A novel therapy for pyridoxine-dependent epilepsy due to biallelic pathogenic variants in ALDH7A1: secondary mitochondrial energy deficiency and improvements of neurodevelopmental outcomes on triheptanoin treatment.

Background Pyridoxine-dependent epilepsy (PDE) due to biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1) is an metabolic disease of lysine catabolism. Current standard treatment includes pyridoxine, arginine, and lysine- or protein-restricted diet. Pyridoxine treats seizures. Arginine and lysine- or protein-restricted diet decrease elevated α-aminoadipic semialdehyde (α-AASA) and Δ1- piperideine-6-carboxylate (P6C) levels to improve neurodevelopmental outcomes. We previously reported abnormalities in tricarboxylic acid (TCA) cycle and electron transport chain in PDE-ALDH7A1. We report a new patient with PDE-ALDH7A1 who did not show any improvements in neurodevelopment on the current standard therapy. We hypothesized that triheptanoin will provide substrate to TCA cycle and improve abnormal energy metabolism leading to improvements in neurodevelopmental outcome. Objective To treat this patient with triheptanoin to improve neurodevelopmental outcome. Design Due to complex I deficiency and lack of response to the current standard therapy, we applied triheptanoin novel therapy. Methods A 4-year-old male had compound heterozygous variants in ALDH7A1 and markedly elevated urine α-AASA. The goal dose of triheptanoin was 50% of the estimated energy requirement (EER). We assessed efficacy of triheptanoin using neuropsychological assessments. We measured 6-oxopipecolic acid using liquid chromatography tandem mass spectrometry. Results Triheptanoin was started at 10 mL/day. There was nausea up to 3 weeks after each dose increase, which has improved allowing us to increase triheptanoin gradually. The maximum actual dose of triheptanoin was 40% of EER. Cognitive composite score improved from 16% to 63% on treatment. All chemistry and biochemical investigations were normal. 6-oxopipecolic acid levels did not normalize. Triheptanoin treatment seemed to be safe and tolerated well. Conclusion Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.