Targeting Lysine α-Ketoglutarate Reductase to Treat Pyridoxine-Dependent Epilepsy
Year: 2025
Type: article
Abstract: Pyridoxine-dependent epilepsy (PDE), a rare autosomal recessively inherited metabolic disease, results from mutations in ALDH7A1, a gene crucial for lysine metabolism. Although early high-dose pyridoxine treatment can control seizures, ∼75% of PDE patients still have intellectual disabilities. In this study, we test the hypothesis of substrate reduction therapy for PDE by genetically perturbing lysine α-ketoglutarate reductase (LKR), an enzyme upstream of the defective ALDH7A1, in male and female laboratory mice. A homozygous mutation in LKR completely abolishes the accumulation of toxic lysine catabolism intermediates (α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate), ends the epileptic state, and restores the defective brain development and cognitive impairments in ALDH7A1-deficient mice. Therefore, these genetic data prove the concept of the effectiveness of substrate reduction therapy for PDE via LKR inhibition.
Source: Journal of Neuroscience
Authors: Ziqi Liang, Junjie Wu, Qiang Liu, Dezhe Qin, Min Wang, Xiaofen Zhong, Weixiang Guo
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Awards: G2507645735, G3765102973
OpenAlex ID: W4410142591