection is crucial, as it allows for timely treatment, improving outcomes significantly. In fact, PDE-ALDH7A1 has been proposed as a top priority for newborn screening in the United States.
Researchers have already tested these new biomarkers on dried blood spots from affected patients, showing promise. Studies are ongoing, but if successful, these tests could become a routine part of newborn screening, preventing delays in diagnosis and treatment and potentially saving lives. The hope is that this advancement will soon become a standard practice in identifying and managing PDE-ALDH7A1 in newborns.
