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A mouse study tested whether inhibiting AASS (an enzyme upstream of ALDH7A1) can reduce multiple PDE-related metabolites in brain and other tissues, offering proof-of-principle for a new treatment strategy.
A central challenge in PDE-ALDH7A1 is that even with vitamin B6 supplementation and lysine-reduction strategies, harmful metabolites from lysine breakdown can persist and may contribute to long-term neurological differences. One promising concept is to reduce the flow into the problem area by inhibiting an earlier enzyme: AASS.
Researchers built and compared several mouse models, including an ALDH7A1 knockout model (to mimic PDE), an AASS knockout model, and a double knockout. Using next-generation metabolomics, they measured known PDE biomarkers across brain, liver, and plasma. The double-knockout mice showed significant decreases in several potentially neurotoxic metabolites in brain and liver compared with ALDH7A1-only knockout mice. They also observed reductions in plasma biomarkers, suggesting blood-based monitoring could be useful if this strategy is ever translated to humans.
Why this matters
This is one of the clearest “systems-level” demonstrations in a mammal that upstream AASS inhibition can move multiple biochemical markers in the right direction, supporting a pathway-based approach aimed at more than seizure control alone.
Figure spotlight
The paper’s free full text includes metabolomics comparisons across tissues that show how the metabolite profile shifts with AASS inhibition (see the figures within the open-access article).
Limitations
This is preclinical proof-of-principle in mice. Lowering biomarkers is an important step, but it does not automatically mean improved clinical outcomes in people, and it does not address dosing, delivery, or long-term safety of any human therapy.
Sources
- van Karnebeek CDM et al. “New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse.” Brain Communications (2025). DOI: 10.1093/braincomms/fcaf397 (PubMed: 41221123; Free full text: PMC12598649)
Safety note: This summary is educational and not medical advice.
