Targeting lysine α-ketoglutarate reductase to treat pyridoxine-dependent epilepsy

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, about 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. Significance statement ALDH7A1 encodes an aldehyde dehydrogenase also known as antiquitin, which functions in lysine and hydroxylysine degradation. Mutations in ALDH7A1 cause pyridoxine-dependent epilepsy (PDE), an autosomal recessive inborn error of metabolism. Although early high-dose pyridoxine treatment can control seizures, approximately 75% of patients with PDE still have intellectual disabilities. In this study, we show that a homozygous mutation in lysine α-ketoglutarate reductase (LKR), an enzyme upstream of the defective ALDH7A1, completely eradicates the accumulation of toxic intermediates in lysine catabolism, ends the epileptic state, and rectifies the defective brain development and cognitive impairments in ALDH7A1-deficient mice. These findings prove the concept of the effectiveness of substrate reduction therapy for PDE by inhibiting LKR.