New treatment strategy for pyridoxine-dependent epilepsy

Charlie (changing rare disorders of lysine metabolism) is an international research consortium focused on rare inborn errors of lysine metabolism (Charlie | CHARLIE PROJECT). As one of the research partners, the German Mouse Clinic has been working with teams of clinicians and researchers from the Netherlands and the USA on a new potential treatment approach for pyridoxine dependent epilepsy (PDE). The results were published in Brain Communications.

PDE caused by ALDH7A1 mutations leads to severe seizures that usually do not respond to standard anti-seizure medications. Treatment with pharmacologic doses of pyridoxine (vitamin B6) results in clinical improvement and seizure control, although the majority of patients continue to have an intellectual and developmental disability (IDD).

PDE-ALDH7A1 is caused by the deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase, the enzyme that oxidizes α-AASA during the lysine degradation pathway. When the enzyme is missing, α-AASA and other related substances build up in the body and are believed to be neurotoxic. To find better therapies, the CHARLIE team tested whether blocking an upstream enzyme—AASS (2 aminoadipic semialdehyde synthase)—could prevent the accumulation of toxic metabolites. Using CRISPR/Cas9, the researchers created mice lacking both the Aldh7a1 gene and the Aass gene. This double knockout model allowed them to test if inhibiting AASS could help treat PDE.

They analyzed brain, liver, and plasma samples using next generation metabolomics to measure all known PDE biomarkers. The results clearly showed that in double knockout mice, the levels of toxic metabolites (including P6C, pipecolic acid, 6 oxo pipecolic acid, and others) were significantly reduced compared to mice lacking only Aldh7a1. Importantly, the reduction was seen not only in the tissues but also in plasma, suggesting a reliable monitoring option in human patients.

Overall, this study provides the first clear evidence that upstream inhibiting AASS is a promising new therapeutic strategy for PDE ALDH7A1 and has the potential to be more effective than current therapeutic approaches, especially if treated early in life.

Original publication:
van Karnebeek CDM, Gailus-Durner V, Engelke UF, Seisenberger C, Marschall S, Dragano NRV, da Silva-Buttkus P, Leuchtenberger S, Fuchs H, Hrabě de Angelis M, Wevers RA, Coughlin CR, Lefeber DJ. New treatment for pyridoxine-dependent epilepsy due to ALDH7A1 deficiency: first proof-of-principle of upstream enzyme inhibition in the mouse. Brain Commun. (2025) https://pubmed.ncbi.nlm.nih.gov/41221123/.